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The brain-gut-microbiome axis (BGMA) is a pivotal contributor to human health. A large body of research, especially from animal models, has revealed bidirectional, causal relationships between the BGMA and sex. In particular, sex steroids appear to be affected by the BGMA, to influence the BGMA, and to moderate environmental effects on the BGMA. However, animal research on the relationship between sex and the BGMA has not translated well to human models. We contend that this is due in part to an oversimplified approach to sex: although BGMA researchers have traditionally approached sex as a unidimensional, dichotomous variable, it is in fact multidimensional and is comprised of both multi-categorical and continuous dimensions. We also contend that research on the BGMA in humans should approach gender as a variable that is distinct from sex and that gender may influence the BGMA through pathways that are independent from the effects of sex alone. Research practices that consider the complexity and distinctiveness of sex and gender in relation to the human BGMA will not only yield improved understanding of this consequential system, but will also enhance the development of treatments for adverse health outcomes with BGMA-related etiologies. We conclude with recommendations for the implementation of such practices.

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Previous work has shown an important role for neuroligins in promoting the formation of synaptic connections in cultured cells. Although neuroligins enhance both excitatory and inhibitory synapse formation, individual neuroligin isoforms have been shown to preferentially localize to either glutamatergic or GABAergic synapses. Current evidence points to an important role for both the extracellular and intracellular domains of neuroligins in their synaptic localization. Although postsynaptic density protein 95 (PSD-95) has been shown to be involved in the recruitment of neuroligin 1 to excitatory synapses, the localization of neuroligin 2 (NL2) and neuroligin 3 (NL3) to excitatory and inhibitory synapses is less well defined. We assessed the roles of gephyrin and PSD-95, postsynaptic scaffolding molecules exclusively localized to inhibitory and excitatory synapses, respectively, in localizing NL2 and NL3 in primary neuronal cultures. We demonstrate that knockdown of gephyrin results in a significant shift of NL2 from inhibitory to excitatory synaptic contacts, while knockdown of PSD-95 leads to a partial shift of NL2 and NL3 from excitatory to inhibitory contacts. Furthermore, analysis of specific domain deletions within the C-terminal, intracellular domain of NL2 reveals that the region between amino acids 716 and 782 is required for the normal synaptic clustering of this protein. Together, these data suggest that intracellular mechanisms are involved in the targeting of different neuroligin family members to synapses (216).

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OBJECTIVE: To correlate disease course and complications in children with juvenile dermatomyositis (JDM) and polymyositis (JPM) with specific features of muscle pathology on biopsy. METHODS: This is a retrospective cohort analysis of 59 children diagnosed with JDM or JPM between 1965 and 1998 and followed at the Cincinnati Children's Hospital Medical Center (CCHMC) for a mean duration of 7.3 years (range 1.1-24.5 years). Disease course was characterized as limited, chronic non-ulcerative or chronic ulcerative, similar to previously defined disease course subtypes reported by Crowe et al.(1). All subjects had diagnostic muscle biopsies performed at CCHMC and had disease for at least two years' duration in order to classify their disease course as either limited or chronic. Features of muscle histopathology that were evaluated included loss of the intramuscular capillary bed, infarct, perifascicular myopathy, direct immunofluorescence (DIF) staining of the intramuscular vasculature and specifically, the locale of DIF staining, i.e., small arteries or capillaries. Disease complications that were assessed included calcinosis, contractures, muscle atrophy, lipodystrophy, gastrointestinal ulceration, cutaneous ulceration and death. Data analysis was completed using Chi-square or Fisher's exact tests and logistic regression modeling. RESULTS: Twenty-two children (37%) had limited disease, 24 (41%) had chronic non-ulcerative disease and 13 (22%) had chronic ulcerative disease. Neither loss of the intramuscular capillary bed nor perifascicular myopathy on muscle biopsy significantly correlated with disease course or the various complications evaluated in this study. DIF staining of intramuscular vessels overall was not significantly associated with clinical disease course, but the localization of DIF staining to intramuscular arteries (rather than to capillaries) was significantly associated with the outcome of chronic ulcerative disease. Nine of the 13 children with chronic ulcerative disease had DIF-arterial staining on muscle biopsy (69%), significantly greater than DIF-arterial staining in children with limited disease (32% had DIF-arterial staining) (p = 0.04), chronic non-ulcerative disease (8% had DIF-arterial staining) (p = 0.0002), and non-ulcerative disease overall (limited + chronic non-ulcerative disease groups combined) (20% had DIF-arterial staining), with p = 0.001. Additionally, lack of DIF-arterial staining on biopsy was significantly correlated with patients not having gastrointestinal ulceration (p = 0.002), cutaneous ulceration (p = 0.004) and/or death (p = 0.02) as disease-related complications. Infarct on muscle biopsy was significantly associated with the development of chronic ulcerative disease (p = 0.02), being present on biopsy in 23% of children with chronic ulcerative disease compared with none of the patients with chronic non-ulcerative disease and 4% of those with limited disease. Infarct on muscle biopsy correlated with the outcomes of death (p = 0.01) and gastrointestinal ulceration (p = 0.03), but not with the development of cutaneous ulceration (p = 0.18). CONCLUSION: DIF-arterial staining and infarct on muscle biopsy are significantly associated with the development of chronic ulcerative disease in JDM and JPM, while perifascicular myopathy and loss of the intramuscular capillary network are not associated with disease course. The presence of DIF-arterial staining and infarct on biopsy should suggest early use of second-line therapeutic agents to more quickly bring disease activity under control.

