Gautam Hebbar

Diverse roles of leptin in the gastrointestinal tract: Modulation of motility, absorption, growth, and inflammation

OBJECTIVE Leptin was discovered in 1994 as a hormone produced by adipose tissue with a modulatory effect on feeding behavior and weight control. Recently, the stomach has been identified as an important source of leptin and growing evidence has shown diverse functions for leptin in the gastrointestinal tract. METHODS Using leptin as a keyword in PubMed, more than 17 000 articles were identified, of which more than 500 articles were related to the role of leptin in the gastrointestinal tract. Available abstracts were reviewed and more than 200 original articles were reviewed in detail. RESULTS The available literature demonstrated that leptin can modulate several important functions of the gastrointestinal tract. Leptin interacts with the vagus nerve and cholecystokinin to delay gastric emptying and has a complex effect on motility of the small bowel. Leptin modulates absorption of macronutrients in the gastrointestinal tract differentially in physiologic and pathologic states. In physiologic states, exogenous leptin has been shown to decrease carbohydrate absorption and to increase the absorption of small peptides by the PepT1 di-/tripeptide transporter. In certain pathologic states, leptin has been shown to increase absorption of carbohydrates, proteins, and fat. Leptin has been shown to be upregulated in the colonic mucosa in patients with inflammatory bowel disease. Leptin stimulates gut mucosal cell proliferation and inhibits apoptosis. These functions have led to speculation about the role of leptin in tumorigenesis in the gastrointestinal tract, which is complicated by the multiple immunoregulatory effects of leptin. CONCLUSION Leptin is an important modulator of major aspects of gastrointestinal tract functions, independent of its more well-described roles in appetite regulation and obesity.

Plasma Metabolomics in Human Pulmonary Tuberculosis Disease: A Pilot Study

We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution.

High-dose vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial.

BACKGROUND Tuberculosis, including multidrug-resistant tuberculosis (MDR-TB), is a major global health problem. Individuals with tuberculosis disease commonly exhibit vitamin D deficiency, which may adversely affect immunity and the response to therapy. OBJECTIVE We determined whether adjunctive high-dose vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease. DESIGN The study was a double-blind, randomized, placebo-controlled, intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi, Georgia. Subjects were randomly assigned to receive oral vitamin D3 [50,000 IUs (1.25 mg) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk] or a placebo concomitant with standard first-line antituberculosis drugs. The primary outcome was the time for the conversion of a Mycobacterium tuberculosis (Mtb) sputum culture to negative. RESULTS Baseline characteristics between groups were similar. Most subjects (74%) were vitamin D deficient (plasma 25-hydroxyvitamin D [25(OH)D] concentration <50 nmol/L). With vitamin D3, plasma 25(OH)D concentrations peaked at ∼250 nmol/L by 8 wk and decreased to ∼125 nmol/L at week 16. Adverse events and plasma calcium concentrations were similar between groups. In 192 subjects with culture-confirmed tuberculosis, an adjusted efficacy analysis showed similar median culture-conversion times between vitamin D3 and placebo groups [29 and 27 d, respectively; HR: 0.86; 95% CI: 0.63, 1.18; P = 0.33). Eight-week culture-conversion rates were also similar (84.0% and 82.1% for vitamin D3 and placebo, respectively; P = 0.99). CONCLUSION A high-dose vitamin D3 regimen safely corrected vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort. This trial was registered at clinicaltrials.gov at NCT00918086.

Nutritional Interventions for Cancer-Induced Cachexia

Cancer-induced cachexia remains a significant cause of morbidity and mortality in cancer treatment. Cancer research and development continues at an aggressive pace and yet a degree of cancer-induced cachexia is experienced by up to 80% of advanced stage cancer patients. Unfortunately, there are no established treatment regimens for this condition. Weight loss and fatigue consistently appear in patient oncologic histories and progress notes. However, few oncologists fully understand the pathologic mechanisms causing cachexia resulting in wellmeaning advice to increase caloric intake with minimal results. Our goal is to describe the pathologic basis of cancer-induced cachexia and to detail accompanying metabolic derangements. Understanding the causes of cachexia sheds light on the subsequent need for multi-modality therapy including clinical intervention with specialized nutrition support, drug therapy, lifestyle and diet changes. In addition to nutrition support modalities, practicing oncologists may prescribe medical therapies designed to increase body weight and lean body mass, including megestrol acetate, tetrahydrocannibinol, oxandrolone, and non-steroidal anti-inflammatory drugs. A variety of experimental therapies are also being investigated for cancer-induced cachexia including tumor necrosis factor-alpha inhibitors and ghrelin infusions. We review the available data to support nutrition-oriented interventions in cancer-induced cachexia, including omega-3 fatty acids, aminoacid loading/protein supplementation, parenteral and enteral nutrition support, and food-derived compounds such as curcumin, reservatrol, and pomegranate.

Amino acid composition in parenteral nutrition: what is the evidence?

