Peoria campus of the University of Illinois System

To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in greater than or equal to 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.

A multicenter, ongoing study of early-diagnosed cases of systemic sclerosis and comparison patients with systemic lupus erythematosus, polymyositis/dermatomyositis, and Raynaud's phenomenon was conducted in order to develop classification criteria for systemic sclerosis. Preliminary criteria are proposed namely, the finding of either the sole major criterion, i.e., proximal scleroderma, or two or more of the minor criteria, i.e., 1) sclerodactyly, 2) digital pitting scars of fingertips or loss of substance of the distal finger pad, and 3) bilateral basilar pulmonary fibrosis. When applied to the case and comparison patients included in this study, these proposed criteria had a 97% sensitivity for definite systemic sclerosis and 98% specificity.

This document serves as an update of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2009 clinical guidelines for the diagnosis and management of gastroesophageal reflux disease (GERD) in infants and children and is intended to be applied in daily practice and as a basis for clinical trials. Eight clinical questions addressing diagnostic, therapeutic and prognostic topics were formulated. A systematic literature search was performed from October 1, 2008 (if the question was addressed by 2009 guidelines) or from inception to June 1, 2015 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Clinical Trials. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to define and prioritize outcomes. For therapeutic questions, the quality of evidence was also assessed using GRADE. Grading the quality of evidence for other questions was performed according to the Quality Assessment of Studies of Diagnostic Accuracy (QUADAS) and Quality in Prognostic Studies (QUIPS) tools. During a 3-day consensus meeting, all recommendations were discussed and finalized. In cases where no randomized controlled trials (RCT; therapeutic questions) or diagnostic accuracy studies were available to support the recommendations, expert opinion was used. The group members voted on each recommendation, using the nominal voting technique. With this approach, recommendations regarding evaluation and management of infants and children with GERD to standardize and improve quality of care were formulated. Additionally, 2 algorithms were developed, 1 for infants <12 months of age and the other for older infants and children.

BACKGROUND: The Patient Determined Disease Steps (PDDS) is a promising patient-reported outcome (PRO) of disability in multiple sclerosis (MS). To date, there is limited evidence regarding the validity of PDDS scores, despite its sound conceptual development and broad inclusion in MS research. This study examined the validity of the PDDS based on (1) the association with Expanded Disability Status Scale (EDSS) scores and (2) the pattern of associations between PDDS and EDSS scores with Functional System (FS) scores as well as ambulatory and other outcomes. METHODS: 96 persons with MS provided demographic/clinical information, completed the PDDS and other PROs including the Multiple Sclerosis Walking Scale-12 (MSWS-12), and underwent a neurological examination for generating FS and EDSS scores. Participants completed assessments of cognition, ambulation including the 6-minute walk (6 MW), and wore an accelerometer during waking hours over seven days. RESULTS: There was a strong correlation between EDSS and PDDS scores (ρ = .783). PDDS and EDSS scores were strongly correlated with Pyramidal (ρ = .578 &ρ = .647, respectively) and Cerebellar (ρ = .501 &ρ = .528, respectively) FS scores as well as 6 MW distance (ρ = .704 &ρ = .805, respectively), MSWS-12 scores (ρ = .801 &ρ = .729, respectively), and accelerometer steps/day (ρ = -.740 &ρ = -.717, respectively). CONCLUSION: This study provides novel evidence supporting the PDDS as valid PRO of disability in MS.

