Headache

Anticonvulsant drugs for acute and chronic pain.

2010-01-24T07:00:00.000-08:00

Cochrane Database Syst Rev. 2010; CD001133Wiffen PJ, Collins S, McQuay HJ, Carroll D, Jadad A, Moore RABACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for chronic neuropathic pain, especially when the pain is lancinating or burning. Readers are referred to reviews of carbamazepine and gabapentin in T he Cochrane Library which replace the information on those drugs in this review. Other drugs remain unchanged at present in this review OBJECTIVES: To evaluate the analgesic effectiveness and adverse effects of anticonvulsant drugs for pain management in clinical practice . Migraine and headache studies are excluded in this revision. SEARCH STRATEGY: Randomised trials of anticonvulsants in acute, chronic or cancer pain were identified by MEDLINE (1966-1999), EMBASE (1994-1999), SIGLE (1980 to 1999) and the Cochrane Controlled Trials Register (CENTRAL/CCTR) (The Cochrane Library Issue 3, 1999). In addition, 41 medical journals were hand searched. Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. Date of most recent search: September 1999. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of anticonvulsant drugs in patients, with subjective pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent review authors, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal, for individual studies and for pooled data. MAIN RESULTS: Twenty-three trials of six anticonvulsants were considered eligible (1074 patients).The only placebo-controlled study in acute pain found no analgesic effect of sodium valproate.Three placebo-controlled studies of carbamazepine in trigeminal neuralgia had a combined NNT (95% confidence interval (CI)) for effectiveness of 2.5 (CI 2.0 to 3.4). A single placebo-controlled trial of gabapentin in post-herpetic neuralgia had an NNT of 3.2 (CI 2.4 to 5.0). For diabetic neuropathy NNTs for effectiveness were as follows: (one RCT for each drug) carbamazepine 2.3 (CI 1.6 to 3.8), gabapentin 3.8 (CI 2.4 to 8.7) and phenytoin 2.1 (CI 1.5 to 3.6).Numbers-needed-to-harm (NNHs) were calculated where possible by combining studies for each drug entity irrespective of the condition treated. The results were, for minor harm, carbamazepine 3.7 (CI 2.4 to 7.8), gabapentin 2.5 (CI 2.0 to 3.2), phenytoin 3.2 (CI 2.1 to 6.3). NNHs for major harm were not statistically significant for any drug compared with placebo.Phenytoin had no effect in irritable bowel syndrome, and carbamazepine little effect in post-stroke pain. Clonazepam was effective in one study of temporomandibular joint dysfunction. AUTHORS' CONCLUSIONS: Although anticonvulsants are used widely in chronic pain surprisingly few trials show analgesic effectiveness. Only one study identified considered cancer pain. There is no evidence that anticonvulsants are effective for acute pain. In chronic pain syndromes other than trigeminal neuralgia, anticonvulsants should be withheld until other interventions have been tried. While gabapentin is increasingly being used for neuropathic pain the evidence would suggest that it is not superior to carbamazepine.

Standardizing Emergency Department-based Migraine Research: An Analysis of Commonly Used Clinical Trial Outcome Measures.

2010-01-19T18:22:00.000-08:00

Acad Emerg Med. 2010 Jan; 17(1): 72-79Friedman BW, Bijur PE, Lipton RBAbstract Objectives: Although many high-quality migraine clinical trials have been performed in the emergency department (ED) setting, almost as many different primary outcome measures have been used, making data aggregation and meta-analysis difficult. The authors assessed commonly used migraine trial outcomes in two ways. First, the authors examined the association of each commonly used outcome versus the following patient-centered variable: the research subject's wish, when asked 24 hours after investigational medication administration, to receive the same medication the next time they presented to an ED with migraine ("would take again"). This variable was chosen as the criterion standard because it provides a simple, dichotomous, clinically sensible outcome, which allows migraineurs to factor important intangibles of efficacy and adverse effects of treatment into an overall assessment of care. The second part of the analysis assessed how sensitive to true efficacy each outcome measure was by calculating sample size requirements based on results observed in previously conducted clinical trials. Methods: This was a secondary analysis of data previously collected in four ED-based migraine randomized trials performed between 2003 and 2007. In each of these trials, subjects were asked 24 hours after administration of an investigational medication whether or not they would want to receive the same medication the next time they came to the ED with a migraine. Odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for sex and medication received, were calculated as measures of association between the most commonly used outcome measures and "would take again." The sensitivity of each outcome measure to treatment efficacy was determined by calculating the sample size that would be required to detect a statistically significant result using estimates of that outcome obtained in two clinical trials. Results: Data from 378 subjects were used for this analysis. Adjusted ORs for association of "would take again" and other commonly used primary headache outcomes are as follows: achieving a pain-free state by 2 hours, OR = 3.1 (95% CI = 1.8 to 5.4); sustained pain-free status, OR = 4.5 (95% CI = 1.9 to 11.0); and no need for rescue medication, OR = 3.7 (95% CI = 2.1 to 6.6). An improvement on a standardized 11-point pain scale of >/=33% had an adjusted OR = 5.2 (95% CI = 2.2 to 12.4). The best performing alternate outcome, >/=33% improvement, correctly classified 288 subjects and misclassified 77 subjects when compared to "would take again." At least 33% improvement and pain-free by 2 hours required the smallest sample sizes, while sustained pain-free and "would take again" required many more subjects. Conclusions: "Would take again" was associated with all migraine outcome measures we examined. No individual outcome was more closely associated with "would take again" than any other. Even the best-performing alternate outcome misclassified more than 20% of subjects. However, sample sizes based on "would take again" tended to be larger than other outcome measures. On the basis of these findings and this outcome measure's inherent patient-centered focus, "would take again," included as a secondary outcome in all ED migraine trials, is proposed. ACADEMIC EMERGENCY MEDICINE 2010; 17:72-79 (c) 2010 by the Society for Academic Emergency Medicine.

Symptomatic trigeminal autonomic cephalalgias.

2010-01-19T01:44:00.000-08:00

Neurologist. 2009 Nov; 15(6): 305-12Cittadini E, Matharu MSBACKGROUND: The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes characterized by strictly unilateral head pain that occurs in association with ipsilateral cranial autonomic features. The group includes cluster headache, paroxysmal hemicrania, and short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. These syndromes differ in attack duration and frequency as well as the response to therapy. Most of the cases of these syndromes are primary headaches, though numerous symptomatic cases have been described albeit that it is difficult to establish a causal relationship with the underlying pathology in most cases. REVIEW SUMMARY: We reviewed the literature to identify the cases of symptomatic TACs that were likely to be secondary to the reported underlying lesion. We also attempted to identify any clinical features that may be pointers for distinguishing these cases from primary cases and thereby inform the diagnostic workup of these disorders. CONCLUSION: Forty cases of symptomatic TACs were identified. These symptomatic headaches were associated with atypical phenotypes, abnormal examination, and poor treatment response though a significant minority had a typical presentation. A relatively high proportion of all TACs were secondary to pituitary tumors. It is difficult to draw up guidelines for the diagnostic workup required on the basis of this small retrospective case series. It remains unclear whether every TAC patient requires neuroimaging, though if it is considered then magnetic resonance imaging is the preferred modality. In addition, we suggest that all TAC patients should be carefully assessed for pituitary disease related symptoms but further investigations with magnetic resonance imaging of the pituitary gland and pituitary hormonal profile should only be undertaken in patients with atypical features, abnormal examination, or those resistant to the appropriate medical treatment.

Incidence of Intracranial Arterial Dissection in Non-emergency Outpatients Complaining of Headache: Preliminary Investigation with MRI/MRA Examinations.

2010-01-18T17:25:00.000-08:00

Acta Neurochir Suppl. 2010; 107: 41-4Manabe H, Yonezawa K, Kato T, Toyama K, Haraguchi K, Ito TPurpose: Headache is recognized as one of the specific signs of intracranial arterial dissection (ICrAD). We clarified the incidence of ICrAD in non-emergency outpatients complaining of headache and the nature of headache observed in case of ICrAD. Patient population and methods: Consecutive non-emergency outpatients coming to the neurological and neurosurgical departments and who underwent MRI and MRA examinations were included in this study. The diagnosis of ICrAD was made when patients met the following two conditions: (1) pearl-and-string sign, pearl sign, or string sign on MRA, and (2) high arterial wall signal on T1 images or intimal flap on T2 images. If possible, cerebral angiography and/or black blood MRI and/or surface-image MRI was also performed in cases meeting these criteria. Results: (1) Headache group (172 patients): severe headache was seen in five patients and headache of sudden onset in three. Arterial dissection was diagnosed in eight patients (4.7%, including seven cases of asymptomatic vertebral dissection and one of basilar dissection). The headache noted in most cases of ICrAD was similar to that experienced in daily life. (2) Non-headache group (201 patients): complaints included vertigo/dizziness in 52 patients, gait disturbance in 28, weakness of the arm or leg in 20, and limb numbness in 18, syncope attack in 14, and others in 69. Arterial dissection was diagnosed in six patients (3.0%, including one case of asymptomatic basilar and two of vertebral artery dissection, symptomatic two vertebral and one basilar dissection). Conclusion: We obtained no evidence of significant difference in the incidence of ICrAD in non-emergency outpatients with (4.7%) and without headache (3.0%). The nature of the headache in the cases of ICrAD was similar to that experienced in daily life. ICrAD with nonspecific headache is more common than previously thought.

[SSRI discontinuation syndrome: incidence and differences on three groups of patients treated with paroxetine]

2010-01-18T01:26:00.000-08:00

Riv Psichiatr. 2009 May-Jun; 44(3): 169-75Rusconi AC, Carlone C, Muscillo M, de' FM, Podda L, Piccione MIn recent years, many cases have been published about the appearance of a specific syndrome after the suspension or the sharp reduction in dose of antidepressants. Most of the reports and records relating to the very short half-life SSRI paroxetina. The following work intended to investigate the syndrome, its impact and its correlation with some parameters: age, sex, diagnosis, time of taking and antidepressant drug, therapeutic compliance, suspension and symptoms. The study, lasting approximately 6 months, was conducted with 148 outpatient, all treated with paroxetine.This paper highlights how the discontinuation syndrome is rare in individuals who received antidepressant treatment for short periods, and how it is, rather, much more common in cases of depression NAS, followed by panic attacks, compared with case of major depression. A positive correlation seems to be also with sex (having observed that go more frequently to meet withdrawal symptoms subjects male), and with age, patients being young adults between 35 and 55 years. The symptoms reported were very similar among all patients: headache, dizziness, abdominal pain and perineal, elevated pressure, anxiety, depersonalization and derealization, nightmares. Interestingly, the total absence of symptoms related to the original diagnosis of the disorder. Going to investigate the causal event for the emergence of the discontinuation syndrome, it was possible to divide the cases examined in three categories: independent suspension without medical opinion, suspension accelerated (both conditions due to outpatients) and finally patients that, although they had followed all the guidelines for suspension of the drug, had gone to meet equally symptoms. The syndrome can be prevented reducing very gradually the antidepressant dosage, while if there are symptoms it is indicated to reintroduce the drug and then scale or replance it with a different molecule.

Exploratory randomized clinical study of pagoclone in persistent developmental stuttering: the EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study.

2010-01-17T22:11:00.000-08:00

J Clin Psychopharmacol. 2010 Feb; 30(1): 48-56Maguire G, Franklin D, Vatakis NG, Morgenshtern E, Denko T, Yaruss JS, Spotts C, Davis L, Davis A, Fox P, Soni P, Blomgren M, Silverman A, Riley GINTRODUCTION: Stuttering is a speech disorder in which the flow of speech is disrupted by repetitions, prolongation, and blocks of sounds, syllables, or words. No pharmacological treatments are approved for use in stuttering, and the most common form of treatment is speech therapy. This study was designed to assess the safety, tolerability, and effectiveness of pagoclone during 8 weeks of double-blind treatment followed by a 1-year open-label extension in patients who stutter. METHODS: An 8-week, multicenter, parallel-group, 2-arm, randomized (ratio 2:1 pagoclone-placebo), double-blind study with a 1-year open-label extension conducted at 16 US centers, including men and women aged 18 to 65 years who developed stuttering before 8 years of age. Twice-daily dosing with pagoclone (n = 88 patients) or matching placebo (n = 44 patients), with primary and secondary efficacy variables defined a priori, including Stuttering Severity Instrument Version 3 outcomes, clinician global impressions of improvement, and the change in the percentage of syllables stuttered. RESULTS: Pagoclone produced an average 19.4% reduction in percentage of syllables stuttered compared with 5.1% reduction for placebo. During open-label treatment, a 40% reduction in the percent syllables stuttered was observed after 1 year of treatment with pagoclone. The most commonly reported adverse event during double-blind treatment was headache (12.5% pagoclone patients, 6.8% placebo patients). DISCUSSION: Pagoclone was effective in reducing symptoms of stuttering and was well tolerated. In light of its favorable tolerability profile, as well as consistency of effects across multiple efficacy variables, pagoclone may have potential as a pharmacological treatment of stuttering. LIMITATIONS: The main limitation of this study was the adequacy of the number of subjects who participated because this study was conducted as a pilot investigation. Furthermore, as this condition waxes and wanes, the assessment of stuttering within the clinic setting may not be an adequate reflection of the stuttering of the patients within the community.

Health problems among the street children of Dharan municipality.

2010-01-16T23:12:00.000-08:00

Kathmandu Univ Med J (KUMJ). 2009 Jul-Sep; 7(27): 272-9Thapa K, Ghatane S, Rimal SPBACKGROUND: The street children, a marginalised and vulnerable population to poor health, have grown all over the world and also in our country. The continuous exposure to harsh environment and nature of their life style threatens their mental, physical, social and spiritual well being. With the increasing number the problem is also growing at an alarming proportion. It is therefore important to have baseline data on their health problems. OBJECTIVES: This study was conducted to identify the physical health problems among the street children of Dharan Municipality, Nepal. MATERIALS AND METHODS: This is a cross sectional descriptive study. Forty eight subjects were included in the study. Research instruments included an interview schedule, physical health examination performa and lab investigations (i.e. blood for haemoglobin, urine routine examination/microscopic examination, stool routine examination/ microscopic examination). RESULTS: Study results showed that 68.8% of the street children were between 11-15 years of age, 95.8% were males. Out of the total subjects 81.2% were found to be rag pickers. Research findings reveal that 100% of the subjects had at least one or more health problems. The study revealed that majority 87.5% had the habit of cigarette smoking, 50% had habit of consuming alcohol and 72.9% had the habit of taking drug. Dendrite (glue sniffing) was the only drug used by the respondents in this study. The most common health problems were head lice infestation (81.2%), headache (66.7%), cut injury (60.4%), common cold (52.1%), dental caries (52%), burning micturation (47.9%), cough (47.9%), underweight (43.8%), abdominal pain (39.6%), tinnitus (37.55%), gum bleeding (33.3%), joint pain (31.2%), eye inflammation (25%), leg cramps (25%), palpable lymph nodes (25%), chest pain (18.8%), skin lesions (16.7%), abnormal vision (8.3%). CONCLUSION: Most of the diseases were due to poor health habits. It was found that the nature of work, their life styles and the different types of behaviour they adapt finally lead them to many health problems. The health problem can be prevented, if an integrated program that involves all the issues are developed and implemented.

Safety and efficacy of desloratadine in subjects with seasonal allergic rhinitis or chronic urticaria: results of four postmarketing surveillance studies.

2010-01-15T17:21:00.000-08:00

Clin Drug Investig. 2010; 30(2): 109-22Bachert C, Maurer MAllergic rhinitis (AR) and chronic urticaria (CU) are common diseases with symptoms that impair quality of life. Second-generation antihistamines (e.g. cetirizine, desloratadine, fexofenadine, loratadine and mizolastine) are recommended first-line treatment for both conditions; however, studies of clinically relevant differences among these agents are lacking. The aim of this investigation was to evaluate the safety, tolerability and efficacy of desloratadine 5 mg once daily in four postmarketing surveillance studies in subjects with seasonal AR (SAR) or chronic idiopathic urticaria (CIU) in real-world clinical practice settings. This programme of prospective surveillance studies was conducted in Germany between February 2001 and March 2002 in allergy; dermatology; ear, nose and throat; or general practice settings. Subjects (total number 77 880) were aged >/=12 years and met the requirements for treatment of SAR or CIU with desloratadine as outlined in the package insert. All subjects received oral desloratadine 5 mg once daily for a mean duration of up to 40.4 days. Adverse events (AEs) were reported throughout the studies; serious AEs were recorded for up to 30 days after treatment. Investigators and subjects both rated tolerability at the end of treatment. Symptom severity and sleep and daily activity impairment were evaluated at baseline and after treatment using 4-point scales (0 = none; 1 = mild; 2 = moderate; 3 = severe). A post hoc subanalysis assessed desloratadine efficacy and onset of symptom relief in subjects who had received monotherapy with another second-generation antihistamine. A total of 386 AEs were reported by 287 subjects (0.37%) in the four studies. The most commonly reported treatment-related AEs were fatigue (0.07%), headache (0.07%), dry mouth (0.04%) and nausea (0.03%). Tolerability was rated as excellent/good by 99.1% of investigators and 98.5% of subjects. Desloratadine therapy significantly reduced nasal and ocular symptom severity, itching and wheals, and sleep and activity disruption (p < 0.0001), as indicated by a reduction in mean total and individual symptom scores, and reported impairment of sleep and daily activities. The efficacy of desloratadine was rated as significantly greater by 59.4-88.0% of subjects who had previously received monotherapy with cetirizine, fexofenadine, loratadine or mizolastine (p < 0.01 for all). The percentage of subjects who rated onset of symptom relief with desloratadine as faster than previous treatment ranged from 51.6% to 82.4%. Desloratadine was safe, well tolerated and efficacious in this series of surveillance studies. A post hoc analysis of subjects who had received previous monotherapy with a second-generation antihistamine found that most subjects rated efficacy as higher than their previous treatment, with a faster onset of symptom relief.

Thai venous stroke prognostic score: TV-SPSS.

2010-01-14T17:09:00.000-08:00

J Med Assoc Thai. 2009 Nov; 92(11): 1413-22Poungvarin N, Prayoonwiwat N, Ratanakorn D, Towanabut S, Tantirittisak T, Suwanwela N, Phanthumchinda K, Tiamkoa S, Chankrachang S, Nidhinandana S, Laptikultham S, Limsoontarakul S, Udomphanthuruk SBACKGROUND AND OBJECTIVE: Prognosis of cerebral venous sinus thrombosis (CVST) has never been studied in Thailand. A simple prognostic score to predict poor prognosis of CVST has also never been reported. The authors are aiming to establish a simple and reliable prognostic score for this condition. MATERIAL AND METHOD: The medical records of CVST patients from eight neurological training centers in Thailand who received between April 1993 and September 2005 were reviewed as part of this retrospective study. Clinical features included headache, seizure, stroke risk factors, Glasgow coma scale (GCS), blood pressure on arrival, papilledema, hemiparesis, meningeal irritation sign, location of occluded venous sinuses, hemorrhagic infarction, cerebrospinal fluid opening pressure, treatment options, length of stay, and other complications were analyzed to determine the outcome using modified Rankin scale (mRS). Poor prognosis (defined as mRS of 3-6) was determined on the discharge date. RESULTS: One hundred ninety four patients' records, 127 females (65.5%) and mean age of 36.6 +/- 14.4 years, were analyzed Fifty-one patients (26.3%) were in the poor outcome group (mRS 3-6). Overall mortality was 8.4%. Univariate analysis and then multivariate analysis using SPSS version 11.5 revealed only four statistically significant predictors influencing outcome of CVST They were underlying malignancy, low GCS, presence of hemorrhagic infarction (for poor outcome), and involvement of lateral sinus (for good outcome). Thai venous stroke prognostic score (TV-SPSS) was derived from these four factors using a multiple logistic model. CONCLUSION: A simple and pragmatic prognostic score for CVST outcome has been developed with high sensitivity (93%), yet low specificity (33%). The next study should focus on the validation of this score in other prospective populations.

Clinical Trial and Post-Licensure Safety Profile of a Prophylactic Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine.

2010-01-14T01:36:00.000-08:00

Pediatr Infect Dis J. 2009 Nov 30; Block SL, Brown DR, Chatterjee A, Gold MA, Sings HL, Meibohm A, Dana A, Haupt RM, Barr E, Tamms GM, Zhou H, Reisinger KSBACKGROUND:: We describe the safety of the human papillomavirus (HPV)-6/11/16/18 vaccine using updated clinical trial data (median follow-up time of 3.6 years) and summarize up to 3 years of post-licensure surveillance. METHODS:: In 5 clinical trials, 21,480 girls/women aged 9 to 26 years and boys aged 9 to 16 years received >/=1 dose of HPV-6/11/16/18 vaccine or placebo. All serious and nonserious adverse experiences (AEs) and new medical conditions were recorded for the entire study period(s). As of June 2009, >25 million doses of HPV-6/11/16/18 vaccine had been distributed in the United States with >50 million doses globally. Post-licensure safety as summarized by the Centers for Disease Control and Prevention using the United States Vaccine Adverse Event Reporting System database is also reported. RESULTS:: Eight subjects experienced a treatment-related serious AE (0.05% vaccine; 0.02% placebo). Of 18 deaths (0.1% vaccine; 0.1% placebo), all were considered unrelated to study treatment. New medical conditions which were potentially consistent with autoimmune phenomena were reported in 2.4% of both vaccine and placebo recipients. Pain, the most common injection-site AE, occurred more frequently with vaccine (81% vaccine; 75% placeboaluminum; 45% placebo-saline). No differences were seen in the incidence of the most common nonserious AEs-headache and pyrexia. The Vaccine Adverse Event Reporting System has received 14,072 reports for the HPV-6/11/16/18 vaccine since licensure, with only 7% being serious AEs, about half the average reported for licensed vaccines in general. CONCLUSIONS:: HPV-6/11/16/18 vaccination was associated with more injection-site pain than placebo but similar incidences of systemic and serious AEs and new medical conditions potentially consistent with autoimmune phenomena. Based on review of post-licensure safety information, the benefits of vaccination to prevent the majority of genital tract precancers and cancers continue to far outweigh its risks.

Cervicocranial arterial dissection: experience of 73 patients in a single center.

2010-01-13T21:18:00.000-08:00

Surg Neurol. 2009 Dec; 72 Suppl 2: S20-7; discussion S27Huang YC, Chen YF, Wang YH, Tu YK, Jeng JS, Liu HMBACKGROUND: Arterial dissection involving cervicocranial arteries usually results in ischemia or SAH. This study correlated the clinical manifestations, image characteristics, and outcome of arterial dissection and compared the differences between arterial dissection of anterior and posterior circulation at our institute. METHODS: Clinical symptoms and neuroradiologic findings were retrospectively analyzed in 73 patients (6-75 years old) who had a spontaneous arterial dissection of cervicocranial vessels verified by angiography or MRI. Twenty-four cases of ACAD and 49 cases of PCAD were included in this study. RESULTS: The leading presentation of arterial dissection of ACAD group was ischemic stroke (79.2%), and that of posterior circulation was SAH (44.9%), followed by ischemic stroke (42.8%). In the ACAD group, the extracranial ICA was more commonly involved (62.5%), with long segmental narrowing the most common angiographic finding. In the PCAD group, the intracranial VA was more commonly involved (81.6%), with alternating narrowing and dilatation the leading angiographic picture. All the cases presenting with ischemic stroke or headache were conservatively treated with anticoagulants or antiplatelets, except for one treated with intra-arterial thrombolysis for thromboembolism in basilar artery at an early stage. One of them died of progressed brainstem infarct in spite of anticoagulation therapy. All the others reached improved or stable clinical condition. Eighteen cases were treated by surgical or endovascular intervention. None of them had rebleeding. Of the 5 patients with SAH due to dissecting lumens without treatment, 2 died of rebleeding. CONCLUSIONS: Ischemia is the predominant presentation of ACAD; and PCAD has similar occurrence of SAH and ischemia. Intracranial arterial dissection is not uncommon; and it should be kept in the list of differential diagnosis of young stroke. Aggressive treatment of arterial dissection presenting with SAH should be considered; otherwise, rebleeding may occur.

Cluster Headache is Associated With the Alcohol Dehydrogenase 4 (ADH4) Gene.

2010-01-13T06:15:00.000-08:00

Headache. 2009 Nov 17; Rainero I, Rubino E, Gallone S, Fenoglio P, Negro E, De Martino P, Savi L, Pinessi L(Headache 2009;**:**-**) Background/Objectives.- Alcohol is a well-known trigger factor for cluster headache attacks during the active phases of the disease. The alcohol dehydrogenase (ADH) pathway, which converts alcohol to the toxic substance acetaldehyde, is responsible for most of the alcohol breakdown in the liver. Humans have 7 ADH genes, tightly clustered on chromosome 4q21-q25, that encode different ADH isoforms. The ADH4 gene encodes the class II ADH4 pi subunit, which contributes, in addition to alcohol, to the metabolization of a wide variety of substrates, including retinol, other aliphatic alcohols, hydroxysteroids, and biogenic amines. The purpose of this study was to investigate the association of genetic variants within the ADH4 gene with cluster headache susceptibility and phenotype. Methods.- A total of 110 consecutive unrelated cluster headache patients and 203 age- and sex-matched healthy controls of Caucasian origin were involved in the study. Patients and controls were genotyped for 2 bi-allelic single nucleotide polymorphisms (SNPs) of the ADH4 gene: SNP1 - rs1800759 and SNP2 - rs1126671. Allele, genotype, and haplotype frequencies of the examined polymorphisms were compared between cases and controls. Results.- Genotype frequencies of the rs1126671 polymorphism resulted significantly different between cluster headache patients and controls (chi(2) = 10.269, P = .006). The carriage of the AA genotype, in comparison with remaining genotypes, was associated with a significantly increased disease risk (OR = 2.33, 95% CI: 1.25-4.37). Haplotype analysis confirmed the association between the ADH4 gene and the disease. No association between different clinical characteristics of cluster headache and the examined polymorphisms was found. Conclusion.- Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease.

