A combined Nissen plus Hill hybrid repair for paraesophageal hernia improves clinical outcomes and reduces long-term recurrences compared with laparoscopic Nissen alone

Journal of Gastrointestinal Surgery

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Association between sleep duration and obesity is modified by dietary macronutrients intake in Korean

Obesity Research & Clinical Practice

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Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with HCV genotype 2, 3, 4, or 6 infections in an open-label, phase 2 trial

Gastroenterology

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Trends in diabetes and obesity in Samoa over 35 years, 1978–2013

Diabetic Medicine

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nab-Paclitaxel/gemcitabine as second-line therapy after FOLFIRINOX failure in advanced pancreatic cancer

Pancreatology

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A hands-free region-of-interest selection interface for solo surgery with a wide-angle endoscope: preclinical proof of concept

Surgical Endoscopy

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Low fat-containing elemental formula is effective for postoperative recovery and potentially useful for preventing chyle leak during postoperative early enteral nutrition after esophagectomy

Clinical Nutrition

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Brown adipose tissue is involved in diet-induced thermogenesis and whole-body fat utilization in healthy humans

International Journal of Obesity

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Prevalence and risk factors for viral blipping in chronic hepatitis B patients treated with nucleos (t) ide analogues

Journal of Viral Hepatitis

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The safety of laparoscopic sleeve gastrectomy among diabetic patients

Surgical Endoscopy

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Helicobacter pylori infection contributes to placental impairment in preeclampsia: Basic and clinical evidences

Helicobacter

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Prognostic factors for long-term infliximab treatment in Crohn's disease patients: A 20-year single centre experience

Alimentary Pharmacology and Therapeutics

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Integrated low-intensity biofeedback therapy in fecal incontinence: Evidence that good in-home anal sphincter exercise practice makes perfect

Neurogastroenterology & Motility

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Rate of organ space infection is reduced with the use of an air leak test during major hepatectomies

Journal of Gastrointestinal Surgery

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Seroprevalence of hepatitis B virus surface antigen (HBsAg) among clients visiting Tefera Hailu memorial hospital, Sekota, Northern Ethiopia

BMC Infectious Diseases

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Weight gain in insulin treated patients by BMI categories at treatment initiation: New evidence from real-world data in patients with type 2 diabetes

Diabetes, Obesity and Metabolism

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Twenty-year experience with laparoscopic inguinal hernia repair in infants and children: Considerations and results on 1833 hernia repairs

Surgical Endoscopy

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The relationship between early weight loss and weight loss at 1 year with naltrexone ER/bupropion ER combination therapy

International Journal of Obesity

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Mucosal perforation during laparoscopic surgery for achalasia: impact of preoperative pneumatic balloon dilation

Surgical Endoscopy

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Saffron ( Crocus sativus ) pretreatment confers cardioprotection against ischemia-reperfusion injuries in isolated rabbit heart

Abstract

Restoration of blood flow to the ischemic myocardium is imperative to avoid demise of cardiomyocytes, but is paradoxically associated with irreversible damage to cardiac tissues due to the excessive generation of reactive oxygen species (ROS). We have previously reported that saffron, a natural antioxidant, attenuated ischemia-reperfusion (IR) injuries in vitro; however, its role in a meaningful cardiac recovery remains unknown. Here, we show that saffron supplement (oral administration for 6 weeks) reduced myocardial damage and restored cardiac function in an IR model of rabbit hearts. This was evidenced by improved left ventricle pressure, heart rate and coronary flow, and left ventricle end diastolic pressure (LVEDP) in IR hearts (isolated from rabbits pre-exposed to saffron (S/IR)). Electrophysiological recordings revealed a significant decline in both premature ventricle contraction and ventricle tachycardia/fibrillation in S/IR compared to IR hearts. This was paralleled by increased expression of the contractile proteins α-actinin and Troponin C in the myocardium of S/IR hearts. Histological examination combined to biochemical analysis indicated that hearts pre-exposed to saffron exhibited reduced infarct size, lower lipid peroxidation, with increased glutathione peroxidase activity, and oxidation of nitro blue tetrazolium (by reactive oxygen species). Furthermore, in contrast with IR hearts, saffron pretreatment induced restoration of the phosphorylation level of the survival proteins Akt and 4EBP1 and reduced activity of p38. Collectively, our data demonstrate that the natural antioxidant saffron plays a pivotal role in halting IR-associated cardiac injuries and emerges as a novel preventive tool for ischemic heart disease.