Background and Objective. There seems to be a strong causal relationship between allergy and the origins of asthma. Susceptibility to both is determined by a combination of genetics and environment acting through a complex network of cytokines. Nearly 90% of affected children have positive skin tests indicating the presence of specific immunoglobulin E (IgE), with sensitivity to house dust mite, Alternaria, cockroach, cat, and dog most closely linked to the disease. Greater exposure to house dust mite during infancy leads to earlier onset of wheezing, and elevated serum IgE levels correlate with the appearance of asthma symptoms. Specific IgE binds to high-affinity (FcεRI) receptors on mast cells and basophils. The IgE-mediated reactions that follow exposure of sensitized mast cells to an allergen are designated early- and late-phase asthmatic responses (EAR and LAR). EAR is characterized by release of histamine and other preformed mediators within 1 hour of allergen exposure. It is often followed by LAR, an infiltration of the airways by inflammatory cells associated with an episode of more prolonged, and usually more severe airflow obstruction, 4 to 8 hours after antigen exposure. Chronic airway symptoms result from persistent LAR caused by continuous allergen exposure. IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity. IgE-mediated mast cell activation contributes to chronic tissue eosinophilia and airway remodeling, with permanent loss in pulmonary function. Omalizumab (rhuMAb-E25) is a recombinant, humanized, monoclonal anti-IgE antibody of mouse origin developed for the treatment of IgE-mediated diseases. Omalizumab binds to free IgE at the same site as the high-affinity receptor. Although it attaches to free IgE, it does not bind to IgA, IgG, or cell-bound IgE. It therefore does not induce cross-linking of cell-bound IgE, which would lead to the release of allergic mediators. It has been reported to decrease serum IgE levels in a dose-dependent manner, inhibit EAR and LAR, and cause a down-regulation of FcεRI receptors on basophils. Omalizumab has been reported to be safe and effective in improving asthma control and reducing the requirement for oral and inhaled corticosteroids. This double-blind, randomized, placebo-controlled study evaluated the safety, steroid-sparing effects, and impact on disease exacerbations of omalizumab in the treatment of childhood asthma. Methods. Participants were 334 males and premenarchal females aged 6 to 12 years, with moderate to severe allergic asthma requiring treatment with inhaled corticosteroids. During a run-in phase, all children were switched to equivalent doses of beclomethasone dipropionate (BDP), and the dose was adjusted to assure maintenance of asthma control achieved with previous corticosteroid treatment. Children were randomized to subcutaneously administered placebo (N = 109) or omalizumab (N = 225) at a dose based on body weight and initial serum IgE (0.016 mg/kg/IgE [IU/mL] per 4 weeks). BDP dose (initial range 168–420 μg/d) was kept stable for 16 weeks (stable-steroid phase), reduced over 8 weeks to the minimum effective dose (steroid-reduction phase), and maintained constant for the final 4 weeks. Results. More participants in the omalizumab group decreased their BDP dose, and their reduction was greater than that of the placebo group (median reduction 100% vs 66.7%). BDP was withdrawn completely in 55% of the omalizumab group versus 39% of the placebo group. The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the omalizumab group. The treatment differences were statistically significant during the steroid-reduction phase, during which fewer participants in the omalizumab group had asthma exacerbation episodes (18.2% vs 38.5%), and the mean number of episodes per patient was smaller than with placebo (0.42 vs 2.72). Five asthma exacerbations requiring hospitalization all occurred in the placebo group. Participants' and investigators' global evaluations of treatment effectiveness were more favorable for omalizumab than placebo. Investigators rated effectiveness excellent for 31.5% of the omalizumab group versus 16.3% of the placebo group and good for 44.7% of the omalizumab group versus 32.7% of the placebo group. There was little change in asthma symptom scores or spirometry measurements during either the stable-steroid or steroid dose-reduction phase, with minimal differences between the treatment groups. The requirement for rescue medication in the omalizumab group during both the stable-steroid and steroid dose-reduction phases was consistently lower than at baseline. At week 28, the median number of puffs of rescue medication taken daily was 0 in the omalizumab group and 0.46 in the placebo group. The change from baseline was significant in favor of omalizumab. Over the entire treatment period, patients in the omalizumab group missed a mean of 0.65 school days, compared with a mean of 1.21 days in the placebo group. The mean number of unscheduled medical contacts attributable to asthma-related medical problems was significantly smaller in the omalizumab group than in the placebo group throughout the treatment period (0.15 vs 5.35). Median reduction in serum free IgE was 95% to 99% among omalizumab patients. Median free IgE ranged from 133 to 790 IU/mL at baseline and was in the range of 6 to 9 IU/mL during the treatment period. The dosing scheme used in the trial therefore effectively reduced serum IgE in patients with initial concentrations as high as 1300 IU/mL. There was no reduction in free IgE in the placebo group. Omalizumab treatment was well tolerated. There were no serious treatment-related adverse events. The frequency and types of all adverse events were similar in the omalizumab and placebo groups. The majority of adverse events were mild to moderate in severity. No adverse events suggestive of serum sickness or immune complex formation were observed. Study-drug–related adverse events occurred more frequently in the omalizumab group than in the placebo group (6.2% vs 0.9%). Urticaria was reported in 9 omalizumab patients (4%) compared with 1 (0.9%) placebo patient and was mild or moderate in nearly all cases. Conclusion. Treatment with omalizumab is safe in children with asthma. It reduces the requirement for inhaled corticosteroids while protecting against disease exacerbation.