Thromboembolic complications of intravenous immunoglobulin (IVIG) in an immunocompromised patient with Chronic Lymphocytic Leukemia: a case report.

2010-01-13T04:30:00.000-08:00

Cases J. 2009; 2: 9078Milani C, Dalia SM, Colvin GAINTRODUCTION: Infectious complications represent a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The etiology is postulated to be secondary to aberrations in cell-mediated immunity, as well as to therapy-related immunosuppression. Hypogammaglobulinemia, which occurs in virtually all patients with CLL, may be profound and correlates with disease duration and stage. Intravenous immunoglobulin (IVIG) therapy has been used successfully to prevent and treat infections in this cohort of patients. However IVIG administration and treatment is not benign and should be used with caution given the potential manifestations of thromboembolic complications. High concentration and rapid infusion rate of the IVIG, as well as increased dose and osmolarity of the solution are thought to predispose to thrombotic events. Serum viscosity is the implicated mechanism for compromised blood flow and predisposition of high-risk patients to cardiovascular or cerebrovascular infarction. We report a case of IVIG related thromboembolic manifestations in a CLL patient, to highlight the importance of risk stratifying patients prior to treatment administration. CASE PRESENTATION: We present a 55-year-old Caucasian man with CLL who presented to our clinic with neutropenic fevers following a cycle of chemotherapy. Laboratory parameters revealed hypogammaglobulinemia prompting IVIG administration. Shortly thereafter, he developed a massive cascade of thromboembolic phenomena precipitating his demise. CONCLUSION: The current consensus surrounding IVIG is that of a relatively safe treatment, with minor adverse effects such as hypertension, fever and chills, nausea, myalgias, or headache. However our report highlights the importance of proceeding with caution in the application of this therapy, as it's proclivity for thrombotic complications has not been fully elucidated in patients with underlying malignancies. Pre-existing thrombogenic risk factors should be carefully evaluated in patients undergoing treatment with IVIG. Clinical evaluation, with careful attention to vascular history and underlying co-morbidities can potentially unmask the high-risk patient where IVIG could be lethal.

Improving the clinical diagnosis of influenza--a comparative analysis of new influenza A (H1N1) cases.

2010-01-12T06:45:00.000-08:00

PLoS One. 2009; 4(12): e8453Ong AK, Chen MI, Lin L, Tan AS, Nwe NW, Barkham T, Tay SY, Leo YSBACKGROUND: The presentation of new influenza A(H1N1) is broad and evolving as it continues to affect different geographic locations and populations. To improve the accuracy of predicting influenza infection in an outpatient setting, we undertook a comparative analysis of H1N1(2009), seasonal influenza, and persons with acute respiratory illness (ARI) in an outpatient setting. METHODOLOGY/PRINCIPAL FINDINGS: Comparative analyses of one hundred non-matched cases each of PCR confirmed H1N1(2009), seasonal influenza, and ARI cases. Multivariate analysis was performed to look for predictors of influenza infection. Receiver operating characteristic curves were constructed for various combinations of clinical and laboratory case definitions. The initial clinical and laboratory features of H1N1(2009) and seasonal influenza were similar. Among ARI cases, fever, cough, headache, rhinorrhea, the absence of leukocytosis, and a normal chest radiograph positively predict for both PCR-confirmed H1N1-2009 and seasonal influenza infection. The sensitivity and specificity of current WHO and CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. However, the combination of WHO ILI criteria with the absence of leukocytosis greatly improved the accuracy of diagnosing H1N1(2009) and seasonal influenza (positive LR of 7.8 (95%CI 3.5-17.5) and 9.2 (95%CI 4.1-20.3) respectively). CONCLUSIONS/SIGNIFICANCE: The clinical presentation of H1N1(2009) infection is largely indistinguishable from that of seasonal influenza. Among patients with acute respiratory illness, features such as a temperature greater than 38 degrees C, rhinorrhea, a normal chest radiograph, and the absence of leukocytosis or significant gastrointestinal symptoms were all positively associated with H1N1(2009) and seasonal influenza infection. An enhanced ILI criteria that combines both a symptom complex with the absence of leukocytosis on testing can improve the accuracy of predicting both seasonal and H1N1-2009 influenza infection.

Safety and effectiveness of coadministration of guanfacine extended release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder.

2010-01-11T07:58:00.000-08:00

J Child Adolesc Psychopharmacol. 2009 Oct; 19(5): 501-10Spencer TJ, Greenbaum M, Ginsberg LD, Murphy WROBJECTIVE: The aim of this study was to evaluate the safety and effectiveness of guanfacine extended release (GXR) administered concomitantly with psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and suboptimal response to a psychostimulant alone. DESIGN AND METHODS: This was a multicenter, open-label, 9-week, dose-escalation study of 75 subjects with ADHD treated with methylphenidate (MPH) or amphetamine (AMP) alone for at least 1 month, yet with suboptimal control of ADHD symptoms. Sixty-three subjects (84.0%) completed the study. Patients received GXR in addition to their psychostimulant. Starting with 1 mg/day, GXR was increased weekly to the highest tolerated dose (1, 2, 3, or 4 mg/day), which was maintained through week 6. GXR was then titrated downward in 1-mg weekly decrements from week 7 through week 9. Psychostimulant treatment regimens were continued until at least week 7. MAIN OUTCOME MEASURES: Safety assessments included adverse events (AEs), vital signs, physical examination, clinical laboratory tests, the Pediatric Daytime Sleepiness Scale, and the Pittsburgh Side Effects Rating Scale. Efficacy was assessed using the ADHD Rating Scale IV (ADHD-RS-IV), the Conners' Parent Rating Scale-Revised Short Form, Clinical Global Impressions, Parent Global Assessment, and Child Health Questionnaire-Parent Form. RESULTS: The most common treatment-related AEs were upper abdominal pain (25.3%), fatigue (24.0%), irritability (22.7%), headache (20.0%), and somnolence (18.7%). Most AEs were mild to moderate in severity. Investigator-rated AEs due to blood pressure decreases, heart rate, or electrocardiogram findings were infrequent. Mean changes from baseline (psychostimulant monotherapy just prior to receiving GXR) to end point in ADHD-RS-IV total score were statistically significant overall: -16.1 (p < 0.0001). Significant improvement in both subscales of the ADHD-RS-IV was observed. Improvement of symptoms was observed in a majority of subjects. CONCLUSION: Coadministration of GXR and MPH or AMP was generally safe and associated with statistically significant and clinically meaningful ADHD symptom improvement in children and adolescents.

Results of a meta-analysis comparing the tolerability of lercanidipine and other dihydropyridine calcium channel blockers.

2010-01-10T03:00:00.000-08:00

Clin Ther. 2009 Aug; 31(8): 1652-63Makarounas-Kirchmann K, Glover-Koudounas S, Ferrari PBackground: Results from clinical studies suggest that the dihydropyridine calcium channel blocker (CCB) lercanidipine may be associated with a lower incidence of peripheral edema than are older dihydro-pyridine CCBs. OBJECTIVE: The objective of the present study was to conduct a meta-analysis of published data from randomized controlled trials (RCTs) to assess the relative risk (RR) of dihydropyridine CCB-specific adverse events with lercanidipine versus the older dihydro-pyridine CCBs (first generation: amlodipine, felodipine, and nifedipine), and versus the other lipophilic dihy-dropyridine CCBs (second generation: lacidipine and manidipine). METHODS: A systematic literature search (all years through August 11, 2008) of MEDLINE, EMBASE, and the Cochrane Library was conducted for English-language reports of single- or double-blind RCTs of > or = 4 weeks' duration that compared the tolerability of lercanidipine with other dihydropyridine CCBs in participants with mild (140-159/90-99 mm Hg) to moderate (160-179/100-109 mm Hg) hypertension. RESULTS: Eight RCTs (6 used first-generation drugs, and 4 used second-generation drugs) met the criteria for inclusion. Efficacy outcomes for lowering blood pressure did not differ statistically between lercanid-ipine and either generation of medications. Compared with the first generation, lercanidipine was associated with a reduced risk of peripheral edema (52/742 with lercanidipine vs 88/627 with first generation; RR = 0.44 [95% CI, 0.31-0.62]), but not flushing or headache. The frequency of peripheral edema, flushing, and headache did not differ statistically between lercanidi-pine and the second-generation drugs. Study participants were less likely to withdraw from the RCTs because of peripheral edema (RR = 0.24 [95% CI, 0.12-0.47]) or any adverse event (RR = 0.51 [95% CI, 0.33-0.77]) when treated with lercanidipine rather than a drug from the first generation, but not when treated with lercanidipine rather than second-generation drugs. CONCLUSION: In this meta-analysis, lercanidipine was associated with a lower risk of peripheral edema and a lower risk of treatment withdrawal because of peripheral edema than were the first-generation, but not the second-generation, dihydropyridine CCBs.

Sudden sensorineural hearing loss associated with vardenafil.

2010-01-08T07:44:00.000-08:00

Pharmacotherapy. 2010 Jan; 30(1): 112Snodgrass AJ, Campbell HM, Mace DL, Faria VL, Swanson KM, Holodniy MThe phosphodiesterase type 5 (PDE-5) inhibitors-sildenafil, vardenafil, and tadalafil-are used primarily in erectile dysfunction, but sildenafil is also indicated for pulmonary hypertension. Common adverse effects of vardenafil include headache, flushing, nasal congestion, dyspepsia, and nausea. Recently, PDE-5 inhibitors have been associated with adverse vision effects, and emerging evidence now indicates that they may also be responsible for hearing changes and hearing loss. We describe a patient who developed unilateral sudden sensorineural hearing loss possibly related to the use of vardenafil for erectile dysfunction. To our knowledge, only one other case of hearing loss related to this drug class has been published. Our patient was a 57-year-old man who came to the emergency department with right-sided mild-to-moderate hearing loss in the 500-3000-Hz range, confirmed by audiogram, that occurred after ingestion of vardenafil. The patient was hospitalized 2 days later for administration of intravenous dexamethasone, followed by oral prednisone. He reported that his hearing had improved on the fourth hospital day and was discharged 3 days later, continuing to taper the prednisone on an outpatient basis. A repeat audiogram after 10 days of corticosteroid therapy confirmed that his hearing in the 500-3000-Hz range was within normal limits. Use of the Naranjo adverse drug reaction probability scale indicated a possible (score of 3) adverse reaction of sudden sensorineural hearing loss associated with vardenafil consumption. We also performed an analysis of hearing loss cases related to PDE-5 inhibitors in the United States Food and Drug Administration's Adverse Event Reporting System database to compare the characteristics of our patient with those of other reported adverse event cases. Based on the temporal relation of the sudden sensorineural hearing loss to this patient's drug consumption, we propose that the vardenafil is a likely cause of the hearing loss. This case provides further evidence that PDE-5 inhibitor consumption should be considered as a possible cause in patients presenting with sudden sensorineural hearing loss.

Pain and Pain Management for Children in Greifswald and East Pomerania: Comparison with the Results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS).

2010-01-07T13:39:00.000-08:00

Gesundheitswesen. 2010 Jan 4; Franze M, Fendrich K, Schmidt CO, Splieth C, Hoffmann WAIM OF THE STUDY: Pain in children and adolescents in Germany is a common health problem which has a high socioeconomic impact. There have been no studies allowing a reliable estimation of the prevalence of pain in children in the 5 (th) grade (age range 9-13 years) in schools in the region of the city of Greifswald and the administrative district East Pomerania. This population-based cross-sectional study examined the prevalence of pain in children, the treatment of pain and compared these data with the results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). METHODS: Data were collected within the extended dental school examination in autumn 2007 including a self-completion questionnaire for the students. Also the parents answered a self-completion questionnaire containing questions on their children's socio-economic status. The pain and sociodemographic questions are compatible with those used in the "German Health Survey for Children and Adolescents" (KiGGS). RESULTS: Students from 19 schools completed a questionnaire on general pain (n=852, proportion of response: 93.2%, mean age: 10 years). Comparing to the KiGGS the overall 3-month prevalence is much higher (95.5%). For boys and girls headache is the pain associated with the most burden ("Hauptschmerz"). ? of the girls (27.9%) and 1/5 (22.4%) of the boys reported their pain with the most burden during the last 3 months with a frequency of at least one time per week. Students with low socio-economic status took medication against pain ("Hauptschmerz") less frequently than students with high socio-economic status. Because of their pain ("Hauptschmerz") students with low socio-economic status visited a doctor less often than students with a mean or high socio-economic status. CONCLUSION: Compared to other epidemiological studies, pain is also a common health problem for children in the city of Greifswald and the administrative district East Pomerania. The data base enables comprehensive conclusions on the health-related state of students in Greifswald/East Pomerania. Further studies should examine additional factors on medication and the degree of doctor?s visits, e. g., parental attitudes towards medication and parental motivation towards the degree of visiting a doctor.

Clinical features of 337 patients with recurrent nasopharyngeal carcinoma.

2010-01-06T08:09:00.000-08:00

Ai Zheng. 2010 Jan; 29(1): 76-80Li JX, Lu TX, Huang Y, Han F, Chen CY, Xiao WWBackground and Objective: Although appropriate radiotherapy and combined treatments are widely used for the patients with primary nasopharyngeal carcinoma (NPC), local or regional recurrence rates are still high. According to clinical performance, pathology, and diagnostic imaging of the patients with the first recurrence of NPC, this study analyzed the clinical features of recurrent NPC to provide a reference for tracking the rules of recurrence after the treatment of patients with NPC. Methods: The clinical data of 337 patients diagnosed with recurrent NPC for the first time were collected. The diagnoses were based on pathology and/or imaging and the patients were treated at the Sun Yat-sen University Cancer Center between January 1999 and December 2004. Data used for statistical analysis included clinical performance during the patient visit, the extension of the invasion as shown on imaging, pathologic features, Epstein-Barr virus (EBV) serology, restaging, etc. Results: Patients were staged according to the system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) in 2002. Patients with diseases at stages I/II accounted for 25.2%, while those with stage III/IV accounted for 74.8%. The median interval of relapse was 25 months. Patients had local recurrence (69.4%), regional recurrence (4.5%), or both (26.1%). Epistaxis and headache were the most common symptoms. Abduct dysfunction and facial numbness induced by cranial nerve damage were the most common signs. The probability of invasion of structures adjacent to the nasopharynx, such as the oropharynx, the prestyloid space, and the carotid sheath area, was low in patients with recurrent NPC. By contrast, the probability of invasion of structures far from the nasopharynx, such as the base of the skull, the paranasal sinuses, cranial nerves, the cavernous sinus, the brain, the pterygopalatine fossa, the infratemporal fossa, the orbital apex, and the soft palate, was higher in recurrent NPC. Conclusions: The most common interval of relapse is about 2 years. The relapsed disease is usually more widespread and located deeper. Most recurrent NPC is advanced disease.

"Functional" or "psychosomatic" symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression: time to amend the diagnostic cri

2010-01-05T04:05:00.000-08:00

Neuro Endocrinol Lett. 2009 Nov 25; 30(5): FULL TITLE: "Functional" or "psychosomatic" symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression: time to amend the diagnostic criteria for major depression and the rating scales that measure severity of illness. BACKGROUND: Major depression is characterized by multifarious symptoms and symptoms clusters, such as the melancholic and anxiety symptom clusters. There is a strong comorbidity and a biological similarity between major depression and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). AIM: The aim of the present study was to examine "psychosomatic" symptoms reminiscent of ME/CFS in major depression. Toward this end, we examined the 12-item Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale and the Hamilton Depression Rating Scale (HDRS) in 103 major depressed patients by means of multivariate pattern recognition methods. RESULTS: Our findings support the existence of two factors, i.e. a fatigue and somatic (F& S) factor, i.e aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, irritability, irritable bowel, headache, and a subjective experience of infection; and a depression factor, i.e. sadness, irritability, sleep disorders, autonomic symptoms, and a subjective experience of infection. Cluster analysis performed on the 12 FF items found two different clusters, which were separated by highly significant differences in the F& S items, the most significant being a subjective experience of infection, aches and pain, muscular tension, fatigue, concentration difficulties and failing memory. Multivariate analyses showed that the differences between both clusters were quantitatively, and not qualitatively, and reflected the severity of the F& S dimension. There was a strong association between the F& S symptoms and melancholia and chronic depression. Treatment resistant depression was characterized by higher scores on the depression factor score. There was a strong correlation between the HDRS score and the FF items, fatigue, a subjective experience of infection, and sadness. CONCLUSIONS: Our findings show that F& S symptoms are a major feature of depression and largely predict severity of illness, and chronic and melancholic depression. It is concluded that the diagnostic criteria of depression and melancholia and rating scales to measure severity of illness should be modified to include the F& S symptom profile.

"Functional" or "psychosomatic" symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression: time to amend the diagnostic cri

2010-01-04T07:37:00.000-08:00

Electronic Momentary Assessment of Weather Changes as a Trigger of Headaches in Children.

2010-01-03T07:52:00.000-08:00

Headache. 2009 Dec 21; Connelly M, Miller T, Gerry G, Bickel J(Headache 2009;**:**-**) Background.- Variables that are thought to precipitate migraine or tension-type headache episodes in children hitherto have only been studied using retrospective reports. As such, there is little empirical evidence to support the actual predictive association between presumed headache triggers and actual headache occurrence in children. Objective.- The present study sought to determine if fluctuations in weather, a commonly reported headache trigger in children, predict increased likelihood of headache occurrence when evaluated using rigorous prospective methodology ("electronic momentary assessment"). Methods.- Twenty-five children (21 girls, 4 boys) between the ages of 8-17 years attending a new patient neurology clinic appointment and having a diagnosis of chronic migraine, chronic tension-type, or episodic migraine headache (with or without aura) participated in the study. Children completed baseline measures on headache characteristics, presumed headache triggers, and mood and subsequently were trained in the use of electronic diaries to record information on headaches. Children then completed thrice daily diaries on handheld computers for a 2-week time period (42 assessments per child) while data on weather variables (temperature, dew point temperature, barometric pressure, humidity, precipitation, and sunlight) in the child's geographic location were recorded each time a diary was completed. Data were analyzed using multilevel models. Results.- Of the weather variables, relative humidity and presence of precipitation were significantly predictive of new headache onset, with nearly a 3-fold increase in probability of headache occurrence during times of precipitation or elevated humidity in the child's area, b = 0.38, t(821) = 2.10, P = .04, and b = 0.02, t(821) = 2.81, P = .01, respectively. These associations remained after accounting for fluctuations in mood, and associations were not significantly stronger in children who at baseline thought that weather was a headache trigger for them. Changes in temperature, dew point temperature, barometric pressure, and sunlight were not significantly predictive of new headache episode occurrence in this sample. Conclusions.- Results of the present study lend some support to the belief commonly held by children with recurrent headaches that weather changes may contribute to headache onset. Although electronic momentary assessment methodology was found to be feasible in this population and to have the potential to identify specific headache triggers for children, it remains to be determined how best (or even whether) to incorporate this information into treatment recommendations.

Headache: What Do Children and Mothers Expect From Pediatricians?

2010-01-01T06:16:00.000-08:00

Headache. 2009 Dec 21; Raieli V, Compagno A, Pandolfi E, La Vecchia M, Puma D, La Franca G, Ragusa D(Headache 2009;**:**-**) Background.- Headache is a frequent occurrence among children and adolescents, and one of the most common causes of medical consultation. While serious conditions presenting headache as the chief complaint are not common in the pediatric population, enormous sums are invested to perform very expensive and often unnecessary diagnostic investigations. Pediatricians should adopt a flexible and diversified diagnostic/therapeutic approach and, at the same time, should not forget to take into consideration the demands, expectations, and worries of children and their parents. Objective.- The aim of this study was to assess simultaneously children's and mothers' expectations from the pediatric consultation concerning headache, and pediatricians' opinions about said expectations. In addition, we attempted to investigate mothers', children's, and pediatricians' opinions about symptomatic and prophylactic treatment of headache. Method.- A total of 100 young headache sufferers, 50 were male and 50 were female, from 10 to 16 years of age, were enrolled in this study. Two diversified, self-administered, ad hoc questionnaires about their expectations from the pediatric treatment of headache and about symptomatic and prophylactic treatment were delivered to each patient and their mother, to which they responded separately. A third self-administered questionnaire was delivered to a sample of 50 pediatricians. Results.- Our study showed that children and their mothers sometimes have different expectations about the consultation of the pediatrician and of the headache specialist. Frequency of pain was the main reason for pediatric consultation for 70% of mothers, whereas only 2% of them (as opposed to what pediatricians believed) consulted the pediatrician because they were worried about a tumor. Moreover, a high percentage of children and mothers expected from the pediatric consultation to be reassured that it is not a serious illness and to find out the causes of headache (60% and 47%, and 45% and 62%, respectively). A total of 26% of children wanted to know the progression of headache in the future, but only 3% of mothers shared the same demand. With regard to their expectations, pediatricians agree only in part with children and their mothers. On the contrary, the majority of children (68%), mothers (49%), and pediatricians (90%) agree that a symptomatic treatment was necessary in the presence of a severe pain. In addition, 61% of children, 37% of mothers, and 74% of pediatricians believed that a prophylactic treatment was necessary when the pain is severe and long-lasting. Conclusion.- Pediatricians sometimes do not consider sufficiently children's and mothers' wishes and expectations and, consequently, could limit the outcome of their diagnostic-therapeutic approach. This is particularly important because, in the developmental age, an accurate recognition of patients' and parents' expectations represents an essential requirement for a favorable outcome of the consultation.

"Functional" or "psychosomatic" symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression: time to amend the diagnostic cri

2009-12-30T14:25:00.000-08:00

[Post-encephalitic syndrome in patients with tick-borne encephalitis]

2009-12-30T00:27:00.001-08:00

Acta Med Croatica. 2009 Oct; 63(4): 269-78MisiÄ Majerus L, DakoviÄ Rode O, RuziÄ SabljiÄ EBACKGROUND: It was 55 years ago when the first patients with tick-borne encephalitis (TBE) were diagnosed in the Koprivnica-Krizevci County. Since then, we have acquired some new knowledge about the disease. TBE is an endemic disease and the second most common tick-borne disease following Lyme borreliosis in our country, with an average morbidity rate of 12 patients per year and predominance of male individuals older than 50. There are no specific risk groups because such patients have been continuously vaccinated for the past 27 years. In 88.0% of patients, the infection is manifested as aseptic meningitis and meningoencephalitis with a biphasic course. As opposed to detailed descriptions of acute morbidity, there are few reports on the course of disease and its outcome. OBJECTIVES: The aim of the study was to assess the presence of post-encephalitic syndrome (PES) in patients with TBE, to evaluate its incidence and demonstrate its characteristics. PATIENTS AND METHODS: This prospective study was conducted from 1995 to 2008 and enrolled PES patients treated at Department of Infectious Diseases, Dr. Tomislav Bardek General Hospital in Koprivnica during the study period. The study included patients of both sexes older than 14 years with recent TBE virus infection, patients with clear temporal correlation between acute morbidity and PES onset, and patients where any other cause of PES was ruled out. The immunoenzyme linked assay (ELISA) was used for detection of serum IgM and IgG antibodies. Recent TBE virus infection was detected in 133 patients. Nine of these patients refused further cooperation, and the remaining 124 patients, 80 male (64.5%) and 44 female (35.4%), aged 16-76, were included in the study. We longitudinally examined the manifestation and characteristics of PES in each patient during a 3-year period (and longer if necessary). Study patients were divided into three groups of mild, moderate and severe PES based on data collected and entered into specially prepared questionnaire and by qualitative analysis of PES effect on their daily habits and activities. RESULTS: Out of 124 patients included in the study, 60 (48.3%) had no symptoms/signs of PES, or these were mild and of short duration 15 (12.0%). The remaining 49 (39.5%) patients developed moderate (30/47.0%) or severe (19/30.0%) PES lasting for 3-18 months, with significant impact on their daily habits and activities requiring some adjustment. The main characteristics of PES were mental disorders, balance and movement coordination disorders, headache, general malaise, and reduced working ability. PES was recorded in 35 (28.2%) patients with meningoencephalitis and 14 (11.2%) patients with meningoencephalomyelitis. Permanent sequels were left over in 11 (17.1%) patients: spinal nerve paresis in five (4.0%), hearing impairment in six (5.6%), dysarthria in two (1.6%) patients, and severe mental disorder in one (0.8%) patient. In three patients we recorded simultaneous permanent spinal nerve paralysis and permanent deafness. During our longitudinal study three (2.5%) patients died. CONCLUSION: The study undoubtedly confirmed the presence of PES in our patients with TBE. Moderate and severe PES has a significant impact on the patient quality of life, demands patient adjustment, and increases expenses of long-term sick-leave and rehabilitation.