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KV7/M channels as targets for lipopolysaccharide-induced inflammatory neuronal hyperexcitability

Abstract

Acute brain insults and many chronic brain diseases manifest an innate inflammatory response. The hallmark of this response is glia activation, which promotes repair of damaged tissue, but also induces structural and functional changes that may lead to an increase in neuronal excitability. We have investigated the mechanisms involved in the modulation of neuronal activity by acute inflammation. Initiating inflammatory responses in hippocampal tissue rapidly led to neuronal depolarization and repetitive firing even in absence of active synaptic transmission. This action was mediated by a complex metabotropic purinergic and glutamatergic glia-to-neuron signalling cascade, leading to the blockade of neuronal K_V7/M channels by Ca²⁺ released from internal stores. These channels generate the low voltage-activating, noninactivating M-type K⁺ current (M-current) that controls intrinsic neuronal excitability, and its inhibition was the predominant cause of the inflammation-induced hyperexcitability. Our discovery that the ubiquitous K_V7/M channels are the downstream target of the inflammation-induced cascade, has far reaching implications for the understanding and treatment of many acute and chronic brain disorders.

This article is protected by copyright. All rights reserved

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Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long-term intermittent hypoxia

Abstract

Rodents exposed to chronic intermittent hypoxia (IH), simulating blood O₂ saturation profiles during obstructive sleep apnea (OSA), have been shown to exhibit heightened carotid body (CB) chemosensory reflex and hypertension. CB chemosensory reflex activation also results in unstable breathing with apneas. However, the effect of chronic IH on breathing is not known. In the present study, we examined the effects of chronic IH on breathing along with blood pressure (BP) and assessed whether the autonomic responses are normalized after recovery from chronic IH. Studies were performed on adult, male, Sprague-Dawley rats exposed to either short-term (ST, 10d) or long-term (LT, 30d)-IH. Rats exposed to either ST- or LT-IH exhibited hypertension, irregular breathing with apneas, augmented CB chemosensory reflex as indicated by elevated CB neural activity and plasma catecholamine levels, and elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla (AM). All these effects were normalized after recovery from ST-IH, but not from LT-IH. Analysis of the molecular mechanisms underlying the persistent effects of LT-IH revealed increased DNA methylation of genes encoding anti-oxidant enzymes (AOEs). Treatment with decitabine, a DNA methylation inhibitor, either during LT-IH or during recovery from LT-IH, prevented DNA methylation, normalized the expression of AOE genes, ROS levels, CB chemosensory reflex, BP and stabilized breathing. These results suggest that persistent cardiorespiratory abnormalities caused by LT-IH are mediated by epigenetic re-programming of the redox state in the CB chemosensory reflex pathway.

This article is protected by copyright. All rights reserved

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Unexpected reductions in regional cerebral perfusion during prolonged hypoxia

Hypoxia causes an increase in global cerebral blood flow, which maintains global cerebral oxygen delivery and metabolism. Yet neurological deficits are abundant under hypoxic conditions. We investigated regional cerebral microvascular responses to acute (2 h) and prolonged (10 h) poikilocapnic normobaric hypoxia. We found that 2 h of hypoxia caused an expected increase in frontal cortical grey matter perfusion, but unexpected perfusion decreases in regions of the brain normally associated with the "default mode" or "task negative" network. After 10 h in hypoxia, decreased blood flow to the major nodes of the default mode network became more pronounced and wide spread. Use of a hypercapnic challenge (5% CO₂) confirmed that these reduction in CBF from hypoxia were related to vasoconstriction. Our findings demonstrate steady-state deactivation of the default network under acute hypoxia, which become more pronounced over time. Moreover, these data provide a unique insight into the nuanced localized cerebrovascular response to hypoxia not attainable through traditional methods. That reduced perfusion was observed in the posterior cingulate and cuneal cortex, regions thought to play a role in declarative and procedural memory, provides an anatomical mechanism through which hypoxia may cause deficits in working memory.

