Faculty Bibliography

Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in Gba^L444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations. Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type.

BACKGROUND:When administered as a continuous infusion, ketamine is known to be a potent analgesic and general anaesthetic. Recent studies suggest that a single low-dose administration of ketamine can provide a long-lasting effect on mood, but its effects when given in the postoperative period have not been studied. OBJECTIVE:We hypothesised that a single low-dose administration of ketamine after bariatric surgery can improve pain and mood scores in the immediate postoperative period. DESIGN/METHODS:We performed a randomised, double-blind, placebo-controlled study to compare a single subanaesthetic dose of ketamine (0.4 mg kg) with a normal saline placebo in the postanaesthesia care unit after laparoscopic gastric bypass and gastrectomy. SETTING/METHODS:Single-centre, tertiary care hospital, October 2014 to January 2018. PATIENTS/METHODS:A total of 100 patients were randomised into the ketamine and saline groups. INTERVENTION/METHODS:Patients in the ketamine group received a single dose of ketamine infusion (0.4 mg kg) in the postanaesthesia care unit. Patients in the placebo groups received 0.9% saline. OUTCOME MEASURES/METHODS:The primary outcome was the visual analogue pain score. A secondary outcome was performance on the short-form McGill's Pain Questionnaire (SF-MPQ). RESULTS:There were no significant differences in visual analogue pain scores between groups (group-by-time interaction P = 0.966; marginal group effect P = 0.137). However, scores on the affective scale of SF-MPQ (secondary outcome) significantly decreased in the ketamine group as early as postoperative day (POD) 2 [mean difference = -2.2 (95% bootstrap CI -2.9 to 1.6), Bonferroni adjusted P < 0.001], compared with placebo group in which the scores decreased only by POD 7. Scores on the total scale of SF-MPQ for the ketamine group were smaller compared with the placebo group (P = 0.034). CONCLUSION/CONCLUSIONS:Although there was no significant difference between ketamine and placebo for the primary outcome measure, patients who received ketamine experienced statistically and clinically significant improvement in their comprehensive evaluation of pain, particularly the affective component of pain, on POD 2. However, future studies are needed to confirm the enduring effects of ketamine on the affective response to postoperative pain. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT02452060.

The association of early trauma exposure with current cognition was examined in a research series of 56 schizophrenia cases with respect to the BDNF Val66Met polymorphism (rs6265, Val66Val, Val66Met, Met66Met), as met allele carriers have reduced neurotrophic activity. The Perceptual Organization Index had a significant negative correlation with trauma exposures only in met carriers, including early physical abuse, general trauma after age 18 years, and physical abuse. Within the Val66Val subgroup, there were no significant correlations between WAIS indices and traumatic experiences.

Introduction: This study examines the use of dialysis services by end-stage renal disease (ESRD) patients following the Superstorm Sandy-related, months-long closure of the New York campus of the US Department of Veterans Affairs (VA) New York Harbor VA Healthcare System (NYHHS, Manhattan VAMC). Methods: Outpatient visits, dialysis care, emergency department visits, and hospitalizations at VA and non-VA facilities for 47 Manhattan VAMC ESRD patients were examined 12 months pre- and post-Sandy using VA administrative and clinical data. Results: The Brooklyn campus of NYHHS, which is within ten miles of Manhattan VAMC, experienced the largest increase in the number of dialysis encounters after the closure. Dialysis encounters for VA patients also increased at non-VA facilities, rising on average, to 106 per month. For the James J Peters Bronx VAMC, the number of total dialysis encounters for Manhattan VAMC patients fluctuated between 39 and 43 per month, dropping to less than 30 after the Manhattan VAMC dialysis unit reopened. Conclusion: Manhattan VAMC ESRD patients used nearby alternate VA sites and non-VA clinics for their care during the closure of the Manhattan VAMC dialysis unit. The VA electronic health records played an important role in ensuring continuity of care for patients who exclusively used VAMC facilities post-Sandy because patient information was immediately accessible at other VA facilities. The events related to Superstorm Sandy highlight the need for dialysis providers to have a comprehensive disaster plan, including nearby alternate care sites that can increase service capacity when a dialysis facility is closed because of a disaster.

Motherhood in mammals involves tremendous changes throughout the body and central nervous system, which support attention and nurturing of infants. Maternal care consists of complex behaviors, such as nursing and protection of the offspring, requiring new mothers to become highly sensitive to infant needs. Long-lasting neural plasticity in various regions of the cerebral cortex may enable the perception and recognition of infant cues, important for appropriate caregiving responses. Recent findings have demonstrated that the neuropeptide oxytocin is involved in a number of physiological processes, including parturition and lactation and dynamically shaping neuronal responses to infant stimuli as well. Here, we review experience-dependent changes within the cortex occurring throughout motherhood, focusing on plasticity of the somatosensory and auditory cortex. We outline the role of oxytocin in gating cortical plasticity and discuss potential mechanisms regulating oxytocin release in response to different sensory stimuli.