This study consisted of two interrelated parts. In the first part, the adequacy of pain relief in hospitalized post-surgical patients was assessed and described and in the second part ways in which nurses on the same units chose analgesic medications were examined and analyzed. Pain was considered a subjective experience. Patients were interviewed, and their charts reviewed on the third postoperative day. The sample included 109 patients in 5 central Illinois hospitals. After all patient interviews were completed, 121 nurses on the same units responded to a questionnaire which included clinical vignettes. Results of the patient interviews indicated that 75.2% of these patients were in moderate or marked pain distress and that a general question did not adequately assess pain. Chart review indicated that these patients were actually receiving less narcotic analgesics than they could receive. Nurses were overly concerned about the possibility of addiction; choices of analgesic medications seemed irrational; and knowledge of the drugs was inadequate. Moreover, these nurses indicated that complete pain relief after surgery was not their major goal. In 2 sets of identical vignettes where the only difference was the sex of the patient, nurses selected less medication for pain for female patients (P < 0.001 and P < 0.025 respectively). Factors that nurses consider in administering and choosing postoperative analgesia are described.

Deposits of amyloid beta-protein (Abeta) in neuritic plaques and cerebral vessels are a pathological hallmark of Alzheimer's disease. Fibrillar Abeta deposits are closely associated with inflammatory responses such as activated microglia in brain with this disease. Increasing lines of evidence support the hypothesis that activated microglia, innate immune cells in the CNS, play a pivotal role in the progression of the disease: either clearing Abeta deposits by phagocytic activity or releasing cytotoxic substances and pro-inflammatory cytokines. Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia. To investigate the role of TLR4 in the amyloidogenesis in vivo, we determined the amounts of cerebral Abeta in Alzheimer's disease mouse models with different genotypes of TLR4 using three distinct methods. We show that mouse models (Mo/Hu APPswe PS1dE9 mice) homozygous for a destructive mutation of TLR4 (Tlr(Lps-d)/Tlr(Lps-d)) had increases in diffuse and fibrillar Abeta deposits by immunocytochemistry, fibrillar Abeta deposits by thioflavine-S staining and buffer-soluble and insoluble Abeta by ELISA in the cerebrum, as compared with TLR4 wild-type mouse models. Although the differences in these parameters were less significant, mouse models heterozygous for the mutation (Tlr(Lps-d)/) showed co-dominant phenotypes. Consistent with these observations in vivo, cultured microglia derived from Tlr(Lps-d)/Tlr(Lps-d) mice failed to show an increase in Abeta uptake after stimulation with a TLR4 ligand but not with a TLR9 ligand in vitro. Furthermore, activation of microglia (BV-2 cell) with a TLR2, TLR4 or TLR9 ligand, markedly boosted ingestion of Abeta in vitro. These results suggest that TLR signalling pathway(s) may be involved in clearance of Abeta-deposits in the brain and that TLRs can be a therapeutic target for Alzheimer's disease.

