Quantitative and Qualitative Changes in Peripheral Chemoreceptor Activity in Preterm Infants.

Rationale: Preterm infants are at risk for ventilatory control instability that may be due to aberrant peripheral chemoreceptor activity. Although term infants have increasing peripheral chemoreceptor contribution to overall ventilatory drive with increasing postnatal age, how peripheral chemoreceptor contribution changes in preterm infants with increasing postmenstrual age is not known. Objectives: To evaluate peripheral chemoreceptor activity between 32 and 52 weeks postmenstrual age in preterm infants, using both quantitative and qualitative measures. Methods: Fifty-five infants born between 24 weeks, 0 days gestation and 28 weeks, 6 days gestation underwent hyperoxic testing at one to four time points between 32 and 52 weeks postmenstrual age. Quantitative [Formula: see text] decreases were calculated, and qualitative responses were categorized as apnea, continued breathing with a clear reduction in [Formula: see text], sigh breaths, and no response. Measurements and Main Results: A total of 280 hyperoxic tests were analyzed (2.2 ± 0.3 tests per infant at each time point). Mean peripheral chemoreceptor contribution to ventilatory drive was 85.2 ± 20.0% at 32 weeks and 64.1 ± 22.0% at 52 weeks. Apneic responses were more frequent at earlier postmenstrual ages. Conclusions: Among preterm infants, the peripheral chemoreceptor contribution to ventilatory drive was greater at earlier postmenstrual ages. Apnea was a frequent response to hyperoxic testing at earlier postmenstrual ages, suggesting high peripheral chemoreceptor activity. A clearer description of how peripheral chemoreceptor activity changes over time in preterm infants may help explain how ventilatory control instability contributes to apnea and sleep-disordered breathing later in childhood. Clinical trial registered with www.clinicaltrials.gov (NCT03464396).

Impact of routine surveillance biopsy intensity on the diagnosis of moderate to severe cellular rejection and survival after pediatric heart transplantation.

Data are lacking on RSB intensity and outcomes after pediatric heart transplantation. PHTS centers received a survey on RSB practices from 2005 to present. PHTS data were obtained for 2010-2013 and integrated with center-matched survey responses for analysis. Survey response rate was 82.6% (38/46). Centers were classified as low-, moderate-, and high-intensity programs based on RSB frequency (0-more than 8 RSB/y). RSB intensity decreased with increasing time from HT. Age at HT impacted RSB intensity mostly in year 1, with little to no impact in later years. Most centers have not replaced RSB with non-invasive methods, but many added ECHO and biomarker monitoring. Higher RSB intensity was not associated with decreased 4-year mortality (P=.63) or earlier detection of moderate to severe (ISHLT grade 2R/3R) cellular rejection (RSBMSR) in the first year (P=.87). First-year RSBMSR incidence did not differ with intensity or age at HT. Significant variability exists in RSB intensity, but with no impact on timing and incidence of RSBMSR or 4-year mortality. Reduction in RSB frequency may be safe in certain patients after pediatric HT.

Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury.

OBJECTIVE: To evaluate the clinical effectiveness of bolus-dose fentanyl and midazolam to treat episodic intracranial hypertension in children with severe traumatic brain injury. DESIGN: Retrospective cohort. SETTING: PICU in a university-affiliated children's hospital level I trauma center. PATIENTS: Thirty-one children 0-18 years of age with severe traumatic brain injury (Glasgow Coma Scale score of ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic intracranial hypertension. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The area under the curve from high-resolution intracranial pressure-time plots was calculated to represent cumulative intracranial hypertension exposure: area under the curve for intracranial pressure above 20 mm Hg (area under the curve-intracranial hypertension) was calculated in 15-minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic intracranial hypertension. Our primary outcome measure, the difference between predrug and postdrug administration epochs (Δarea under the curve-intracranial hypertension), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism, and time after injury; time after injury correlated with Δarea under the curve-intracranial hypertension. In a mixed-effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, intracranial hypertension increased after administration of fentanyl and/or midazolam (overall aggregate mean Δarea under the curve-intracranial hypertension = +17 mm Hg × min, 95% CI, 0-34 mm Hg × min; p = 0.04). The mean Δarea under the curve-intracranial hypertension increased significantly after administration of high-dose fentanyl (p = 0.02), low-dose midazolam (p = 0.006), and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age-dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean Δarea under the curve-cerebral perfusion pressure). CONCLUSIONS: Bolus dosing of fentanyl and midazolam fails to reduce the intracranial hypertension burden when administered for episodic intracranial hypertension. Paradoxically, we observed an overall increase in intracranial hypertension burden following drug administration, even after accounting for within-subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design.

Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without type 2 diabetes.

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

Potentially driver-impairing (PDI) medication use in medically impaired adults referred for driving evaluation.

BACKGROUND: Potentially driver-impairing (PDI) medications have been associated with poorer driving performance and increased risk of motor vehicle collision. OBJECTIVES: To describe the frequency of medication use and to determine the association between routine use of PDI medications and performance on driving and cognitive tests. METHODS: A total of 225 drivers with medical impairment (mean age 68 ± 12.8 years, 62.2% male) were referred to an occupational therapy-based driving evaluation clinic. Medication lists were reviewed to identify PDI drugs, as defined by a previous study examining medications and crash risk. Outcome variables included road testing on the modified Washington University Road Test and cognitive scores on Trail Making Test Parts A and B, Snellgrove Maze Task, Clock Drawing Task, Driving Health Inventory (DHI) Useful Field of View, DHI Motor Free Visual Perceptual Test, Epworth Sleepiness Scale (ESS), Geriatric Depression Scale, and Functional Assessment Questionnaire. RESULTS: PDI medication use was documented in 68.9% of the sample, with the average subject taking 1.4 PDI drugs. Drivers taking routine PDI medications had a mean ESS score of 7.8 compared to 6.0 in the control group, suggesting increased somnolence (P = .007). Total number of routine medications, regardless of PDI designation, also correlated positively with ESS scores (P = .023). CONCLUSIONS: Use of PDI medications was associated with informant ratings of daytime drowsiness on the ESS, which has been linked to motor vehicle crash risk. Further investigation of individual drug classes is warranted using larger sample sizes and a high-powered study design.

Primary care visits for asthma monitoring over time and association with acute asthma visits for urban Medicaid-insured children.

OBJECTIVES: To examine the association between numbers of primary care provider (PCP) visits for asthma monitoring (AM) over time and acute asthma visits in the emergency department (ED) and at the PCP for Medicaid-insured children. METHODS: We prospectively enrolled 2-10 years old children during ED asthma visits. We audited hospital and PCP records for each subject for three consecutive years. We excluded subjects also receiving care from asthma subspecialists. PCP AM visits were those with documentation that suggested discussion of asthma management but no acute asthma symptoms or findings. PCP "Acute Asthma" visits were those with documentation of acute asthma symptoms or findings, regardless of treatment. ED asthma visits were those with documented asthma treatment. Generalized liner models were used to analyze the association between numbers of AM visits and acute asthma visits to the ED and PCP. RESULTS: One hundred three subjects were analyzed. Over the 3 years, the mean number of AM visits/child was 2.5 ± 2.3 (standard deviation), range 0-10. Only 50% of subjects had at least 1 PCP visit with an asthma controller medication documented. The mean number of ED asthma visits/child was 3.2 ± 2.8; range 1-18. The mean number of PCP Acute Asthma visits/child was 0.7 ± 1.6; range 0-11. Increasing AM visits was associated with more ED visits (estimate 0.088; 95% CI 0.001, 0.174), and more PCP Acute Asthma visits (estimate 0.297; 95% CI 0.166, 0.429). Increasing PCP visits for any diagnosis was not associated with ED visits (estimate 0.021; 95% CI -0.018, 0.06). CONCLUSIONS: Asthma monitoring visits and documented controller medication for these urban Medicaid-insured children occurred infrequently over 3 years, and having more asthma monitoring visits was not associated with fewer ED or PCP acute asthma visits.

Management and Microbiology of Perforated Appendicitis in Pediatric Patients: A 5-Year Retrospective Study.

