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Background: Insufficient support for balancing career and family responsibilities hinders retention of physician-scientists. Programs to improve retention of this important group of faculty are crucial. Understanding the experiences of program implementers is key to refining and improving program offerings. Methods: We conducted an interpretive, descriptive, and qualitative study as part of an ongoing evaluation of the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists (FRCS) awards. We conducted telephone interviews with 12 program directors representing all 10 US medical schools who received the Doris Duke funding in 2016. Results: Of the 12 participants, 10 were women (83.3%). Participating program directors perceived the FRCS award as capable of producing paradigmatic changes regarding how responsibilities at home and work in academic medicine are viewed and integrated by early-career faculty members. The main qualitative themes that captured directors' experiences implementing the program were as follows: (1) championing a new paradigm of support, (2) lessons learned while implementing the new paradigm, (3) results of the new paradigm, and (4) sustaining the paradigm. Conclusions: These findings may help to inform development of similar programs to retain and support the career progress of physician-scientists with extraprofessional caregiving responsibilities. The interviews illuminate ways in which the Doris Duke FRCS award has driven institutional culture change by normalizing discussion and prompted reassessment of extraprofessional challenges and how best to aid early-career faculty members in overcoming these challenges.

Objective. This report describes a new fatal syndrome observed in adolescent males at the initial presentation of diabetes mellitus. The features include hyperglycemic hyperosmolar coma complicated by a malignant hyperthermia-like picture with fever, rhabdomyolysis, and severe cardiovascular instability. Design. Case series. Setting. Pediatric intensive care units of 3 tertiary care facilities in the United States. Patients. Six adolescent males, 5/6 obese with acanthosis nigricans, 4/6 black. Results. Four of 6 patients died. Four of 6 patients did not have significant ketosis. Six of 6 patients had increased temperature after the administration of insulin. Conclusions. The underlying etiology of this syndrome remains unclear. Possibilities include an underlying metabolic disorder such as a fatty acid oxidation defect, an unrecognized infection, exposure to an unknown toxin, or a genetic predisposition to malignant hyperthermia. Evaluation for all these possibilities and empiric treatment with dantrolene should be considered for this type of patient until this syndrome is better characterized. Pediatrics 2003;111-1447-1452; diabetes mellitus, rhabdomyolysis, malignant hyperthermia, obesity. ABBREVIATIONS. DKA, diabetic ketoacidosis; HHNS, hyperglycemic hyperosmolar nonketotic syndrome; BG, blood glucose., Diabetes mellitus is one of the most common chronic disorders of childhood. It is rarely fatal at presentation. There are 2 well-described, life-threatening, acute metabolic complications of diabetes mellitus: diabetic [...]

O-linked glycosylation on Ser/Thr with single N-acetylglucosamine (O-GlcNAcylation) is a reversible modification of many cytosolic/nuclear proteins, regulated in part by UDP-GlcNAc levels. Transgenic (T) mice that overexpress GLUT1 in muscle show increased basal muscle glucose transport that is resistant to insulin stimulation. Muscle UDP-GlcNAc levels are increased. To assess whether GLUT4 is a substrate for O-GlcNAcylation, we translated GLUT4 mRNA (mutated at the N-glycosylation site) in rabbit reticulocyte lysates supplemented with [[sup.35]S]methionine. O-GlcNAcylated proteins were galactosylated and separated by lectin affinity chromatography; >20% of the translated GLUT4 appeared to be O-GlcNAcylated. To assess whether GLUT4 or GLUT4-associated proteins were O-GlcNAcylated in muscles, muscle membranes were prepared from T and control (C) mice labeled with UDP-[[sup.3]H]galactose and immunoprecipitated with anti-GLUT4 IgG (or nonimmune serum), and N-glycosyl side chains were removed enzymatically. Upon SDS-PAGE, several bands showed consistently two- to threefold increased labeling in T vs. C. Separating galactosylated products by lectin chromatography similarly revealed approximately threefold more O-GlcNAc-modified proteins in T vs. C muscle membranes. RL-2 immunoblots confirmed these results. In conclusion, chronically increased glucose flux, which raises UDP-GlcNAc in muscle, results in enhanced O-GlcNAcylation of membrane proteins in vivo. These may include GLUT4 and/or GLUT4-associated proteins and may contribute to insulin resistance in this model. glucose transporter 4; glucose transporter 4-associated proteins; O-linked glycosylation on serine/threonine with single N-acetylglucosamine of membrane proteins; transgenic mice overexpressing glucose transporter 1 in muscle; rabbit reticulocyte lysate

Objective: (1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder, which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. (2) Determine whether C-peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome. Methods: N = 44 (25F/19M) participants with genetically confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010 to 2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta-cell function was assessed by determination of C-peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C-peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C-peptide decline during an intervention trial. Results: 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C-peptide significantly decreased with increasing duration of diabetes mellitus (p < 0.0001); an optimal break point in C-peptide decline was identified to occur between 0.1 and 2.3 years after diabetes mellitus diagnosis. Twenty patients per group (active vs. control) were estimated to be needed to detect a 60% slowing of C-peptide decline during the first 2.3 years following diabetes diagnosis. Conclusion: C-peptide declines over time in Wolfram syndrome and could potentially be used as a marker of diabetes progression in interventional studies for Wolfram syndrome, especially within the first 2 years after diabetes diagnosis. 2022, 2, Downloaded fromr [ABSTRACT FROM AUTHOR]

GLUT-1 glucose transporter overexpression in muscle of transgenic mice minimizes insulin-induced glucose disposal while GLUT-4 overexpression in fat and muscle enhances whole body glucose release under hyperinsulinemic euglycemic clamp conditions. The degree of glucose transporter expression in fat and muscle can influence fuel metabolism and whole body glucose homeostasis.