Criteria for the classification of juvenile rheumatoid arthritis were analyzed in a detailed database of 250 children in order to assess the accuracy of diagnosis and validity of onset types and course subtypes. A number of conclusions have been derived from this study: All definitions of the 1973 criteria for classification of juvenile rheumatoid arthritis should be retained. The addition of onset types to the 1976 revision of the criteria has been validated. The course of the disease after the onset period of 6 months is as important to the outcome of a group of children as is the onset type. The current classification should be broadened to include the course subtypes.

INTRODUCTION: Cathepsin B is of significant importance to cancer therapy as it is involved in various pathologies and oncogenic processes in humans. Numerous studies have shown that abnormal regulation of cathepsin B overexpression is correlated with invasive and metastatic phenotypes in cancers. Cathepsin B is normally associated with the lysosomes involved in autophagy and immune response, but its aberrant expression has been shown to lead to cancers. AREAS COVERED: This review highlights the oncogenic role of cathepsin B, discusses the regulation of cathepsin B in light of oncogenesis, discusses the role of cathepsin B as a signaling molecule, and highlights the therapeutic potential of targeting cathepsin B. EXPERT OPINION: Targeting cathepsin B alone does not appear to abolish tumor growth, and this is probably because cathepsin B appears to have diverse functions and influence numerous pathways. It is not clear whether global suppression of cathepsin B activity or expression would produce unintended effects or cause the activation or suppression of unwanted pathways. A localized approach for targeting the expression of cathepsin B would be more relevant. Moreover, a combination of targeting cathepsin B with other relevant oncogenic molecules has significant therapeutic potential.

OBJECTIVES: Dizziness and vertigo account for about 4 million emergency department (ED) visits annually in the United States, and some 160,000 to 240,000 (4% to 6%) have cerebrovascular causes. Stroke diagnosis in ED patients with vertigo/dizziness is challenging because the majority have no obvious focal neurologic signs at initial presentation. The authors sought to compare the accuracy of two previously published approaches purported to be useful in bedside screening for possible stroke in dizziness: a clinical decision rule (head impulse, nystagmus type, test of skew [HINTS]) and a risk stratification rule (age, blood pressure, clinical features, duration of symptoms, diabetes [ABCD2]). METHODS: This was a cross-sectional study of high-risk patients (more than one stroke risk factor) with acute vestibular syndrome (AVS; acute, persistent vertigo or dizziness with nystagmus, plus nausea or vomiting, head motion intolerance, and new gait unsteadiness) at a single academic center. All underwent neurootologic examination, neuroimaging (97.4% by magnetic resonance imaging [MRI]), and follow-up. ABCD2 risk scores (0-7 points), using the recommended cutoff of ≥4 for stroke, were compared to a three-component eye movement battery (HINTS). Sensitivity, specificity, and positive and negative likelihood ratios (LR+, LR-) were assessed for stroke and other central causes, and the results were stratified by age. False-negative initial neuroimaging was also assessed. RESULTS: A total of 190 adult AVS patients were assessed (1999-2012). Median age was 60.5 years (range = 18 to 92 years; interquartile range [IQR] = 52.0 to 70.0 years); 60.5% were men. Final diagnoses were vestibular neuritis (34.7%), posterior fossa stroke (59.5% [105 infarctions, eight hemorrhages]), and other central causes (5.8%). Median ABCD2 was 4.0 (range = 2 to 7; IQR = 3.0 to 4.0). ABCD2 ≥ 4 for stroke had sensitivity of 61.1%, specificity of 62.3%, LR+ of 1.62, and LR- of 0.62; sensitivity was lower for those younger than 60 years old (28.9%). HINTS stroke sensitivity was 96.5%, specificity was 84.4%, LR+ was 6.19, and LR- was 0.04 and did not vary by age. For any central lesion, sensitivity was 96.8%, specificity was 98.5%, LR+ was 63.9, and LR- was 0.03 for HINTS, and sensitivity was 99.2%, specificity was 97.0%, LR+ was 32.7, and LR- was 0.01 for HINTS "plus" (any new hearing loss added to HINTS). Initial MRIs were falsely negative in 15 of 105 (14.3%) infarctions; all but one was obtained before 48 hours after onset, and all were confirmed by delayed MRI. CONCLUSIONS: HINTS substantially outperforms ABCD2 for stroke diagnosis in ED patients with AVS. It also outperforms MRI obtained within the first 2 days after symptom onset. While HINTS testing has traditionally been performed by specialists, methods for empowering emergency physicians (EPs) to leverage this approach for stroke screening in dizziness should be investigated.

