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Background Necrotizing meningoencephalitis (NME, aka Pug dog encephalitis) is an inflammatory brain condition associated with advanced disease at initial presentation, rapid progression, and poor response to conventional immunomodulatory therapy. Hypothesis/objectives That genetic risk for NME, defined by a common germline DNA haplotype located on chromosome 12, is associated with altered blood cytokine concentrations and leukocyte subsets in asymptomatic Pugs. Animals Forty Pug dogs asymptomatic for NME from a hospital sample. Methods Prospective observational cohort study, including germline genome-wide genotyping, plasma cytokine determination by multiplexed profiling, and leukocyte subset characterization by flow cytometric analysis. Results Seven (18%) dogs were high risk, 10 (25%) medium risk, and 23 (58%) low risk for NME, giving a risk haplotype frequency of 30%. High and medium risk Pugs had significantly lower proportion of CD4+ T cells (median 22% [range, 7.3%-38%] vs 29% [range, 16%-41%], P = .03) and higher plasma IL-10 concentrations than low-risk Pugs (median 14.11 pg/mL [range, 9.66-344.19 pg/mL] vs 12.21 pg/mL [range, 2.59-18.53 pg/mL], P = .001). No other variables were significantly associated with the NME haplotype-based risk. Conclusions and clinical importance These data suggest an immunological underpinning to NME and a biologic rationale for future clinical trials that investigate novel diagnostic, preventative, and therapeutic strategies for this disease.

COVID-19 has caused global dramatic change in medical practices including the introduction of temporary screening and assessment areas outside the footprint of the main hospital structures. Following the initial surge of patients with novel coronavirus (2019-nCoV) in the United States, our medical center rapidly designed and constructed an alternative assessment and treatment site in a converted parking garage deck for emergency department patients with suspected or confirmed 2019-nCoV. During the first month after opening, 651 patients were treated in this alternative assessment area including 54 patients who tested positive for 2019-nCoV. This accounted for 55% of the 98 patients with confirmed novel coronavirus (2019-nCoV) who were treated in our ED. This report provides a blueprint for the necessary steps, materials, labor needs and barriers, both anticipated and unanticipated, to rapidly construct an alternative ED treatment site during a pandemic.

Background Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings. Methods The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data. Results We present 12 participants that illustrate how clinical practices such as phenotype‐driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses. Conclusion These examples demonstrate that when a diagnosis is elusive, an iterative patient‐specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.

GABAA receptors containing α5 subunits (GABAAα5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABAAα5–deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABAAα5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABAAα5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl-N-[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human α5–containing GABAA receptors with a Ki of 7.9 nM, and showed functionally selective GABAAα5 NAM activity for GABA-induced Cl− channel activity with a maximum 44.4% inhibition and an EC50 of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1–20 mg/kg) dose-dependently occupied hippocampal GABAAα5 in a range of 40%–90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3–20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)–induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABAAα5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.

Family medicine is redefining itself in the wake of the Future of Family Medicine Project, the move to the Patient-Centered Medical Home, and the 2010 Patient Protection and Affordable Care Act's emphasis on primary care. This effort has included representing family doctors as physicians who "care for the whole person" and who "specialize in you." Many patients believe that whole person care involves attention to spirituality and wish to share their beliefs in the medical encounter. This national survey investigated whether a random sample of family medicine residents were willing to address spirituality upon patient request. With varying degrees of willingness, most doctors said that they would discuss patient beliefs if asked. Denominational preference, residency training in addressing spirituality, and self-rated spirituality were all predictive of the strength of reported willingness. These results indicate that training in addressing spirituality may create residents more likely to discuss the topic in clinical practice.

Patients believe that spirituality informs health; frequently, they wish to share their beliefs with physicians. Although a large number of physicians believe it their responsibility to be aware of patient beliefs, many do not address spirituality because they do not believe it their role to do so. These physicians would perhaps feel differently if presented with evidence that associated spirituality with positive health outcomes. This national sample of family medicine residents were asked if, presented with evidence that spirituality was associated with improved outcomes, they would be more likely to initiate discussions of spirituality with patients. To varying degrees, most residents agreed that they would be more willing to initiate spirituality discussions if presented with good evidence. Geographic region of training, religious preference, and Spiritual Well-Being Scale quartile predicted both strength of agreement and whether a resident would be as responsive to spirituality oriented research as to investigations of traditional therapeutic modalities. Although residents indicated that they would be more responsive to publications on traditional medical therapies, familiarity with the spirituality literature as part of a residency educational curriculum may help break down barriers to addressing this issue with patients.