INTRODUCTION: This study aims to assess the current epidemiology and microbiology of perforated appendicitis, how antibiotic choice and duration correlate with meaningful clinical outcomes, and whether serial white blood cell (WBC) counts provide clinical value. METHODS: Five-year retrospective cohort study, 2015-2019, among 333 consecutive children, ages 0-18 years, treated at St. Louis Children's Hospital for perforated appendicitis. Main outcomes included length of stay (LOS), postoperative abscess formation, and readmission. Statistical analysis was performed with uni- and multi-variate analyses. RESULTS: Intra-abdominal cultures most commonly grew Bacteroides fragilis (52%) and Escherichia coli (50%). Patients who initially received broad-spectrum antibiotics (meropenem, piperacillin-tazobactam, fourth-generation cephalosporins) for perforated appendicitis had greater rates of postoperative abscess formation (25% vs. 12%, p < 0.01) and LOS (7.0 vs. 5.7 days, p < 0.01). Similarly, antibiotics at time of discharge were associated with greater postoperative abscess formation (22% vs. 9%, p < 0.01) and LOS (6.4 vs. 5.6 days, p = 0.02). However, discharge with strictly oral antibiotics was not correlated with greater LOS, postoperative abscess formation, or readmission rates compared to discharge without antibiotics. Serial WBC counts had no predictive value for LOS, postoperative abscess formation, or readmission. CONCLUSIONS: Bacteroides fragilis and E. coli were the most common intra-abdominal microbes for perforated appendicitis among our cohort. In non-critically ill children, the routine use of broad-spectrum antibiotics or continuation of antibiotics beyond discharge was not correlated with improved clinical outcomes. Additionally, WBC counts were not correlated with meaningful clinical outcomes.

Cholinergic signaling mediates the effects of xenin-25 on secretion of pancreatic polypeptide but not insulin or glucagon in humans with impaired glucose tolerance.

We previously demonstrated that infusion of an intestinal peptide called xenin-25 (Xen) amplifies the effects of glucose-dependent insulinotropic polypeptide (GIP) on insulin secretion rates (ISRs) and plasma glucagon levels in humans. However, these effects of Xen, but not GIP, were blunted in humans with type 2 diabetes. Thus, Xen rather than GIP signaling to islets fails early during development of type 2 diabetes. The current crossover study determines if cholinergic signaling relays the effects of Xen on insulin and glucagon release in humans as in mice. Fasted subjects with impaired glucose tolerance were studied. On eight separate occasions, each person underwent a single graded glucose infusion- two each with infusion of albumin, Xen, GIP, and GIP plus Xen. Each infusate was administered ± atropine. Heart rate and plasma glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide (PP) levels were measured. ISRs were calculated from C-peptide levels. All peptides profoundly increased PP responses. From 0 to 40 min, peptide(s) infusions had little effect on plasma glucose concentrations. However, GIP, but not Xen, rapidly and transiently increased ISRs and glucagon levels. Both responses were further amplified when Xen was co-administered with GIP. From 40 to 240 min, glucose levels and ISRs continually increased while glucagon concentrations declined, regardless of infusate. Atropine increased resting heart rate and blocked all PP responses but did not affect ISRs or plasma glucagon levels during any of the peptide infusions. Thus, cholinergic signaling mediates the effects of Xen on insulin and glucagon release in mice but not humans.

Impact of age on incidence and prevalence of moderate-to-severe cellular rejection detected by routine surveillance biopsy in pediatric heart transplantation.

