BYPASS-OMA: Hypoglycemic Hyperinsulinemic Nesidioblastosis after Gastric Bypass Surgery-A Case Report and Review of the Literature.

This rare case vignette describes hypoglycemic, hyperinsulinemic nesidioblastosis in a female patient with prior Roux-en-Y gastric bypass. The patient presented with severe symptomatic hypoglycemia resistant to IV dextrose and diazoxide, requiring surgical resection. Traditional imaging found nonspecific findings, and biochemical analysis was inconsistent with insulinoma. A gallium-68 dotatate PET scan was utilized to successfully localize the tumor in the distal pancreas. She underwent laparoscopic resection of the distal pancreatic lesion with resolution of her symptoms and return to euglycemia. The histological evaluation confirmed the diagnosis of nesidioblastosis. Nesidioblastosis is a rare complication of bariatric surgery that may be more clinically relevant with rising prevalence of obesity. Diagnosis with conventional imaging modalities may be challenging; however, the dotatate PET scan may have high utility in detecting lesions. It is essential for clinicians to consider nesidioblastosis in the differential diagnosis of hyperinsulinemic hypoglycemic conditions and recognize there may be a link with increasing rates of bariatric surgery.

Long-term Outcomes of Children With Pediatric Feeding Disorders Treated in an Inpatient Multidisciplinary Program.

ABSTRACT: The purpose of this longitudinal observational study was to evaluate the effectiveness of a multidisciplinary inpatient treatment model for feeding disorders by analyzing long-term nutritional and health outcomes 12 months following discharge. Fifty patients completed the study. Average caloric intake by mouth as a percentage of goal for gastrostomy tube (GT)-dependent patients (n = 31) increased from pre-admit, week 1, and week 2 of the inpatient program (30%, 70%, and 84%, respectively), and was sustained from week 3 to 12-month follow-up (85% and 86%, respectively). Eighty-one percentage were discharged without GT support and 65% remained off GT support at 12 months. Oral supplement dependence for non-GT patients (n = 19) decreased from pre-admit, discharge, and 12-month follow-up (51%, 31%, and 19% of caloric intake, respectively). BMI z-scores improved during and after treatment. The present study demonstrated an effective approach for treatment of pediatric feeding disorders, including decreased reliance on oral supplementation and GT dependence.

Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia.

KEY POINTS: We hypothesized that hypoxia inducible factor 1α (HIF-1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time-dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF-1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild-type mice with CH. Conditional deletion of HIF-1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO2 , and there were no changes in the HVR in normoxic mice. HIF-1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH. ABSTRACT: Chronic hypoxia (CH) produces a time-dependent increase of resting ventilation and the hypoxic ventilatory response (HVR) that is called ventilatory acclimatization to hypoxia (VAH). VAH involves plasticity in arterial chemoreceptors and the CNS [e.g. nucleus tractus solitarius (NTS)], although the signals for this plasticity are not known. We hypothesized that hypoxia inducible factor 1α (HIF-1α), an O2 -sensitive transcription factor, is necessary in the NTS for normal VAH. We tested this in two mouse models using loxP-Cre gene deletion. First, HIF-1α was constitutively deleted in CNS neurons (CNS-HIF-1α-/- ) by breeding HIF-1α floxed mice with mice expressing Cre-recombinase driven by the calcium/calmodulin-dependent protein kinase IIα promoter. Second, HIF-1α was deleted in NTS neurons in adult mice (NTS-HIF-1α-/- ) by microinjecting adeno-associated virus that expressed Cre-recombinase in HIF-1α floxed mice. In normoxic control mice, HIF-1α deletion in the CNS or NTS did not affect ventilation, nor the acute HVR (10-15 min hypoxic exposure). In mice acclimatized to CH for 1 week, ventilation in hypoxia was blunted in CNS-HIF-1α-/- and significantly decreased in NTS-HIF-1α-/- compared to control mice (P < 0.0001). These changes were not explained by differences in metabolic rate or CO2 . Immunofluorescence showed that HIF-1α deletion in NTS-HIF-1α-/- was restricted to glutamatergic neurons. The results indicate that HIF-1α is a necessary signal for VAH and the previously described plasticity in glutamatergic neurotransmission in the NTS with CH. HIF-1α deletion had no effect on the increase in normoxic ventilation with acclimatization to CH, indicating this is a distinct mechanism from the increased HVR with VAH.

Provider Networks in the Neonatal Intensive Care Unit Associate with Length of Stay.

We strive to understand care coordination structures of multidisciplinary teams and to evaluate their effect on post-surgical length of stay (PSLOS) in the Neonatal Intensive Care Unit (NICU). Electronic health record (EHR) data were extracted for 18 neonates, who underwent gastrostomy tube placement surgery at the Vanderbilt University Medical Center NICU. Based on providers' interactions with the EHR (e.g. viewing, documenting, ordering), provider-provider relations were learned and used to build patient-specific provider networks representing the care coordination structure. We quantified the networks using standard network analysis metrics (e.g., in-degree, out-degree, betweenness centrality, and closeness centrality). Coordination structure effectiveness was measured as the association between the network metrics and PSLOS, as modeled by a proportional-odds, logistical regression model. The 18 provider networks exhibited various team compositions and various levels of structural complexity. Providers, whose patients had lower PSLOS, tended to disperse patient-related information to more colleagues within their network than those, who treated higher PSLOS patients (P = 0.0294). In the NICU, improved dissemination of information may be linked to reduced PSLOS. EHR data provides an efficient, accessible, and resource-friendly way to study care coordination using network analysis tools. This novel methodology offers an objective way to identify key performance and safety indicators of care coordination and to study dissemination of patient-related information within care provider networks and its effect on care. Findings should guide improvements in the EHR system design to facilitate effective clinical communications among providers.