This article is protected by copyright. All rights reserved

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Sequence determinants of subtype-specific actions of KCNQ channel openers

Abstract

Retigabine is the first approved anti-epileptic drug that acts via activation of voltage-gated potassium channels, targeting KCNQ channels that underlie the neuronal M-current. Retigabine exhibits little specificity between KCNQ2-5, due to conservation of a Trp residue in the pore domain that binds to the drug. The retigabine analog ICA-069673 ('ICA73') exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, roughly two-fold enhancement of peak current, and pronounced subtype specificity for KCNQ2 over KCNQ3. Based on ICA73 sensitivity of chimeric constructs of the transmembrane segments of KCNQ2 and KCNQ3, this drug appears to interact with the KCNQ2 voltage sensor (S1-S4) rather than the pore region targeted by retigabine. KCNQ2 point mutants in the voltage sensor were generated based on KCNQ2/KCNQ3 sequence differences, and screened for ICA73 sensitivity. These experiments reveal that KCNQ2 residues F168 and A181 in the S3 segment are essential determinants of ICA73 subtype specificity. Mutations at either position in KCNQ2 abolish the ICA73-mediated gating shift, while retaining retigabine sensitivity. Interestingly, A181P mutant channels show little ICA73-mediated gating shift, but retain current potentiation by the drug. Mutations (L198F and P211A) that introduce these critical KCNQ2 residues at corresponding positions in KCNQ3 transplant partial ICA73 sensitivity. These findings demonstrate that retigabine and ICA73 act via distinct mechanisms, and reveal specific residues that underlie subtype specificity of KCNQ channel openers.

This article is protected by copyright. All rights reserved

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"Twin" Biliary Trees in a Patient with Heterotaxy Syndrome.

No abstract available

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The effect of 1 year of Alagebrium and moderate-intensity exercise training on left ventricular function during exercise in seniors: a randomized controlled trial

Sedentary aging leads to left ventricular (LV) and vascular stiffening due in part to advanced glycation end-products (AGEs) cross-linking of extracellular matrix proteins. Vigorous lifelong exercise ameliorates age-related cardiovascular (CV) stiffening and enhances exercise LV function, although this effect is limited when exercise is initiated later in life. We hypothesized that exercise training might be more effective at improving the impact of age-related CV stiffening during exercise when combined with an AGE cross-link breaker (Alagebrium). Sixty-two seniors (≥60 yr) were randomized into four groups: sedentary + placebo, sedentary + Alagebrium, exercise + placebo, and exercise + Alagebrium for 1 yr. Moderate-intensity aerobic exercise was performed 3-4 sessions/wk; controls underwent similar frequency of yoga/balance training. Twenty-four similarly-aged, lifelong exercisers (4–5 sessions/wk) served as a comparator for the effect of lifelong exercise on exercising LV function. Oxygen uptake (Douglas bags), stroke index (SI; acetylene rebreathing), and effective arterial elastance (Ea) were collected at rest and submaximal and maximal exercise. Maximum O₂ uptake (23 ± 5 to 25 ± 6 ml·kg^–1·min^–1) increased, while SI (35 ± 11 to 39 ± 12 ml/m²) and Ea (4.0 ± 1.1 to 3.7 ± 1.2 mmHg·ml^–1·m^–2) were improved across all conditions with exercise, but remained unchanged in controls (exercise x time, P ≤ 0.018). SI or Ea were not affected by Alagebrium (medication x time, P ≥ 0.468) or its combination with exercise (interaction P ≥ 0.252). After 1 yr of exercise plus Alagebrium, exercise SI and Ea remained substantially below that of lifelong exercisers (15–24 and 9–22%, respectively, P ≤ 0.415). In conclusion, Alagebrium plus exercise had no synergistic effect on exercise LV function and failed to achieve levels associated with lifelong exercise, despite a similar exercise frequency.

