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Amyotrophic lateral sclerosis is a late-onset adult neurodegenerative disease, although there is mounting electrophysiological and pathological evidence from patients and animal models for a protracted preclinical period of motor neuron susceptibility and dysfunction, long before clinical diagnosis. The key molecular mechanisms linked to motor neuron vulnerability in amyotrophic lateral sclerosis have been extensively studied using transcriptional profiling in motor neurons isolated from adult mutant superoxide dismutase 1 mice. However, neonatal and embryonic motor neurons from mutant superoxide dismutase 1 mice show abnormal morphology and hyperexcitability, suggesting preceding transcriptional dysregulation. Here, we used RNA sequencing on motor neurons isolated from embryonic superoxide dismutase 1 G93A mice to determine the earliest molecular mechanisms conferring neuronal susceptibility and dysfunction known in a mouse model of amyotrophic lateral sclerosis. Transgenic superoxide dismutase 1 G93A mice expressing the spinal motor neuron homeobox HB9:green fluorescent protein reporter allowed unambiguous identification and isolation of motor neurons using fluorescence-activated cell sorting. Gene expression profiling of isolated motor neurons revealed transcriptional dysregulation in superoxide dismutase 1 G93A mice as early as embryonic Day 12.5 with the majority of differentially expressed genes involved in RNA processing and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-mediated glutamate receptor signalling. We confirmed dysregulation of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2, at transcript and protein levels, in embryonic superoxide dismutase 1 G93A mouse motor neurons and human motor neurons derived from amyotrophic lateral sclerosis patient induced pluripotent stem cells harbouring pathogenic superoxide dismutase 1 mutations. Mutant superoxide dismutase 1 induced pluripotent stem cell-derived motor neurons showed greater vulnerability to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-mediated excitotoxicity, consistent with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2 downregulation. Thus, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2 deficiency leading to enhanced α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor signalling, calcium influx, hyperexcitability, and chronic excitotoxicity is a very early and intrinsic property of spinal motor neurons that may trigger amyotrophic lateral sclerosis pathogenesis later in life. This study reinforces the concept of therapeutic targeting of hyperexcitability and excitotoxicity as potential disease-modifying approaches for amyotrophic lateral sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting motor neurons which shows sexual dimorphism in its incidence, age of onset, and progression rate. All steroid hormones, including androgens, estrogens, and progestogens, have been implicated in modulating ALS. Increasing evidence suggests that steroid hormones provide neuroprotective and neurotrophic support to motor neurons, either directly or via surrounding glial cell interactions, by activating their respective nuclear hormone receptors and initiating transcriptional regulatory responses. The SOD1G93A transgenic mouse also shows sex-specific differences in age of onset and progression, and remains the most widely used model in ALS research. To provide a more comprehensive understanding of the influences of steroid hormone signaling in ALS, we systemically characterized sex hormone receptor expression at transcript and protein levels, cellular localization, and the impact of disease course in lumbar spinal cords of male and female SOD1G93A mice. We found that spinal motor neurons highly express nuclear androgen receptor (AR), estrogen receptor (ER)α, ERβ, and progesterone receptor with variations in glial cell expression. AR showed the most robust sex-specific difference in expression and was downregulated in male SOD1G93A mouse spinal cord, in association with depletion in 5α-reductase type 2 isoform, which primarily metabolizes testosterone to 5α-dihydrotestosterone. ERα was highly enriched in reactive astrocytes of SOD1G93A mice and ERβ was strongly upregulated. The 5α-reductase type 1 isoform was upregulated with disease progression and may influence local spinal cord hormone levels. In conclusion, steroid hormone receptor expression is dynamic and cell-type specific in SOD1G93A mice which may provide targets to modulate progression in ALS., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

TDP-43 is a major protein component of pathological neuronal inclusions that are present in frontotemporal dementia and amyotrophic lateral sclerosis. We report that TDP-43 plays an important role in dendritic spine formation in the cortex. The density of spines on YFP+ pyramidal neurons in both the motor and somatosensory cortex of Thy1-YFP mice, increased significantly from postnatal day 30 (P30), to peak at P60, before being pruned by P90. By comparison, dendritic spine density was significantly reduced in the motor cortex of Thy1-YFP::TDP-43A315T transgenic mice prior to symptom onset (P60), and in the motor and somatosensory cortex at symptom onset (P90). Morphological spine-type analysis revealed that there was a significant impairment in the development of basal mushroom spines in the motor cortex of Thy1-YFP::TDP-43A315T mice compared to Thy1-YFP control. Furthermore, reductions in spine density corresponded to mislocalisation of TDP-43 immunoreactivity and lowered efficacy of synaptic transmission as determined by electrophysiology at P60. We conclude that mutated TDP-43 has a significant pathological effect at the dendritic spine that is associated with attenuated neural transmission., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Opioid analgesics misuse is a significant military health concern recognized as a priority issue by military leadership. Opioids are among those most commonly prescribed medications in the military for pain management. The military has implemented opioid risk mitigation strategies, including the Sole Provider Program and the Controlled Drug Management Analysis and Reporting Tool, which are used to identify and monitor for risk and misuse. However, there are substantial opportunities to build on these existing systems to better ensure safer opioid prescribing and monitor for misuse. Opioid risk mitigation strategies implemented by the civilian sector include establishing clinical guidelines for opioid prescribing and prescription monitoring programs. These strategies may help to inform opioid risk mitigation in the military health system. Reducing the risk of opioid misuse and improving quality of care for our Warfighters is necessary. This must be done through evidence-based approaches with an investment in research to improve patient care and prevent opioid misuse as well as its sequelae., (Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.)