Protein-energy wasting (PEW) is a major diet-related complication in hemodialysis (HD) patients. Nutrient-based dietary guidelines emphasize animal-based protein foods for preventing and managing PEW in HD patients. Although dietary protein intake is important for protein anabolism, other dietary factors contribute to PEW. In this article, we examine the diet-related etiologies of PEW in HD patients, and discuss how they may be affected differently by animal- and plant-based protein foods. In general, animal foods are superior sources of protein, but may contribute more to metabolic derangements that cause PEW. Given the potential mixed effects of animal-based protein foods on PEW, human research studies are needed to determine the impact of liberalizing the diet to allow plant-based protein foods on protein status.

Previous studies have shown that tumor necrosis factor alpha (TNFα) is significantly increased in complete Freund's adjuvant (CFA)-treated temporomandibular joint (TMJ) tissues. However, it is unclear whether TNFα in the trigeminal nociceptive system contributes to the development of TMJ pain. In the present study, we investigated the role of TNFα in trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) in CFA-induced inflammatory TMJ pain. Intra-TMJ injection of CFA (10 μl, 5 mg/ml) induced inflammatory pain in the trigeminal nerve V2- and V3-innervated skin areas of WT mice, which was present on day 1 after CFA and persisted for at least 10 days. TNFα in both TG and Sp5C of WT mice was upregulated after CFA injection. The CFA-induced TMJ pain was significantly inhibited in TNFα KO mice. The immunofluorescence staining showed that intra-TMJ CFA injection not only enhanced co-localization of TNFα with Iba1 (a marker for microglia) in both TG and Sp5C but also markedly increased the expression of TNFα in the Sp5C neurons. By the methylated DNA immunoprecipitation assay, we also found that DNA methylation at the TNF gene promoter region in the TG was dramatically diminished after CFA injection, indicating that epigenetic regulation may be involved in the CFA-enhanced TNFα expression in our model. Our results suggest that TNFα in the trigeminal nociceptive system plays a critical role in CFA-induced inflammatory TMJ pain.

BACKGROUND:The current opioid epidemic highlights the urgent need for effective adjuvant therapies to complement postoperative opioid analgesia. Intra-operative ketamine infusion has been shown to reduce postoperative opioid consumption and improve pain control in opioid-tolerant patients after spinal fusion surgery. Its efficacy for opioid-naïve patients, however, remains controversial. OBJECTIVE:We hypothesised that low-dose ketamine infusion after major spinal surgery reduces opioid requirements in opioid-tolerant patients, but not in opioid-naïve patients. DESIGN/METHODS:Randomised placebo-controlled prospective study. SETTING/METHODS:Single-centre, tertiary care hospital, November 2012 until November 2014. PATIENTS/METHODS:A total of 129 patients were classified as either opioid-tolerant (daily use of opioid medications during 2 weeks preceding the surgery) or opioid-naïve group, then randomised to receive either ketamine or placebo; there were thus four groups of patients. All patients received intravenous hydromorphone patient-controlled analgesia postoperatively. INTERVENTION/METHODS:Patients in the ketamine groups received a ketamine infusion (bolus 0.2 mg kg over 30 min followed by 0.12 mg kg h for 24 h). Patients in the placebo groups received 0.9% saline. MAIN OUTCOME MEASURES/METHODS:The primary outcome was opioid consumption during the first 24 h postoperatively. The secondary outcome was numerical pain scores during the first 24 h and central nervous system side effects. RESULTS:Postoperative hydromorphone consumption was significantly reduced in the opioid-tolerant ketamine group, compared with the opioid-tolerant placebo group [0.007 (95% CI 0.006 to 0.008) versus 0.011 (95% CI 0.010 to 0.011) mg kg h, Bonferroni corrected P < 0.001]. There was no difference in hydromorphone use between the opioid-naïve groups (0.004 and 0.005 mg kg h in the opioid-naïve ketamine and placebo group, respectively, P = 0.118). Pain scores did not differ significantly between the opioid-tolerant ketamine group and the opioid-naïve groups. There was no significant difference in side effects among groups. CONCLUSION/CONCLUSIONS:Postoperative low-dose ketamine infusion reduces opioid requirements for the first 24 h following spinal fusion surgery in opioid-tolerant, but not in opioid-naïve patients. TRIAL REGISTRATION/BACKGROUND:NCT03274453 with clinicaltrials.gov.