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Predictive Value of Fecal Calprotectin in Pediatric GVHD.

No abstract available

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Adenomyomatosis of the Gallbladder with Pancreaticobiliary Maljunction in a Child.

No abstract available

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Specialized Imaging and Procedures in Pediatric Pancreatology: A NASPGHAN Clinical Report.

Objectives: An increasing number of children are being diagnosed with pancreatitis and other pancreatic abnormalities. Dissemination of the information regarding existing imaging techniques and endoscopic modalities to diagnose and manage pancreatic disorders in children is sorely needed. Methods: We conducted a review of the medical literature on the use of the following imaging and procedural modalities in pediatric pancreatology: transabdominal ultrasonography (TUS), computed tomography (CT), magnetic resonance imaging (MRI)- magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreatography (ERCP). Recommendations for current utilization as well as future research were identified. Results: TUS offers non-invasive images of the pancreas but has limitations to details of parenchyma and ductal structures. CT offers improved detail of pancreatic parenchyma, solid masses, and traumatic injuries, but requires relatively high levels of ionizing radiation and does not adequately assess ductal anatomy. MRI/MRCP offers detailed intrinsic tissue assessment and pancreatic ductal characterization, but requires longer image acquisition time and is relatively poor at imaging calcifications. EUS provides excellent evaluation of pancreatic parenchyma and ductal anatomy, but can be subjective and operator dependent and requires sedation or anesthesia. EUS offers the capacity to obtain tissue samples and drain fluid collections and ERCP offers the ability to improve drainage by performing sphincterotomy or placing pancreatic stents across duct injuries and strictures. Conclusions: Various imaging modalities may be utilized in pediatric pancreatology, but TUS and MRI/MRCP are favored. Interventional therapeutic maneuvers primarily involve use of ERCP and EUS. Future research is necessary to optimize equipment, expertise, and appropriate indications. (C) 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Comparison of Nasal Potential Difference and Intestinal Current Measurements as Surrogate Markers for CFTR function.

Background: Nasal Potential Difference (NPD) measurement is part of the diagnostic criteria for Cystic Fibrosis (CF) and now used routinely as an endpoint in clinical trials of correcting the basic defect in CF. Intestinal Current Measurement (ICM(, measured ex vivo on a rectal biopsy, has been used to study Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function but has not been compared to NPD in the same subject in adults and children. The aim of the study is to evaluate the potential usefulness of ICM as a marker of CFTR function for treatment studies compared NPD in patients with CF and in healthy control subjects. Methods: ICM and NPD were performed on healthy controls and CF patients. The healthy adults were individuals undergoing routine screening colonoscopy at the Beth Israel Deaconess Medical Center. The healthy children were undergoing colonoscopy for suspicion of inflammation in Hadassah Hebrew University Medical Center. The CF adults were recruited from Boston Children's Hospital CF Center and CF Center Worcester Mass, the children with CF from Hadassah CF Center. Results: ICM measurements in healthy control subjects (n = 16) demonstrated a mean (+/-SE) carbachol response of 16.0 (2.2) [mu]A/cm2, histamine response of 13.2 (2.1) [mu]A/cm2 and a forskolin response of 6.3 (2.0) [mu]A/cm2. Basal NPD of -15.9 (1.9) and response to Cl- free+Isoproterenol of -13.8 (2.0). These responses were inverted in CF subjects (n = 12) for ICM parameters with carbachol response of -3.0 (0.5) [mu]A/cm2, histamine -1.0 (0.8) [mu]A/cm2 and a forskolin response of 0.5 (0.3) and also for NPD parameters; Basal NPD of -42.2 (4.3) and response to Cl- free+Isoproterenol of 4.3 (0.7). Pearson correlation test showed the comparability of ICM and NPD in assessing CFTR function. Conclusion: ICM is equivalent to NPD in the ability to distinguish CF patients from controls and could be used as surrogate markers of CFTR activity in treatment protocols. (C) 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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The Natural History of Primary Sclerosing Cholangitis in Children: A Large Single Center Longitudinal Cohort Study.