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The reactions of 2-propen-1-ol (allyl alcohol) were studied on clean and O-covered Mo(110) to understand the effect of resonance stabilization and the presence of surface oxygen on reaction selectivity. Propene is the only gaseous hydrocarbon product evolved from allyl alcohol reaction on O-covered Mo(110). Water and dihydrogen are also produced, along with a small amount of adsorbed carbon. We estimated, using X-ray photoelectron spectroscopy, that approximately 70% of the 0.11 ML of 2-propen-1-ol that reacts forms propene. In contrast, the dominant reaction pathway on the clean surface is nonselective decomposition to adsorbed carbon and hydrogen, leading to a 23% selectivity for propene formation. On both clean and O-covered Mo(110), X-ray photoelectron spectroscopy and infrared spectroscopy identify allyloxy as the reaction intermediate yielding propene. These results are discussed in the context of propene oxidation and periodic trends in reactivity.

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OBJECTIVE: To evaluate shifts in respiratory care practice in the context of changing healthcare system and market dynamics. STUDY DESIGN: Telephone survey, structured interview, and case studies. METHODS: We conducted a telephone survey of 471 respiratory care practitioners (RCPs), drawn from the membership database of the American Association for Respiratory Care. We also interviewed 10 employers of RCPs and conducted 2 in-depth case studies to supplement our survey results. We used several statistical techniques to analyze our data, including calculation of population-weighted descriptive statistics and multivariate regression models. RESULTS: Changes in the healthcare system have prompted RCPs to broaden their practice settings, skills, and responsibilities. Respiratory care practitioners are taking part in managed care-related activities, such as cost control and disease management. We found that the need for certain skills and responsibilities varies by practice setting. In our interviews, employers considered RCPs cost effective providers for certain services. CONCLUSIONS: The practice of respiratory care is evolving to meet the changing needs of the healthcare system. A key challenge is to ensure appropriate growth and development of the respiratory care profession, as well as the delivery of appropriate services under new care management settings and processes.