Switching from oral extended-release methylphenidate to the methylphenidate transdermal system: continued attention-deficit/hyperactivity disorder symptom control and tolerability after abrupt convers

2009-12-04T00:05:00.001-08:00

Curr Med Res Opin. 2009 Nov 16; Arnold LE, Bozzolo DR, Hodgkins P, McKay M, Beckett-Thurman L, Greenbaum M, Bukstein O, Patel AAbstract Objective: To evaluate symptom control and tolerability after abrupt conversion from oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). Methods: In a 4-week, prospective, multisite, open-label study, 171 children (164 intent-to-treat) with diagnosed ADHD aged 6-12 years abruptly switched from a stable dose of oral ER-MPH to MTS in nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. After the first week on the scheduled dose, the dose was titrated to optimal effect. The primary effectiveness outcome was the change from baseline (while taking ER-MPH) to week 4 in ADHD-Rating Scale-IV (ADHD-RS-IV) total scores. Adverse events (AEs) were assessed throughout the study. Results: Most subjects (58%) remained on the initial MTS dose defined by the dose-transition schedule; 38% increased and 4% decreased their MTS dose for optimization. MTS dose optimization resulted in significantly better ADHD-RS-IV total (mean +/- SD) scores at week 4 than at baseline (9.9 +/- 7.47 vs. 14.1 +/- 7.48; p < 0.0001). The most commonly reported AEs included headache, decreased appetite, insomnia, and upper abdominal pain. Four subjects (2.3%) discontinued because of application site reactions and three discontinued because of other AEs. Conclusions: Abrupt conversion from a stable dose of oral ER-MPH to MTS was accomplished using a predefined dose-transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH. Limitations of this study included its open-label sequential design without placebo, which could result in spurious attribution of improvement to the study treatment and precluded superiority determinations of MTS over baseline ER-MPH treatment. The apparent superiority of MTS was likely due to more careful titration and clinical monitoring rather than the product itself. ClinicalTrials.gov: NCT00151983.

Pharmacokinetics and tolerability of single escalating doses of fampridine sustained-release tablets in patients with multiple sclerosis: A phase I-II, open-label trial.

2009-11-30T22:58:00.001-08:00

Clin Ther. 2009 Oct; 31(10): 2206-2214Vollmer T, Henney HRBackground: Fampridine (4-aminopyridine) is a potassium channel-blocking agent that has been reported to have therapeutic potential for improving walking and mobility in patients with multiple sclerosis (MS). A sustained-release (SR) formulation of fampridine was developed to improve the agent's pharmacokinetic profile by extending its t((1/2)) relative to that of immediaterelease fampridine. Objectives: The primary study objective was to examine the pharmacokinetics of fampridine SR tablets after single escalating doses in patients with MS. Tolerability was evaluated as a secondary end point. Methods: This multicenter, Phase I-II, open-label trial evaluated the dose proportionality and tolerability of 4 single doses of fampridine SR (5, 10, 15, and 20 mg) in patients with MS. There was a 4-day washout between doses. Blood samples were collected immediately before drug administration, hourly for the first 8 hours after administration, and at 10, 12, 14, 18, and 24 hours after administration. The pharmacokinetic parameters evaluated included C(max), T(max), AUC, elimination rate constant, apparent elimination t((1/2)), and apparent CL/F. Twelve-lead ECGs were obtained at baseline (0.5 hour before dosing) and at 1, 4, 12, and 24 hours after drug administration to evaluate potential effects on the QTc interval. All adverse events, abnormal laboratory values, and ECG abnormalities were recorded and evaluated for clinical relevance. Adverse-event data were monitored for 24 hours after the last dose, and patients were instructed to report any adverse events for 14 days after the conclusion of the study. Results: Twenty-four white patients were enrolled (58% female; mean [SD] age, 45.4 [7.3] years; weight range, 47.8-87.1 kg), and 23 completed the study. Mean plasma concentrations and AUC values were dose proportional. T(max) occurred at 3.36 to 3.92 hours after dosing; the apparent elimination t((1/2)) was 5.47 hours. Both sex and weight affected the pharmacokinetic parameters of fampridine SR. Eleven treamentrelated adverse events were reported in 10 patients, with dizziness being the most common (7 incidents reported by 6 patients [1 at 10 mg, 3 at 15 mg, and 3 at 20 mg]). Other adverse events included amblyopia, asthenia, headache, and ataxia. All treatmentrelated adverse events were mild to moderate in severity, with the exception of 1 case of dizziness (20 mg) that was considered severe. No serious adverse events were reported, and no clinically significant changes in corrected QT intervals were observed. No patients with-drew due to treatment-related adverse events. Conclusion: In these patients with MS, fampridine SR (5-20 mg) had a potentially advantageous pharmacokinetic profile relative to that associated with immediate-release fampridine and was generally well tolerated.

Potential interactions between cilostazol and probucol: A two-part, single-dose, open-label study in healthy Korean male volunteers.

2009-11-29T22:59:00.001-08:00

Clin Ther. 2009 Oct; 31(10): 2098-2106Kim KP, Kim BH, Lim KS, Kim TE, Shin SG, Jang IJ, Yu KSBackground: Combined therapy with cilostazol, an antiplatelet agent, and probucol, an antihyperlipidemic agent, has been reported to prevent restenosis after percutaneous transluminal coronary angioplasty. However, the potential for pharmacokinetic drug interactions between the 2 agents has not been evaluated. Objectives: The aims of this study were to compare the pharmacokinetic properties of cilostazol and probucol administered alone and together in healthy Korean male volunteers. Methods: This open-label study in healthy adult (age 20-40 years) male volunteers consisted of 2 parts. Part A had a 1-sequence, 2-period crossover design in which each subject received cilostazol 100 mg (1 tablet) in period 1 and cilostazol 100 mg (1 tablet) plus probucol 500 mg (2 tablets) in period 2. Part B had a parallel-group design in which one group received probucol 250 mg (1 tablet) and the other received probucol 250 mg (1 tablet) and cilostazol 100 mg (1 tablet). Geometric mean ratios for C(max) and AUC were compared by ANOVA, and pharmacokinetic parameters were also compared by t tests. Tolerability was evaluated based on adverse events, ECGs, vital signs, and clinical laboratory test results. Results: Twelve healthy volunteers completed part A; their mean age was 24.1 years (range, 21-29 years), mean height 171.8 cm (range, 163-177 cm), and mean weight 65.2 kg (range, 56.3-77.6 kg). Of the 20 healthy volunteers enrolled in part B, 19 completed the study; their mean age was 25.1 years (range, 21-34 years), mean height 173.2 cm (range, 162-183 cm), and mean weight 65.5 kg (54.0-78.0 kg). The pharmacokinetic parameters of cilostazol and probucol did not differ significantly when the 2 agents were administrated alone or together. In part A, the geometric mean ratios for C(max) and AUC(0-60h) between coadministration and single administration of cilostazol were 0.8882 (90% CI, 0.7873-1.002) and 1.013 (90% CI, 0.8643-1.188), respectively, for cilostazol; 0.8758 (90% CI, 0.7584-1.011) and 0.9785 (90% CI, 0.7600-1.260) for the OPC-13015 metabolite; and 0.8730 (90% CI, 0.7486-1.018) and 1.004 (90% CI, 0.8847-1.140) for the OPC-13213 metabolite. In part B, the geometric mean ratios for C(max) and AUC(0-648)h between coadministration and single administration of probucol were 1.134 (90% CI, 0.8177-1.572) and 1.070 (90% CI, 0.7364-1.555), respectively. Twenty-five adverse events were reported by 9 subjects in part A; the most frequently reported were headache (10 events) and nausea (4 events). Twenty adverse events were reported by 10 subjects in part B; the most frequently reported were headache (4 events) and productive cough (3 events). No clinically significant changes were noted in vital signs, ECGs, or laboratory values. Conclusion: In these healthy Korean male volunteers, coadministration of single doses of cilostazol and probucol had no significant effects on the pharmacokinetics of either drug. ClinicalTrials.gov identifier: NCT00549978.

Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volu

2009-11-28T05:42:00.001-08:00

Clin Ther. 2009 Oct; 31(10): 2224-2232Parrillo-Campiglia S, Ercoli MC, Umpierrez O, RodrÃguez P, MÃ¡rquez S, Guarneri C, Estevez-Parrillo FT, Laurenz M, Estevez-Carrizo FEBackground: Imatinib is a tyrosine kinase inhibitor that has been established as a highly effective therapy for chronic myelogenous leukemia and gastrointestinal stromal tumors. A new generic, once-daily 400-mg tablet of imatinib has been developed by a pharmaceutical company in Argentina, where the regulatory standard for marketing authorization of an imatinib generic is in vitro dissolution testing. Objective: The aim of this study was to assess the bioequivalence of a new generic film-coated test tablet formulation versus a film-coated reference tablet formulation of imatinib 400 mg. The local manufacturer seeks to validate the in vitro performance of this new formulation with a bioequivalence study. Methods: A randomized, open-label, single-dose, fasting, 2-period, 2-sequence crossover design with a 2-week washout period was used in this study. The study population consisted of healthy male South American (Uruguayan) volunteers, who were assigned in a 1:1 ratio to a randomized sequence (test-reference or reference-test). In each period, the test or reference formulation was administered after an overnight fast. During the 72-hour follow-up period, participants were monitored for vital signs and symptoms. Blood samples were collected at 15 time points, including baseline, until 72 hours. Physical examination and laboratory tests (blood, urine) were repeated 1 week after study completion. A noncompartmental model was used to determine the pharmacokinetic parameters of imatinib. The 90% CIs of the test/reference ratios for AUC(0-infinity) and C(max) were determined; the test and reference formulations were considered bioequivalent if the 90% CIs were between 0.80 and 1.25. Adverse events were assessed by a nurse who administered a questionnaire while the healthy volunteers were admitted in the unit. Results: The bioequivalence study was conducted in 30 Uruguayan male volunteers. Demographic characteristics (mean [SD]) included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71 (0.09) m; and body mass index, 24.3 (3.0) kg/m2. The mean (SD) of AUC(0-infinity) was 38,179 (15,504) ng/mL . h(-1) for the test formulation and 40,554 (17,027) ng/mL . h(-1) for the reference formulation. The mean of Cmax for the test formulation was 2472 (933) ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the reference formulation was 2566 (963) ng/mL, and the mean T(max) was 3.63 (1.20) hours. The point estimates (90% CIs) for the test/reference ratios of the log-transformed AUC- and C(max) mean values were 0.95 (0.87-1.03) and 0.97 (0.89-1.05), respectively, which met the regulatory criteria for bioequiv-alence. Thirty-four mild to moderate adverse events were reported (13 with the test formulation and 21 with the reference formulation), and no serious or unexpected adverse events were observed during the study. The adverse events included 16 cases of headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of diarrhea. Conclusions: The results of this study suggest that the test formulation of imatinib met the regulatory criteria for bioequivalence to the reference formulation in these healthy fasting male volunteers. Both formulations were generally well tolerated and appeared to have a similar adverse-event profile.

Comparison of the pharmacokinetics of ticlopidine between administration of a combined fixed-dose tablet formulation of ticlopidine 250 mg/Ginkgo extract 80 mg, and concomitant administration of ticlo

2009-11-27T20:18:00.001-08:00

Clin Ther. 2009 Oct; 31(10): 2249-2257Kim TE, Kim BH, Kim J, Kim KP, Yi S, Shin HS, Lee YO, Lee KH, Shin SG, Jang IJ, Yu KSBackground: Ticlopidine is an antiplatelet agent used for the prevention of vascular accidents. In clinical practice in Korea, ginkgo extract may be administered along with ticlopidine to enhance the inhibition of platelet aggregation. Objective: To meet the requirements for marketing a combined fixed-dose formulation in Korea, the investigators compared the pharmacokinetic characteristics of ticlopidine in a combined fixed-dose tablet of ticlopidine/ginkgo extract with the concomitant administration of ticlopidine and ginkgo extract tablets. Methods: An open-label, 2-period, 2-treatment, single-dose, randomized-sequence crossover study was conducted in healthy Korean male volunteers. Subjects were randomly allocated to 2 sequence groups. In one period, a combined ticlopidine 250 mg/ ginkgo extract 80-mg fixed-dose tablet was administered and, in the other period, ticlopidine 250-mg and ginkgo extract 80-mg tablets were concomitantly administered. A 7-day washout separated the 2 periods. For analysis of pharmacokinetic properties, including C(max), T(max), t((1/2)), AUC(0-infinity), and AUC(0-last), serial blood sampling was performed up to 48 hours after study drug administration during each period. Ticlopidine concentrations in plasma were determined by a validated method using LC-MS/MS. In order for the 2 treatments to be considered bioequivalent, the 90% CI of the geometric means ratios for C(max) and AUC needed to be between 80% and 125%. Bleeding time was determined before dosing (0 hour) and at 5 and 24 hours after dosing. Adverse events (AEs) were identified through patient interview, recording of blood pressure, heart rate, and body temperature, physical examination, 12-lead ECG, and laboratory assessments. Results: Twenty-four healthy Korean male subjects (mean [range] age, 23.9 [22-38] years; height, 174.0 [162-184] cm; weight, 67.4 [56-80] kg) completed the study. Median (range) T(max) of ticlopidine was 1.5 (0.5-2.0) hours in both groups. The mean (SD) t((1/2)) of ticlopidine in the combined fixed-dose formulation and the concomitant administration groups was 19.5 (3.4) and 19.0 (3.3) hours after study drug administration, respectively. The geometric means ratios of ticlopidine AUC(0-last), AUC(0-infinity), and C(max) between the combined fixed-dose formulation and concomitant administration were 1.04 (90% CI, 0.96-1.13), 1.04 (90% CI, 0.96-1.13), and 1.09 (90% CI, 0.96-1.23), respectively. The mean (SD) bleeding time at predose (0), and 5 and 24 hours after dose administration was 4.5 (1.6) to 5.4 (1.7) minutes in the combined fixed-dose formulation group and 4.4 (1.6) to 5.1 (1.1) minutes in the concomitant administration group. Five subjects (3 in the combined fixed-dose formulation group and 2 in the concomitant administration group) had bleeding times >8 minutes, but this was not considered to be clinically significant. A total of 24 AEs were reported in 13 of 24 subjects: nausea (3 cases), diarrhea (3), dizziness (3), epigastric discomfort (2), headache (2), rhinorrhea (2), purulent sputum (2), dyspepsia (1), upper abdominal pain (1), cough (1), pharyngolaryngeal pain (1), oropharyngeal swelling (1), dysphonia (1), and dysphagia (1). All were considered mild or moderate in nature. There was no statistically significant difference between the 2 treatments in the number of AEs or in the number of subjects who reported an AE. Conclusion: Administration of a single dose of a combined fixed-dose formulation of ticlopidine 250 mg/ ginkgo extract 80-mg tablets and concomitant administration of ticlopidine and ginkgo extract tablets did not result in statistically significant differences in the pharmacokinetics of ticlopidine in these healthy Korean male volunteers.

Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volu

2009-11-24T20:18:00.001-08:00

Comparison of the pharmacokinetics of ticlopidine between administration of a combined fixed-dose tablet formulation of ticlopidine 250 mg/Ginkgo extract 80 mg, and concomitant administration of ticlo

2009-11-23T20:26:00.001-08:00

Switching from oral extended-release methylphenidate to the methylphenidate transdermal system: continued attention-deficit/hyperactivity disorder symptom control and tolerability after abrupt convers

2009-11-19T00:32:00.001-08:00

Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing.

2009-11-18T01:20:00.001-08:00

Drug Saf. 2009; 32(12): 1123-34Alcorn N, Saunders S, Madhok REvidence is accumulating for the early sustained usage of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis. Leflunomide was licensed for the treatment of rheumatoid arthritis in 1998. Postmarketing surveillance, case reports and observational studies have highlighted less common or unexpected adverse events. Therefore, it is appropriate that we review the benefit-risk profile of leflunomide after 10 years of widespread usage. A wide-based search of relevant literature was performed to formulate this assessment. The improvements in rheumatoid arthritis shown by double-blind, randomized controlled trials (RCTs) of leflunomide have now been shown to be maintained beyond 4 years in open-label extension studies. Leflunomide is comparable to methotrexate, but better than sulfasalazine at 24 months in only one study. However, tolerance in clinical practice research shows higher than expected withdrawal rates due to both toxicity and lack of efficacy when compared with methotrexate and placebo. Adverse events reported include gastrointestinal upset, hypertension, headache, hepatotoxicity and hair loss, as well as predisposition to infection and peripheral neuropathy. The incidence of gastrointestinal adverse effects for leflunomide is similar to sulfasalazine but higher than those seen with methotrexate. Serious drug-induced hepatotoxicity leading to hospitalization is rare (0.02%), but isolated fatalities from liver failure have been documented. It is considered likely, but not yet proven, that there may be an increased incidence of weight loss and interstitial lung disease with leflunomide. Leflunomide in combination with methotrexate or sulfasalazine is an effective regimen in RCTs utilizing placebo controls, but more research is needed to confirm its effectiveness in combination with other DMARDs, particularly biologicals. The active metabolite of leflunomide is teratogenic in animal studies and is also found in breast milk. Therefore, contraception is advised in both males and females of child-bearing potential. There are genetic, pharmacokinetic and biochemical reasons to explain variation in both patient response and adverse event profile. Hence, blood and blood pressure monitoring are recommended and therapeutic drug monitoring should be considered in clinical nonresponders. Leflunomide is an effective DMARD that sustains a clinical and radiological response comparable to sulfasalazine and methotrexate. However, adverse effects necessitate frequent monitoring. It should be used with caution in those of child-bearing potential and with pre-existing lung and liver disease.

The synthetic Plasmodium falciparum circumsporozoite peptide PfCS102 as a malaria vaccine candidate: a randomized controlled phase I trial.

2009-11-16T20:40:00.001-08:00

PLoS One. 2009; 4(10): e7304Audran R, Lurati-Ruiz F, Genton B, Blythman HE, Ofori-Anyinam O, Reymond C, Corradin G, Spertini FBACKGROUND: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults. METHODOLOGY AND PRINCIPAL FINDINGS: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma responses than Montanide formulations. CONCLUSIONS/SIGNIFICANCE: PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 microg formulated with AS02A appeared the most appropriate choice for such studies. TRIAL REGISTRATION: Swissmedic.ch 2002 DR 1227.

Human metapneumovirus infection in hematopoietic stem cell transplant recipients.

2009-11-13T14:29:00.001-08:00

Transpl Infect Dis. 2009 Oct 29; Debur MC, Vidal LR, Stroparo E, Nogueira MB, Almeida SM, Takahashi GA, Rotta I, Pereira LA, Silveira CS, Bonfim CM, Raboni SMM.C. Debur, L.R. Vidal, E. Stroparo, M.B. Nogueira, S.M. Almeida, G.A. Takahashi, I. Rotta, L.A. Pereira, C.S. Silveira, C.M. Bonfim, S.M. Raboni. Human metapneumovirus infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2009. All rights reserved Abstract: Human metapneumovirus (hMPV) was described in 2001 and has been associated with both upper and lower respiratory tract infection (URTI and LRTI, respectively), especially in children, the elderly, and in immunocompromised patients. The objective of this study was to identify hMPV as the etiological agent of acute respiratory infection in hematopoietic stem cell transplant (HSCT) patients and to determine the clinical features of hMPV infection in these patients. Methods. The study was performed retrospectively in 769 respiratory samples obtained from immunocompromised patients submitted to HSCT over a period of 6 years. RNA was extracted by the guanidinium thiocyanate method, and reverse transcription polymerase chain reaction assay was performed to amplify a 928pb fragment of the hMPV N gene. Results. hMPV was present in 19 (2.5%) samples. The mean age of infected patients was 18.3+/-10.8 (range, 3-41). Sixty-six percent of hMPV infections occurred during autumn, winter, and spring months. Three episodes showed co-infection with more than 1 virus. Two patients (11.1%) were infected a few days into the conditioning period and 9 (50%) in the first 3 months after the transplant. The majority of patients (72.2%) presented URTI alone with flu-like symptoms (cough, fever, headache, wheezing), while 5 patients (27.8%) had LRTI (pneumonia). No patient died from complications associated with the hMPV infection. Conclusions. hMPV has been reported as a respiratory pathogen in HSCT patients. We suggest that hMPV infection should be routinely investigated in this population, mainly in children, to prevent nosocomial transmission during transplant proceedings and to avoid the risk of progressing to complications due to LRTI.

Role of non-group a streptococci in acute pharyngitis.

2009-11-12T20:00:00.001-08:00

J Am Board Fam Med. 2009 Nov-Dec; 22(6): 663-9Tiemstra J, Miranda RLBACKGROUND: The role of non-group A streptococci (non-GAS) as pathogens of acute pharyngitis is controversial. Data are limited and conflicting on whether these bacteria are true pathogens of pharyngitis and whether treatment is indicated in all cases or just select cases. However, non-GAS are well-documented as being pathogens of other diseases, including neonatal sepsis, pneumonia, endocarditis, and urinary tract infections. If non-GAS are pathogens of acute pharyngitis, treatment may speed recovery as well as prevent complications. The objective of this study was to determine whether, in cases of pharyngitis in which non-GAS is identified on culture, the clinical signs and symptoms resemble those of group A streptococcal pharyngitis thus implicating them as true pathogens or if they resemble culture-negative pharyngitis, suggesting these cases are viral in etiology. Method: This was a 3-group retrospective case-control study (N = 915; mean age, 26 years). Cases included all patients with non-GAS identified on culture (n = 180). The control group 1 consisted of all patients with GAS infection identified by a rapid strep test or culture (n = 145); control group 2 included all patients with a negative rapid strep test and culture (presumed viral pharyngitis; n = 584). Multivariate analysis was used to compare the prevalence of 5 clinical features among the groups. RESULTS: The presence of headache and fever was significantly associated with streptococcal infection, with no difference between GAS and non-GAS infection. Exudates and lymphadenopathy were also significantly associated with both GAS and non-GAS infection compared with viral infection. When 2 criteria were present, the risk of any streptococcal infection rose to 55% (27% for non-GAS or GAS); when 3 or more criteria were present, the rate of any streptococcal infection rose to 81% (non-GAS infection, 34%; GAS infection, 47%). CONCLUSION: In this predominantly young, adult population with acute pharyngitis, non-GAS infection was as common as GAS infection and was associated with the same clinical features typically associated with GAS. Although the benefits of treating non-GAS pharyngitis in terms of either symptomatic relief or prevention of sequelae are unproven, clinicians may want to consider treating patients with proven or presumptive non-GAS pharyngitis who fail to respond to symptomatic therapy or who are at increased risk for sequelae of group B or group C streptococcal infections, such as those patients who are or have close contact with pregnant women, neonates, and elderly or immunocompromised persons. Further study is needed to determine whether patients with non-GAS pharyngitis benefit from targeted antibiotic treatment.

Gastric leptomeningeal carcinomatosis: Multi-center retrospective analysis of 54 cases.

2009-11-08T23:20:00.001-08:00

World J Gastroenterol. 2009 Oct 28; 15(40): 5086-90Oh SY, Lee SJ, Lee J, Lee S, Kim SH, Kwon HC, Lee GW, Kang JH, Hwang IG, Jang JS, Lim HY, Park YS, Kang WK, Kim HJAIM: To identify the clinical features and outcomes of infrequently reported leptomeningeal carcinomatosis (LMC) of gastric cancer. METHODS: We analyzed 54 cases of cytologically confirmed gastric LMC at four institutions from 1994 to 2007. RESULTS: The male-to-female ratio was 32:22, and the patients ranged in age from 28 to 78 years (median, 48.5 years). The majority of patients had advanced disease at initial diagnosis of gastric cancer. The clinical or pathologic tumor, node and metastasis stage of the primary gastric cancer was IV in 38 patients (70%). The median interval from diagnosis of the primary malignancy to the diagnosis of LMC was 6.3 mo, ranging between 0 and 73.1 mo. Of the initial endoscopic findings for the 45 available patients, 23 (51%) of the patients were Bormann type III and 15 (33%) patients were Bormann type IV. Pathologically, 94% of cases proved to be poorly differentiated adenocarcinomas. Signet ring cell component was also observed in 40% of patients. Headache (85%) and nausea/vomiting (58%) were the most common presenting symptoms of LMC. A gadolinium-enhanced magnetic resonance imaging was conducted in 51 patients. Leptomeningeal enhancement was noted in 45 cases (82%). Intrathecal (IT) chemotherapy was administered to 36 patients-primarily methotrexate alone (61%), but also in combination with hydrocortisone/+/- Ara-C (39%). The median number of IT treatments was 7 (range, 1-18). Concomitant radiotherapy was administered to 18 patients, and concomitant chemotherapy to seven patients. Seventeen patients (46%) achieved cytological negative conversion. Median overall survival duration from the diagnosis of LMC was 6.7 wk (95% CI: 4.3-9.1 wk). In the univariate analysis of survival duration, hemoglobin, IT chemotherapy, and cytological negative conversion showed superior survival duration (P = 0.038, P = 0.010, and P = 0.002, respectively). However, in our multivariate analysis, only cytological negative conversion was predictive of relatively longer survival duration (3.6, 6.7 and 14.6 wk, P = 0.030, RR: 0.415, 95% CI: 0.188-0.918). CONCLUSION: Although these patients had a fatal clinical course, cytologic negative conversion by IT chemotherapy may improve survival.