Objectives: Data regarding pediatric PSC natural history are limited. We describe a large pediatric PSC cohort with longitudinal follow-up. Methods: Records review of pediatric PSC patients diagnosed between 1984 and 2014. Results: N = 120 (63% M) aged 1-21y (median 14y) at diagnosis. 27% (31/113) had ASC (autoimmune sclerosing cholangitis), 24% had exclusive small duct PSC, METAVIR stage was F3-F4 in 41%. 81% of PSC patients had IBD; most had ulcerative/indeterminate colitis (72/97), typically pancolitis (40/72). PSC-IBD was more common than ASC-IBD (85% vs. 68%, P = 0.03). Median follow-up was 3.7y (IQR 1.5, 6.9). Median GGT decreased from baseline of 221 U/L (IQR 110, 425) to 104 U/L by 1y post-diagnosis ([IQR 18,229], P

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GCTA-GREML accounts for LD [Biological Sciences]

In a recent publication in PNAS, Krishna Kumar et al. (1) claim that "GCTA applied to current SNP data cannot produce reliable or stable estimates of heritability." We show below that those claims are false due to their misunderstanding of the theory and practice of random-effect models underlying genome-wide complex...

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Intermuscular adipose tissue and thigh muscle area dynamics during an 18-month randomized weight loss trial

It remains unclear whether intermuscular adipose tissue (IMAT) has any metabolic influence or whether it is merely a marker of abnormalities, as well as what are the effects of specific lifestyle strategies for weight loss on the dynamics of both IMAT and thigh muscle area (TMA). We followed the trajectory of IMAT and TMA during 18-mo lifestyle intervention among 278 sedentary participants with abdominal obesity, using magnetic resonance imaging. We measured the resting metabolic rate (RMR) by an indirect calorimeter. Among 273 eligible participants (47.8 ± 9.3 yr of age), the mean IMAT was 9.6 ± 4.6 cm². Baseline IMAT levels were directly correlated with waist circumference, abdominal subdepots, C-reactive protein, and leptin and inversely correlated with baseline TMA and creatinine (P < 0.05 for all). After 18 mo (86.3% adherence), both IMAT (–1.6%) and TMA (–3.3%) significantly decreased (P < 0.01 vs. baseline). The changes in both IMAT and TMA were similar across the lifestyle intervention groups and directly corresponded with moderate weight loss (P < 0.001). IMAT change did not remain independently associated with decreased abdominal subdepots or improved cardiometabolic parameters after adjustments for age, sex, and 18-mo weight loss. In similar models, 18-mo TMA loss remained associated with decreased RMR, decreased activity, and with increased fasting glucose levels and IMAT (P < 0.05 for all). Unlike other fat depots, IMAT may not represent a unique or specific adipose tissue, instead largely reflecting body weight change per se. Moderate weight loss induced a significant decrease in thigh muscle area, suggesting the importance of resistance training to accompany weight loss programs.

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Physiological impact of patent foramen ovale on pulmonary gas exchange, ventilatory acclimatization, and thermoregulation