BACKGROUND: The effect of age at transplant on rejection detected by routine surveillance biopsy (RSB) in pediatric heart transplant (HT) recipients is unknown. We hypothesized there would be low diagnostic yield and decreased prevalence of rejection detected on RSB in infants (age <1 year) when compared with children (age 1 to 9 years) and adolescents (age 10 to 18 years). METHODS: We utilized Pediatric Heart Transplant Study (PHTS) data from 2010 to 2013 to analyze moderate-to-severe (ISHLT Grade 2R/3R) cellular rejection (MSR) detected only on RSB (RSBMSR). RESULTS: RSB detected 280 of 343 (81.6%) episodes of MSR. RSBMSR was detected in all age groups even >5 years after HT. Infant RSBMSR had a greater proportion (p = 0.0025) occurring >5 years after HT (39.2 vs 18.4 vs 10.8%) and a lower proportion (p = 0.0009) occurring in the first year after HT (25.5 vs 60.6 vs 51.7%) compared with children and adolescents, respectively. Freedom from RSBMSR was 87 ± 7% in infants, 76 ± 6% in children and 73 ± 7% in adolescents 4 years after HT. In 1-year survivors who had RSBMSR in the first year after HT, the risk of RSBMSR occurring in Years 2 to 4 was significantly (p < 0.0001) greater than patients without RSBMSR in the first year (hazard ratio 21.28, 95% confidence interval 10.87 to 41.66), regardless of recipient age. CONCLUSIONS: RSBMSR exists in all age groups after pediatric HT with long-term follow-up. The prevalence in infant recipients is highest >5 years after HT. Those with RSBMSR in the first year after HT are at a high risk for recurrent rejection regardless of age at HT.

Lumbar Cerebrospinal Fluid Biomarkers of Posthemorrhagic Hydrocephalus of Prematurity: Amyloid Precursor Protein, Soluble Amyloid Precursor Protein α, and L1 Cell Adhesion Molecule.

BACKGROUND: Intraventricular hemorrhage (IVH) is the most frequent, severe neurological complication of prematurity and is associated with posthemorrhagic hydrocephalus (PHH) in up to half of cases. PHH requires lifelong neurosurgical care and is associated with significant cognitive and psychomotor disability. Cerebrospinal fluid (CSF) biomarkers may provide both diagnostic information for PHH and novel insights into its pathophysiology. OBJECTIVE: To explore the diagnostic ability of candidate CSF biomarkers for PHH. METHODS: Concentrations of amyloid precursor protein (APP), soluble APPα (sAPPα), soluble APPß, neural cell adhesion molecule-1 (NCAM-1), L1 cell adhesion molecule (L1CAM), tau, phosphorylated tau, and total protein (TP) were measured in lumbar CSF from neonates in 6 groups: (1) no known neurological disease (n = 33); (2) IVH grades I to II (n = 13); (3) IVH grades III to IV (n = 12); (4) PHH (n = 12); (5) ventricular enlargement without hydrocephalus (n = 10); and (6) hypoxic ischemic encephalopathy (n = 13). CSF protein levels were compared using analysis of variance, and logistic regression was performed to examine the predictive ability of each marker for PHH. RESULTS: Lumbar CSF levels of APP, sAPPα, L1CAM, and TP were selectively increased in PHH compared with all other conditions (all P < .001). The sensitivity, specificity, and odds ratios of candidate CSF biomarkers for PHH were determined for APP, sAPPα, and L1CAM; cut points of 699, 514, and 113 ng/mL yielded odds ratios for PHH of 80.0, 200.0, and 68.75, respectively. CONCLUSION: Lumbar CSF APP, sAPPα, L1CAM, and TP were selectively increased in PHH. These proteins, and sAPPα, in particular, hold promise as biomarkers of PHH and provide novel insight into PHH-associated neural injury and repair.

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus.

INTRODUCTION: Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value. METHODS: CSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPß, Aß42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC. RESULTS: CSF levels of APP, sAPPα, sAPPß, Aß42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPß (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC. CONCLUSIONS: CSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment.

Hormonal Responses to Cholinergic Input Are Different in Humans with and without Type 2 Diabetes Mellitus.

UNLABELLED: Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01434901.

Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery.