Anterior communicating artery aneurysm related to visual symptoms.

2009-11-07T16:45:00.001-08:00

J Korean Neurosurg Soc. 2009 Sep; 46(3): 232-8Park JH, Park SK, Kim TH, Shin JJ, Shin HS, Hwang YSOBJECTIVE: Intracranial aneurysms are sometimes presented with visual symptoms by their rupture or direct compression of the optic nerve. It is because their prevalent sites are anatomically located close to the optic pathway. Anterior communicating artery is especially located in close proximity to optic nerve. Aneurysm arising in this area can produce visual symptoms according to their direction while the size is small. Clinical importance of visual symptoms presented by aneurysmal optic nerve compression is stressed in this study. METHODS: Retrospective analysis of ruptured anterior communicating artery aneurysms compressing optic apparatus were carried out. Total 33 cases were enrolled in this study. Optic nerve compression of the aneurysms was confirmed by the surgical fields. RESULTS: In 33 cases among 351 cases of ruptured anterior communicating artery aneurysms treated surgically, from 1991 to 2000, the dome of aneurysm was compressed in optic pathway. In some cases, aneurysm impacted into the optic nerve that deep hollowness was found when the aneurysm sac was removed during operation. Among 33 cases, 10 cases presented with preoperative visual symptoms, such as visual dimness (5), unilateral visual field defect (2) or unilateral visual loss (3), 20 cases had no visual symptoms. Visual symptoms could not be checked in 3 cases due to the poor mental state. In 6 cases among 20 cases having no visual symptoms, optic nerve was deeply compressed by the dome of aneurysm which was seen in the surgical field. Of 10 patients who had visual symptoms, 8 showed improvement in visual symptoms within 6 months after clipping of aneurysms. In 2 cases, the visual symptoms did not recover. CONCLUSION: Anterior communicating artery aneurysm can cause visual symptoms by compressing the optic nerve or direct rupture to the optic nerve with focal hematoma formation. We emphasize that cerebral vascular study is highly recommended to detect intracranial aneurysm before its rupture in the case of normal CT findings with visual symptoms and frequent headache.

Nonsteroidal, antiinflammatory drug-induced gastrointestinal injuries and related adverse reactions: Epidemiology, pathogenesis and management.

2009-11-04T01:33:00.001-08:00

Saudi J Gastroenterol. 2007 Jul-Sep; 13(3): 107-13Al Mofleh IA, Al Rashed RSA large proportion of the population all over the world consumes acetylsalicylic acid (ASA: aspirin) or other nonsteroidal, antiinflammatory drugs (NSAIDs). This is associated with a considerable morbidity and mortality. Elderly patients, patients with prior history of peptic ulcer disease (PUD) or its complications, those who require high doses of NSAIDs and those undergoing concomitant therapy with corticosteroids or anticoagulants, are at particularly high risk of developing gastroduodenal injuries and related adverse reactions. Gastroduodenal mucosal injuries induced by NSAIDs vary from subtle microscopic to gross macroscopic changes including ulcers. These injuries are induced by both topical and systemic actions of NSAIDs. Inhibition of gastroduodenal cyclooxygenase (COX) enzyme by NSAIDs is considered to be a major pathogenetic factor. Reactive oxygen species (ROS) appear also to play a significant role in the pathogenesis of mucosal injury. Withdrawal of NSAIDs is preferably the first therapeutic option; however, it is not feasible in the majority of patients. Therefore, several drugs including antisecretory drugs (ASDs-proton pump inhibitors and Histamine-2 receptor antagonists) and misoprostol, a prostaglandin analog are used for the prevention and treatment of NSAID-induced gastroduodenal injuries. Among ASDs, proton pump inhibitors (PPIs) are the most commonly used drugs. The antiulcerogenic effect of PPIs is similar to that of misoprostol and superior to standard doses of histamine-2 receptor antagonists (H2-RAs). The adverse effects of m,isoprostol such as diarrhea, abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, constipation, abortifacient and teratogenicity limit its general use. Aside from their antisecretory action, PPIs also possess an antioxidative effect. PPI maintenance is recommended in chronic NSAID treatment in those with an increased risk of complications and is more effective than Helicobacter pylori eradication. Low PPI dosage maintenance is as effective as a standard dosage regimen. The effect of H. pylori eradication remains controversial. It is advocated in naomicronve NSAID users, in chronic users with recent ulcer or ulcer complications and in those with an increased risk of ulcer and ulcer complications. In addition, some herbs have shown inhibition of gastric mucosal damage experimentally induced by necrotizing agents through their antisecretory and antioxidant properties.

Preoperative evaluation of chronic rhinosinusitis patients by conventional radiographies, computed tomography and nasal endoscopy.

2009-10-31T00:45:00.001-07:00

Kulak Burun Bogaz Ihtis Derg. 2009 Jul-Aug; 19(4): 184-91KasapoÄlu F, Onart S, Basut OOBJECTIVES: The aim of this study was to compare the efficacy of conventional radiography (CR), computed tomography (CT) and nasal endoscopy for the preoperative evaluation of chronic rhinosinusitis in patients with persistent complaints despite appropriate medical therapy. PATIENTS AND METHODS: Forty-three patients (26 males, 17 females; mean age 43 years; range 15 to 73 years) were prospectively evaluated. All patients underwent detailed physical examination, CR and coronal high resolution CT of paranasal sinuses. Thirty of them were evaluated with detailed nasal rigid and/or flexible endoscopy as well. The anatomic variations and mucosal changes in paranasal sinuses were noted. The specificity and sensitivity of CR was calculated using CT findings as a reference point. Surgery was performed on two of the other three patients because of obstructive symptoms of middle turbinate. Paradoxal middle turbinate surgery was performed on one patient due to a headache of rhinogenic origin. RESULTS: In our study 40 (93%) of all patients showed mucosal abnormalities on CT. Computed tomography scanning of the patients revealed anatomic variations in 74.4% of the cases. Mucosal pathology was most frequently observed in the anterior ethmoid region (middle meatus). While we found mucosal anomalies in 47.4% of all sinuses using CR, 42.2% of these cases were confirmed with CT. Also, 19.5% of all sinuses evaluated as normal with CR presented pathologic findings on CT. An overall correlation of 75.3% was observed between CR and CT, while diagnostic nasal endoscopy and CT findings were correlated at a rate of 87%. CONCLUSION: (i) While no ipsilateral maxillary or frontal sinus disease was detected when no abnormality in the anterior ethmoid region and infundibulum was observed endoscopically in the presence of mucosal abnormalities similar abnormalities were seen at the same side for maxillary or frontal sinuses. (ii) Anatomic variations of nasal and paranasal sinuses may be considered as etiologic and predisposing factors of chronic rhinosinusitis. (iii) Conventional radiography should not be used as a single diagnostic tool in preoperative evaluation; however, due to its high sensitivity, CR technique may be used alone in the diagnosis and follow-up of maxillary sinus disease. (iv) Nasal endoscopy may reduce unnecessary diagnostic CT scanning procedures.

Needle-Free Subcutaneous Sumatriptan (Sumavel DosePro): Bioequivalence and Ease of Use.

2009-10-28T23:31:00.001-07:00

Headache. 2009 Oct 22; Brandes JL, Cady RK, Freitag FG, Smith TR, Chandler P, Fox AW, Linn L, Farr SJ(Headache 2009;**:**-**) Background.- Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. Objectives.- To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. Methods.- Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System((R))) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. Results.- For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. Conclusions.- Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.

Pediatric colloid cysts of the third ventricle: management considerations.

2009-10-28T21:27:00.001-07:00

Acta Neurochir (Wien). 2009 Oct 25; Kumar V, Behari S, Kumar Singh R, Jain M, Jaiswal AK, Jain VKPURPOSE: Pediatric colloid cysts (CC) have a congenital origin, and yet, there are very few studies focussing exclusively on their occurrence in the pediatric population. Pediatric CC has been associated with more aggressive clinical and radiological patterns than their adult counterparts. In this study, undertaken on children with anterior third ventricular CC, excised using the interhemispheric transcallosal approach, the characteristic clinicoradiological features and management options are studied. METHODS: Five pediatric patients (aged 16 years or less; mean age 13.8 years; mean duration of symptoms:7.6 months) out of 38 patients with CC operated between 1995 to 2009 were included. The clinical manifestations included those of raised intracranial pressure (n = 4); exacerbation of occipital headache on reading (n = 1); secondary optic atrophy (n = 3); and, drop attacks (n = 1). On computed tomography scan, the cyst was hyperdense, enhancing in two patients and not enhancing in three patients. All had bilateral lateral ventricular dilatation with periventricular lucency. On magnetic resonance imaging (n = 3), the cyst was T1 hypointense and T2 isointense in one, hyperintense on both T1 and T2 with a hypointense capsule and nonenhancing on contrast in one (with a giant colloid cyst), and T1 hyperintense and T2 hypointense in one patient. An interhemispheric, transcallosal trajectory combined with transforminal approach (n = 3); combined transforminal and subchoroidal approaches (n = 1); and, interforniceal approach (n = 1) were used. RESULTS: Total excision was performed in four patients. In one patient, a small part of capsule was left attached to thalamostriate vein. Symptoms of raised intracranial pressure showed improvement in all the patients with resolution of hydrocephalus. There was no tumor recurrence at follow-up. CONCLUSIONS: Pediatric colloid cysts are rarer than their adult counterparts due to their late detection only after manifestations of raised intracranial pressure, visual or cognitive dysfunction or drop attacks occur. Their radiological appearance varies depending upon the amount of mucoid content, cholesterol, proteins, and water content. The fast development of clinical manifestations in children may be related to rapid enlargement of cyst due to higher water content within them. The transcallosal approach is the "gold standard" of surgery and usually ensures gratifying and lasting results.

Long-term tolerability of the methylphenidate transdermal system in pediatric attention-deficit/hyperactivity disorder: a multicenter, prospective, 12-month, open-label, uncontrolled, phase III extens

2009-10-25T22:04:00.001-07:00

Clin Ther. 2009 Aug; 31(8): 1844-55Findling RL, Wigal SB, Bukstein OG, Boellner SW, Abikoff HB, Turnbow JM, Civil RBACKGROUND: Short-term treatment with the meth-ylphenidate transdermal system (MTS) has been well tolerated in several clinical trials in children with attention-deficit/hyperactivity disorder (ADHD). However, the effects of long-term use have not been systematically evaluated. OBJECTIVES: The primary objective of this study was to assess the 12-month tolerability of MTS in children with ADHD. Effectiveness was a secondary objective. METHODS: This Phase III study was a multicenter, 12-month, open-label, flexible-dose extension of 4 previous trials. In those studies, children aged 6 to 12 years with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria) received MTS, osmotic-release oral system methylphenidate, or placebo. At entry into the present study, the children either continued to receive their optimal dose of MTS (10, 15, 20, or 30 mg per 9-hour patch wear time) or underwent dose titration over 4 weeks to an optimal MTS dose, which was continued for the remainder of the study. Tolerability was evaluated based on adverse events (AEs), physical examinations, vital signs, electrocardiograms, laboratory tests, the Children's Sleep Habits Questionnaire, and the occurrence of application-site reactions. RESULTS: Of 327 enrolled subjects, 326 received treatment and 157 completed the study. The majority of enrolled subjects were male (64.8%) and white (73.7%), with a mean (SD) age of 9.2 (1.9) years. Two hundred sixty-five (81.3%) of the 326 subjects who received MTS reported AEs. AEs led to study discontinuation in 29 subjects (8.9%). The majority (98.3%) of treatment-emergent AEs were of mild or moderate severity. The most common AEs were decreased appetite (24.8%), headache (16.6%), upper respiratory tract infection (12.3%), cough (11.7%), pyrexia (10.1%), and decreased weight (10.1%). Of the 1118 AEs, 40.8% were considered possibly or probably related to study treatment. Three serious AEs (facial contusion, ankle fracture, and syncope) occurred and were considered unrelated to study treatment. Based on data collected across all study visits, application-site reactions generally consisted of mild erythema associated with mild discomfort at the patch site. Application-site reactions accounted for 22 (6.7%) study discontinuations. CONCLUSIONS: Slightly less than half (48.0%) of subjects completed this 12-month, open-label extension study of MTS. Most AEs were mild to moderate in severity and, with the exception of application-site reactions, were typical of those previously observed with methylphenidate. ClinicalTrials.gov identifier: NCT00151957.

Ginkgo biloba for attention-deficit/hyperactivity disorder in children and adolescents: A double blind, randomized controlled trial.

2009-10-24T01:20:00.001-07:00

Prog Neuropsychopharmacol Biol Psychiatry. 2009 Oct 5; Salehi B, Imani R, Mohammadi MR, Fallah J, Mohammadi M, Ghanizadeh A, Tasviechi AA, Vossoughi A, Rezazadeh SA, Akhondzadeh SBACKGROUND: Although stimulants are highly effective in controlling the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), some children will not respond to, or are intolerant of stimulants. Thus, the desire for safe and effective nonstimulant medications has risen during the past several years. Ginkgo biloba has been suggested in the treatment of dementia and memory impairment. We hypothesized that Ginkgo biloba would be beneficial for treatment of ADHD, and this could be evaluated in a double blind, randomized, parallel group comparison of Ginkgo biloba (Ginko T.D. Tolidaru, Iran) and methylphenidate. METHODS: Fifty outpatients (39 boys and 11 girls) with a DSM-IV-TR diagnosis of ADHD were study population of this trial. Subjects were recruited from an outpatient child and adolescent clinic for a 6week double blind, randomized clinical trial. All study subjects were randomly assigned to receive treatment using tablet of Ginko T.D. at a dose of 80-120mg/day depending on weight (80mg/day for 30Kg) (group 1) or methylphenidate at a dose of 20-30mg/day depending on weight (20mg/day for 30Kg) (group 2) for a 6week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent ADHD Rating Scale- IV. Patients were assessed at baseline and at 21 and 42days after the medication started. RESULTS: Significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores. The changes at the endpoint compared to baseline were: -6.52+/-11.43 (mean+/-S.D.) and -15.92+/-11.44 (mean+/-S.D.) for Ginko T.D. and methyphenidate, respectively for Parent ADHD Rating Scale. The changes at the endpoint compared to baseline were: -0.84+/-6.79 (mean+/-S.D.) and -14.04+/-8.67 (mean+/-S.D.) for Ginko T.D. and methyphenidate, respectively for Teacher ADHD Rating Scale. The difference between the Ginko T.D. and methylphenidate groups in the frequency of side effects was not significant except for decreased appetite, headache and insomnia that were observed more frequently in the methylphenidate group. CONCLUSION: The results of this study suggest that administration of Ginkgo biloba was less effective than methylphenidate in the treatment of ADHD.

Clinical and Economic Comparison of Frovatriptan Versus other Oral Triptans in the Treatment of Acute Migraine in the Real-World Setting.

2009-10-21T21:46:00.001-07:00

Clin Drug Investig. 2009 Nov 1; 29(11): 693-702Guidotti M, Ravasio RTriptans (serotonin 5-HT(1B/1D) receptor agonists) such as frovatriptan have been shown to be highly effective and well tolerated in the treatment of patients with acute migraine. However, the large number of available triptans has led to the issue of how best to decide which triptan should be prescribed at an individual patient level. This review focuses on frovatriptan and highlights parameters that affect oral triptan choice, discusses the results of several open-label clinical and post-marketing surveillance studies of frovatriptan, and compares these naturalistic data with those from similar studies of other oral triptans. Efficacy data obtained from these trials are used to compare costs of treating migraine with frovatriptan and other oral triptans in four European countries. Studies of triptans in migraine have used several outcomes deemed important to patients, including complete pain relief, absence of recurrence, rapid onset of action, no side effects, restoration of functional ability, improvements in quality of life, and cost. In contrast to indirect evidence from some individual randomized, double-blind studies, results from open-label naturalistic studies and a meta-analysis of 31 placebo-controlled efficacy studies suggest that frovatriptan is associated with a lower rate of migraine recurrence than with other triptans in a real-world clinical setting (17% for frovatriptan 2.5 mg vs 23-40% for other triptans in the meta-analysis). It is likely that this may be due to the terminal elimination half-life of this agent (about 26 hours), which is longer than that of other triptans. Naturalistic studies indicate that the long duration of action of frovatriptan appears to confer other benefits such as greater patient satisfaction, with over 90% of patients and doctors rating frovatriptan therapy as 'very good' or 'good'. The cost of treatment with different triptans based on the number of tablets required per episode varies widely in each of the four countries analysed (&U20AC;4.95-7.98 in France, &U20AC;6.78-12.58 in Germany, &U20AC;4.32-9.73 in the UK and &U20AC;6.69-10.36 in Italy, based on lowest possible costs for branded versions in 2008) due to differences in both the acquisition costs of these agents and in the headache recurrence rates. Frovatriptan compares favourably with other available triptans with regard to cost per migraine attack on this basis, although head-to-head studies are required to confirm these data. The low rate of headache recurrence with frovatriptan compared with other oral triptans, and the associated lower treatment costs, deserve consideration when choosing an oral triptan for the treatment of patients with acute migraine.

The number and nature of emergency department encounters in patients with deep brain stimulators.

2009-10-12T18:38:00.001-07:00

J Neurol. 2009 Oct 8; Resnick AS, Foote KD, Rodriguez RL, Malaty IA, Moll JL, Carden DL, Krock NE, Medley MM, Burdick A, Haq IU, Okun MSDeep brain stimulation (DBS) has become an increasingly common modality for control of several neurological disorders such as Parkinson's disease, dystonia, essential tremor (ET), and others. Our experience has demonstrated the need for emergency physicians to familiarize themselves with the potential complications of the DBS device as well as the device itself. Therefore, our aim in this paper was to elucidate the number and nature of DBS and non-DBS presentations to the emergency department (ED) and to educate and familiarize ED physicians about DBS devices and their potential complications. We also aimed to devise a simple protocol for DBS management so that all ED physicians would have access to the knowledge or referral capabilities when managing a DBS patient. The objective of the present study was to review the number and nature of ED encounters in patients with deep brain stimulation (DBS) devices implanted for movement and neuropsychiatric disorders. Methods: The series of encounters reviewed included 215 unique patients with DBS implantation who were identified using an IRB approved database and a paper chart review. Patients in the study included those implanted at University of Florida (UF), as well as those implanted at outside institutions, so long as they were followed at UF. The cohort included n = 215 DBS patients. 25.6% of all 215 patients presented to the ED at least once, with the most common presentation occurring as a result of a decline in mental status when taking into account all visits (6%). Reasons for presentation to the ED included neurological (54.6%), infections/hardware issues (27.9%), orthopedic/focal problems (10.5%), and medical issues (7%). In total, 29 patients arrived at the ED for DBS related issues (23.2%). Of those who presented to the ED (n = 55), the average age was 53.1 (range 10-80 years). Headache was the most common complaint within the neurological category (22.1%), followed by change in mental status (15.1%), and syncope (9.3%). When examining the data by ED diagnosis, change in mental status occurred most commonly in Parkinson's disease (19.6%). Falls were most common in essential tremor (27.2%), and headache occurred most commonly in the dystonia group (52.1%). Across all diseases, mental status change was the most common indication for an ED encounter (6%). Parkinson disease patients most commonly presented with altered mental status (8%), essential tremor patients revealed a high preponderance of falls (6.5%), and dystonia patients tended to present with headache (7.1%). It was concluded that a large number of patients with DBS will present to the ED for many reasons, the majority of which will not be direct complications of their DBS device. Neurological issues were the most common chief complaint, with individual differences depending on the underlying disease. It is important for ED physicians to consider non-DBS related complaints in the presentation of these unique patients since these issues comprise the majority of the ED visits. However, when properly evaluating these patients, management of their DBS device, or referrals to neurosurgery and neurology, if necessary, are imperative. In addition to device management, regular ED standards of care should apply to this special cohort of patients.

Topiramate for Migraine Prevention in a Naturalistic Setting: Results From an Open Label, Flexible Dose Study.

2009-10-09T02:28:00.001-07:00

Headache. 2009 Oct 5; Nelles G, DelbrÃ¼ck A, Schulze L, Kademann B, Bornhoevd K, SchÃ¤fer S, SchÃ¤uble BBackground.- Headaches are one of the most common neurological symptoms and migraines are the most common primary headache disorder. The global prevalence of migraines is around 10% and the condition is associated with a high burden of disease. Despite an abundance of good quality evidence, only 1 in 5 of patients who fulfill the criteria for preventive migraine therapy are appropriately treated. Data on patient outcomes with preventive medication derive mostly from specialized academic centers, which contrasts with normal clinical practice where the majority of patients are treated outside tertiary care centers. Objective.- To explore tolerability, safety and efficacy outcomes of patients receiving topiramate for migraine prevention in a naturalistic setting. Methods.- After a 4-week prospective baseline, patients with a diagnosis of migraine according to International Headache Society criteria and eligible for migraine prevention were treated with flexible dosing of topiramate for 24 weeks (core phase), and optionally for a total of 48 weeks. The primary safety analysis included adverse events (AEs) during the core phase. For the main efficacy measures, the absolute changes from baseline to end of core phase as well as last follow-up visit were calculated for migraine days per 4 weeks, migraine attacks per 4 weeks, mean maximum visual analogue scale of migraine headache per 4 weeks and mean maximum pain intensity of migraine headache (4-point scale) per 4 weeks. In addition, changes in individual quality of life aspects were captured. Results.- The intention-to-treat population (ITT) consisted of 161 patients (90.7% female, mean age 45.7 +/- 11.1 years). Topiramate median dose was 45.7 mg/day at endpoint. Some 74.1% of patients reported treatment emergent AEs, most frequently paresthesias (18.4%) and nausea (12.4%). Some 20.0% of patients withdrew from the study due to AEs. The mean number of migraine days per 4 week decreased from 6.2 +/- 3.9 days at baseline to 3.9 +/- 3.5 days at last core visit (P < .001). Mean maximum pain intensity per 4 week changed from 7.0 +/- 2.3 at baseline to 4.7 +/- 3.2 at last visit core phase (P < .001). Consumption of triptans and analgesics reduced during the course of the core phase (P < .005). Fifty-one percent of all patients experienced at least a 50% reduction in migraine days during the core phase. Conclusion.- Topiramate used for migraine prevention in non-academic institutions is generally safe, well tolerated and results in good control of migraine headaches and improvement in several aspects of quality of life.

[Value of colour Doppler ultrasonography in relation to pretest probability in giant cell (temporal) arteritis]

2009-10-08T18:11:00.001-07:00

Dtsch Med Wochenschr. 2009 Oct; 134(42): 2109-15Stammler F, Grau C, Schnabel ABACKGROUND: Colour Doppler sonography (CDS) is an established technique in the diagnosis of giant-cell (temporal) arteritis (GCA). The predictive value of its diagnostic criteria for GCA (halo sign or stenosis) is related to the pretest probability (PTP), a measure of probability of presence of a target disease before the result of a diagnostic test is known. PATIENTS AND METHODS: A total of 182 (average age 69 years, 69% women) patients of the Rheumatology Center Baden-WÃ¼rttemberg were investigated. Based on the diagnostic criteria of the American College of Rheumatology (ACR) they were assigned to one of three groups, before a CDS was performed: group 1 (n= 139) patients with "isolated" polymyalgia rheumatica (PMR) and a low PTP for GCA; group 2 (n=19) patients with intermediate PTP and nonspecific headache and fewer than three ACR criteria for GCA); and group 3 (n=224) patients with a high PTP and new headache loclized to the temporal artery and at least three ACR criteria for GCA. RESULTS: The halo sign (periluminal dark halo) of more than 0.3 mm was present in 26% of group 1. 42% of those in group 2 and 83% of those in group 3. A stenosis or occlusion of the temporal artery was present in 3.5% (group 1), 5% (group 2) and 46% (group 3), respectively. 3 of 24 patients of group 3 also had a stenosis of the axillary or brachial artery. Concordance between clinical criteria and CDS (normal CDS in patients with PMR but no headache or abnormal CDS and clinically suspected BCA was found in 123 of 182 patients (67.5%). In these patients biopsy of the temporal artery ("gold standard" for the diagnosis of GCA) was not recommended. Temporal artery biopsy was, however, recommended in all patients with discordant findings (abnormal CDS with PMR but no headache or normal CDS with clinically suspected GCA, and also those with intermediary PTP (32%). A biopsy was performed in 42 of these patients after informed consent had been obtained. This demonstrated vasculitis in 11 of 25 patients with PMR (PPV in group 1: 0.44). But biopsies were negative in all four patients with clinically suspected GCA and normal CDS (NPV in group 3:1). In the intermediary group biopsy demonstrated vasculitits in 5 of 6 patients with an abnormal CDS (PPV 0.63), while 4 of 5 patients with a normal CDS had a normal biopsy (NPV 0.8). CONCLUSION: Taking into account pretest probability, an RCA can be accurately diagnosed or excluded by CDS in two thirds of patients without biopsy. When performed by an experienced investigator CDS is a basic part in the diagnosis of CDA.

Levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children.

2009-10-08T02:23:00.001-07:00

Clin Ther. 2009 Aug; 31(8): 1664-87Singh-Franco D, Ghin HL, Robles GI, Borja-Hart N, Perez ABACKGROUND: Levocetirizine (LCZ) is a second-generation antihistamine that was approved in January 2008 for the relief of symptoms of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), and chronic idiopathic urticaria (CIU) in adults and children aged > or = 6 years. OBJECTIVES: This article reviews the available literature on the pharmacokinetics and pharmacodynamics, clinical efficacy and tolerability, and effect on quality of life (QoL) of LCZ. METHODS: A search of the English-language literature was performed using the following databases: MEDLINE (1966-February 2009), International Pharmaceutical Abstracts (19 70-February 2009), Database of Abstracts of Reviews of Effectiveness, Cochrane Database of Systematic Reviews, EMBASE Drugs & Pharmacology (1991-February 2009), Blackwell Synergy, CINAHL Plus with Full Text, EBSCOhost, ScienceDirect, and Wiley Interscience. The search terms were levocetirizine, allergic rhinitis, chronic idiopathic urticaria, antihistamine, pharmacokinetics, quality of life, drug interactions, case reports, and cost. Publications describing studies of > or = 2 weeks' duration that concerned the efficacy, tolerability, pharmacoeconomics, and/or QoL effects of LCZ were included in the review. RESULTS: In 4 studies in adult patients with moderate to severe PAR, LCZ 5 mg/d was associated with significant improvements in symptom scores for sneezing, rhinorrhea, and ocular/nasal pruritus at 4 to 6 weeks compared with placebo (P < or = 0.05). In 3 studies, nasal congestion scores were significantly improved within 4 to 6 weeks compared with placebo (P < 0.001). LCZ 5 mg/d was associated with improvements compared with placebo in scores for the ability to do housework, complete work activities, and engage in outdoor activities at 6 months (P < or = 0.011). In a 6-week study in children with moderate to severe SAR, LCZ 5 mg/d was associated with significant improvements compared with placebo in sneezing, rhin-orrhea, and itchy nose (P < 0.004); significant improvements in symptoms from baseline were also seen in a 4-week study in adults with SAR (P < 0.001). One study in patients with SAR reported no significant difference between LCZ and fluticasone compared with fluticasone monotherapy in terms of improvement in QoL, nasal airflow obstruction, sneezing, or pruritus. In a 6-week study in patients with moderate to severe CIU, LCZ 5 mg/d was significantly more effective than placebo in reducing overall CIU symptoms (P < 0.05). In two 4-week studies, one comparing LCZ 5 mg/d with placebo and the other comparing it with desloratadine (DSL), LCZ was significantly more effective than either comparator in terms of improvement in scores for pruritus severity (P < or = 0.001 vs placebo; P < 0.004 vs DSL) and duration (P < or = 0.001 vs placebo; P = 0.009 vs DSL). LCZ was significantly more effective than placebo (but not DSL) in reducing the number and size of wheals (both, P = 0.001). In a 12-week, open-label, crossover study, patients reported significantly longer symptom relief with cetirizine than LCZ (P < 0.005). The most commonly reported adverse events in two 6-month studies in adults with PAR treated with LCZ 5 mg/d included headache (23.8%), pharyngitis (19.4%), influenza (14.6%), fatigue (8.3%), and somnolence (8.3%). There is serious concern about the possibility of febrile seizures in infants treated with LCZ. Three pharmacoeconomic studies of LCZ 5 mg/d were identified, one comparing it with placebo in patients with PAR, one comparing it with placebo in patients with CIU, and another comparing it with second-generation antihistamines and montelukast in patients with PAR. Because of design limitations and differences in comparators in these studies, it was not possible to determine the cost-effectiveness of LCZ in the treatment of PAR or CIU. CONCLUSIONS: In the studies reviewed, LCZ 5 mg/d was effective in reducing symptoms of PAR, SAR, and CIU and improving QoL, with an acceptable tolerabili-ty profile. There is a need for studies of longer durations, head-to-head comparisons against other anti-histamines, drug-interaction studies, safety studies in infants, and cost-effectiveness analyses.

Diagnostic value of S100B and neuron-specific enolase in mild pediatric traumatic brain injury.

2009-10-07T02:17:00.001-07:00

J Neurosurg Pediatr. 2009 Oct; 4(4): 339-44Geyer C, Ulrich A, GrÃ¤fe G, Stach B, Till HObject During recent years, several biomarkers have been introduced for use in the diagnosis of traumatic brain injury (TBI). The primary objective of this investigation was to determine if S100B (or S100 calcium-binding protein B) and neuron-specific enolase (NSE) serum concentrations can effectively be used to discriminate between symptomatic and asymptomatic children with minor head trauma. Methods The authors conducted a prospective clinical study that involved patients age 6 months to 15 years who had sustained minor head trauma. Children with concomitant extracranial injuries were excluded. Blood samples were obtained within 6 hours of injury to measure S100B and NSE levels in serum. The authors defined 2 diagnostic groups: a mild TBI group (patients with Glasgow Coma Scale [GCS] scores of 13-15) in whom there were clinical signs of concussion (short loss of consciousness, amnesia, nausea, vomiting, somnolence, headache, dizziness, or impaired vision) and a head contusion group (patients with a GCS score of 15) in whom symptoms were absent. Both S100B and NSE concentrations were compared between the 2 groups. Secondary end points were defined as follows: correlation of S100B/NSE and a) the presence of scalp lacerations, b) GCS score, c) age, and d) correlation between S100B and NSE. Results One hundred forty-eight patients were enrolled (53 in the contusion group, 95 in the mild TBI group). After adjusting for differences in age and time of injury to blood sample withdrawal, there was no significant difference in S100B or NSE between patients in the 2 groups. Scalp lacerations and GCS score had no affect on posttraumatic S100B or NSE concentrations. The correlation between S100B and NSE was significant. Both markers showed a significant negative correlation with age. Conclusions The authors demonstrated that S100B and NSE do not discriminate between symptomatic and asymptomatic children with minor head injury. There seem to be limitations in marker sensitivity when investigating pediatric patients with mild TBI.

Preliminary results, methodological considerations and recruitment difficulties of a randomised clinical trial comparing two treatment regimens for patients with headache and neck pain.

2009-10-06T22:40:00.001-07:00

BMC Musculoskelet Disord. 2009 Sep 23; 10(1): 115De Hertogh W, Vaes P, Devroey D, Louis P, Carpay H, Truijen S, Duquet W, Oostendorp RABSTRACT: BACKGROUND: Headache is a highly prevalent disorder. Irrespective of the headache diagnosis it is often accompanied with neck pain and -stiffness. Due to this common combination of headache and neck pain, physical treatments of the cervical spine are often considered. The additional value of these treatments to standard medical care or usual care (UC) is insufficiently documented. We therefore wanted to compare the treatment effects of UC alone and in combination with manual therapy (MT) in patients with a combination of headache and neck pain. UC consisted of a stepped treatment approach according to the Dutch General Practitioners Guideline for headache, the additional MT consisted of articular mobilisations and low load exercises. Due to insufficient enrolment the study was terminated prematurely. We aim to report not only our preliminary clinical findings but also to discuss the encountered difficulties and to formulate recommendations for future research. METHODS: A randomised clinical trial was conducted. Thirty-seven patients were included and randomly allocated to one of both treatment groups. The treatment period was 6 weeks, with follow-up measurements at weeks 7, 12 and 26. Primary outcome measures were global perceived effect (GPE) and the impact of the headache using the Headache Impact Test (HIT-6). Reduction in headache frequency, pain intensity, medication intake, absenteeism and the use of additional professional help were secondary outcome measures RESULTS: Significant improvements on primary and secondary outcome measures were recorded in both treatment groups. No significant differences between both treatment groups were found. The number of recruited patients remained low despite various strategies. CONCLUSION: It appears that both treatment strategies can have equivalent positive influences on headache complaints. Additional studies with larger study populations are needed to draw firm conclusions. Recommendations to increase patient inflow in primary care trials, such as the use of an extended network of participating physicians and of clinical alert software applications, are discussed. Trial registration number NCT00298142.

Biomechanics of whiplash injury.

2009-10-05T17:48:00.001-07:00

Chin J Traumatol. 2009 Oct; 12(5): 305-14Chen HB, Yang KH, Wang ZGDespite a large number of rear-end collisions on the road and a high frequency of whiplash injuries reported, the mechanism of whiplash injuries is not completely understood. One of the reasons is that the injury is not necessarily accompanied by obvious tissue damage detectable by X-ray or MRI. An extensive series of biomechanics studies, including injury epidemiology, neck kinematics, facet capsule ligament mechanics, injury mechanisms and injury criteria, were undertaken to help elucidate these whiplash injury mechanisms and gain a better understanding of cervical facet pain. These studies provide the following evidences to help explain the mechanisms of the whiplash injury: (1) Whiplash injuries are generally considered to be a soft tissue injury of the neck with symptoms such as neck pain and stiffness, shoulder weakness, dizziness, headache and memory loss, etc. (2) Based on kinematical studies on the cadaver and volunteers, there are three distinct periods that have the potential to cause injury to the neck. In the first stage, flexural deformation of the neck is observed along with a loss of cervical lordosis; in the second stage, the cervical spine assumes an S-shaped curve as the lower vertebrae begin to extend and gradually cause the upper vertebrae to extend; during the final stage, the entire neck is extended due to the extension moments at both ends. (3) The in vivo environment afforded by rodent models of injury offers particular utility for linking mechanics, nociception and behavioral outcomes. Experimental findings have examined strains across the facet joint as a mechanism of whiplash injury, and suggested a capsular strain threshold or a vertebral distraction threshold for whiplash-related injury, potentially producing neck pain. (4) Injuries to the facet capsule region of the neck are a major source of post-crash pain. There are several hypotheses on how whiplash-associated injury may occur and three of these injuries are related to strains within the facet capsule connected with events early in the impact. (5) There are several possible injury criteria to correlate with the duration of symptoms during reconstructions of actual crashes. These results form the biomechanical basis for a hypothesis that the facet joint capsule is a source of neck pain and that the pain may arise from large strains in the joint capsule that will cause pain receptors to fire.

Allodynia in migraine: association with comorbid pain conditions.

2009-10-05T02:08:00.001-07:00

Headache. 2009 Oct; 49(9): 1333-44Tietjen GE, Brandes JL, Peterlin BL, Eloff A, Dafer RM, Stein MR, Drexler E, Martin VT, Hutchinson S, Aurora SK, Recober A, Herial NA, Utley C, White L, Khuder SABACKGROUND: Cutaneous allodynia (CA) in migraine is a clinical manifestation of central nervous system sensitization. Several chronic pain syndromes and mood disorders are comorbid with migraine. In this study we examine the relationship of migraine-associated CA with these comorbid conditions. We also evaluate the association of CA with factors such as demographic profiles, migraine characteristics, and smoking status that may have an influence on the relationships of CA to pain and mood. METHODS: Data are from a cross-sectional multicenter study of comorbid conditions in persons seeking treatment in headache clinics. Diagnosis of migraine was determined by a physician based on the International Classification of Headache Disorders-II criteria. Participants completed a self-administered questionnaire ascertaining sociodemographics, migraine-associated allodynia, physician-diagnosed comorbid medical and psychiatric disorders, headache-related disability, current depression, and anxiety. RESULTS: A total of 1413 migraineurs (mean age = 42 years, 89% women) from 11 different headache treatment centers completed a survey on the prevalence of comorbid conditions. Aura was reported by 38% and chronic headache by 35% of the participants. Sixty percent of the study population reported at least one migraine-related allodynic symptom, 10% reported > or =4 symptoms. Symptoms of CA were associated with female gender, body mass index, current smoking, presence of aura, chronic headaches, transformed headaches, severe headache-related disability, and duration of migraine illness from onset. The prevalence of self-reported physician diagnosis of comorbid pain conditions (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and psychiatric conditions (current depression and anxiety) was also associated with symptoms of CA. Adjusted ordinal regression indicated a significant association between number of pain conditions and severity of CA (based on symptom count). Adjusting for sociodemographics, migraine characteristics, and current depression and anxiety, the likelihood of reporting symptoms of severe allodynia was much higher in those with 3 or more pain conditions (odds ratio = 3.03, 95% confidence interval: 1.78-5.17), and 2 pain conditions (odds ratio = 2.67, 95% confidence interval: 1.78-4.01) when compared with those with no comorbid pain condition. CONCLUSION: Symptoms of CA in migraine were associated with current anxiety, depression, and several chronic pain conditions. A graded relationship was observed between number of allodynic symptoms and the number of pain conditions, even after adjusting for confounding factors. This study also presents the novel association of CA symptoms with younger age of migraine onset, and with cigarette smoking, in addition to confirming several previously reported findings.

The measurement of craniocervical posture: A simple method to evaluate head position.

2009-10-04T23:22:00.001-07:00

Int J Pediatr Otorhinolaryngol. 2009 Sep 26; Cuccia AM, Carola COBJECTIVE: Some studies have correlated craniocervical posture (CCP) with pharyngeal airway space diameter, breathing conditions, neck pain, headache, dentofacial structures and temporomandibular disorders. Several methods have been suggested in an attempt to establish the best way of evaluating head position using teleradiographs and cephalometric analysis. The objectives of this study therefore were to describe a method of measuring the natural head position (NHP) without exposure to radiation or fixture of the cephalostat, and then to test whether there might be a simple method of reproducing this position in the cephalostat to make lateral cephalograms in the study of CCP. METHODS: The sample consisted of 50 healthy children (28 females and 22 males with a mean age of 10.9+/-4.9 years). Each subject was asked to place their feet in a standardized positions (a 30 degrees angle between the medial border of the feet with heels together using a V-podalic stabilizer), to tilt the head backwards and forwards to a decreasing extent until a natural head balance was reached, to adopt a natural posture of the shoulders, and to allow both arms to hang free. A self-adhesive circular reflecting cutaneous marker was applied to three points to enable a better view of the landmarks: the most anterior point of the frontonasal suture (N), the auricular tragus (Tr) and the most prominent spinous process of the seventh cervical vertebra (C(7)). An operator marked the specific anatomical points of the children's profiles with a felt-tip pen on a mirror placed to one side of the patient and fixed on the wall: the N point, the Tr point, the most inferior point of the chin in the lateral view (Me) and the deepest point on the posterior contour of the cervical lordosis. A digital body posture measuring system captured a first image of each subject in NHP (T0). Five minutes later, with the same position and orientation of the feet, the operator placed the head of the subject in the cephalostat so that the new head position coincided with the head position previously registered in the mirror and a second picture was taken (T1). After a further 5min, the subject was asked to place himself in NHP again, similarly repositioning their own feet to check the precision of the method of positioning, and a third picture was taken (T2). Three craniocervical angular measurements were taken for head posture measurement: N-Tr-Vert, determined by the extended line from the N point to the Tr point and the vertical line projected onto the image by a line (Vert); C(7)-Tr-Vert, determined by the extended line from C(7) to Tr and Vert; and C(7)-Tr-N, the angle between C(7)-Tr line and Tr-N line. In order to determine the stability of all the measurements of head position at T1, T2 and T3, a paired-sample t-test was used using an alpha of 0.05 and a power of 0.90. RESULTS: It was found that there were no statistically significant differences in head position between the pictures at T0, T1 and T2 (N-Tr-Vert, C(7)-Tr-Vert and C(7)-Tr-N, P>0.05). CONCLUSION: This method was a good procedure for evaluating head posture without exposure to radiation. The results also suggest that a simple and rapid method can be used to apply a craniostat to the patient when a radiograph is required without modifying the NHP.

Safety and tolerability of short-term preventive frovatriptan: a combined analysis.

2009-10-02T22:02:00.001-07:00

Headache. 2009 Oct; 49(9): 1298-314MacGregor EA, Brandes JL, Silberstein S, Jeka S, Czapinski P, Shaw B, Pawsey SOBJECTIVE: To assess the safety and tolerability profile of the 5-HT(1B/1D) agonist frovatriptan (Frova(R), Endo Pharmaceuticals Inc., Chadds Ford, PA, USA) when used as a 6-day regimen for the short-term prevention of menstrual migraine scheduled over multiple perimenstrual periods. BACKGROUND: Two randomized controlled trials have established the efficacy of a 6-day regimen of frovatriptan for reducing the incidence and severity of menstrual migraine over 1 to 3 perimenstrual periods; long-term data are needed to further assess the safety and tolerability profile of this regimen. METHODS: Two multinational trials were included in the analysis: Study 1 was a randomized, placebo-controlled double-blind parallel trial (3 perimenstrual periods treated) with an open-label extension (3 additional perimenstrual periods treated), and Study 2 was a long-term (12 perimenstrual periods treated over 12-15 months) open-label study. Enrolled women experienced menstrual migraine defined as predictable migraine attacks that started -2 days to +3 (Study 1) or +4 (Study 2) days relative to the first day of menses and that occurred in at least 2 out of 3 menstrual cycles. Frovatriptan or placebo was given 2 days before anticipated menstrual migraine and continued for 6 days. Adverse events, serious adverse events, vital signs, cardiovascular events, electrocardiograms, and laboratory parameters were assessed and recorded periodically and summarized using descriptive statistics. Adverse event data from Study 1 and Study 2 were compared using event rates. RESULTS: The demographic characteristics of the 2 study populations were similar: the mean age was approximately 38 years, > or =94% of participants were white, and 85% reported menstrual migraine began on days -2 to +1 of the menstrual cycle. The mean reported history of menstrual migraine was approximately 11 years. A large percentage of the respective safety populations completed each study or study period: 87% (362/416) and 88% (273/309) completed the double-blind period and open-label periods of Study 1, respectively, and 59% (308/525) completed treatment of 12 perimenstrual periods in Study 2. Major reasons for discontinuation in Study 1 included adverse events (5%, double-blind period) and "other" (10% double-blind period and 5% open-label period). In Study 2, major reasons for discontinuation included patient request (17.3%) and adverse event (10.2%). The most common treatment emergent adverse events in the double-blind period of Study 1 (placebo vs frovatriptan twice daily) were upper respiratory infection (9% vs 9%), nausea (6% vs 8%), dizziness (7% vs 7%), fatigue (4% vs 7%), dysmenorrhea (3% vs 7%), influenza (3% vs 6%), neck pain (4% vs 6%), and migraine (4% vs 4%). With the exception of migraine (which was reported using a different method in each study), prevalence rates for Studies 1 and 2 were numerically similar. The most frequently reported cardiovascular adverse events during double-blind treatment (placebo vs frovatriptan twice daily) were chest discomfort (2% and 3%), chest pain (2% and 2%), and hypertension (0 and 2%). The corresponding adverse event rates in Study 2 were 2% (chest pain), 3% (chest discomfort), and 3% (hypertension). In both studies, most adverse events were of mild or moderate intensity and their incidence numerically declined with each perimenstrual period/cycle, as did the incidence of menstrual migraine. The observed rate of intercurrent migraine in Study 2 over 12 perimenstrual periods was 1.5 per month, compared with 1.7 at baseline. There was no observable increase in the first occurrence of migraine in the 5 days following the perimenstrual period, indicating a lack of rebound headache. CONCLUSIONS: During treatment of up to 12 perimenstrual periods over a 12- to 15-month period, the safety and tolerability of frovatriptan for short-term prevention of menstrual migraine was similar to that observed with acute use of triptans. Adverse events were generally mild or moderate in severity, there was no evidence of an increased risk of cardiovascular adverse events relative to acute treatment, and rebound headache was not evident. A short-term regimen with frovatriptan presents a safe and viable treatment option for preventing predictable migraine such as menstrual migraine.

Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study.

2009-09-30T18:15:00.001-07:00

Lancet. 2009 Sep 14; Kuppermann N, Holmes JF, Dayan PS, Hoyle JD, Atabaki SM, Holubkov R, Nadel FM, Monroe D, Stanley RM, Borgialli DA, Badawy MK, Schunk JE, Quayle KS, Mahajan P, Lichenstein R, Lillis KA, Tunik MG, Jacobs ES, Callahan JM, Gorelick MH, Glass TF, Lee LK, Bachman MC, Cooper A, Powell EC, Gerardi MJ, Melville KA, Muizelaar JP, Wisner DH, Zuspan SJ, Dean JM, Wootton-Gorges SL, BACKGROUND: CT imaging of head-injured children has risks of radiation-induced malignancy. Our aim was to identify children at very low risk of clinically-important traumatic brain injuries (ciTBI) for whom CT might be unnecessary. METHODS: We enrolled patients younger than 18 years presenting within 24 h of head trauma with Glasgow Coma Scale scores of 14-15 in 25 North American emergency departments. We derived and validated age-specific prediction rules for ciTBI (death from traumatic brain injury, neurosurgery, intubation >24 h, or hospital admission >/=2 nights). FINDINGS: We enrolled and analysed 42 412 children (derivation and validation populations: 8502 and 2216 younger than 2 years, and 25 283 and 6411 aged 2 years and older). We obtained CT scans on 14 969 (35.3%); ciTBIs occurred in 376 (0.9%), and 60 (0.1%) underwent neurosurgery. In the validation population, the prediction rule for children younger than 2 years (normal mental status, no scalp haematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 s, non-severe injury mechanism, no palpable skull fracture, and acting normally according to the parents) had a negative predictive value for ciTBI of 1176/1176 (100.0%, 95% CI 99.7-100 0) and sensitivity of 25/25 (100%, 86.3-100.0). 167 (24.1%) of 694 CT-imaged patients younger than 2 years were in this low-risk group. The prediction rule for children aged 2 years and older (normal mental status, no loss of consciousness, no vomiting, non-severe injury mechanism, no signs of basilar skull fracture, and no severe headache) had a negative predictive value of 3798/3800 (99.95%, 99.81-99.99) and sensitivity of 61/63 (96.8%, 89.0-99.6). 446 (20.1%) of 2223 CT-imaged patients aged 2 years and older were in this low-risk group. Neither rule missed neurosurgery in validation populations. INTERPRETATION: These validated prediction rules identified children at very low risk of ciTBIs for whom CT can routinely be obviated. FUNDING: The Emergency Medical Services for Children Programme of the Maternal and Child Health Bureau, and the Maternal and Child Health Bureau Research Programme, Health Resources and Services Administration, US Department of Health and Human Services.

Should clinicians routinely determine rhinitis subtype on initial diagnosis and evaluation? A debate among experts.

2009-09-30T02:29:00.001-07:00

Clin Cornerstone. 2009; 9(3): 54-60Quan M, Casale TB, Blaiss MSRhinitis is one of the most prevalent conditions affecting Americans today. Twenty to 40 million Americans (10%-30% of adults and up to 40% of children) are estimated to have allergic rhinitis. In recent decades, its prevalence in Western societies has increased dramatically, and studies from around the world are reporting similar trends. Although studies have traditionally reported a 3:1 ratio of allergic to nonallergic rhinitis, recent data suggest that as many as 87% of patients with rhinitis may have mixed rhinitis, a combination of both allergic and nonallergic rhinitis. Untreated or inappropriately managed rhinitis can significantly affect a patient's quality of life and ability to perform activities of daily living. It is often associated with concomitant conditions, such as fatigue, headache, sleep disturbance, cognitive impairment, and respiratory conditions, complicated by rhinitis, including asthma and sinusitis. It is a significant cause of morbidity, health care expenditure, reduced work productivity, and absences from school. According to the recently released updated practice parameters, The Diagnosis & Management of Rhinitis, rhinitis is characterized by the presence of one or more of the following nasal symptoms: Congestion, Rhinorrhea (anterior and posterior), Sneezing, Itching. Inflammation is normally associated with rhinitis, but certain subtypes of the disease, such as vasomotor (increasingly known as chronic idiopathic rhinitis) or nonallergic rhinitis and atrophic rhinitis, are not predominantly inflammatory. The diagnosis of rhinitis may appear to be a fairly straightforward undertaking; however, rhinitis is composed of numerous subtypes and etiologies, and differentiating them can be a challenge for primary care practitioners. Further complicating matters is the fact that many patients have both an allergic and a nonallergic component to their rhinitis. Whether or not identification of rhinitis subtype should be an integral component of initial diagnosis remains an area of controversy. While standard treatment for allergic and nonallergic rhinitis is often the same, certain subtypes of the disease do not respond well to the usual first-line treatments for allergic rhinitis. Identification of subtype, therefore, can potentially have important implications for treatment choice. In the following section, we present a discussion between 2 members of the Respiratory & Allergic Disease (RAD) Foundation, Thomas B. Casale, MD, and Michael S. Blaiss, MD. Drs. Casale and Blaiss debate the question, "Should clinicians routinely determine rhinitis subtype on initial diagnosis and evaluation?" Each expert was randomly assigned a position to take: Dr. Casale's views represent the "pro" argument while Dr. Blaiss was asked to speak to the "con" argument. The debate concludes with a synthesis of their arguments and final points, including important takeaway messages for the primary care practitioner.

Influence of age, gender, and race on pharmacokinetics, pharmacodynamics, and safety of fesoterodine.