The foramen ovale, which is part of the normal fetal cardiopulmonary circulation, fails to close after birth in ~35% of the population and represents a potential source of right-to-left shunt. Despite the prevalence of patent foramen ovale (PFO) in the general population, cardiopulmonary, exercise, thermoregulatory, and altitude physiologists may have underestimated the potential effect of this shunted blood flow on normal physiological processes in otherwise healthy humans. Because this shunted blood bypasses the respiratory system, it would not participate in either gas exchange or respiratory system cooling and may have impacts on other physiological processes that remain undetermined. The consequences of this shunted blood flow in PFO-positive (PFO+) subjects can potentially have a significant, and negative, impact on the alveolar-to-arterial oxygen difference (AaDO₂), ventilatory acclimatization to high altitude and respiratory system cooling with PFO+ subjects having a wider AaDO₂ at rest, during exercise after acclimatization, blunted ventilatory acclimatization, and a higher core body temperature (~0.4^°C) at rest and during exercise. There is also an association of PFO with high-altitude pulmonary edema and acute mountain sickness. These effects on physiological processes are likely dependent on both the presence and size of the PFO, with small PFOs not likely to have significant/measureable effects. The PFO can be an important determinant of normal physiological processes and should be considered a potential confounder to the interpretation of former and future data, particularly in small data sets where a significant number of PFO+ subjects could be present and significantly impact the measured outcomes.

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Camel genetics and caravan trade in antiquity [Biological Sciences]

Almathen et al. (1) find a high level of genetic diversity across the whole dromedary distribution range. The results are inconsistent with the hypothesis of negative correlation between high polymorphism and distance from the center of domestication (2). The lack of phylogeographic pattern demonstrates the mobility of the camel and...

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Correcting the dynamic response of a commercial esophageal balloon-catheter

It is generally recommended that an esophageal balloon-catheter possess an adequate frequency response up to 15 Hz, such that parameters of respiratory mechanics may be quantified with precision. In our experience, however, we have observed that some commercially available systems do not display an ideal frequency response (<8-10 Hz). We therefore investigated whether the poor frequency response of a commercially available esophageal catheter may be adequately compensated using two numerical techniques: 1) an exponential model correction, and 2) Wiener deconvolution. These two numerical techniques were performed on a commercial balloon-catheter interfaced with 0, 1, and 2 lengths of extension tubing (90 cm each), referred to as configurations L0, L90, and L180, respectively. The frequency response of the balloon-catheter in these configurations was assessed by empirical transfer function analysis, and its "working" range was defined as the frequency beyond which more than 5% amplitude and/or phase distortion was observed. The working frequency range of the uncorrected balloon-catheter extended up to only 10 Hz for L0, and progressively worsened with additional tubing length (L90 = 3 Hz, L180 = 2 Hz). Although both numerical methods of correction adequately enhanced the working frequency range of the balloon-catheter to beyond 25 Hz for all length configurations (L0, L90, and L180), Wiener deconvolution consistently provided more accurate corrections. Our data indicate that Wiener deconvolution provides a superior correction of the balloon-catheter's dynamic response, and is relatively more robust to extensions in catheter tube length compared with the exponential correction method.

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Genome-wide map of UV damage formation and repair [Genetics]

UV-induced DNA lesions are important contributors to mutagenesis and cancer, but it is not fully understood how the chromosomal landscape influences UV lesion formation and repair. Genome-wide profiling of repair activity in UV irradiated cells has revealed significant variations in repair kinetics across the genome, not only among large chromatin...

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Influence of the contractile properties of muscle on motor unit firing rates during a moderate-intensity contraction in vivo

It is suggested that firing rate characteristics of motor units (MUs) are influenced by the physical properties of the muscle. However, no study has correlated MU firing rates at recruitment, targeted force, or derecruitment with the contractile properties of the muscle in vivo. Twelve participants (age = 20.67 ± 2.35 yr) performed a 40% isometric maximal voluntary contraction of the leg extensors that included linearly increasing, steady force, and decreasing segments. Muscle biopsies were collected with myosin heavy chain (MHC) content quantified, and surface electromyography (EMG) was recorded from the vastus lateralis. The EMG signal was decomposed into the firing events of single MUs. Slopes and y-intercepts were calculated for 1) firing rates at recruitment vs. recruitment threshold, 2) mean firing rates at steady force vs. recruitment threshold, and 3) firing rates at derecruitment vs. derecruitment threshold relationships for each subject. Correlations among type I %MHC isoform content and the slopes and y-intercepts from the three relationships were examined. Type I %MHC isoform content was correlated with MU firing rates at recruitment (y-intercepts: r = –0.577; slopes: r = 0.741) and targeted force (slopes: r = 0.853) vs. recruitment threshold and MU firing rates at derecruitment (y-intercept: r = –0.597; slopes: r = 0.701) vs. derecruitment threshold relationships. However, the majority of the individual MU firing rates vs. recruitment and derecruitment relationships were not significant (P > 0.05) and, thus, revealed no systematic pattern. In contrast, MU firing rates during the steady force demonstrated a systematic pattern with higher firing rates for the lower- than higher-threshold MUs and were correlated with the physical properties of MUs in vivo.