OBJECTIVE: To study, for the first time, service utilization and costs in fibromyalgia, a prevalent syndrome associated with high levels of pain, functional disability, and emotional distress. METHODS: Five hundred thirty-eight fibromyalgia patients from 6 rheumatology centers were enrolled in a 7-year prospective study of fibromyalgia outcome. Patients were assessed every 6 months with validated, mailed questionnaires which included questions regarding fibromyalgia symptoms and severity, utilization of services, and work disability. RESULTS: Fibromyalgia patients averaged almost 10 outpatient medical visits per year, and when nontraditional treatments were considered, this number increased to approximately 1 visit per month. Patients were hospitalized at a rate of 1 hospitalization every 3 years. In each 6-month study period, patients used a mean of 2.7 fibromyalgia-related drugs. Costs increased over the course of the study. The mean yearly per-patient cost in 1996 dollars was $2,274. However, results were skewed by high utilizers, and many patients used few services and had limited costs. Total costs and utilization were independently associated with the number of self-reported comorbid or associated conditions, functional disability, and global disease severity. Compared with patients with other rheumatic disorders, those with fibromyalgia were more likely to have lifetime surgical interventions, including back or neck surgery, appendectomy, carpal tunnel surgery, gynecologic surgery, abdominal surgery, and tonsillectomy, and were more likely than other rheumatic disease patients to report comorbid or associated conditions. Almost 50% of hospitalizations occurring during the study were related to fibromyalgia-associated symptoms. CONCLUSION: The average yearly cost for service utilization among fibromyalgia patients is $2,274. Fibromyalgia patients have high lifetime and current rates of utilization of all types of medical services. They report more symptoms and comorbid or associated conditions than patients with other rheumatic conditions, and symptom reporting is linked to service utilization and, to a lesser extent, functional disability and global disease severity.

Abstract This article reviews bioconversion of plant materials such as wheat straw (WS), corn stover (CS), barley straw (BS), and switchgrass (SG) to butanol and process technology that converts these materials into this superior biofuel. Successful fermentation of low‒value WS makes butanol fermentation economically attractive. Simultaneous hydrolysis, fermentation, and product recovery has been successfully performed in a single reactor using WS and C. beijerinckii P260. Research on the production of butanol from other agricultural residues including CS, BS, and SG has steadily progressed. Use of several product‒recovery technologies such as liquid‒liquid extraction, gas stripping, perstraction, and pervaporation has been successfully applied in laboratory‒scale bioreactors. It is expected that these recovery technologies will play a major role in commercialization of this fermentation. By employing in line / in situ product‒recovery systems during fermentation, butanol toxicity to the culture has been drastically reduced. In addition to the use of low‒cost plant materials for the production of this biofuel, process integration is expected to play a major role in the economics of this product. © 2008 Society of Chemical Industry and John Wiley &amp; Sons, Ltd