Background: Racial disparities in hypertension control are well documented, yet the contribution of providers to these disparities remains unclear. The objective of this study was to examine whether provider management of uncontrolled hypertension differed by patient race., Methods: In a retrospective cohort of 16,881 hypertensive adults in six academic primary care practices from 1/2004 to 12/2006, we evaluated hypertension control in black vs. white patients according to expert guidelines and, among those with uncontrolled hypertension, whether antihypertensive drugs were intensified by providers. Generalized estimating equations accounted for clustering and adjusted sequentially and additively for patient, provider, and practice characteristics, as well as health-care utilization and antihypertensive medication potency., Results: Black patients' visits (55.5% of 132,730 visits) had a higher unadjusted odds (1.63, 95% confidence interval (CI) 1.57-1.69) of uncontrolled hypertension than white patients' visits; the fully adjusted odds ratio remained significant (1.40, CI 1.33-1.48, P < 0.001). Among 66,327 visits with uncontrolled hypertension, no intensification of antihypertensive drugs was less likely for blacks' visits before adjustment (0.80, CI 0.76-0.83, P < 0.001) but moderated in the fully adjusted model (adjusted odds ratio 0.93, CI 0.87-0.99, P < 0.05) compared with whites' visits. Accounting for provider race, intensification was more likely at black patients' visits compared with white patients' visits., Conclusions: In our study, black patients had poorer hypertension control, and providers were more likely to intensify antihypertensive drugs at visits of black compared with white patients as appropriate. These data suggest that more research is needed to understand racial disparities in hypertension control.

Objective: To evaluate HIV quality of care using a symptom-based, patient-centered framework., Methods: An expert panel developed 13 quality indicators for three common symptoms: cough with fever and/or shortness of breath; severe or persistent diarrhea; and significant weight loss. A nationally representative probability sample of HIV-infected adults was interviewed between 1996 and 1997., Participants: were asked about the presence and severity of HIV symptoms during the preceding 6 months, and care received. Variation in adherence to the indicators was assessed by symptom type and patient characteristics., Results: In all, 2864 (71%) patients completed interviews and 920 reported being at least moderately bothered with one of the three symptoms. Of these, 41, 74, and 65% of patients with a symptom of cough, weight loss, or diarrhea, respectively, reported receiving all indicated care. Performance was better for patients with more severe HIV, measured as a CD4 cell count <50 cells/microliter, compared with those with less severe HIV, measured as CD4 cell count >500 cells/microliter (43% versus 60%; P = 0.02). Uninsured patients had worse performance than Medicare patients (45% versus 62%; P = 0.04), but care did not differ by patient's age, gender, ethnicity, HIV risk factor, providers' HIV patient load, or region. Only CD4 count remained significantly associated with performance in the multivariate analyses., Conclusions: Symptom-based quality indicators may provide a useful supplement to conventional measures. Patients with HIV reported substantial underuse of services for common, burdensome symptoms. Although adherence to quality indicators was better for patients with more advanced HIV disease, many still received suboptimal care. Vulnerable patient groups generally did not receive worse quality of care, suggesting that symptom-based measures of quality may measure domains that are distinct from those captured by conventional indicators.

We examined the effect of drug treatment in 1996 on repeated (> or =2) emergency department visits and hospitalization in 1997 in a cohort of New York State Medicaid-enrolled human immunodeficiency virus (HIV)-positive and HIV-negative drug users. In HIV-positive drug users, the adjusted odds of repeated emergency department visits were increased for those receiving no long-term treatment (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.04-2.75), whereas the adjusted odds for those receiving methadone treatment and those receiving drug-free treatment for > or =6 months did not differ. The adjusted odds of hospitalization in the HIV-positive group were higher for those receiving long-term methadone treatment (OR, 1.69; 95% CI, 1.14-2.55) and for those receiving no long-term treatment (OR, 1.91; 95% CI, 1.29-2.88), compared with those receiving drug-free treatment. In the HIV-negative group, these associations were similar but weaker. For both HIV-positive and HIV-negative drug users, long-term drug-free treatment was at least as effective as long-term methadone treatment in reducing use of services indicative of poorer access to care and/or poorer health.