2009-09-29T18:40:00.001-07:00

Int J Clin Pharmacol Ther. 2009 Sep; 47(9): 570-8Malhotra BK, Wood N, Sachse RObjective: Fesoterodine, a new antimuscarinic agent for overactive bladder, undergoes immediate and extensive hydrolysis by nonspecific esterases to 5-hydroxymethyl tolterodine (5-HMT), the metabolite principally responsible for its antimuscarinic activity. Formation of 5-HMT does not require cytochrome P450 (CYP)-mediated metabolism, but its further metabolism and inactivation involves CYP3A4 and CYP2D6 isoenzymes. Subject age, gender, and race can play a key role in inter-subject variability in pharmacokinetics and thus efficacy and safety of drugs. This article examines the effects of age, gender, and race on the pharmacokinetics and pharmacodynamics of fesoterodine. Methods: Data from two randomized, double-blind, placebo-controlled, parallel-group trials in healthy subjects are presented: Study 1 investigated the effects of race (white vs. black men) and Study 2 investigated the effects of age (young vs. old men) and gender (elderly men vs. elderly women) on the pharmacokinetics and pharmacodynamics of single doses of fesoterodine 8 mg. In both studies, the primary endpoints were area under the concentration-time curve up to the last sample (AUC0-tz) and maximum concentration (Cmax) of 5-HMT in plasma. Pharmacodynamic variables included spontaneous salivary secretion (Studies 1 and 2) and residual urine volume (Study 2 only). The two studies included 5 groups of 16 subjects each (randomized 3 : 1 to fesoterodine or placebo): white men aged 18 - 45 years, black men aged 18 - 45 years (Study 1); young white men aged 18 - 40 years, elderly white men aged > 65 years, and elderly white women aged > 65 years (Study 2). Results: There were no clinically meaningful differences in the primary endpoints between white and black subjects or between young white men, elderly white men, and elderly white women. Mean AUC0-tz was 70.7 ng/ml x h in whites and 64.1 ng/ml x h in blacks; mean Cmax was 6.1 and 5.5 ng/ml in whites and blacks, respectively. Mean AUC0-tz in young white men, elderly white men, and elderly white women was 49, 48, and 54 ng/ml x h, respectively; mean Cmax in young white men, elderly white men, and elderly white women was 4.1, 3.8, and 4.6 ng/ml, respectively. Consistent with the anticholinergic pharmacology of fesoterodine, declines in salivary volume were observed in both studies, and elevations in residual urinary volume were observed, especially in elderly subjects, in Study 2. Fesoterodine was well tolerated, with common adverse events such as headache and dry mouth recognized as antimuscarinic class effects. Conclusions: Subject demographics, such as age, gender, and race, do not have a clinically meaningful effect on 5-HMT pharmacokinetics or pharmacodynamics after single-dose administration of fesoterodine 8 mg; thus, no dosage adjustment is required for fesoterodine based on age, gender, or race.

Devic's Syndrome as Initial Presentation of Systemic Lupus Erythematosus.

2009-09-21T17:23:00.001-07:00

Am J Med Sci. 2009 Sep; 338(3): 245-7Karim S, Majithia VBACKGROUND:: Devic's syndrome or neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with optic neuritis, myelitis involving 3 or more contiguous spinal cord segments, and seropositivity for NMO-IgG antibody. CASE:: A 22-year-old African American woman P1G0 at 22 weeks of gestation presented with weakness for 1 week. The weakness initially started in the left lower extremity and then involved the other extremities. She also had horizontal diplopia, temporal headache, and arthralgias. On physical examination, she had a discoid rash behind the left ear, muscle strength 3/5 in the upper and 0/5 in the lower extremities, and hyporeflexia. She had lymphopenia, a highly positive antinuclear antibody, and SS-A/ SS-B antibodies. The magnetic resonance imaging of the patient showed abnormal cord signal within brain and cervical and thoracic spine. Salivary gland biopsy revealed mild lymphoplasmacytic inflammation. The NMO antibody was positive. A diagnosis of Devic's syndrome associated with probable systemic lupus erythematosus (SLE) was made. She was treated with pulse IV solumedrol and plasmapheresis for 4 days. The patient improved clinically with treatment, but the fetus developed bradycardia, which was treated with IV dexamethasone. DISCUSSION AND CONCLUSION:: There is a debate about the relationship of NMO with autoimmune disorders, such as SLE or Sjogren syndrome. If clinically evident SLE or Sjogren or positive autoantibodies coexist with NMO signs and symptoms, the neurologic process could be an independent association due to NMO or may be a vasculitic complication of the systemic disease. Our case highlights these issues, difficulty in making a correct diagnosis, and choosing the appropriate management. Further case studies are needed to explore these important issues.

Granulomatous hypophysitis: two case reports and literature review.

2009-09-15T18:22:00.000-07:00

Granulomatous hypophysitis (GRH) is extremely rare and commonly presents with chronic inflammatory of the enlarged pituitary gland. In our study, 66-year-old and 57-year-old women, both Chinese, were diagnosed with GRH presenting preoperatively definite imageology characters as pituitary adenoma.

The 66-year-old woman presented with a year of headache, half a year of gradual decrease of visual acuity, and one month of right ptosis. Serum prolactin level was slightly elevated. Screening computed tomography (CT) scanning revealed typical low density mass found on the enlarged sella, which demonstrated invasive extension from the sella to the right cavernous sinus by contrast enhanced magnetic resonance imaging (MRI).

Consequently, the patient was diagnosed with probable invasive pituitary adenoma. The other 57-year-old woman complained a light headache and had been previously treated as nonfunctional pituitary adenoma in other hospital. Finally these two patients underwent transsphenoidal microsurgery and were diagnosed with GRH according to postoperative histopathology.

They then were treated with steroid. During the follow-up, the clinical symptoms such as headache, visual damage, and ptosis vanished, and the mass of the sellae dramatically shrank on repeated MR images. Clinically and radiologically, GRH is a rare sellar entity easily to be misdiagnosed as a pituitary adenoma.

Trans-sphenoidal surgery can decompress the optical nerve or oculomotornerve as a therapeutic strategy, and support biopsy or further pathological diagnosis. However, the hormonal therapy should be emphasized both as diagnostic and therapeutic strategies. Conservative and tentative steroid treatment should be performed in preoperative period without acute nerve damage.

"Granulomatous hypophysitis: two case reports and literature review"
J Zhejiang Univ Sci B. 2009 Jul; 10(7): 552-8Shi J, Zhang JM, Wu Q, Chen G, Zhang H, Bo WL

Health status and perception of pain

2009-09-15T04:39:00.000-07:00

Osteoarthritis (OA) is the most frequent rheumatic joint disease and its occurrence is growing due to prolonged life expectancy and an increasing number of elderly individuals in the population.

The main objective of this study was to compare the burden of disease, assessed by measures of pain and health-related quality of life (HRQoL), between female patients with hand osteoarthritis (HOA) and rheumatoid arthritis (RA).

Methods:
One hundred and ninety female HOA patients were compared with 194 female RA patients of the same age. HRQoL was measured with the Arthritis Impact Measurement 2 Scale (Aims2), the 36-item Short-Form Health Survey (SF-36) and its preference-based single index measure SF-6D, the Health Assessment Questionnaire (HAQ), the modified HAQ (MHAQ), self-efficacy scales, and visual analogue scales (VAS) for pain and fatigue. We also compared levels of fibromyalgia (FM)-like symptoms (headache, muscle pain, numbness, and concentration problems).

Scores were compared by a multivariate analysis of covariance (ANCOVA), adjusted for age, number of comorbidities, and years of education. Sime's procedure was used to adjust for multiple testing.

Results:
RA patients had significantly lower levels of physical functioning compared to HOA patients, whereas pain measured on the Arthritis Impact Measurement Scale 2 (AIMS2) was significantly worse in HOA as compared with RA. The HOA patients also had worse scores for FM-like symptoms. SF-6D utility scores in HOA and RA were similar (0.63 and 0.64, respectively).

Conclusions:
The overall impact of the disease on HRQoL was similar between RA and HOA patients, based on the SF-6D scores. Physical function was worse in RA patients, but HOA patients reported worse scores in pain measures and FM-like symptoms.

"Health status and perception of pain: a comparative study between female patients with hand osteoarthritis and rheumatoid arthritis"
Scand J Rheumatol. 2009 Jul 6; 1-7Slatkowsky-Christensen B, Mowinckel P, Kvien T

Toxic effects of PCb/PCDF to human observed in Yusho and other poisonings

2009-09-15T02:03:00.000-07:00

Yusho PCB poisoning occurred in 1968, when the human environment had been polluted with PCBs and related compounds. The causal rice oil was contaminated with large amounts of PCBs and PCDFs by accidental leakage at the rice oil producing Kanemi Company on February 7-15, 1968.

Much less concentrations of PCBs were identified in the rice oil produced and shipped from the Company before and after the critical days. Concentration trend of PCBs and TEQ in human body were examined for 40 years from 1968 to present.

Concentrations in the blood of heavily exposed Yusho patients and normal Japanese were PCBs : 80 and 1.5 microg/g-fat, and TEQ : 60 and 0.1 ng/g-fat, respectively, in 1969, and decreased to PCBs : 1 and 0.2 microg/g-fat, and TEQ : 0.5 and 0.02 ng/g-fat, respectively, in 2007.

PCBs and PCDFs have been persistently retained in human body for 40 years. Serious cases of Yusho and Yucheng having very high PCB, PCDF concentrations in blood have suffered from severe chloracne, pigmentation, eye discharge and others at the first stage and recovered very slowly with a lapse of several years.

However, their hormone mediated signs and symptoms, such as high triglyceride and thyroxin levels in serum, disorder of immunoglobulin, goiter, decrease of sperm mobility, disorder of teeth and joints conditions, decrease of IQ score in children, headache and numbness, etc, are persisting for more than 30 years.

The residents in East Slovakia who have been exposed to PCBs wasted from a PCB factory and have about 3 times higher blood PCB concentrations than the controls, have suffered from disorder of FT4 and T3 levels in serum, disorder of thyroid grand and thymus, dental defects in enamel developmental, hearing impairment at low frequency tone, tendency to diabetes and others.

Residents in the Great Lakes area, USA, whose blood PCB levels are estimated to be higher than other places, have shown disorder of thyroid, T4, TSH levels, endometriosis, joint disorder, and low IQ score in children. The levels of PCBs and PCDFs in the blood of Yusho patients and Controls are compared to the normal levels of estradiol, testosterone and thyroxin. In the blood of Yusho patients, concentrations of single congeners of PCB118, PCB153, PCB156 and PentaCDF are high enough to disturb the hormonal effects.

Blood PCB concentrations in normal Japanese are higher than the FT3 and FT4 levels, indicating hormonal disturbance will be easily produced. PCBs are metabolized to produce HO-PCBs, which bind to TTR and retain in blood medium. Blood HO-PCB concentrations in Yusho patients and normal persons are higher than the FT3, FT4 levels in serum.

Therefore, the hormonal effects of thyroxin will be disturbed in Yusho and normal persons. As HO-PCB will be easily transferred to fetus through placenta, fetus development will be possible to be disturbed. In Yusho and other cases, PCBs and TEQ (PentaCDF, PCB118 etc) were ingested together and the strong enzyme inducers of PentaCDF and others have metabolized PCBs to HO-PCBs, which have retained in the blood.

Complex reactions of PCDFs, PCBs and HO-PCBs have disturbed the hormonal effects and the induced symptoms and diseases would have been caused.

"Toxic effects of PCb/PCDF to human observed in Yusho and other poisonings"
Fukuoka Igaku Zasshi. 2009 May; 100(5): 141-55Masuda Y

Two cases of brain haemorrhage secondary to developmental venous anomaly trombosis

2009-09-14T16:15:00.000-07:00

We report two cases of intracraneal brain haemorrhage secondary to developmental venous anomaly trombosis recently treated at our Department. First patient was a 28-year old woman on oral contraceptive treatment for a month who was referred to our Department with sudden-onset conscious level deterioration after presenting 24 hours previously with headache, vomits and hemiparesis.

Computed Tomography revealed a predominant hypodense area containing hyperdense foci causing mild mass effect and midline-shift in keeping with a haemorrhagic infarction occupying almost completely the right frontal lobe.

On CT, magnetic resonance (MR) and magnetic resonance angiography (MRA) there was a prominent tubular structure adjacent to the hematoma in keeping with a partly thrombosed vessel. Urgent craniotomy and partial hematoma evacuation was performed.

Digital subtraction angiography confirmed the presence of a filling defect within the draining vein of a typical caputmedusae pattern developmental venous anomaly (DVA). Systemic anticoagulation was started and four days after surgery sedation was reversed and the patient awoke with normal conscious level although mild (4/5) hemiparesis persisted.

Second patient was a 38-year old male evaluated in the Emergency Department due to tonic-clonic seizures in the left side followed by altered sensation in the same distribution. Initial CT revealed an intracranial bleed.

After contrast administration there was an anomalous vessel in the same location that was confirmed angiographically represented a partly thrombosed DVA. Conservative management was favoured and the patient was discharged from hospital without clinical neurological deficits.

"Two cases of brain haemorrhage secondary to developmental venous anomaly trombosis. Bibliographic review"
Neurocirugia (Astur). 2009 Jun; 20(3): 265-271Abarca-Olivas J, Botella-AsunciÃ³n C, ConcepciÃ³n-AramendÃa LA, CortÃ©s-Vela JJ, Gallego-LeÃ³n JI, Ballenilla-Marco F

History of migraine with aura and cortical spreading depression from 1941 and onwards.

2009-09-14T06:25:00.001-07:00

Cephalalgia. 2009 Sep 9; Tfelt-Hansen PCSeveral personal descriptions of migraine with aura from 1870 onwards reported a slow, gradual progression of symptoms. Lashley in 1941 meticulously chartered his own auras and concluded that the symptomatology reflected a cortical process progressing with a speed of 3 mm/min across the primary visual cortex. LeÃ£o described cortical spreading depression (CSD) in rabbits in 1944 and noticed its similarity to the migraine aura. Despite these scattered pieces of evidence, the prevailing theory was that the migraine aura was caused by a vasospasm and cortical ischaemia. The advent of a technique for measurements of regional cerebral blood flow (rCBF) in 1974 made it possible to detect spreading oligaemia during migraine aura. Between 1981 and 1990 a series of studies of rCBF during migraine attacks showed reduced brain blood flow posteriorly spreading slowly and contiguously anteriorly and crossing borders of supply of major cerebral arteries. These observations refuted the ischaemic hypothesis. The human studies showed initial hyperaemia followed by prolonged hypoperfusion. The relation between aura and CSD was known to cause short-lasting, and therefore not obvious vasodilation and it was considerably strengthened by the demonstration of a long-lasting oligaemia in rats in the wake of CSD. In the primates CSD is not easily elicited, but it has in recent years been clearly demonstrated in patients with brain trauma and stroke. Finally, mutations for familial hemiplegic migraine have been expressed in mice and lower the threshold for CSD. The seminal papers on rCBF and CSD published in the 1980s caused a dramatic shift in our concepts of migraine aura. They moved attention from ischaemia to CSD and thereby to the brain itself, and paved the way for subsequent discoveries of brainstem mechanisms.

Nitroglycerin provocation in normal subjects is not a useful human migraine model?

2009-09-13T17:36:00.001-07:00

Cephalalgia. 2009 Sep 9; Tvedskov JF, Iversen HK, Olesen J, Tfelt-Hansen PProvoking delayed migraine with nitroglycerin in migraine sufferers is a cumbersome model. Patients are difficult to recruit, migraine comes on late and variably and only 50-80% of patients develop an attack. A model using normal volunteers would be much more useful, but it should be validated by testing the response to drugs of known efficacy in acute migraine. Furthermore, treatment during headache rather than pretreatment is the most naturalist method. To fulfil these requirements we used continuous long-lasting infusion of glyceryl trinitrate (GTN) 0.25 microg kg(-1) min(-1) for 140 min and gave aspirin 1000 mg, zolmitriptan 5 mg or placebo to normal healthy volunteers. The design was double-blind, placebo-controlled three-way crossover. Our hypothesis was that these drugs would be effective in the treatment of the mild constant headache induced by long-lasting GTN infusion. The headaches did not fulfil the International Headache Society diagnostic criteria for migraine without aura. Moreover, there was no effect on headache of either zolmitriptan or aspirin. Thus our hypothesis was disproved and we conclude that our model is not valid for the testing of new acute antimigraine drugs. Our experiment suggests that headache caused by direct nitric oxide (NO) action in the continued presence of NO is very resistance to analgesics and to specific acute migraine treatments. This suggests that NO works very deep in the cascade of events associated with vascular headache, whereas tested drugs work higher in the cascade. The model suggested here should therefore be tested with other headache/migraine-provoking agents that supposedly work higher in the cascade of events. The need for human models persists, but the solution to this problem is still pending.

Response after One Dose of a Monovalent Influenza A (H1N1) 2009 Vaccine -- Preliminary Report.

2009-09-12T15:57:00.001-07:00

N Engl J Med. 2009 Sep 10; Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, Dawson G, Hu W, Leggio C, Washington D, Basser RLBACKGROUND: A novel influenza A (H1N1) 2009 virus is responsible for the first influenza pandemic in 41 years. A safe and effective vaccine is urgently needed. A randomized, observer-blind, parallel-group trial evaluating two doses of an inactivated, split-virus 2009 H1N1 vaccine in healthy adults between the ages of 18 and 64 years is ongoing at a single site in Australia. METHODS: This preliminary report evaluates the immunogenicity and safety of the vaccine 21 days after the first of two scheduled doses. A total of 240 subjects, equally divided into two age groups (/=50 years), were enrolled and underwent randomization to receive either 15 mug or 30 mug of hemagglutinin antigen by intramuscular injection. We measured antibody titers using hemagglutination-inhibition and microneutralization assays at baseline and 21 days after vaccination. The coprimary immunogenicity end points were the proportion of subjects with antibody titers of 1:40 or more on hemagglutination-inhibition assay, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in the geometric mean titer. RESULTS: By day 21 after vaccination, antibody titers of 1:40 or more were observed in 116 of 120 subjects (96.7%) who received the 15-mug dose and in 112 of 120 subjects (93.3%) who received the 30-mug dose. No deaths, serious adverse events, or adverse events of special interest were reported. Local discomfort (e.g., injection-site tenderness or pain) was reported by 46.3% of subjects, and systemic symptoms (e.g., headache) by 45.0% of subjects. Nearly all events were mild to moderate in intensity. CONCLUSIONS: A single 15-mug dose of 2009 H1N1 vaccine was immunogenic in adults, with mild-to-moderate vaccine-associated reactions. (ClinicalTrials.gov number, NCT00938639.) Copyright 2009 Massachusetts Medical Society.

A Randomized, Placebo-Controlled, Dose-Escalation Study to Determine the Safety, Tolerability, and Immunogenicity of an HPV-16 Therapeutic Vaccine in HIV-Positive Participants With Oncogenic HPV Infec

2009-09-11T17:52:00.001-07:00

J Acquir Immune Defic Syndr. 2009 Aug 5; Anderson JS, Hoy J, Hillman R, Barnden M, Eu B, McKenzie A, Gittleson COBJECTIVE:: Study aimed to assess safety, tolerability, and immunogenicity of novel therapeutic HPV-16 E6E7 ISCOMATRIX vaccine for treatment of human papilloma virus (HPV)-related anal intraepithelial neoplasia in HIV-infected men who have sex with men with moderate immunosuppression. DESIGN:: Randomized, multicenter, blinded, placebo-controlled, dose-escalating study investigating 3 different doses of vaccine and different dose schedule. Primary objective to determine safety and tolerability, including clinical status, maintenance of virological control, and CD4 cell count for more than 252 days. RESULTS:: Thirty-five men who have sex with men enrolled; median age 47 years; current CD4 count 627 cells per milliliter; nadir CD4 count 154 cells per milliliter; 94% current antiretrovirals; 100% high-risk HPV types; 69% abnormal anal cytology; and 34% anal intraepithelial neoplasia 1-3 on high-resolution anoscopy. No dose-limiting toxicities or serious adverse events in HPV-16 vaccine recipients. Most HPV-16 vaccine recipients reported moderate/severe short-term injection site reactions and systemic reactions including headache, myalgia, and fatigue. CD4 cell counts remained stable. Five participants had transiently detectable viral loads. Ninety-six percent of vaccine recipients had at least a 4-fold increase in HPV-16 antibody from prevaccination levels. Seventy-one percent had at least a 3-fold increase in interferon-gamma responses to E6E7 peptides. CONCLUSIONS:: The novel therapeutic HPV-16 E6E7 ISCOMATRIX vaccine seemed safe and reasonably well tolerated. The therapeutic vaccine induces strong and durable antibody responses and moderate interferon-gamma levels that fell to prevaccination levels by week 24.

A Randomized, Placebo-Controlled, Dose-Escalation Study to Determine the Safety, Tolerability, and Immunogenicity of an HPV-16 Therapeutic Vaccine in HIV-Positive Participants With Oncogenic HPV Infec

2009-09-10T23:35:00.001-07:00

Topiramate modulates excitability of the occipital cortex when measured by transcranial magnetic stimulation.

2009-09-10T17:44:00.000-07:00

Cephalalgia. 2009 Sep 3; Aurora SK, Barrodale PM, Vermaas AR, Rudra CSummary The aim of this study was to measure differences in occipital cortex excitability in migraineurs before and after administration of topiramate. We have previously demonstrated occipital cortex hyperexcitability in migraine using an objective technique of magnetic suppression of perceptual accuracy (MSPA). We hypothesized that a neuromodulator such as topiramate would demonstrate differences in MSPA in migraine compared with baseline. Ten migraine patients were recruited. To assess inhibitory function MSPA was measured using the following protocol. Timed transcranial magnetic stimulation were delivered at interstimulus intervals (ISI) varying from 40 to 190 ms (eight stimulations at each ISI) at 60% stimulus intensity. Subjects were asked to report letters projected at a fixed luminance on the screen. Visual suppression was calculated based on the number of errors the subjects made using automated analysis. This procedure was repeated at a minimum of two different dosages of topiramate when it was titrated for optimal migraine control. The interim dose was that at which an improvement in headache frequency was first observed, and the optimal dose was that at which the patient had a >/= 50% reduction in headache frequency, or had reached a 100-mg dose. The mean [standard error (s.e.)] level of letters reported correct at baseline at 100-ms ISI was 91.6 (3.4) compared with 48.5 (6.0) (P = 0.001) at an optimal dose of topiramate. Dose ranged from 50 to 100 mg; the average dose was 75 mg. The interim dose for most patients was 50 mg; the mean (s.e.) percentage of letters reported correct at interim was 75.9 (6.2) compared with baseline (P = 0.01). Mean number of headaches at baseline was 27 per month, compared with eight headaches per month at interim dose and four headaches per month at optimal dose. There was no significant correlation between mean change in frequency of headache and mean change in inhibition from baseline to optimal dose (0.04, P = 0.89). Topiramate modulates occipital cortex excitability in chronic migraine possibly via mechanisms of cortical inhibition. Since there was not a strong correlation between the degree of inhibition and reduction of migraine frequency, it would appear that topiramate did have an independent effect on cortical excitability that was not dependent on reduction in migraine frequency.

Safety of anti-IgE treatment with omalizumab in children with seasonal allergic rhinitis undergoing specific immunotherapy simultaneously.

2009-09-09T23:26:00.001-07:00

Pediatr Allergy Immunol. 2009 Sep 2; Kamin W, Kopp MV, Erdnuess F, Schauer U, Zielen S, Wahn UKamin W, Kopp MV, Erdnuess F, Schauer U, Zielen S, Wahn U. Safety of anti-IgE treatment with omalizumab in children with seasonal allergic rhinitis undergoing specific immunotherapy simultaneously. Pediatr Allergy Immunol 2009. (c) 2009 John Wiley & Sons A/SIntroduction Seasonal allergic rhinitis (SAR) affects at least 10-25% of the Caucasian race and about 40% of patients are children. Standard treatment of SAR is specific immunotherapy (SIT), but anti-allergic drugs can significantly enhance efficacy of SIT. One candidate is the humanized monoclonal anti-IgE antibody omalizumab. Material and Methods Randomized, double-blind, placebo-controlled, multi-centre trial in Germany. A total of 221 children were randomly assigned to four different groups and treated with SIT (either grass or birch pollen), starting at least 14 wk before the local birch pollen season. After the 12-wk SIT titration phase, either anti-IgE (omalizumab) or placebo (NaCl 0.9%) therapy was added. This combination therapy with SIT and anti-IgE or placebo lasted 24 wk. To record local reactions and adverse events (AE), the injection site was examined by a clinician 20 min after application of study medication. Further, patients stated any AE and the use of rescue medication by means of a diary 3 days after every injection. Finally, any AE or serious adverse event (SAE) reported by the patients was specified on a standard form by clinicians. Overall tolerance was judged by the doctors according to the patient's diaries. To test differences between the groups, we used either the two-sided Wilcoxon rank-sum test or the two-sided chi-square test. Results Tolerability of SIT and omalizumab treatment was good (82% of patients). Only some AE with possible causal relationship to treatment occurred slightly more often in the verum groups, i.e. local reactions (16.8 vs. 12.3%) and gastrointestinal (2.7 vs. 0.9%) and ear symptoms (1.8 vs. 0%). Most AE (93.4% in omalizumab and 87.2% in placebo group) were judged by the patients as mild to moderate. SAE were restricted to four patients with asthma in the placebo group, two subjects with headache in the verum group and three patients with infections (two in verum and one in placebo group). Only the cases of asthma were judged to be possibly related to study medication. Further, redness and swelling at the SIT injection site appeared significantly more often in the placebo group which suggests a positive effect of omalizumab on local reaction induced by SIT. Conclusion Omalizumab represents an important clinical advance in the management of allergic diseases and can be considered to be safe in children.