OBJECTIVE: To determine the intermediate and long-term outcomes of fibromyalgia in patients seen in rheumatology centers in which there is special interest in the syndrome. METHODS: We conducted a longitudinal outcome study by mailed comprehensive Health Assessment Questionnaire administered every 6 months to 538 patients, from 6 rheumatology centers, whose median duration of disease at first assessment was 7.8 years. The final assessment took place after 7 years. In addition, there was study followup on 85 patients who had attended the Wichita center for > 10 years. RESULTS: Although functional disability worsened slightly and health satisfaction improved slightly, measures of pain, global severity, fatigue, sleep disturbance, anxiety, depression, and health status were markedly abnormal at study initiation and were essentially unchanged over the study period. Correlations between first and last assessment values were as high as r = 0.82. For some variables, abnormalities were 3 times greater at one center compared with another. CONCLUSION: Patients with established fibromyalgia, seen in rheumatology centers in which there a special interest in the disease and followed up for as long as 7 years, have markedly abnormal scores for pain, functional disability, fatigue, sleep disturbance, and psychological status, and these values do not change substantially over time. Half the patients are dissatisfied with their health, and 59% rate their health as fair or poor. There are marked differences in disease severity among the various centers, but < 14% of the variance in outcomes can be explained by demographic or center factors. Values at the first assessment are predictive of final values.

BACKGROUND: Abeta deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses such as activated microglia and increased cytokines. Accumulating evidence supports the hypothesis that innate immune/inflammatory responses play a pivotal role in the pathogenesis of AD: either beneficial or harmful effects on the AD progression. The molecular mechanisms by which the innate immune system modulates the AD progression are not well understood. Toll-like receptors (TLRs) are first-line molecules for initiating the innate immune responses. When activated through TLR signaling, microglia respond to pathogens and damaged host cells by secreting chemokines and cytokines and express the co-stimulatory molecules needed for protective immune responses to pathogens and efficient clearance of damaged tissues. We previously demonstrated that an AD mouse model homozygous for a destructive mutation of TLR4 has increases in diffuse and fibrillar Abeta deposits as well as buffer-soluble and insoluble Abeta in the brain as compared with a TLR4 wild-type AD mouse model. Here, we investigated the roles of TLR4 in Abeta-induced upregulation of cytokines and chemokines, Abeta-induced activation of microglia and astrocytes and Abeta-induced immigration of leukocytes. METHODS: Using the same model, levels of cytokines and chemokines in the brain were determined by multiplex cytokine/chemokine array. Activation of microglia and astrocytes and immigration of leukocytes were determined by immunoblotting and immunohistochemistry followed by densitometry and morphometry, respectively. RESULTS: Levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10 and IL-17 in the brains of TLR4 wild-type AD mice were significantly higher than those in TLR4 wild-type non-transgenic littermates. Such increases in cytokines were not found in TLR4 mutant AD mice as compared with TLR4 mutant non-transgenic littermates. Although expression levels of CD11b (a microglia marker) and GFAP (a reactive astrocyte marker) in the brains of TLR4 mutant AD mice were higher than those in TLR4 wild type AD mice, no difference was found in levels of CD45 (common leukocyte antigen). CONCLUSION: This is the first demonstration of TLR4-dependent upregulation of cytokines in an AD mouse model. Our results suggest that TLR4 signaling is involved in AD progression and that TLR4 signaling can be a new therapeutic target for AD.