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OBJECTIVE: To develop, validate, and determine the measurement characteristics of a quantitative tool for assessing the severity of muscle involvement in children with idiopathic inflammatory myopathies. METHODS: The Childhood Myositis Assessment Scale (CMAS) was developed from 2 existing observational functional assessment tools to assess muscle function in the areas of strength and endurance across a wide range of ability and ages. The 14 ordinal items included were chosen to assess primarily axial and proximal muscle groups and are ranked with standard performance and scoring methods. Following the development of the CMAS, a training video and written instructions were developed and reviewed by the physicians participating in this study. Subsequently, utilizing a randomized block design, 12 physicians independently scored 10 children (9 with dermatomyositis, 1 with polymyositis; ages 4-15 years) twice in one day (morning and afternoon) on the CMAS. A pediatric physical therapist performed quantitative manual muscle strength testing (MMT) twice on each child (morning and afternoon), including the neck, trunk, and proximal and distal extremity muscle groups. RESULTS: The CMAS has a potential range of 0-51, with higher scores indicating greater muscle strength and endurance. The observed mean for the 10 patients was 36.4 (median 44, SD 14.1, observed range 5-51). The total score for the CMAS correlated with the physician's global assessment (by visual analog scale) of disease activity, the MMT score, serum creatine kinase level, and the Juvenile Arthritis Functional Assessment Report score. The score on the CMAS was not correlated with patient age. Interrater reliability (Kendall's coefficient of concordance) ranged from 0.77 to 1.0 for individual items (all P < 0.001), and overall, it was 0.95 (P < 0.001). Intrarater reliability for the individual physicians was measured by correlation of the CMAS scores for each patient on 2 separate evaluations and ranged from 0.97 to 0.99, with an overall correlation for all physicians of 0.98 (all P < 0.001). CONCLUSION: The CMAS demonstrated an acceptable range of observed scores, excellent convergent validity, and excellent inter- and intrarater reliability. The CMAS is validated to quantitatively assess muscle function in the areas of strength and endurance in children with idiopathic inflammatory myopathies. It can be used in routine clinical care as well as therapeutic trials.

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BACKGROUND: A primary leiomyosarcoma of the parotid gland has been reported only three times in the English literature. This type of tumor represents an extremely rare group of salivary gland neoplasm. METHODS: A 44 year old man was initially seen with a 5 cm right parotid mass which was resected with a total parotidectomy, preserving the facial nerve. The patient had no palpable cervical lymph nodes. RESULTS: The majority of the specimen was made up of a relatively well demarcated tumor 5 cm in diameter. The tumor was noted to contain moderate to poorly differentiated primary leiomyosarcoma of the parotid. CONCLUSIONS: A primary leiomyosarcoma of the parotid gland is an extremely rare existing entity. A review of the literature reveals that primary leiomyosarcoma and other sarcomas of the major salivary glands may share similar histogenesis and biologic behavior with their soft tissue counterparts.

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OBJECTIVE: Approximately 25% of patients with subarachnoid hemorrhage (SAH) have electrocardiographic (ECG) abnormalities consistent with myocardial ischemia or myocardial infarction (MI), and their cardiac prognosis remains unclear. The objective of this study was to determine the cardiac and all-cause mortality rate of a series of patients with SAH with ECG changes consistent with ischemia or MI. METHODS: Using an existing database of patients with SAH and predetermined ECG criteria for ischemia or MI, a study group of patients with abnormal ECG results within 3 days of presentation and before aneurysm surgery was identified. Database patients without abnormal ECG results served as a control group. Cardiac mortality, defined as death resulting from arrhythmia, congestive heart failure, or cardiogenic shock, was assessed by chart review. RESULTS: Of 439 patients with SAH in the database, 58 met the criteria for the study group. Forty-one of these patients were treated neurosurgically. No deaths resulting from cardiac causes occurred, and 20 patients died as a result of noncardiac causes. In a multivariable analysis, age older than 65 years and Hunt and Hess grade of at least 3 were predictive of all-cause mortality. ECG abnormalities, however, were not a statistically significant predictor. CONCLUSION: In patients with SAH and ECG readings consistent with ischemia or MI, the risk of death resulting from cardiac causes is low, with or without aneurysm surgery. The ECG abnormalities are associated with more severe neurological injury but are not independently predictive of all-cause mortality.