In this paper we analyse the possibility that the early hominin Ardipithecus ramidus had vocal capabilities far exceeding those of any extant non-human primate. We argue that erect posture combined with changes in craniofacial morphology, such as reduced facial and jaw length, not only provide evidence for increased levels of pro-sociality, but also increased vocal ability. Reduced length of the face and jaw, combined with a flexed cranial base, suggests the larynx in this species was situated deeper in the neck than in chimpanzees, a trait which may have facilitated increased vocal ability. We also provide evidence that Ar. ramidus, by virtue of its erect posture, possessed a degree of cervical lordosis significantly greater than chimpanzees. This is indicative of increased mobility of the larynx within the neck and hence increased capacity to modulate vocalisations. In the paleoanthropological literature, these changes in early hominin skull morphology have to date been analysed in terms of a shift in mating and social behaviour, with little consideration given to vocally mediated sociality. Similarly, in the literature on language evolution there is a distinct lacuna regarding links between craniofacial correlates of social and mating systems and vocal ability. These are surprising oversights given that pro-sociality and vocal capability require identical alterations to the common ancestral skull and skeletal configuration. We therefore propose a model which integrates data on whole organism morphogenesis with evidence for a potential early emergence of hominin socio-vocal adaptations. Consequently, we suggest vocal capability may have evolved much earlier than has been traditionally proposed. Instead of emerging in the Homo genus, we suggest the palaeoecological context of late Miocene and early Pliocene forests and woodlands facilitated the evolution of hominin socio-vocal capability. We also propose that paedomorphic morphogenesis of the skull via the process of self-domestication enabled increased levels of pro-social behaviour, as well as increased capacity for socially synchronous vocalisation to evolve at the base of the hominin clade.

To further our understanding of the consequences of training in recovery principles and practices, this study examined ACT team workers' responses to a state-wide recovery training initiative. Analysis of trainees' comments revealed ten themes expressing endorsement of or difficulties with recovery-oriented practices. Trainees' comments supporting a recovery orientation described service recipients in holistic terms and described using various techniques to attain "client-centered" goals. Recovery-oriented tasks that posed dilemmas for trainees were: reconciling system-centered goals with recipients' goals, establishing collaborative relationships with recipients, and using a recovery orientation with recipients who are in crisis and/or who "don't admit to being mentally ill."

Patients with pancreatic tumors that induce hypoglycemia present with a myriad of symptoms. Laboratory testing can frequently result in data challenging to the clinician to confirm the biochemical diagnosis. Proinsulin, in addition to insulin levels, may be essential in evaluating and diagnosing an insulinoma. The objective of this case report is to demonstrate the potential importance of proinsulin levels in the evaluation of tumor-induced hypoglycemia. We report a 49-year-old woman with an unusual clinical presentation. Unlike many patients with tumor-induced hypoglycemia, her fasting glucose levels were fairly unimpressive, her insulin levels were undetectable during a prolonged fast, and she had elevated proinsulin levels. The inpatient fast was remarkable for levels of serum glucose 53 mg/dl or higher, a serum insulin

Aim This study evaluated a framework for nursing managers which entailed supporting and challenging participants to critically analyse the effectiveness of their workplace behaviours in facilitated discussion groups using context-laden real-life scenarios. Background Leadership development in nursing managers has been shown to reduce burnout and promote workplace satisfaction. Method Ninety per cent of nursing managers (n = 63) employed in the organisation participated in the study. Data relating to burnout, workplace satisfaction and leadership practices were collected prior to and after participation in the support and challenge framework. Qualitative feedback was sought through a survey administered at follow-up. Result Nursing Unit Managers were significantly less satisfied in their intrinsic domain of workplace satisfaction at follow-up. Qualitative feedback indicated that participants experienced benefits related to networking, personal development and role development. Conclusion The experience of critiquing and challenging leadership when shared with peers who practice in a similar context was qualitatively reported as beneficial and valuable, in spite of a decrease in workplace satisfaction. Implications for nursing management Nursing manager's leadership development is a continuous process. Supporting and challenging nursing managers is likely to generate uncertainty related to self and role. The sharing and testing of this uncertainty with peers is welcomed and warrants further exploration.