Nonradioactive in situ hybridization methods with digoxigenin-labeled cRNA probes were used to localize two glutamic acid decarboxylase (GAD) mRNAs in rat brain. These mRNAs encode two forms of GAD that both synthesize GABA but differ in a number of characteristics including their molecular size (65 and 67 kDa). For each GAD mRNA, discrete neuronal labeling with high cellular resolution and low background staining was obtained in most populations of known GABA neurons. In addition, the current methods revealed differences in the intensity of labeling among neurons for each GAD mRNA, suggesting that the relative concentrations of each GAD mRNA may be higher in some groups of GABA neurons than in others. Most major classes of GABA neurons were labeled for each GAD mRNA. In some groups of GABA neurons, the labeling for the two mRNAs was virtually identical, as in the reticular nucleus of the thalamus. In other groups of neurons, although there was substantial labeling for each GAD mRNA, labeling for one of the mRNAs was noticeably stronger than for the other. In most brain regions, such as the cerebellar cortex, labeling for GAD67 mRNA was stronger than for GAD65 mRNA, but there were a few brain regions in which labeling for GAD65 mRNA was more pronounced, and these included some regions of the hypothalamus. Finally, some groups of GABA neurons were predominantly labeled for one of the GAD mRNAs and showed little or no detectable labeling for the other GAD mRNA, as, for example, in neurons of the tuberomammillary nucleus of the hypothalamus where labeling for GAD67 mRNA was very strong but no labeling for GAD65 mRNA was evident. The findings suggest that most classes of GABA neurons in the central nervous system (CNS) contain mRNAs for at least two forms of GAD, and thus, have dual enzyme systems for the synthesis of GABA. Higher levels of one or the other GAD mRNA in certain groups of GABA neurons may be related to differences in the functional properties of these neurons and their means of regulating GABA synthesis.

Suicide is an important public health problem for which we have an inadequate public health database. In the United States, decisions about whether deaths are listed as suicides on death certificates are usually made by a coroner or medical examiner. These certification decisions are frequently marked by a lack of consistency and clarity, and laws and procedures for guiding these decisions vary from state to state and even from county to county. Without explicit criteria to aid in this decision making, coroners or medical examiners may be more susceptible to pressures from families or communities not to certify specific deaths as suicide. In addition, coroners or medical examiners may certify similar deaths differently at different times. The degree to which suicides may be underreported or misclassified is unknown. This makes it impossible to estimate accurately the number of deaths by suicide, to identify risk factors, or to plan and evaluate preventive interventions. To remedy these problems, a working group representing coroners, medical examiners, statisticians, and public health agencies developed operational criteria to assist in the determination of suicide. These criteria are based on a definition of suicide as "death arising from an act inflicted upon oneself with the intent to kill oneself." The purpose of these criteria is to improve the validity and reliability of suicide statistics by: (1) promoting consistent and uniform classifications; (2) making the criteria for decision making in death certification explicit; (3) increasing the amount of information used in decision making; (4) aiding certifiers in exercising their professional judgment; and (5) establishing common standards of practice for the determination of suicide.

To test the hypothesis that plasma tryptophan and/or its transport ratio is decreased in primary fibromyalgia (PF), we measured plasma tryptophan and its transport ratio in 29 patients with PF and 30 healthy controls without significant pain, in a blinded manner. Twenty-one other amino acids were also similarly analyzed among these study subjects. Transport ratio of tryptophan was found to be significantly (p less than 0.01) decreased in PF compared with the control group (0.09 +/- 0.02 vs 0.10 +/- 0.02). Plasma tryptophan level was lower in PF (45 +/- 10 nmol/ml) than in healthy controls (51 +/- 15 nmol/ml), showing a trend towards significance (p less than 0.09). Additionally, plasma histidine and serine levels were found to be significantly (p less than 0.01) lower in patients with PF than in controls. Our results suggest that a decreased brain serotonin level, as possibly reflected by a decreased transport ratio of plasma tryptophan, may play a pathophysiologic role in PF.

Clinical features and psychological status determined by the Minnesota Multiphasic Personality Inventory (MMPI) in 103 patients with primary fibromyalgia syndrome (PFS) were analyzed by univariate and multivariate techniques to determine if clinical features were related to psychological status or were intrinsic to PFS per se. The central features of PFS, e.g., number of pain sites, number of tender points, fatigue, and poor sleep, were independent of psychological status. However, discriminant analysis identified 4 variables--patient-reported depression, anxiety, stress, and pain severity--which together predicted 3 MMPI subgroups with an accuracy of 55% (P less than 0.001); the only musculoskeletal feature--pain severity--alone provided an accuracy of only 34% (P greater than 0.05). These data suggest a new concept, that the central features of fibromyalgia are independent of the psychological status and are more likely related to the PFS itself. However, pain severity may be influenced by psychological factors.