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of enteroendocrine cells located in the proximal small intestine. Many effects of Xen are mediated by neurotensin receptor-1 on neurons. In healthy humans with normal glucose tolerance (NGT), Xen administration causes diarrhea and inhibits postprandial glucagon-like peptide-1 (GLP-1) release but not insulin secretion. This study determines (i) if Xen has similar effects in humans with Roux-en-Y gastric bypass (RYGB) and (ii) whether neural pathways potentially mediate effects of Xen on glucose homeostasis. Eight females with RYGB and no history of type 2 diabetes received infusions with 0, 4 or 12pmol Xen/kg/min with liquid meals on separate occasions. Plasma glucose and gastrointestinal hormone levels were measured and insulin secretion rates calculated. Pancreatic polypeptide and neuropeptide Y levels were surrogate markers for parasympathetic input to islets and sympathetic tone, respectively. Responses were compared to those in well-matched non-surgical participants with NGT from our earlier study. Xen similarly increased pancreatic polypeptide and neuropeptide Y responses in patients with and without RYGB. In contrast, the ability of Xen to inhibit GLP-1 release and cause diarrhea was severely blunted in patients with RYGB. With RYGB, Xen had no statistically significant effect on glucose, insulin secretory, GLP-1, glucose-dependent insulinotropic peptide, and glucagon responses. However, insulin and glucose-dependent insulinotropic peptide secretion preceded GLP-1 release suggesting circulating GLP-1 does not mediate exaggerated insulin release after RYGB. Thus, Xen has unmasked neural circuits to the distal gut that inhibit GLP-1 secretion, cause diarrhea, and are altered by RYGB.

Intravenous home inotropic use is safe in pediatric patients awaiting transplantation.

BACKGROUND: Intravenous inotropic therapy can be used to support children awaiting heart transplantation. Although use of this therapy is discouraged in adults because of poor outcomes, its use in children, particularly outpatient, has had limited evaluation. We aimed to evaluate the safety and efficacy of this practice. METHODS AND RESULTS: A retrospective analysis of an intent to treat protocol was completed on United Network for Organ Sharing status 1A patients discharged on inotropic therapy from 1999 until 2012. Intravenous inotropic therapy was initiated for cardiac symptoms not amenable to oral therapy. Patients who were not status 1A or required >1 inotrope were excluded. Efficacy was analyzed by time to first event: transplantation; readmission until transplantation; improvement leading to inotrope withdrawal; or death. Safety included analysis of infection rates, line malfunctions, temporary hospitalization, neurological events, and arrhythmias. One hundred six patients met inclusion criteria. The mean age was 10.1±6.4 years, 47% of patients had congenital heart disease, and 80% of these patients had single ventricle physiology. In patients without congenital heart disease, 53% had dilated cardiomyopathy, 91% of patients received milrinone, 85% of patients underwent transplantation, 8% of patients successfully weaned from support as outpatients, whereas 6% died. Fifty percent of patients were readmitted before transplantation or weaning from support, of which 64% required only 1 readmission. The majority of readmissions were for heart failure. CONCLUSIONS: Outpatient intravenous inotropic therapy can be safely used as a bridge to transplantation in pediatric patients. A minority of patients can discontinue inotropic therapy because of clinical improvement.

Global biochemical profiling identifies ß-hydroxypyruvate as a potential mediator of type 2 diabetes in mice and humans.

Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are incretins secreted by respective K and L enteroendocrine cells after eating and amplify glucose-stimulated insulin secretion (GSIS). This amplification has been termed the "incretin response." To determine the role(s) of K cells for the incretin response and type 2 diabetes mellitus (T2DM), diphtheria toxin-expressing (DT) mice that specifically lack GIP-producing cells were backcrossed five to eight times onto the diabetogenic NONcNZO10/Ltj background. As in humans with T2DM, DT mice lacked an incretin response, although GLP-1 release was maintained. With high-fat (HF) feeding, DT mice remained lean but developed T2DM, whereas wild-type mice developed obesity but not diabetes. Metabolomics identified biochemicals reflecting impaired glucose handling, insulin resistance, and diabetes complications in prediabetic DT/HF mice. ß-Hydroxypyruvate and benzoate levels were increased and decreased, respectively, suggesting ß-hydroxypyruvate production from d-serine. In vitro, ß-hydroxypyruvate altered excitatory properties of myenteric neurons and reduced islet insulin content but not GSIS. ß-Hydroxypyruvate-to-d-serine ratios were lower in humans with impaired glucose tolerance compared with normal glucose tolerance and T2DM. Earlier human studies unmasked a neural relay that amplifies GIP-mediated insulin secretion in a pattern reciprocal to ß-hydroxypyruvate-to-d-serine ratios in all groups. Thus, K cells may maintain long-term function of neurons and ß-cells by regulating ß-hydroxypyruvate levels.