Paratuberculosis progresses more quickly in young red deer than in sheep or cattle. This study describes the clinical, immunological and pathological changes over a 50-week period in fourteen 4-month-old red deer that received heavy oral challenge withMycobacterium aviumsubsp.paratuberculosis(MAP). At 4 and 12 weeks post challenge they were anaesthetized and a section of jejunal lymph node was surgically removed for culture, histopathology, and genetic studies. All 14 deer became infected, none were clinically affected, and they had varying degrees of subclinical disease when killed at week 50. Week 4 biopsies showed no paratuberculosis lesions, but MAP was cultured from all animals. At weeks 12 and 50 histopathological lesions ranged from mild to severe with corresponding low-to-high antibody titres, which peaked at 12–24 weeks. IFN-γresponses peaked at 8–15 weeks and were higher in mildly affected animals than in those with severe lesions.

The KCNQ (Kv7) family of voltage gated ion channels conduct a number of hyperpolarising currents in various tissue types, including the heteromultimeric KCNQ2/3 M-current found in sensory neurones. Cell lines constructed using constitutive expression vectors to stably transfect KCNQ2/3, KCNQ4, and KCNQ3/5 genes gave acceptable performance when using rubidium efflux methodology. However, expression levels within the cell population were found to be variable when assessed using conventional electrophysiology. Cell morphology changed during passage and the cell lines were unsuitable for automated electrophysiology recording. Using RheoSwitch™ inducible vector technology we have created new stable cell lines where the production of ion channel can be closely controlled by addition of an inducer agent. Putative clones were screened using IonWorks® Quattro™ recording in single hole PatchPlate™ mode. For each of the three cell lines, clones were identified displaying more than 60% of the cells having greater than 0.5nA of current. The performance of the clones in single hole mode was suitable for progression to Population Patch Clamp™ (PPC) mode recording. Each cell line displayed acceptable seal properties and current amplitudes, KCNQ2/3 26±5 MΩ, 0.77±0.19 nA (n=250); KCNQ4 112±49 MΩ, 0.44±0.07 nA (n=372) and KCNQ3/5 159±44 MΩ, 0.84±0.50 nA (n=124). In addition, each cell line each cell line displayed the appropriate pharmacology for regitabine, linopridine, XE991, TEA and bepridil. The cell lines are suitable for compound screening and selectivity profiling using automated and conventional electrophysiology.

The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.

An estimated 10% to 20% of women develop postpartum depression (PPD) within 6 months after delivery, and the rate may exceed 25% in those having a previous episode. More than half of women with PPD remain symptomatic after 1 year. Because PPD may be underdiagnosed-as many believe to be the case-a cross-sectional questionnaire-based survey concerning screening practices was undertaken in 298 members of the Washington Academy of Family Physicians who regularly saw postpartum women and children less than 12 months of age. Except for the timing, the diagnostic criteria for PPD were identical to those for major depression. Slightly more men than women were questioned. Respondents had an average age of 44 years. Most of the participants worked in group practices. They had been out of residency for 12 years on average. Nearly one third of physicians always screened for PPD, and another 40% often screened women at routine postpartum gynecologic visits. Only approximately 6% of respondents never screened for PPD. Nearly half the physicians screened for PPD at well-child visits. Approximately 30% of physicians who did screen for PPD used a validated screening tool, most often a validated clinical interview. The most popular questionnaire-type screening tool was the Beck Depression Inventory. Most respondents had received some type of formal training in PPD. In general, the physicians regarded PPD as a common, serious, and treatable illness. On multivariate analysis, factors that were significantly associated with more frequent screening included being female, training in PPD during residency, training through medical literature, agreement on the importance of screening for PPD, and rejection of the idea that screening takes too much effort. Training in PPD, using a simple validated screening tool, should be a routine part of the curriculum in all family medicine residency programs. PPD should be presented as a common, readily diagnosed, and treatable disorder.