Poor adherence to antiretroviral treatment regimens has serious consequences for human immunodeficiency virus-infected patients, including failure to prevent viral replication and an increased risk of developing viral resistance. Recent data suggest that the level of medication adherence required for optimal treatment effectiveness is extremely high. Treatment adherence can be measured by use of a variety of methods, including patients' self-reports, pharmacy-based approaches, pill counts, and electronic monitoring. However, these measures of adherence have different strengths and weaknesses in regard to practical application and identifying deficient adherence. All patients receiving antiretroviral therapy require support to insure a high level of treatment adherence, but the evidence about effective interventions is limited. Emerging evidence suggests adherence interventions should employ a multidisciplinary effort involving health care providers, social support networks, family, and friends. Although such programs will require a substantial investment in terms of time and energy, the rewards associated with optimal treatment adherence are worth the effort.

Rivulus marmoratus is the only known vertebrate with obligate, synchronous hermaphroditic fertilization. Males can be experimentally induced in the laboratory and are rare or absent in most populations, but at the isolated Twin Cays, Belize, locality, males are relatively abundant. At this locality, evidence of outcrossing has been documented in this otherwise automictic cloning species. Phylogenetic analysis of restriction sites and sequence characters revealed that all Florida and Belize western Caribbean populations (including Twin Cays) are phyletically indistinguishable yet divergent from eastern populations in Brazil and the Bahamas. Further, these western lineages shared a common ancestor more recently than all other populations. Therefore, the Twin Cays population is not a remnant ancestral outcrossing population. Outcrossing is suspected to have evolved as a phenotypically plastic character, and its expression in R. marmoratus may be dormant unless triggered by some ecological factor that is not well understood., (© 1999 The Society for the Study of Evolution.)

Osteoporosis-associated fractures are a major public health problem in the United States. Although clinicians and policy groups have advocated estrogen replacement therapy and other clinical measures to prevent osteoporosis, few studies have assessed whether these measures are being adopted by physicians in practice. The purpose of this study is to evaluate physicians' use of osteoporosis prevention measures and to assess the impact of physician specialty and practice setting on osteoporosis prevention performance. A survey of nearly 300 physicians was carried out in a large metropolitan area. Gynecologists, general internists, and cardiopulmonary specialists were included from one of three practice settings: fee-for-service private practice, full-time academic medicine, or a large health maintenance organization. Most physicians, regardless of clinical specialty or practice setting, report that they advocate exercise and calcium supplementation. Few physicians prescribe estrogen replacement therapy (ERT) for the majority of their postmenopausal patients. Although there are minimal differences among the three types of practice settings examined, ERT varies markedly by clinical specialty. Of the gynecologists surveyed, 37% report prescribing ERT for the majority of their postmenopausal patients to prevent osteoporosis compared to only 7 and 5% of general internists and cardiopulmonary specialists, respectively (chi 2 = 45.3, p less than 0.0001). Although the efficacy of exercise and calcium supplementation to prevent osteoporotic fractures has not been well established, these measures are commonly advocated by both generalists and subspecialists. Although gynecologists are significantly more likely to prescribe ERT to prevent osteoporosis than the other clinical specialists, in general very few physicians prescribe ERT for most postmenopausal patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Extensive variation in the number of metacentric chromosomes exists among populations of the viviparous goodeid fish, Ilyodon furcidens, in the Río Coahuayana basin of south central Mexico (states of Colima and Jalisco). The variation can be divided, somewhat arbitrarily, into four "cytotypes" with 0-2, 0-4, 6 and 10-16 metacentrics. Of these, the first, shared with the closely adjacent Río Armería and similar to other species of Ilyodon, is probably ancestral. The wholly non-Robertsonian nature of the variation and its extent appear to be unprecedented among teleosts, but its uniqueness is difficult to evaulate because fish chromosome data in general may be biased toward both monomorphism and Robertsonian variation. Variation is evident with all cytotypes but has been well characterized for only a single population of the 0-4M cytotype. That population, unlike most of the others, consists of two interbreeding morphs which differ in mouth width. The variation is heterogeneously distributed between the morphs; the significance of this observation is not yet clear. The distribution of the cytotypes is approximately clinal with respect to the number of metacentric chromosomes. Although the cline may be a direct response to some gradient in selection intensity, the possibility that it is the result of secondary contact of previously isolated populations, fostered by tributary transfer, is real. Allozyme comparisons reveal minimal genic divergence among the cytotypes. There are no fixed allelic differences, and the average unbiased genetic distance between the two extreme cytotypes is 0.042. Gene diversity analysis indicates that an average of less than 3% of the total variation (H T = 0.072) is partitioned among cytotypes; about 24% is partitioned among populations within cytotypes. Genic and chromosomal divergence in Ilyodon are clearly uncoupled. Laboratory F 1 , backcross, and F 2 intercytotype hybrids are fully viable, and are indistinguishable in fertility from our stocks derived from single populations. F 3 intercytotype hybrids are also fully viable but have not yet been tested for fertility. This suggests that, during the course of chromosomal evolution, single rearrangement heterozygotes were not appreciably negatively heterotic, even though the rearrangements are probably pericentric inversions. The combined data suggest that the chromosome rearrangements, even in multiple form, do not function as significant isolating mechanisms. Chromosomal evolution in Ilyodon, though quite marked, has apparently not fostered speciation., (© 1985 The Society for the Study of Evolution.)