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Dialectical behavior therapy, an outpatient psychosocial treatment for chronically suicidal women with borderline personality disorder, has been adapted for use in a partial hospital program for women. Patients attend the program for a minimum of five days of individual and group therapy, and full census is 12 women. About 65 percent of participants meet at least three criteria for borderline personality disorder, and most have suicidal and self-injurious behavior. Their comorbid diagnoses include trauma-related diagnoses and anxiety disorders, severe eating disorders, substance abuse, and depression. The partial hospital program is linked to an aftercare program offering six months of outpatient skills training based on dialectical behavior therapy. Both programs focus on teaching patients four skills: mindfulness (attention to one's experience), interpersonal effectiveness, emotional regulation, and distress tolerance. Two years of operation of the women's partial hospital program provides promising anecdotal evidence that dialectical behavioral therapy, an outpatient approach, can be effectively modified for partial hospital settings and a more diverse population.

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OBJECTIVE: To determine whether demographic, clinical, and immunogenetic variables measurable during the first 6 months of illness long-term health outcomes and quality of life in patients with juvenile rheumatoid arthritis (JRA). METHODS: Patient eligibility criteria: (1) first examined in our units between 1958 and 1990 within 6 months of onset of symptoms; (2) diagnosis of JRA by American College of Rheumatology criteria; (3) disease duration of at least 5 years at the time of assessment of outcome. Instruments used: (1) the Health Assessment Questionnaire (HAQ, short form), or Childhood HAQ (CHAQ) to measure disability (0-3 scale), (2) pain, and (3) parental assessment of overall well being, each scored on a 15 cm visual analog scale; (4) the Quality of Life Scales (QOLS) (adults only). Independent variables that showed significant results using univariate tests underwent multiple logistic regression analysis. RESULTS: 227 patients were available for analysis. Mean duration of disease at time of assessment of outcome was 15 years (range 5.3-36.1). Univariate tests allowed 11 variables for disability, 9 for pain, 7 for overall well being, and 4 for QOL into the multivariate analysis. The best predictor of higher disability was the articular severity score (odds ratio, OR, 5.69) while antinuclear antibody positivity foretold less disability (OR 0.29). HLA-DR5 positivity conferred the greatest risk for pain (OR 3.34), while HLA-B5, DR3, and C3 were protective (OR 0.25, 0.28, 0.33, respectively). Early hand involvement was the strongest predictor of poorer overall well being (OR 8.75). Only the erythrocyte sedimentation rate was predictive of future QOL, but the model yielded a low C statistic (< 70%) and the OR 95% confidence limits were extreme (OR 9.77; 95% confidence interval, 1.22-77.8). CONCLUSION: Clinical and immunogenetic variables measurable within 6 months of onset of JRA can be used to predict future disability, pain, and well being. QOL appears more difficult to forecast, perhaps due to the multiple domains that make up this outcome. Further study is needed to identify other genetic and laboratory factors that predict outcome in JRA with greater precision.

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OBJECTIVE: To assess the long-term health outcomes and quality of life of patients with juvenile rheumatoid arthritis (JRA) using health and functional assessment questionnaires in 2 populations, one from the USA and one from Italy. METHODS: Patient eligibility criteria: (1) first examined in our units between 1958 and 1990 during the first 6 months after onset of symptoms, (2) diagnosis of JRA by the American College of Rheumatology criteria, (3) disease duration of at least 5 years at the time of assessment of outcome. Instruments used: (1) the Health Assessment Questionnaire (HAQ, short form, or childhood HAQ (CHAQ), and (2) Quality of Life Scales (QOLS, adults only). Eligible patients were identified by computer search and chart review and were then mailed a packet containing a consent/assent form and the assessment instruments. RESULTS: Of 346 patients who met the eligibility criteria were able to locate 301, and 290 verbally agreed to participate and were mailed packets. Signed consent and complete information were received from 227 of the 290 (78%), 178 from the USA and 49 from Italy. Mean duration of disease at the time of outcome assessment was 15 yrs. 127 had pauciarticular, 55 polyarticular, and 45 systemic onset disease. Mean and (median) scores of the outcomes are shown in the table. [table: see text] CONCLUSION: Long-term outcome, as assessed by the instruments used, is very favorable in most patients with JRA 5 years or more after onset of symptoms.

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