PURPOSE: To revise the American Joint Committee on Cancer staging system for breast carcinoma. MATERIALS AND METHODS: A Breast Task Force submitted recommended changes and additions to the existing staging system that were (1) evidence-based and/or consistent with widespread clinical consensus about appropriate diagnostic and treatment standards and (2) useful for the uniform accrual of outcome information in national databases. RESULTS: Major changes included the following: size-based discrimination between micrometastases and isolated tumor cells; identifiers to indicate usage of innovative technical approaches; classification of lymph node status by number of involved axillary lymph nodes; and new classifications for metastasis to the infraclavicular, internal mammary, and supraclavicular lymph nodes. CONCLUSION: This revised staging system will be officially adopted for use in tumor registries in January 2003.

Topotecan (SKF 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelosuppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (+/- 6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (+/- 1.1)h. Lactone hydrolysis and renal excretion were the major routes of elimination.(ABSTRACT TRUNCATED AT 250 WORDS)

NUDC is a highly conserved protein important for nuclear migration and viability in Aspergillus nidulans. Mammalian NudC interacts with Lis1, a neuronal migration protein important during neocorticogenesis, suggesting a conserved mechanism of nuclear movement in A. nidulans and neuronal migration in the developing mammalian brain (S. M. Morris et al., 1998). To further investigate this possibility, we show for the first time that NudC, Lis1, and cytoplasmic dynein intermediate chain (CDIC) colocalize at the microtubule organizing center (MTOC) around the nucleus in a polarized manner facing the leading pole of cerebellar granule cells with a migratory morphology. In neurons with stationary morphology, NudC is distributed throughout the soma and colocalizes with CDIC and tubulin in neurites as well as at the MTOC. At the subcellular level, NudC, CDIC, and p150 dynactin colocalize to the interphase microtubule array and the MTOC in fibroblasts. The observed colocalization is confirmed biochemically by coimmunoprecipitation of NudC with CDIC and cytoplasmic dynein heavy chain (CDHC) from mouse brain extracts. Consistent with its expression in individual neurons, a high level of NudC is detected in regions of the embryonic neocortex undergoing extensive neurogenesis as well as neuronal migration. These data suggest a biochemical and functional interaction of NudC with Lis1 and the dynein motor complex during neuronal migration in vivo.

Seventeen amide and urea derivatives of bromal and dichloroacetaldehyde and one brominated derivative of butyl acrylamide were synthesized and their physical constants determined. These compounds were subjected to tests for antifungal activity toward Trichophyton rubrum, Microsporum gypsum , and Aspergillus niger . All but one of the bromal compounds studied showed fungus-inhibiting properties; of the dichloroacetaldehyde derivatives, however, only the acrylamide and methacrylamide derivatives indicated activity. Total halogen content and terminal halogen groups appeared to be factors in enhancing the antifungal activity.

High speed cinefluorographic studies were performed on anesthetized primates during graded, experimental blunt impacts of the head or chest. Cineframe data were analyzed frame by frame to identify dynamic anatomic movement patterns during each injury. The results indicate that the brain and heart undergo significant displacements within the first few milliseconds (ms) post-impact and these transient interior motions were correlated with physiologic and pathologic changes as well as impact force and deceleration.

The advent of high-throughput electrophysiology utilizing Population Patch Clamp™ (PPC) technology has allowed the screening of large compound libraries against ion channels representing novel targets in a variety of disease states. Here we report the design and implementation of an assay enabling the screening of 56,000 compounds against human TASK-3, a member of the two-P potassium channel family.cDNA corresponding to the channel of interest was transfected into HEK-293 cells and a stably-expressing clone selected. Ion channel pharmacology was subsequently validated using Ruthenium Red, Lidocaine, Bupivicaine, Quinidine & pH, with all 5 standard inhibitors giving values within two-fold of reported literature values.The biophysical properties of TASK-3 prevents the use of conventional methods of leak calculation, however, given the relatively low seal resistance routinely seen when using IonWorks® platforms in a PPC™ mode, some form of leak correction must be applied. Currents were recorded at 0mV in order to remove any effect of leak and a final addition of a supramaximal concentration of Ruthenium Red was used in order to calculate a current window from which to base the efficacy of compounds on.Assays were performed at pH 7 (EC75) in order to screen for potentiators as well as inhibitors. Data derived from the voltage step to 0mV was analysed using Genedata. Inhibitory compounds showing 150% of control were selected, giving a hit rate of 5%.Using the approaches detailed above, this assay has provided a robust screening platform for large compound collections and could easily be configured for screening other channels where leak subtraction cannot be applied.