[Knowledge, attitudes and practice regarding Dengue in two neighborhoods in Bucaramanga, Colombia]

2009-09-09T02:37:00.001-07:00

Rev Salud Publica (Bogota). 2009 Jan-Feb; 11(1): 27-38CÃ¡ceres-Manrique Fde M, Vesga-GÃ³mez C, Perea-Florez X, Ruitort M, Talbot YOBJECTIVE: Identifying knowledge, attitudes and practice regarding dengue control for guiding prevention and control measures. METHODS: A community survey was carried out using house inspection visits during May 2007 in two neighbourhoods in Bucaramanga having a high incidence of dengue. Mosquito breeding places were identified and education concerning dengue prevention and control measures was provided. EPI-INFO was used for analysing the information so collected. RESULTS: 643 of the 780 households (82.4%) responded to the survey. Most people responding (518) were female (80.6%), average age being 39.6 (16.8 standard deviation (SD)), average schooling lasted 6.2 years (3.5 SD) and average household size was 5 people per house. Regarding dengue, 433 people (67.3%) described it as being a very serious disease; 545 (84.8%) stated that it was transmitted by a mosquito vector and 242 (37.6%) said that it was produced by a virus 59 (9.2%). The symptoms recognised were: fever by 570 people (88.6%), vomiting by 352 (54.7%), diarrhoea by 275 (43.0%), headache by 243 (37.8%), bone pain by 196 (30.5%) and muscle pain by 109 (17.0%). For prevention, 288 (44.7%) avoided stagnant water, 174 (27.2%) washed out their water tanks, 91 (14.2%) fumigated and 101 (15.8%) cleaned their houses. When anybody had dengue, 410 of them (63.8%) would go to a doctor, 129 (20.1%) would go to a hospital and 78 (12.0%) would treat themselves. Larval rate was 26.6% and there had been cases of dengue in 8.4% of the households during the last month. DISCUSSION: Knowledge about dengue was sketchy. Attitudes were favourable regarding dengue control but preventative practice was inadequate. The community must be educated and empowered to ensure their active participation in prevention and control programmes.

Utilization, diagnosis, treatment and cost of migraine treatment in the emergency department.

2009-09-08T17:28:00.001-07:00

Headache. 2009 Sep; 49(8): 1163-73Friedman D, Feldon S, Holloway R, Fisher SOBJECTIVE: To determine the percentages of patients receiving migraine-specific therapy and to estimate the rate of unnecessary neuroimaging studies in the emergency department (ED). METHODS: A retrospective study was conducted analyzing medical records and hospital charge data of ED visits for migraine during 2005 in 2 university-affiliated hospitals. Following a preliminary review of 23 randomly selected ED charts selected to determine the reliability of the coding process, 172 other charts were selected to include 1 visit per patient with a primary discharge diagnosis code of 346.0, 346.1, or 346.9. The diagnosis of migraine was confirmed using predefined criteria. Demographic information, treatment strategies, laboratory and neuroimaging tests, response to therapy, discharge planning, and charge data were evaluated. RESULTS: Of 156 patients with completed visits, neuroimaging studies were performed in 36 patients (23%), and only 4 patients had no documented justification for obtaining imaging studies. Seventy-eight patients (50%) had a potential contraindication to receiving migraine-specific therapy. Nine patients (11.5% of eligible patients) received migraine-specific therapy. Most patients were treated with a combination of parenteral antiemetics, narcotics, or ketorolac. CONCLUSION: This analysis supports previous studies indicating the underutilization of migraine-specific treatment in the ED, and suggests that the ED is generally used as a "last resort" when the patient's home medication fails. Because of various contraindications, migraine-specific medications may not be a treatment option in up to 50% of patients seen in the ED. Although almost all of the neuroimaging studies were justified, the radiology charges were a major contributing factor to the overall financial burden of emergency migraine care.

Pott's puffy tumor in children.

2009-09-08T02:34:00.001-07:00

Childs Nerv Syst. 2009 Sep 2; Tsai BY, Lin KL, Lin TY, Chiu CH, Lee WJ, Hsia SH, Wu CT, Wang HSINTRODUCTION: Pott's puffy tumor is characterized by subperiosteal abscess associated with osteomyelitis of frontal bone. Reports are limited for this rare entity in the antibiotics era but increase during past decade. METHODS: We had clinical analysis of a series with six consecutive pediatric patients of Pott's puffy tumor during 20 years in a tertiary medical center via retrospective chart review. One case was described in detail. RESULTS: Male-to-female ratio was 5:1. The mean age at the time of diagnosis was 13 years-3 months. The risk factors were acute sinusitis in two (33%), chronic sinusitis in two (33%), recent head trauma in two (33%), and acupuncture therapy on skull in one (17%). The commonest presenting symptoms were fever, headache, forehead tenderness, vomiting, and fatigue/malaise (100%). Pott's puffy tumor was diagnosed on average the seventh day after fever, and half had intracranial involvement at diagnosis. All had intracranial infections, and most of them had subdural empyema. The most often involved sinus was frontal sinus (100%). The frontal lobe was the most common site of intracranial infection (100%), two thirds of which are polymicrobial from two or more sites. The initial operation was performed on average on the 5.8th days after diagnosis. Half of the patients underwent reoperation. The mortality rate was 17% (one of six). CONCLUSION: The symptoms of Pott's puffy tumor are inconspicuous even though early intracranial involvement often occurred. The importance of early diagnosis and aggravated and prompt treatment with prolonged antibiotic therapy is emphasized for better outcome.

Risk factors for headache in children.

2009-09-07T17:48:00.001-07:00

Dtsch Arztebl Int. 2009 Jul; 106(31-32): 509-16Gassmann J, Vath N, van Gessel H, KrÃ¶ner-Herwig BBACKGROUND: 10% to 30% of all children worldwide suffer from headaches at least once a week, potentially constituting a serious health problem that may lead to impairment in multiple areas. Therefore, one aim of the epidemiological longitudinal study "Children, Adolescents, and Headache" (KiJuKo) is the study of potential risk factors for the development of recurrent headaches. METHODS: In the first survey (2003), questionnaires were sent to 8800 households with a child between 7 and 14 years of age. Three further surveys followed, one each year from 2004 to 2006. A number of predictors having to do with family characteristics and leisure activities were identified on the basis of the first survey and were then studied in the second survey (n = 2952) with respect to their influence on the new occurrence of headaches. RESULTS: The risk of developing recurrent headaches between the first and the second survey was elevated by a factor of approximately 1.8 for boys who experienced quarrels in the family more than once per week, and by a factor of 2.1 for boys who only "sometimes" had free time for themselves. The risk of developing recurrent headaches was 25% higher in girls whose parents' behavior towards the child positively or negatively reinforced the occurrence of headaches. CONCLUSIONS: These findings are in accordance with those of other studies showing that, for boys, the frequency of quarreling in the family and the extent of leisure time are major factors in the development of recurrent headaches. For girls, the manner in which the parents respond to the child's headache seems to be important.

Epidemiology of Colorado Tick Fever in Montana, Utah, and Wyoming, 1995-2003.

2009-09-06T18:13:00.001-07:00

Vector Borne Zoonotic Dis. 2009 Sep 2; Brackney MM, Marfin AA, Erin Staples J, Stallones L, Keefe T, Black WC, Campbell GLAbstract Colorado tick fever (CTF) is a biphasic, febrile illness caused by a Coltivirus and transmitted by the Rocky Mountain wood tick, Dermacentor andersoni, in the western United States and Canada. Symptoms generally include acute onset of fever, headache, chills, and myalgias; illness often lasts for 3 weeks or more. Laboratory-confirmed cases of CTF were identified from public health department records in Montana, Utah, and Wyoming, and from the Centers for Disease Control and Prevention diagnostic laboratory records. Additional descriptive epidemiologic data were obtained by medical record abstraction. Ninety-one cases were identified from 1995 to 2003, resulting in an overall annual incidence of 2.7 per 1,000,000 population. The annual incidence decreased over the 9-year study period. Cases were 2.5 times more frequent in males than females. The highest incidence of cases occurred in persons aged 51-70. Tick exposure prior to illness onset was reported in 90% of the cases in which a more detailed history was available. The most common symptoms were fever, headache, and myalgia; 18% of the case patients were hospitalized. While there has been an overall decline in the recognized incidence of CTF cases, the reasons for the decline are unknown. Possibilities include a reduced intensity of surveillance and a true decrease in incidence. As more people continue to visit, move to and work in endemic areas, CTF should be considered in anyone presenting with a febrile illness following tick exposure in an endemic area. Heightened awareness for the disease and tick prevention messages should be part of public health measures to further decrease the incidence of disease.

Synovial folds of the lateral atlantoaxial joints: in vivo quantitative assessment using magnetic resonance imaging in healthy volunteers.

2009-09-06T05:30:00.001-07:00

Spine (Phila Pa 1976). 2009 Sep 1; 34(19): E697-702Webb AL, Darekar AA, Sampson M, Rassoulian HSTUDY DESIGN: Analysis of magnetic resonance (MR) images of healthy volunteers. OBJECTIVE: To develop and validate an imaging protocol and measurement technique to describe the morphology and quantify the dimensions of the synovial folds of the lateral atlantoaxial joints in vivo. SUMMARY OF BACKGROUND DATA: The synovial folds of the lateral atlantoaxial joints are considered to be a potential source of neck pain and headache, especially following whiplash injury. Until recently, it has not been possible to image the synovial folds in vivo and consequently their normal morphology is not fully understood. METHODS: MR images of the cervical spine of 17 volunteers (4 male and 13 female) were acquired using a 1.5-tesla scanner. The morphology of the synovial folds at the lateral atlantoaxial joints was described and their presence determined. The volume and cross-sectional area of the ventral and dorsal synovial folds of the right and left lateral atlantoaxial joints were measured and compared. The relationship between the dimensions of the synovial folds and subject age was examined. Twenty synovial folds were measured twice by one observer and once by a second observer for the determination of measurement reliability. RESULTS: There was a significant difference in volume (chi [3] = 17.54, P = 0.000) and cross-sectional area (chi [3] = 18.95, P = 0.000) between the ventral and dorsal synovial folds of the left and right lateral atlantoaxial joints. There was no correlation between synovial fold dimensions and age. The reliability of the measurements ranged from intraclass correlation coefficient 0.95 to 0.99 (intraobserver reliability) and intraclass correlation coefficients 0.75 to 0.82 (interobserver reliability). CONCLUSION: MR imaging was successfully implemented as a noninvasive method for visualizing the synovial folds of the lateral atlantoaxial joints and quantifying their dimensions in healthy volunteers. The results of this study provide a basis for future studies investigating synovial fold pathology in patients with neck pain and headache.

[The hypothalamus in SUNCT syndrome: similarities and differences with the other trigeminal-autonomic cephalalgias.]

2009-09-05T16:28:00.001-07:00

Rev Neurol. 2009 Sep 16-30; 49(6): 313-20Caminero AB, Mateos VINTRODUCTION. SUNCT belongs to the group of trigeminal-autonomic cephalalgias (TAC) -cluster headache and paroxysmal hemicranias-, since its shares a series of features with them. SUNCT was finally included in this group when the hypothalamus was proved to play a key role in its pathophysiology, an aspect that it has in common with other TAC. However, its clinical resemblance to trigeminal neuralgia of the first branch is notable, although it is accepted that the genesis of the trigeminal neuralgia is peripheral. DEVELOPMENT. The article presents the evidence available to date that has made it possible to associate the hypothalamus with SUNCT, as well as outlining its similarities and differences with respect to other TAC. This evidence is clinical, hormonal, from functional neuroimaging (activation of the posteroinferior hypothalamus) and from therapeutic outcomes (with deep hypothalamic stimulation). Likewise, a detailed description is provided of both the neuroanatomical bases (the hypothalamus as part of the neural networks involved in processes concerned with behaviour, memory, antinociceptive control, waking-sleep control and other circadian rhythms, etc.) and the neurochemical bases (orexins, somatostatin and endogenous opiates) that would support the hypotheses which researchers are attempting to establish to fit the evidence discussed earlier, which would have many points that overlap from one TAC to another. CONCLUSIONS. The question as to whether the hypothalamus is the/a generator of TAC or whether it is an element that allows its development remains open to debate, as does the issue of which would be the most plausible explanation for the phenotypic differences between them. Future studies will allow the enigma of SUNCT and the other TAC to be explained.

Increased cerebral output of free radicals during hypoxia; implications for acute mountain sickness?

2009-09-04T18:29:00.001-07:00

Am J Physiol Regul Integr Comp Physiol. 2009 Sep 2; Bailey DM, Taudorf S, Berg RM, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller KThe present study examined if hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten males provided blood samples from the internal jugular vein and radial artery during normoxia and during 9h passive exposure to hypoxia (12.9% O2). Cerebral blood flow was determined via the Kety-Schmidt technique with net exchange calculated by the Fick Principle. AMS and headache was determined using clinically-validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for the direct detection of spin-trapped free radicals and nitric oxide (NO) metabolites. Neuron-specific enolase (NSE), S100beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-vD) and net cerebral output of lipid-derived alkoxyl (LO(*))-alkyl (LC(*)) free radicals and lipid hydroperoxides (P < 0.05 vs. normoxia) that correlated with the increase in AMS/headache scores (r = -0.50 to -0.90, P < 0.05). This was associated with a reduction in the a-vD and hence net cerebral uptake of plasma nitrite and increased cerebral output of 3-NT (P < 0.05 vs. normoxia) that also correlated against AMS/headache scores (r = 0.74 to 0.87, P < 0.05). In contrast, hypoxia did not alter the cerebral exchange of S100beta and both global cerebral oxidative metabolism (CMRO2) and neuronal integrity (NSE) remained preserved (P > 0.05 vs. normoxia). In conclusion, these findings indicate that hypoxia stimulates cerebral oxidative-nitrative stress which has broader implications for other clinical models of human disease characterized by hypoxemia. This may prove a risk factor for AMS by a mechanism that appears independent of impaired BBB function and cerebral oxidative metabolism. Key words: acute mountain sickness, blood-brain barrier, free radicals, hypoxia.

Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents.

2009-09-03T18:43:00.001-07:00

Headache. 2009 Sep; 49(8): 1131-43Akerman S, Holland PR, Lasalandra MP, Goadsby PJOBJECTIVE: To understand the mechanism of action of oxygen treatment in cluster headache. BACKGROUND: Trigeminal autonomic cephalalgias, including cluster headache, are characterized by unilateral head pain in association with ipsilateral cranial autonomic features. They are believed to involve activation of the trigeminovascular system and the parasympathetic outflow to the cranial vasculature from the superior salivatory nucleus (SuS) projections through the sphenopalatine ganglion, via the greater petrosal nerve of the VIIth (facial) cranial nerve. Cluster headache is remarkably responsive to treatment with oxygen, and yet our understanding of its mode of action is unknown. METHODS: Combining models of trigeminovascular nociception and a novel approach that activates the trigeminal-autonomic reflex, using SuS/facial nerve stimulation, we explored the effect of oxygen on trigeminal nerve activation as well as on autonomic responses through blood flow observations of the lacrimal duct/sac. RESULTS: Meningeal vasodilation and neuronal firing in the trigeminocervical complex (TCC), in response to dural electrical stimulation, was unaffected by treatment with 100% oxygen. Stimulation of the SuS via the facial nerve caused only marginal changes in dural blood vessel diameter, but did result in evoked firing in the TCC. Two populations of neurons were characterized, those responsive to 100% oxygen treatment, with a maximal inhibition of 33%, 20 minutes after the start of oxygen treatment (t(15) = 4.4, P < .0001). A second population of neurons were not inhibited by oxygen and tended to have shorter latency. Oxygen also inhibited evoked blood flow changes in the lacrimal sac/duct caused by SuS stimulation. CONCLUSIONS: The data provide the first systematic, experimental evidence for a mechanism of action of oxygen in cluster headache. The data show oxygen has no direct effect on trigeminal afferents, acting specifically on the parasympathetic/facial nerve projections to the cranial vasculature to inhibit both evoked trigeminovascular activation and activation of the autonomic pathway during cluster headache attacks. Moreover, the studies begin to characterize a novel laboratory model for the most painful primary headache syndrome known--cluster headache.

Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures.

2009-09-02T18:32:00.001-07:00

Headache. 2009 Sep; 49(8): 1153-62Silberstein S, Lipton R, Dodick D, Freitag F, Mathew N, Brandes J, Bigal M, Ascher S, Morein J, Wright P, Greenberg S, Hulihan JOBJECTIVE: To define yet more clearly the utility of topiramate in the treatment of chronic migraine, we evaluated prespecified secondary endpoints from a recent randomized, double-blind, placebo-controlled, multicenter clinical trial. BACKGROUND: We previously reported that topiramate 100 mg per day produced a statistically significant reduction in mean monthly migraine/migrainous and migraine headache days compared with placebo treatment and that it was safe and generally well tolerated. METHODS: Variables analyzed included between-treatment group differences in percent responders, change in the mean monthly rate of total headache days and headache-free days, change in average and worst daily headache severity, change in the mean monthly use of acute headache medications, and absolute change and percent change in a headache index. Additional analyses included evaluation of changes in: the associated symptoms of photophobia, phonophobia, and nausea; Migraine-Specific Quality of Life Questionnaire scores; Migraine Disability Assessment Scale scores; and Physician's and Subjects Global Impression of Change. RESULTS: The intent-to-treat population consisted of 306 patients (topiramate, n = 153; placebo, n = 153). Categorical responder rates of reductions in mean monthly migraine/migrainous days for topiramate- vs placebo-treated subjects were as follows: for > or =25% reduction: 68.6% vs 51.6% (P = .005); > or =50%: 37.3% vs 28.8% (P = .093); and > or =75%: 15.0% vs 9.2% (P = .061). The decrease in mean monthly total headache days and headache-free days for topiramate vs placebo treatment was 5.8 vs 4.7 days (P = .067). Compared with placebo, topiramate treatment resulted in statistically significant mean improvements in the Role Restrictive (P = .028) and Emotional Function (P = .036) domains of the Migraine-Specific Quality of Life Questionnaire, in the worst daily severity of migraine (P = .016), severity of photophobia (P = .032), frequency of vomiting (P = .018), photophobia (P = .038), phonophobia (P = .010), unilateral pain (P = .015), pulsatile pain (P = .023), and pain worsened because of physical activity (P = .047). In addition, there were trends observed (favoring topiramate) in average daily severity of migraine (P = .077), acute headache medication use (P = .127), severity of nausea (P = .098), frequency of nausea (P = .166), the Role Preventive domain of the Migraine-Specific Quality of Life Questionnaire (P = .061), and severity of phonophobia (P = .062). CONCLUSIONS: In addition to significantly reducing mean monthly migraine/migrainous and migraine headache days, treatment of chronic migraine with topiramate was effective with regard to several traditionally important and clinically relevant secondary outcomes in migraine prevention trials. Treatment with topiramate was well tolerated and not associated with serious adverse events.

Focus on Aripiprazole: A Review of its use in Child and Adolescent Psychiatry.

2009-09-02T08:09:00.001-07:00

J Can Acad Child Adolesc Psychiatry. 2009 Aug; 18(3): 250-60Greenaway M, Elbe DOBJECTIVE: To review published literature regarding aripiprazole in child and adolescent psychiatry. METHOD: A LITERATURE REVIEW WAS CONDUCTED USING THE MEDLINE SEARCH TERM: 'aripiprazole' with limits: Human trials, English language, All Child (aged 0-18 years). Additional articles were identified from reference information and poster presentation data. RESULTS: Aripiprazole is an atypical antipsychotic which was recently approved for use in Canada, but has been available for several years in the United States. Pharmacologically, aripiprazole is a partial agonist at D(2) and 5-HT(1A) receptors and an antagonist at 5-HT(2A) receptors. Randomized controlled trial data is available showing efficacy for aripiprazole in the treatment of children and adolescents with schizophrenia, bipolar disorder and behavioural problems associated with autism. Open-label evidence is also available for use of aripiprazole in other disorders such as tic disorders, aggression and disruptive behavior disorders. Unlike some other available atypical antipsychotics, there does not appear to be any effect on QTc interval on the electrocardiogram. Adverse effects including extrapyramidal symptoms (EPS), akathisia, sedation, headache, nausea were significant in clinical trials in children and adolescents. The possibility of aripiprazole causing tardive dyskinesia cannot be excluded. In this population, aripiprazole appears to have minimal impact on the metabolic profile compared to most other atypical antipsychotics, with minimal changes in weight or body mass index, no significant changes in glucose or lipid metabolism, and a decrease in serum prolactin. CONCLUSION: Aripiprazole may represent an important alternative for some children and adolescents who have experienced poor efficacy or significant metabolic adverse effects with their current antipsychotic treatment regimen.

Case 149: immune reconstitution inflammatory syndrome.

2009-09-01T08:14:00.001-07:00

Radiology. 2009 Sep; 252(3): 924-8Chen KC, Chen JY, Tung GAHistory A 43-year-old man was admitted for new onset of bitemporal headache, bilateral lower extremity numbness, and generalized tonic-clonic seizure. Physical examination findings were remarkable for bilateral lower extremity weakness. Magnetic resonance (MR) imaging of the brain was performed. Initial analysis of cerebrospinal fluid (CSF) revealed an elevated nucleated cell count, with 92% lymphocytes (normal range, 37%-75%) and 8% monocytes and/or macrophages (normal range, 0%-15%). CSF staining, cell culture, and polymerase chain reaction results were negative for cryptococcus, histoplasmosis, Coccidioides infection, syphilis, cytomegalovirus, West Nile virus, herpes simplex virus, and Epstein-Barr virus. Enzyme immunoassay, Western blot analysis, and indirect immunofluorescence assays were positive for human immunodeficiency virus (HIV) antibodies. The plasma HIV RNA level was 32 806 copies per milliliter, and the CD4(+) T-cell count was 29 cells per microliter (normal range, 500-1800 cells per microliter). The antitoxoplasmosis immunoglobulin G titer was elevated; however, the immunoglobulin M titer was normal. CSF samples from two lumbar punctures did not show signs of acid-fast bacillus growth; however, an antituberculosis regimen was initiated because of positive purified protein derivative skin test results and positive MR findings. In addition, the patient received a 2-week course of sulfadiazine and pyrimethamine to treat toxoplasmosis. Six weeks after presentation, the patient was readmitted for dehydration, mild systemic hypotension, and persistent lower extremity weakness and numbness. Additional MR images of the brain were obtained. At this time, the patient had completed a 5-week course of antituberculosis therapy. Highly active antiretroviral therapy (HAART)-which consisted of efavirenz, emtricitabine, and tenofovir administration-was started during this second hospitalization. While undergoing this treatment, the CD4(+) T-cell count increased to 45 cells per microliter, and plasma HIV RNA was undetectable. Seven weeks after presentation, the patient presented with increasing lightheadedness and persistent bilateral lower extremity weakness and numbness. MR imaging of the brain was performed at admission. CSF staining and cell cultures were negative. During this admission, the CD4(+) T-cell count increased to 63 cells per microliter, and plasma HIV RNA remained undetectable. After 6 weeks of corticosteroid therapy, MR imaging of the brain was performed.

A Randomized, Placebo-Controlled, Dose-Escalation Study to Determine the Safety, Tolerability, and Immunogenicity of an HPV-16 Therapeutic Vaccine in HIV-Positive Participants With Oncogenic HPV Infec

2009-08-31T18:43:00.001-07:00

[A clinical psychopathological study of low back pain in affective disorder]

2009-08-30T15:51:00.001-07:00

Seishin Shinkeigaku Zasshi. 2009; 111(6): 615-27Yoshida K, Kato SThis study was designed to determine the psychopathological characteristics of low back pain. The subjects of this study were inpatients with mood disorder admitted to Jichi Medical University Hospital from April 1997 to March 2006. We extracted patients who complained of pain over one week from those inpatients. Extracted patients were grouped according to the region of pain. The "low back pain" group comprised patients who only complained of low back pain, and the "headache" group constituted patients who only complained of headaches. We compared the two groups regarding items on the face sheet, symptoms of depression, pain. The results of the study are summarized as follows: (1) The low back pain group showed a significantly weaker educational background and more frequent blue-collar workers than the headache group. It was thought that there was some relation between low back pain, the educational background and occupation. (2) The low back pain group showed significantly more complaints of pain before the onset of depression than the headache group. This may indicate that low back pain can be a risk factor of depression. Further consideration is needed. (3) The low back pain group showed a stronger tendency to complain of pain after object loss than the headache group. (4) After low back pain had been resolved, some patients committed suicide. It is important to be aware of this observation. (5) During the early stage of the treatment process, it is important for patients to feel that their doctor is always ready to hear about their anxieties and anger.

Temporal Fossa Hemangiopericytoma: A Case Series.