Predicting road test performance in drivers with stroke.

OBJECTIVE. The aim of this study was to develop a brief screening battery to predict the on-road performance of drivers who had experienced a stroke. METHOD. We examined 72 people with stroke referred by community physicians to an academic rehabilitation center. The outcome variable was pass or fail on the modified Washington University Road Test. Predictor measures were tests of visual, motor, and cognitive functioning. RESULTS. The best predictive model for failure on the road test included Trail Making Test Part A and the Snellgrove Maze Task(®). CONCLUSION. A screening battery that can be performed in less than 5 min was able to assist in the prediction of road test performance in a sample of drivers with stroke. A probability of failure calculator may be useful for clinicians in their decision to refer clients with stroke for a comprehensive driving evaluation.

Pulmonary function improvement after vertebral column resection for severe spinal deformity.

STUDY DESIGN: Retrospective review of prospectively accrued cohorts. OBJECTIVE: We hypothesized that posterior-only vertebral column resection (PVCR) would result in improved postoperative pulmonary function, avoiding pulmonary insults from combined anterior/posterior approaches. SUMMARY OF BACKGROUND DATA: Pulmonary function after PVCR for severe spinal deformity has not been previously studied. Previous studies have demonstrated impaired pulmonary performance after combined anterior/posterior fusions. METHODS: Serial pulmonary function testing (PFTs) in 49 patients (27 pediatric, 22 adult) who underwent PVCR at a single institution was reviewed. Mean age at surgery was 28.7 years (range, 8-74 yr), and mean follow-up was 32 months (range, 23-64 mo). Thoracic PVCRs (T5-T11) were performed in 31 patients and thoracolumbar PVCRs (T12-L5) in 18 patients. RESULTS: Pediatric patients who underwent PVCR experienced both increased mean forced vital capacity (FVC) (2.10-2.43 L, P = 0.0005) and forced expiratory volume in 1 second (FEV1) (1.71-1.98 L, P = 0.001). There were no significant differences in percent-predicted values for FVC (69%-66%, P = 0.51) or FEV1 (64%-63%, P = 0.77). In adult patients, there were no significant changes in FVC (2.73-2.61 L, P = 0.35) or FEV1 (2.22-2.07 L, P = 0.51) after PVCR; also, changes in adult percent-predicted values for FVC (79%-76%, P = 0.47) and FEV1 (78%-74%, P = 0.40) were not significant. In pediatric patients who underwent PVCR, improved PFTs were correlated with younger age (P = 0.02), diagnosis of angular kyphosis (P ≤ 0.0001), no previous spine surgery (P = 0.04), and preoperative halo-gravity traction (P = 0.02). Comparison of PFT changes between patients who underwent PVCR and a control group who underwent combined anterior/posterior approaches revealed no significant differences. CONCLUSION: In pediatric patients, PVCR resulted in small but significant improvements in postoperative FVC and FEV1. In adult patients, no significant increases in PFTs were found. Patients who have the greatest potential for lung and thoracic cage growth after spinal correction are most likely to have improved pulmonary function after PVCR.

A novel low-energy electrotherapy that terminates ventricular tachycardia with lower energy than a biphasic shock when antitachycardia pacing fails.