OBJECTIVE: The objective of this study was to evaluate montelukast 10 mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season. METHODS: This was a multicenter study of 831 patients (ages 15 years-85 years) with seasonal allergen sensitivity, active symptoms of seasonal allergic rhinitis, and active asthma. Following a single-blind, placebo run-in period of 3 days-5 days, patients were randomized to oral montelukast 10 mg (n = 415) or placebo (n = 416) daily during the 2-week, double-blind, active-treatment period. MAIN OUTCOME MEASURES: The primary endpoint was Daily Rhinitis Symptoms score, average of Daytime Nasal Symptoms and Nighttime Symptoms, as self-rated by patients on a 0-3 scale on daily diaries. RESULTS: Montelukast reduced the Daily Rhinitis Symptoms score: difference between montelukast and placebo in mean change from baseline was -0.12 [95% CI -0.18, -0.06; p < or = 0.001]. Similar improvements were seen in Daytime Nasal Symptoms (-0.14 [-0.21, -0.07; p < or = 0.001]) and Nighttime Symptoms (-0.10 [-0.16, -0.04; p < or = 0.001]). Improvements (p < 0.05) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician, and Rhinoconjunctivitis Quality of Life. In exploratory analyses, improvement in rhinitis symptoms was numerically (though not statistically) larger in patients with greater levels of asthma at study start. Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician: mean differences were -0.24 [-0.41, -0.06; p = 0.008] and -0.17 [-0.33, -0.01; p = 0.037]. Similarly, as-needed beta-agonist use (puffs/day) was reduced with montelukast (p < or = 0.005). CONCLUSION: Montelukast provides significant relief from symptoms of seasonal allergic rhinitis, while also conferring a benefit for asthma, in patients with both allergic rhinitis and asthma.

BACKGROUND: Remnant lipoproteins (RLPs), the triglyceride-enriched precursors to low-density lipoprotein, are an emerging risk factor for coronary heart disease (CHD). We sought to determine the association of RLP cholesterol (RLP-C) levels with incident CHD in 2 diverse, prospective, longitudinal observational US cohorts. METHODS AND RESULTS: We analyzed cholesterol levels from serum lipoprotein samples separated via density gradient ultracentrifugation in 4114 US black participants (mean age 53.8 years, 64% women) from the Jackson Heart Study and a random sample of 818 predominantly white participants (mean age 57.3 years, 52% women) from the Framingham Offspring Cohort Study. Multivariable-adjusted hazard ratios (HRs) for RLP-C (the sum of very low-density lipoprotein3 cholesterol and intermediate-density lipoprotein cholesterol) were derived to estimate associations with incident CHD events consisting of myocardial infarction, CHD death, and revascularizations for each cohort separately and as a combined population. There were 146 CHD events in the combined population. After adjustments for age, sex, body mass index, smoking, blood pressure, diabetes, and lipid-lowering therapy for the combined population, RLP-C (HR 1.23 per 1-SD increase, 95% CI 1.06-1.42, P<0.01) and intermediate-density lipoprotein cholesterol (HR 1.26 per 1-SD increase, 95% CI 1.08-1.47, P<0.01) predicted CHD during an 8-year follow-up. Associations were attenuated by high-density lipoprotein cholesterol and ultimately lost significance with inclusion of real low-density lipoprotein cholesterol, which excludes Lp(a) and IDL cholesterol fractions. Similar associations were seen in multivariable analyses within each cohort. CONCLUSION: RLP-C levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing RLP-C to prevent CHD warrant further intensive investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00415415.