Abstract Background Classically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease. Methods Gait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups. Results Across all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs= 0.564, p = 0.045) and dual task forward walking (rs= 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = −0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = −0.64, p = 0.03). Conclusions Quantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and/or brainstem abnormalities. Effective patient-centered treatment paradigms could benefit from a more complete understanding of the progression of motor and other neurological symptom presentation in individuals with WFS.

Abstract Background Wolfram syndrome (WFS) is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS) to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS). Methods A rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease). WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age). Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated. Results The WURS had high inter-rater reliability (ICCs>.93), moderate to high internal consistency reliability (Cronbach’s α = 0.78-0.91) and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (rs>.67, ps>.76, ps=-.86, p=.001). The WURS demonstrated acceptable content validity (Scale-Content Validity Index=0.83). Conclusions These preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS.

Ren, Jian-Ming, Nicole Barucci, Bess A. Marshall, Polly Hansen, Mike M. Mueckler, and Gerald I. Shulman. Transgenic mice overexpressing GLUT-1 protein in muscle exhibit increased muscle glycogenesis after exercise. Am J Physiol Endocrinol Metab 278: E588-E592, 2000.--The purpose of the present study was to determine the rates of muscle glycogenolysis and glycogenesis during and after exercise in GLUT-1 transgenic mice and their age-matched littermates. Male transgenic mice (TG) expressing a high level of human GLUT-1 and their nontransgenic (NT) littermates underwent 3 h of swimming. Glycogen concentration was determined in gastrocnemius and extensor digitorum longus (EDL) muscles before exercise and at 0, 5, and 24 h postexercise, during which food (chow) and 10% glucose solution (as drinking water) were provided. Exercise resulted in ~90% reduction in muscle glycogen in both NT (from 11.2 [+ or -] 1.4 to 2.1 [+ or -] 1.3 [micro]mol/g) and TG (from 99.3 [+ or -] 4.7 to 11.8 [+ or -] 4.3 [micro]mol/g) in gastrocnemius muscle. During recovery from exercise, the glycogen concentration increased to 38.2 [+ or -] 7.3 (5 h postexercise) and 40.5 [+ or -] 2.8 [micro]mol/g (24 h postexercise) in NT mice. In TG mice, however, the increase in muscle glycogen concentration during recovery was greater (to 57.5 [+ or -] 7.4 and 152.1 [+ or -] 15.7 [micro]mol/g at 5 and 24 h postexercise, respectively). Similar results were obtained from EDL muscle. The rate of 2-deoxyglucose uptake measured in isolated EDL muscles was 7- to 10-fold higher in TG mice at rest and at 0 and 5 h postexercise. There was no difference in muscle glycogen synthase activation measured in gastrocnemius muscles between NT and TG mice immediately after exercise. These results demonstrate that the rate of muscle glycogen accumulation postexercise exhibits two phases in TG: 1) an early phase (0-5 h), with rapid glycogen accumulation similar to that of NT mice, and 2) a progressive increase in muscle glycogen concentration, which differs from that of NT mice, during the second phase (5-24 h). Our data suggest that the high level of steady-state muscle glycogen in TG mice is due to the increase in muscle glucose transport activity. swimming; glucose transport; GLUT-1; glycogen

Hsieh, Po-Shiuan, Mary Courtney Moore, Bess Marshall, Michael J. Pagliassotti, Brian Shay, Dennis Szurkus, Doss W. Neal, and Alan D. Cherrington. The head arterial glucose level is not the reference site for generation of the portal signal in conscious dogs. Am. J. Physiol. 277 (Endocrinol. Metab. 40): E678-E684, 1999.--Experiments were performed on twelve 42-h-fasted, conscious dogs to determine whether the head arterial glucose level is used as a reference standard for comparison with the portal glucose level in bringing about the stimulatory effect of portal glucose delivery on net hepatic glucose uptake (NHGU). Each experiment consisted of an 80-min equilibration, a 40-min control, and two 90-min test periods. After the control period, somatostatin was given along with insulin (7.2 pmol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]; 3.5-fold increase) and glucagon (0.6 ng [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]; basal) intraportally. Glucose was infused intraportally (22.2 [micro]mol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]) and peripherally as needed to double the hepatic glucose load. In one test period, glucose was infused into both vertebral and carotid arteries ([HEAD.sub.G]; 22.2 [+ or -] 0.8 [micro]mol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]); in the other test period, saline was infused into the head arteries ([HEAD.sub.S]). One-half of the dogs received [HEAD.sub.G] first. When all dogs are considered, the blood arterial-portal glucose gradients (-0.52 [+ or -] 0.07 vs. -0.49 [+ or -] 0.03 mM) and the hepatic glucose loads (339 [+ or -] 14 vs. 334 [+ or -] 20 [micro]mol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]) were similar in [HEAD.sub.G] and [HEAD.sub.S]. NHGU was 24.1 [+ or -] 3.8 and 25.1 [+ or -] 4.6 [micro]mol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1], and nonhepatic glucose uptake was 46.1 [+ or -] 4.2 and 48.8 [+ or -] 7.0 [micro]mol [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1] in [HEAD.sub.G] and [HEAD.sub.S], respectively. The head arterial glucose level is not the reference standard used for comparison with the portal glucose level in the generation of the portal signal. liver; brain; liver nerve

Background: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. Methods: Individuals with genetically-confirmed WFS (n =19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. Results: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. Conclusions: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well. Trial Registration: Current Clinicaltrials.gov Trial NCT02455414. [ABSTRACT FROM AUTHOR]