OBJECTIVES: The authors sought to develop a low-energy electrotherapy that terminates ventricular tachycardia (VT) when antitachycardia pacing (ATP) fails. BACKGROUND: High-energy implantable cardioverter-defibrillator (ICD) shocks are associated with device failure, significant morbidity, and increased mortality. A low-energy alternative to ICD shocks is desirable. METHODS: Myocardial infarction was created in 25 dogs. Sustained, monomorphic VT was induced by programmed stimulation. Defibrillation electrodes were placed in the right ventricular apex, and coronary sinus and left ventricular epicardium. If ATP failed to terminate sustained VT, the defibrillation thresholds (DFTs) of standard versus experimental electrotherapies were measured. RESULTS: Sustained VT ranged from 276 to 438 beats/min (mean 339 beats/min). The right ventricular-coronary sinus shock vector had lower impedance than the right ventricular-left ventricular patch (54.4 ± 18.1 Ω versus 109.8 ± 16.9 Ω; p < 0.001). A single shock required between 0.3 ± 0.2 J to 5.9 ± 2.5 J (mean 2.64 ± 3.22 J; p = 0.008) to terminate VT, and varied depending upon the phase of the VT cycle in which it was delivered. By contrast, multiple shocks delivered within 1 VT cycle length were not phase dependent and achieved lower DFT compared with a single shock (0.13 ± 0.09 J for 3 shocks, 0.08 ± 0.04 J for 5 shocks, and 0.09 ± 0.07 J for 7 shocks; p < 0.001). Finally, a multistage electrotherapy (MSE) achieved significantly lower DFT compared with a single biphasic shock (0.03 ± 0.05 J versus 2.37 ± 1.20 J; respectively, p < 0.001). At a peak shock amplitude of 20 V, MSE achieved 91.3% of terminations versus 10.5% for a biphasic shock (p < 0.001). CONCLUSIONS: MSE achieved a major reduction in DFT compared with a single biphasic shock for ATP-refractory monomorphic VT, and represents a novel electrotherapy to reduce high-energy ICD shocks.

Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes.

Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion (GSIS). This response is blunted in type 2 diabetes (T2DM). Xenin-25 is a 25-amino acid neurotensin-related peptide that amplifies GIP-mediated GSIS in hyperglycemic mice. This study determines if xenin-25 amplifies GIP-mediated GSIS in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or T2DM. Each fasting subject received graded glucose infusions to progressively raise plasma glucose concentrations, along with vehicle alone, GIP, xenin-25, or GIP plus xenin-25. Plasma glucose, insulin, C-peptide, and glucagon levels and insulin secretion rates (ISRs) were determined. GIP amplified GSIS in all groups. Initially, this response was rapid, profound, transient, and essentially glucose independent. Thereafter, ISRs increased as a function of plasma glucose. Although magnitudes of insulin secretory responses to GIP were similar in all groups, ISRs were not restored to normal in subjects with IGT and T2DM. Xenin-25 alone had no effect on ISRs or plasma glucagon levels, but the combination of GIP plus xenin-25 transiently increased ISR and plasma glucagon levels in subjects with NGT and IGT but not T2DM. Since xenin-25 signaling to islets is mediated by a cholinergic relay, impaired islet responses in T2DM may reflect defective neuronal, rather than GIP, signaling.

Predicting road test performance in drivers with dementia.

OBJECTIVES: To develop a cognitive and functional screening battery for the on-road performance of older drivers with dementia. DESIGN: Prospective observational study. SETTING: On-road driving evaluation clinic at an academic rehabilitation center. PARTICIPANTS: Ninety-nine older people with dementia (63% male, mean age 74.2 ± 9), referred by community physicians to an occupational therapy driving clinic. MEASUREMENTS: The outcome variable was pass or fail on the modified Washington University Road Test. Predictor measures were tests of visual, motor, and cognitive functioning, selected for their empirical or conceptual relationship to the complex task of driving safely. RESULTS: Sixty-five (65%) participants failed the on-road driving test. The best predictive model, with an overall accuracy of up to 85% when participants were blinded, included the Eight-item Informant Interview to Differentiate Aging and Dementia, Clock Drawing Test score, and time to complete the Snellgrove Maze Test or Trail Making Test Part A. Visual and motor functioning were not associated with road test failure. CONCLUSION: A screening battery that could be performed in less than 10 minutes predicted with good accuracy failure rate for the on-road driving test in this sample of older drivers with dementia. A probability of failure calculator is provided from a logistic regression model that may be useful for clinicians in their decision to refer impaired older adults for further testing. More studies are needed in larger community-based samples, along with discussions with patients, families, and clinicians, with regard to acceptable levels of test uncertainty.