The Usher Syndrome Type IIIB Histidyl-tRNA Synthetase Mutation Confers Temperature Sensitivity.

Histidyl-tRNA synthetase (HARS) is a highly conserved translation factor that plays an essential role in protein synthesis. HARS has been implicated in the human syndromes Charcot-Marie-Tooth (CMT) Type 2W and Type IIIB Usher (USH3B). The USH3B mutation, which encodes a Y454S substitution in HARS, is inherited in an autosomal recessive fashion and associated with childhood deafness, blindness, and episodic hallucinations during acute illness. The biochemical basis of the pathophysiologies linked to USH3B is currently unknown. Here, we present a detailed functional comparison of wild-type (WT) and Y454S HARS enzymes. Kinetic parameters for enzymes and canonical substrates were determined using both steady state and rapid kinetics. Enzyme stability was examined using differential scanning fluorimetry. Finally, enzyme functionality in a primary cell culture was assessed. Our results demonstrate that the Y454S substitution leaves HARS amino acid activation, aminoacylation, and tRNAHis binding functions largely intact compared with those of WT HARS, and the mutant enzyme dimerizes like the wild type does. Interestingly, during our investigation, it was revealed that the kinetics of amino acid activation differs from that of the previously characterized bacterial HisRS. Despite the similar kinetics, differential scanning fluorimetry revealed that Y454S is less thermally stable than WT HARS, and cells from Y454S patients grown at elevated temperatures demonstrate diminished levels of protein synthesis compared to those of WT cells. The thermal sensitivity associated with the Y454S mutation represents a biochemical basis for understanding USH3B.

Successful gastrostomy tube weaning program using an intensive multidisciplinary team approach.

OBJECTIVES: The present study evaluated the effectiveness of a multidisciplinary intensive inpatient model for gastrostomy tube (GT) weaning. METHODS: A retrospective chart review was completed on 30 GT-dependent children, ages 3.9 (±1.4) years, admitted to the inpatient feeding program (length of stay 19 days) from May 2009 to December 2011. Administered GT calories were decreased on admission by an average of 73% from home regimen. Patients were offered 3 meals and 2 to 3 snacks/day, including 3 intensive feeding therapy sessions (Monday to Friday), along with psychosocial support, nutrition guidance, and behavioral therapy. Daily calorie counts and weights were recorded. Patients returned for a postdischarge feeding evaluation at an average of 4 months and a clinic visit at 1 year. Data were analyzed using paired samples t tests. RESULTS: Before admission, patients received 69% (±25) of goal calories by GT and 22% (±19) of goal calories orally. During admission, average caloric intake by mouth as a percentage of goal increased during the course of weeks 1, 2, and 3 (68%, 77%, and 82%, respectively), with a statistically significant increase between weeks 1 and 2 (P = 0.001) and 1 and 3 (P = 0.011). At discharge, 90% had discontinued GT feedings. Average percent weight change during admission was 0.2% (±4). At 1 year follow-up, 83% remained successfully off GT feedings. CONCLUSIONS: Children who are GT dependent can be weaned off GT feedings during a 3-week admission using a multidisciplinary feeding model. The therapeutic gains were maintained at 1 year postdischarge.

Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells.

Mutations in the presenilin 1 (PS1) gene lead to early-onset Alzheimer's disease with the S170F mutation causing the earliest reported age of onset. Expression of this, and other PS1 mutations, in SH-SY5Y cells resulted in significant loss of cellular viability compared to control cells. Basal Ca2+ concentrations in PS1 mutants were never lower than controls and prolonged incubation in Ca2+ -free solutions did not deplete Ca2+ stores, demonstrating there was no difference in Ca2+ leak from endoplasmic reticulum (ER) stores in PS1 mutants. Peak muscarine-evoked rises of [Ca2+]i were variable, but the integrals were not significantly different, suggesting, while kinetics of Ca2+ store release might be affected in PS1 mutants, store size was similar. However, when Ca2+ -ATPase activity was irreversibly inhibited with thapsigargin, the S170F and ΔE9 cells showed larger capacitative calcium entry indicating a direct effect on Ca2+ influx pathways. There was no significant effect of any of the mutations on mitochondrial respiration. Amyloid ß(Aß(1-40)) secretion was reduced, and Aß(1-42) secretion increased in the S170F cells resulting in a very large increase in the Aß42/40 ratio. This, rather than any potential disruption of ER Ca2+ stores, is likely to explain the extreme pathology of this mutant.

Respiratory plasticity in response to changes in oxygen supply and demand.

Aerobic organisms maintain O(2) homeostasis by responding to changes in O(2) supply and demand in both short and long time domains. In this review, we introduce several specific examples of respiratory plasticity induced by chronic changes in O(2) supply (environmental hypoxia or hyperoxia) and demand (exercise-induced and temperature-induced changes in aerobic metabolism). These studies reveal that plasticity occurs throughout the respiratory system, including modifications to the gas exchanger, respiratory pigments, respiratory muscles, and the neural control systems responsible for ventilating the gas exchanger. While some of these responses appear appropriate (e.g., increases in lung surface area, blood O(2) capacity, and pulmonary ventilation in hypoxia), other responses are potentially harmful (e.g., increased muscle fatigability). Thus, it may be difficult to predict whole-animal performance based on the plasticity of a single system. Moreover, plastic responses may differ quantitatively and qualitatively at different developmental stages. Much of the current research in this field is focused on identifying the cellular and molecular mechanisms underlying respiratory plasticity. These studies suggest that a few key molecules, such as hypoxia inducible factor (HIF) and erythropoietin, may be involved in the expression of diverse forms of plasticity within and across species. Studying the various ways in which animals respond to respiratory challenges will enable a better understanding of the integrative response to chronic changes in O(2) supply and demand.