2009-08-30T08:13:00.001-07:00

Otol Neurotol. 2009 Aug 24; Heiser MA, Waldron JS, Tihan T, Parsa AT, Cheung SWOBJECTIVE:: Review clinical experience with temporal fossa hemangiopericytomas (HPCs). STUDY DESIGN:: Retrospective case series review. SETTING:: Tertiary referral center. PATIENTS:: Intracranial HPCs within the temporal fossa. INTERVENTIONS:: Craniotomy for either subtotal or gross total tumor excision. MAIN OUTCOME MEASURES:: Determination of clinical outcome (alive with no evidence of disease, alive with disease, and died of disease). RESULTS:: Five cases of HPC involving the temporal fossa were treated at our tertiary referral center for the period from 1995 to 2008. All but 1 patient were men. The age of presentation ranged from 31 to 62 years, and duration of follow-up ranged from 8 to 153 months. Clinical presentation was protean; headache was the most common symptom. Gross total tumor excision was achieved in 2 patients, whereas subtotal tumor excision was achieved in 3 patients. Reasons for subtotal resection included excessive intraoperative blood loss and inextricable tumor. Histologically, all tumors were composed of tightly packed, randomly oriented (jumbled-up) tumor cells with little intervening collagen. CD34 staining mostly highlighted the vascular background. One patient died of disease, 2 patients were alive with disease, and 2 patients had no evidence of disease. CONCLUSION:: Management of temporal fossa HPC is challenging because clinical presentation is often late, and extent of tumor excision is constrained by vital structures in the cranial base and intracranial contents. A multidisciplinary approach with neurosurgery and neurotology undertaken to achieve the most complete tumor resection possible, whereas minimizing morbidity are likely to confer a longer period of symptom-free survival and improves curability of these difficult lesions.

Randomized controlled trial of an Internet-delivered family cognitive-behavioral therapy intervention for children and adolescents with chronic pain.

2009-08-30T03:50:00.001-07:00

Pain. 2009 Aug 18; Palermo TM, Wilson AC, Peters M, Lewandowski A, Somhegyi HCognitive-behavioral therapy (CBT) interventions show promise for decreasing chronic pain in youth. However, the availability of CBT is limited by many factors including distance to major treatment centers and expense. This study evaluates a more accessible treatment approach for chronic pediatric pain using an Internet-delivered family CBT intervention. Participants included 48 children, aged 11-17years, with chronic headache, abdominal, or musculoskeletal pain and associated functional disability, and their parents. Children were randomly assigned to a wait-list control group or an Internet treatment group. Primary treatment outcomes were pain intensity ratings (0-10 NRS) and activity limitations on the Child Activity Limitations Interview, both completed via an online daily diary. In addition to their medical care, the Internet treatment group completed 8weeks of online modules including relaxation training, cognitive strategies, parent operant techniques, communication strategies, and sleep and activity interventions. Youth randomized to the wait-list control group continued with the current medical care only. Findings demonstrated significantly greater reduction in activity limitations and pain intensity at post-treatment for the Internet treatment group and these effects were maintained at the three-month follow-up. Rate of clinically significant improvement in pain was also greater for the Internet treatment group than for the wait-list control group. There were no significant group differences in parental protectiveness or child depressive symptoms post-treatment. Internet treatment was rated as acceptable by all children and parents. Findings support the efficacy and acceptability of Internet delivery of family CBT for reducing pain and improving function among children and adolescents with chronic pain.

[Patients with headache and medication abuse. Indicators of response to ambulatory treatment.]

2009-08-29T15:42:00.001-07:00

Rev Neurol. 2009 Sep 1-15; 49(5): 225-30Gracia-Naya M, Sanchez-Valiente S, Latorre-Jimenez AM, Rios-Gomez C, Santos-Lasaosa S, Mauri-Llerda JA, Garcia-Gomara MJINTRODUCTION. Patients with headache and medication abuse (HMA) are difficult to treat, have a greater tendency towards chronification and a poorer quality of life than those with other types of headache. AIM. To evaluate the indicators showing that these patients are responding to ambulatory treatment. PATIENTS AND METHODS. From a series of patients with migraine, we selected those who satisfied HMA criteria according to the appendix of the 2006 International Classification of the Headache Disease (ICHD-2) and who had never previously undergone treatment. As outpatients, they were advised to stop taking the drug that they were abusing. The treatment of their seizures was adjusted with the most efficient drugs and preventive treatment was started from the outset with topiramate or flunarizine. Patients were grouped according to whether they continued with HMA or not. Comparisons were made between the number of days with headache during the previous month and after four months of treatment and the persistence of abuse. RESULTS. HMA criteria were met by 178 patients (mean age 40.9; 88.7% females). Results showed that 68.5% (122 patients) responded and no longer met HMA criteria after treatment. The treatment used for their seizures (triptans, nonsteroidal antiinflammatory drugs, analgesics) and preventive treatment (topiramate or flunarizine) were similar in both groups. The average number of days with headache prior to treatment was 18.52 in the group that responded and 20.87 (p = 0.0263) in the group that did not respond to treatment. In the group of responders 7.3% dropped out of preventive treatment compared with 35% (p = 0.0001) in the group of non-responders. CONCLUSIONS. A higher number of days with headache during the previous month and withdrawing from preventive treatment were indicators of a bad progression.

[Properties of metabolic substance produced by group A Streptococcus from two food-borne epidemic]

2009-08-28T22:17:00.001-07:00

Kansenshogaku Zasshi. 2009 Jul; 83(4): 380-5Suzuki J, Sakaguchi KWe report the finding for two food-poisonins outbreaks occurring in Tokyo and Chiba in September 2003. Patients in the Tokyo outbreak suffered from fever varying widely from 35.9 degrees C to 39.4 degrees C. Throat pain was predominant, accompanied by headache, cough, and joint pain. Patients in the Chiba outbreak suffered from malaise in addition to the above symptoms. To clarify the relationship between pathology and virulence factors, we studied the properties of hemolysins and proteases produced by the causative bacteria, Streptococcus pyogenes, specifically type T-28 in the Tokyo outbreak and type T-B3264 in the Chiba outbreak. The main S. pyogenes T serotypes isolated in 2003 were types T12, T1, T4, and T3, followed types T-28 and T-B3264. The hemolytic titer of hemolysins, which are metabolic, was 173HD50/mL for T-28 and 147HD50/mL for T-B3264. Hemolysins produced by both strains did not depend on reducing agents and were not inhibited by gamma-globulin or cholesterol, indicating the streptolysin S (SLS) rather than hemolysis inhibition by phospholipids. The fact that the titer increased slightly in the presence of reducing agents indicates that some amount of streptolysin O may also have been present. Protease production was four times greater for T-B3264 than for T-28. Proteases produced by both strains were similarly inhibited by sodium tetrathionate, iodoacetate, and normal serum. The outbreak infection was caused by infiltration of food-borne Streptococcus bacteria via the upper airway during eating. The primary cause of predominant throat pain was thought to be SLS cytotoxicity in the upper respiratory mucous membrane. This toxin was also thought to assist in Streptococcus bacteria infiltration and proliferation. Proteases produced by pathogenic bacteria were thought to have acted on the body as potent virulence factors.

Caffeine's Implications for Women's Health and Survey of Obstetrician-Gynecologists' Caffeine Knowledge and Assessment Practices.

2009-08-28T16:13:00.001-07:00

J Womens Health (Larchmt). 2009 Aug 26; Anderson BL, Juliano LM, Schulkin JAbstract Objective: Caffeine has relevance for women's health and pregnancy, including significant associations with spontaneous abortion and low birth weight. According to scientific data, pregnant women and women of reproductive age should be advised to limit their caffeine consumption. This article reviews the implications of caffeine for women's psychological and physical health, and presents data on obstetrician-gynecologists' (ob-gyns) knowledge and practices pertaining to caffeine. Methods: Ob-gyns (N = 386) who are members of the American College of Obstetricians and Gynecologists' Collaborative Ambulatory Research Network responded to a 21-item survey about caffeine. Results: Although most knew that caffeine is passed through breast milk, only 24.8% were aware that caffeine metabolism significantly slows as pregnancy progresses. Many respondents were not aware of the caffeine content of commonly used products, such as espresso and Diet Coke,((R)) with 14.3% and 57.8% indicating amounts within an accurate range, respectively. Furthermore, ob-gyns did not take into account large differences in caffeine content across different caffeinated beverages with most recommending one to two servings of coffee or tea or soft drinks per day. There was substantial inconsistency in what was considered to be "high levels" of maternal caffeine consumption, with only 31.6% providing a response. When asked to indicate the risk that high levels of caffeine have on various pregnancy outcomes, responses were not consistent with scientific data. For example, respondents overestimated the relative risk of stillbirths and underestimated the relative risk of spontaneous abortion. There was great variability in assessment and advice practices pertaining to caffeine. More than half advise their pregnant patients to consume caffeine under certain circumstances, most commonly to alleviate headache and caffeine withdrawal. Conclusions: The data suggest that ob-gyns could benefit from information about caffeine and its relevance to their clinical practice. The development of clinical practice guidelines for caffeine may prove to be useful.

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device.

2009-08-28T04:41:00.001-07:00

J Pharm Pharmacol. 2009 Sep; 61(9): 1219-28Luthringer R, Djupesland PG, Sheldrake CD, Flint A, Boeijinga P, Danjou P, DemaziÃ¨res A, Hewson GOBJECTIVES: The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. METHODS: The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. KEY FINDINGS: Following intranasal delivery, median t(max) was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean +/- SD values for C(max) were 96 +/- 25, 11 +/- 7 and 16 +/- 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. CONCLUSIONS: Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.

Premature birth--Studies on orthodontic treatment need, craniofacial morphology and function.

2009-08-27T16:00:00.001-07:00

Swed Dent J Suppl. 2009; 9-66Paulsson LA series of studies have been initiated implying a unique opportunity to evaluate and compare malocclusion traits, orthodontic treatment need, craniofacial morphology, mandibular function, signs and symptoms of temporomandibular disorders (TMD) and headache between extremely preterm (EPT; born before the 29th week of gestation) and very preterm (VPT; born between 29 and 32 weeks of gestation) and full-term born children. THIS THESIS WAS BASED ON FOUR STUDIES: Paper I. A systematic literature review was undertaken to answer the following questions: Does prematurity result in alterations of palatal morphology, dental occlusion, tooth-crown dimensions, tooth maturation and eruption? What role does neonatal oral intubation play in the appearance of the alterations? Are the alterations in morphology permanent or transient? The literature search spanned from January 1966 to November 2002 and was later extended to September 2008. Furthermore, a quality analysis of the methodological soundness of the studies in the review was performed. Paper II-IV. The aims were to compare EPT and VPT 8- to 10-year-old children with matched full-term controls considering: Prevalence of malocclusion traits and orthodontic treatment need (Paper II). Craniofacial morphology (Paper III). Mandibular function, signs and symptoms of TMD and headache (Paper IV). KEY FINDINGS IN PAPER I AND THE SUPPLEMENTARY SEARCH: Moderate scientific evidence existed for more malocclusion traits among premature children. Limited evidence was found for no delay in dental eruption, if corrected age was considered for the premature children. Insufficientwas considered for the premature children. Insufficient evidence was found for altered tooth-crown dimensions and permanent alteration of palatal morphology among prematurely children. Thus, further well-designed controlled studies which should also consider orthodontic treatment need, craniofacial morphology, TMD and headache are needed. KEY FINDINGS IN PAPER II-IV: A higher prevalence of malocclusion traits and the assessed need of orthodontic treatment were higher among the preterm children compared with full-term born children (Paper II). Several craniofacial parameters differed significantly between preterm and full-term born children (Paper III). Preterm children did not differ from full-term born children when considering diagnoses according to the Research Diagnostic Criteria for TMD (RDC/TMD), signs and symptoms of TMD or headache (Paper IV). KEY CONCLUSIONS AND CLINICAL IMPLICATIONS: The increased survival rate of very preterm and especially the extremely preterm children contribute to a new group of children in society. The dental clinician should, therefore, be aware of the potential for a higher number of malocclusion traits, more malocclusion traits per individual, greater orthodontic treatment need and altered craniofacial morphology in prematurely born children compared with full-term born children. In spite of this, the prematurely born children had not more TMD or headache than full-term born children at the age of 8-10 years.

Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: a single- and multiple-dose, open-label pharmacokinetic study in Chinese

2009-08-27T02:35:00.001-07:00

Clin Ther. 2009 Jul; 31(7): 1568-75Zhou L, Meng F, Yin O, Wang J, Wang Y, Wei Y, Hu P, Shen ZBACKGROUND: Nilotinib, an oral second-generation Bcr-Abi tyrosine kinase inhibitor, is approved in the United States and European Union for the treatment of Philadelphia chromosome-positive (Ph+), chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) resistant to or intolerant of prior therapy, including imatinib. Information on the pharmacokinetics of nilotinib in Chinese patients with CML is lacking, and regulatory requirements for registration of this drug are needed in China. OBJECTIVES: This study assessed the pharmacokinet-ics of single and multiple oral doses of nilotinib in Chinese patients with CML and compared the pharmacokinetic profiles of nilotinib between the Chinese patients and a subgroup of white patients with CML. METHODS: Chinese patients aged > or =18 years with Ph+ CML-CP, CML-AP, or CML-BC (blast crisis) resistant to or intolerant of imatinib were eligible. Patients were administered oral nilotinib 400 mg BID for 15 days. Serial blood samples were collected before and at 1, 2, 3, 5, 8, and 12 hours after the administration of a single dose (day 1) and multiple doses (day 15, steady state). Serum nilotinib concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay, and pharmacokinetic parameters of nilotinib were calculated using a noncompartmental method. Tolerability was assessed using cardiac assessments; laboratory analysis (hematology, blood chemistry, and urinalysis); and physical examination, including vital signs. RESULTS: Twenty-three patients were enrolled (18 men, 5 women; mean age, 40.0 years; mean weight, 68.3 kg; CML-CP, 22 patients; CML-AP, 1). All 23 patients were included in the tolerability analysis. Two patients withdrew consent and discontinued after administration of the first dose; thus, 21 patients were included in the pharmacokinetic analysis. Median T(max) was ~2 hours after administration of single and multiple doses. At steady state, C(min) was 1025.4 ng/mL and C(max) was 2160.7 ng/mL. Mean AUCs from time 0 to the end of the dosing interval tau (AUC(0-tau)) were 5076.3 and 17,751.3 ng . h/mL at days 1 and 15, respectively, representing an accumulation factor of 3.92. Apparent oral clearance (CL/F) was 0.39 L/h/kg (range, 0.12-0.74 L/h/ kg) at steady state. The study found a 42% intersubject variability in nilotinib pharmacokinetics. Steady-state C(max), C(min), AUC(0-tau), and CL/F were not significantly different from those previously reported in a subgroup of white patients with CML who received the same 400-mg BID dose. Rash (11/23 patients [47.8%]) and elevated bilirubin, headache, and muscle pain (4 patients each [17.4%]) were the most frequently reported nonhematologic adverse events. CONCLUSIONS: In this pharmacokinetic study in Chinese patients with CML resistant to or intolerant of imatinib, nilotinib 400 mg BID was rapidly absorbed after a single dose and multiple doses. The steady-state pharmacokinetic properties in this population were consistent with those reported previously in white patients with CML.

Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: a single- and multiple-dose, open-label pharmacokinetic study in Chinese

2009-08-26T16:11:00.001-07:00

Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit.

2009-08-24T23:02:00.001-07:00

Br J Clin Pharmacol. 2009 Aug; 68(2): 174-80Corrigan B, Feltner DE, Ouellet D, Werth JL, Moton AE, Gibson GAIMS: To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr). METHODS: In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min(-1); n= 6); mild RI (CLcr 51 to < or =80 ml min(-1); n= 6); moderate RI (CLcr >30 to 50 ml min(-1); n= 6); and severe RI (CLcr < or =30 ml min(-1); n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data. RESULTS: PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66-3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CL(R)) clearance rates decreased with deteriorating renal function, whereas area under the concentration-time curve (AUC(0-infinity)) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CL(R) correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group. CONCLUSIONS: PD 0200390 pharmacokinetic parameters (CL/F, CL(R) and AUC(0-infinity)) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.

[Blood-patch: Immediate effective remedy for headaches secondary to dura mater injury.]

2009-08-24T16:14:00.001-07:00

Ann Fr Anesth Reanim. 2009 Aug 17; Hachimi MA, Elkartouti A, Rafik R, Jaafari A, Hannafi M, Mahmoudi AOBJECTIVE: The aim of this study was to evaluate if bed rest during 2h in a supine posture is required to improve the efficacy of the blood-patch procedure. PATIENTS AND METHODS: Patients whose postdural puncture headache remained distressing 48 to 72h after dural tap despite the use of stage II WHO painkillers were included in this prospective single center study lasted for a 2-year period. The patient's own blood injection in the epidural space was performed until discomfort or pain in the lumbar area occurred or was limited to 20ml if no such sensation was observed. After blood had been injected, the patient was allowed to stand up as soon as desired, under close observation. The patient was then discharged to the ward for a 48h follow-up. RESULTS: Nine female and 12 male patients (age: 16-35 years) were included. Headache occurred after spinal anaesthesia in 16 cases, epidural analgesia for delivery in two cases and lumbar puncture by during neurological workup in three cases. Autologous blood volume injected was 20ml in 19 patients and was reduced to 18 and 16ml, respectively, in two patients due to lumbar pain. All blood-patches were technically uneventful and led to immediate headache relief, associated with a feeling of wellbeing and desire to stand up. The 48 following hours were without any incident and painkillers were no more needed. CONCLUSION: In this prospective study, blood-patch was mainly performed after spinal anaesthesia and was associated with a high rate success. This encouraging result suggests that recumbent position maintained for 2h after the blood-patch is performed might not be necessary to obtain full efficacy.

Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: a single- and multiple-dose, open-label pharmacokinetic study in Chinese

2009-08-24T08:21:00.001-07:00

Tick-borne relapsing fever in a new highland endemic focus of western Iran.

2009-08-23T23:31:00.001-07:00

Ann Trop Med Parasitol. 2009 Sep; 103(6): 529-37Moemenbellah-Fard MD, Benafshi O, Rafinejad J, Ashraf HTick-borne relapsing fever (TBRF) is a neglected zoonotic disease caused by infection with spirochaetes of the genus Borrelia. Humans usually contract it from the bite of infected soft ticks of the genus Ornithodoros. In Iran, where the disease is endemic in the mountainous north-western provinces, reports of over 200 cases annually probably under-estimate the true incidence. The species, distribution and infection of ticks that are potential vectors of Borrelia and the clinical and epidemiological characteristics of the local TBRF cases were recently investigated in the villages in and around the county town of Bijar, in north-western Iran. A blood sample from each suspected case of TBRF was checked for B. persica by dark-field microscopy, data were collected on the demographics and clinical manifestations of each confirmed case, and the prevalence of tick infection with borreliae and the monthly incidence of TBRF were evaluated. Between 2000 and 2007, 148 cases of TBRF (each with fever, chills and headache) were passively detected in the town. Most (115) of these were confirmed by microscopy, with the other subjects categorized as probable (21) or suspected cases (12) of TBRF. Most (91%) of the 148 subjects were young people, and most came from rural areas and lived in large households in the old mud-and-thatch houses of Bijar. Most (82%) of the cases occurred during the summer or early autumn. Overall, 8543 soft ticks (Ornithodoros tholozani, O. lahorensis, Argas persicus and A. reflexus) were collected by clustered random sampling. When a random sample of the O. tholozani ticks (96 of the 577 collected) was checked for B. persica infection, by being crushed and then inoculated intraperitoneally into a mouse or suckling Syrian hamster, 19 were found infected. Peaks in the monthly incidence of TBRF occurred as the numbers of O. tholozani in the tick collections peaked, and it seems likely that most of the cases were caused by B. persica transmitted by O. tholozani. Further studies in Iran, to map the geographical variation in the prevalence of soft-tick infection with Borrelia and identify any Borrelia reservoirs, are recommended.

The Efficacy and Safety of Udenafil [Zydena] for the Treatment of Erectile Dysfunction in Hypertensive Men Taking Concomitant Antihypertensive Agents.

2009-08-23T07:24:00.001-07:00

J Sex Med. 2009 Aug 17; Paick JS, Kim SW, Park YK, Hyun JS, Park NC, Lee SW, Park K, Moon KH, Chung WSABSTRACT Introduction. Erectile dysfunction (ED) and hypertension are frequent comorbid conditions. The vasodilating properties of type 5 phosphodiesterase inhibitor (PDE5I) are the major concerns for the treatment of ED patients on antihypertensive medications. Aim. To evaluate the efficacy and safety of Udenafil [Zydena] (Dong-A, Seoul, Korea), a newly developed PDE5I, for the treatment of ED patients on antihypertensive medication. Methods. It was a multicentered, randomized, double-blind, placebo-controlled, fix-dosed clinical trial among 165 ED patients receiving antihypertensive medications. The subjects treated with placebo, 100 mg or 200 mg of Udenafil for 12 weeks were asked to complete the Sexual Encounter Profile (SEP) diary, the International Index of Erectile Function (IIEF), and the Global Assessment Question (GAQ) during the study period. Main Outcome Measures. Primary parameter: the change from baseline for IIEF erectile function domain (EFD) score; Secondary parameters: the IIEF Question 3 and 4, SEP Question 2 and 3, the rate of achieving normal erectile function (EFD >/= 26) and the response to GAQ. Results. Compared to placebo, patients receiving both doses of Udenafil showed significantly improved the IIEF-EFD score. The least squares means for the change from baseline in IIEF-EFD scores were 8.4 and 9.8 for 100 mg and 200 mg Udenafil groups, respectively; those values were significantly higher than that of placebo (2.4, P < 0.0001). Similar results were observed in the comparison of Q3 and Q4 of IIEF, SEP diary and GAQ. Headache and flushing were the most common treatment-emergent adverse events, which were transient and mild-to-moderate in nature. No parameters of efficacy and safety were affected among the subsets stratified according to either the number of antihypertensive medication received or the previous experience of PDE5Is treatment. Conclusion. Udenafil significantly improved erectile function among ED patients with hypertensive symptom treated with concomitant antihypertensive medication. The treatment did not increase the frequency or severity of adverse events. Paick J-S, Kim SW, Park YK, Hyun JS, Park NC, Lee SW, Park K, Moon KH, and Chung WS. The efficacy and safety of Udenafil [Zydena] for the treatment of erectile dysfunction in hypertensive men taking concomitant antihypertensive agents. J Sex Med **;**:**-**.

Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: a single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea.

2009-08-23T00:18:00.001-07:00

Clin Ther. 2009 Jun; 31(6): 1234-43Kim BH, Yi S, Kim J, Lim KS, Kim KP, Lee B, Shin SG, Jang IJ, Yu KSBACKGROUND: Mirodenafil is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction. Mirodenafil has the possibility of being administered with alcohol. OBJECTIVE: This study assessed the hemodynamic effects and pharmacokinetic properties of mirodenafil administered with alcohol. METHODS: This single-dose, randomized-sequence, open-label, crossover study was conducted in healthy male volunteers at the Clinical Trials Center, Seoul National University Hospital, Seoul, Korea. Volunteers were randomly allocated to 1 of 3 randomized-sequence groups, each of which consisted of 3 administration phases, each separated by a 1-week washout period: oral mirodenafil 100 mg, alcohol 0.5 g/kg, and both. Vital signs (systolic blood pressure [SBP], dia-stolic BP [DBP], and pulse rate) were measured before (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours after administration. Because volunteers were given a standardized meal at 4 hours after mirodenafil and/or alcohol administration, hemody-namic results were assessed using the maximum decrease from baseline during a period of up to 4 hours after administration. For pharmacokinetic assessment, serial blood samples were collected before (baseline) and at 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. Tolerability was assessed using monitoring of adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiography. RESULTS: A total of 20 subjects participated in the study (mean [range] age, 25.5 years [20-41 years]; weight, 69.8 kg [57.4-87.2 kg]; and height, 174.7 cm [168-186 cm]). Up to 4 hours after the administration of mirodenafil, alcohol, and mirodenafil + alcohol, the mean (SD) maximum decreases in SBP were 8.5 (3.5), 13.5 (7.8), and 15.1 (6.7) mm Hg, respectively, and the maximum decreases in DBP were 6.4 (4.8), 13.3 (7.4), and 13.8 (5.2) mm Hg. Simultaneous administration of mirodenafil + alcohol was associated with additional mean (95% CI) decreases in SBP and DBP of 1.7 mm Hg (-6.0 to 2.6 mm Hg) and 0.6 mm Hg (-4.7 to 3.6 mm Hg) compared with alcohol alone. Pharmacokinetic parameters of mirodenafil were not significantly different when the drug was administered with or without alcohol. The mean (SD) AUC(0-t) values were 842.0 (434.7) ng/mL/h with mirodenafil and 833.4 (398.2) ng/mL/h with mirodenafil + alcohol. The most common AEs considered at least possibly related to study drug were nasal congestion (7 subjects [35%]), headache (3 [15%]), nausea (1 [5%]), and hiccups (1 [5%]). CONCLUSIONS: The concurrent administration of mirodenafil with alcohol was not associated with clinically significant hemodynamic changes in these healthy male volunteers in Korea. The pharmacoki-netics of mirodenafil were not significantly altered by this concurrent administration. Mirodenafil administered with alcohol had a tolerability profile comparable to that of mirodenafil alone.