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GCTA produces unreliable heritability estimates [Biological Sciences]

In our recent paper in PNAS (1), and subsequently (2), we have analyzed the mathematical model that is stated precisely by Yang et al. (3). As written, their model assumes that (i) the Genetic Relatedness Matrix (GRM) is known exactly, (ii) the phenotypic contributions of each of the P SNPs...

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Auditory Golgi cells are interconnected predominantly by electrical synapses

The mossy fiber-granule cell-parallel fiber system conveys proprioceptive and corollary discharge information to principal cells in cerebellum-like systems. In the dorsal cochlear nucleus (DCN), Golgi cells inhibit granule cells and thus regulate information transfer along the mossy fiber-granule cell-parallel fiber pathway. Whereas excitatory synaptic inputs to Golgi cells are well understood, inhibitory and electrical synaptic inputs to Golgi cells have not been examined. Using paired recordings in a mouse brain slice preparation, we find that Golgi cells of the cochlear nucleus reliably form electrical synapses onto one another. Golgi cells were only rarely electrically coupled to superficial stellate cells, which form a separate network of electrically coupled interneurons in the DCN. Spikelets had a biphasic effect on the excitability of postjunctional Golgi cells, with a brief excitatory phase and a prolonged inhibitory phase due to the propagation of the prejunctional afterhyperpolarization through gap junctions. Golgi cells and stellate cells made weak inhibitory chemical synapses onto Golgi cells with low probability. Electrical synapses are therefore the predominant form of synaptic communication between auditory Golgi cells. We propose that electrical synapses between Golgi cells may function to regulate the synchrony of Golgi cell firing when electrically coupled Golgi cells receive temporally correlated excitatory synaptic input.

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Recording extracellular neural activity in the behaving monkey using a semichronic and high-density electrode system

We describe a technique to semichronically record the cortical extracellular neural activity in the behaving monkey employing commercial high-density electrodes. After the design and construction of low cost microdrives that allow varying the depth of the recording locations after the implantation surgery, we recorded the extracellular unit activity from pools of neurons at different depths in the presupplementary motor cortex (pre-SMA) of a rhesus monkey trained in a tapping task. The collected data were processed to classify cells as putative pyramidal cells or interneurons on the basis of their waveform features. We also demonstrate that short time cross-correlogram occasionally yields unit pairs with high short latency (<5 ms), narrow bin (<3 ms) peaks, indicative of monosynaptic spike transmission from pre- to postsynaptic neurons. These methods have been verified extensively in rodents. Finally, we observed that the pattern of population activity was repetitive over distinct trials of the tapping task. These results show that the semichronic technique is a viable option for the large-scale parallel recording of local circuit activity at different depths in the cortex of the macaque monkey and other large species.

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A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182–187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41–51, 1986). Kalluri et al. (J Neurophysiol 104: 2034–2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (I_KL). To examine the impact of I_KL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (g_Na), low-voltage-activated potassium (g_KL), and high-voltage-activated potassium (g_KH). Consistent with in vitro observations, removing g_KL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of g_KL, spiking occurred only in response to large events with fast onsets. Models without g_KL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing g_KL produced spike trains with irregular interspike intervals. Only models lacking g_KL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.

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