Purpose of reviewComplete parenteral nutrition solutions contain mixed amino acid products providing all nine essential amino acids and a varying composition of nonessential amino acids. Relatively little rigorous comparative efficacy research on altered parenteral nutrition amino acid composition has been published in recent years. Recent findingsLimited data from randomized, double-blind, adequately powered clinical trials to define optimal doses of total or individual amino acids in parenteral nutrition are available. An exception is the growing number of studies on the efficacy of glutamine supplementation of parenteral nutrition or given as a single parenteral agent. Parenteral glutamine appears to confer benefit in selected patients; however, additional data to define optimal glutamine dosing and the patient subgroups who may most benefit from this amino acid are needed. Although some promising studies have been published, little data are available in the current era of nutrition support on the clinical efficacy of altered doses of arginine, branched chain amino acids, cysteine, or taurine supplementation of parenteral nutrition. SummaryDespite routine use of parenteral nutrition, surprisingly little clinical efficacy data are available to guide total or specific amino acid dosing in adult and pediatric patients requiring this therapy. This warrants increased attention by the research community and funding agencies to better define optimal amino acid administration strategies in patient subgroups requiring parenteral nutrition.

Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial.

Objective:To determine whether glutamine (GLN)-supplemented parenteral nutrition (PN) improves clinical outcomes in surgical intensive care unit (SICU) patients. Summary Background Data:GLN requirements may increase with critical illness. GLN-supplemented PN may improve clinical outcomes in SICU patients. Methods:A parallel-group, multicenter, double-blind, randomized, controlled clinical trial in 150 adults after gastrointestinal, vascular, or cardiac surgery requiring PN and SICU care. Patients were without significant renal or hepatic failure or shock at entry. All received isonitrogenous, isocaloric PN [1.5 g/kg/d amino acids (AAs) and energy at 1.3× estimated basal energy expenditure]. Controls (n = 75) received standard GLN-free PN (STD-PN); the GLN group (n = 75) received PN containing alanyl-GLN dipeptide (0.5 g/kg/d), proportionally replacing AA in PN (GLN-PN). Enteral nutrition (EN) was advanced and PN weaned as indicated. Hospital mortality and infections were primary endpoints. Results:Baseline characteristics, days on study PN and daily macronutrient intakes via PN and EN, were similar between groups. There were 11 hospital deaths (14.7%) in the GLN-PN group and 13 deaths in the STD-PN group (17.3%; difference, −2.6%; 95% confidence interval, −14.6% to 9.3%; P = 0.66). The 6-month cumulative mortality was 31.4% in the GLN-PN group and 29.7% in the STD-PN group (P = 0.88). Incident bloodstream infection rate was 9.6 and 8.4 per 1000 hospital days in the GLN-PN and STD-PN groups, respectively (P = 0.73). Other clinical outcomes and adverse events were similar. Conclusions:PN supplemented with GLN dipeptide was safe, but did not alter clinical outcomes among SICU patients.

High dose vitamin D administration in ventilated intensive care unit patients: A pilot double blind randomized controlled trial

Highlights • First double blind RCT of vitamin D therapy in mechanically ventilated patients.• Treatment with placebo, 250,000 IU or 500,000 IU enteral vitamin D3 was well tolerated.• Significant increase in plasma 25(OH)D from baseline to day 7.• Significant decrease in hospital length of stay for vitamin D3 treated subjects.• No change in plasma LL-37 according to treatment group.

Differential regulation of tissue thiol-disulfide redox status in a murine model of peritonitis

BackgroundGlutathione (GSH)/glutathione disulfide (GSSG) and cysteine (Cys)/cystine (CySS) are major redox pools with important roles in cytoprotection. We determined the impact of septic peritonitis on thiol-disulfide redox status in mice.MethodsFVB/N mice (6–12 week old; 8/group) underwent laparotomy with cecal ligation and puncture (CLP) or laparotomy alone (control). Sections of ileum, colon, lung and liver were obtained and GSH, GSSG, Cys and CySS concentrations determined by HPLC 24 h after laparotomy. Redox potential [Eh in millivolts (mV)] of the GSH/GSSG and Cys/CySS pools was calculated using the Nernst equation. Data were analyzed by ANOVA (mean ± SE).ResultsGSH/GSSG Eh in ileum, colon, and liver was significantly oxidized in septic mice versus control mice (ileum: septic −202±4 versus control −228±2 mV; colon: -195±8 versus −214±1 mV; and liver: -194±3 vs. -210±1 mV, all P<0.01). Lung GSH/GSSG redox was similar in each group (−191±3 versus −190±2 mV). In contrast, ileal and colonic Cys/CySS Eh was unchanged with CLP, while liver and lung Cys/CySS Eh became significantly more reducing (liver: septic = −103±3 versus control −90±2 mV; lung: -101±5 versus −81±1 mV, each P<0.05).ConclusionsSeptic peritonitis induced by CLP oxidizes ileal and colonic GSH/GSSG redox but Cys/CySS Eh remains unchanged in these intestinal tissues. In liver, CLP oxidizes the GSH/GSSG redox pool and CyS/CySS Eh becomes more reducing; in lung, CLP does not alter GSH/GSSG Eh, and Cys/CySS Eh is less oxidized. CLP-induced infection/inflammation differentially regulates major thiol-disulfide redox pools in this murine model.

A retrospective review of intensive care management of organophosphate insecticide poisoning: Single center experience.

BACKGROUND Organophosphate (OP) compounds are used as insecticides. Given the widespread availability and use of these chemicals, OP poisoning is quite common following either accidental or intentional exposures. Immediate intensive care management can save lives in these patients. We aimed to investigate intensive care management provided to OP poisoning patients in a tertiary care hospital in Turkey. SUBJECTS AND METHODS This was a retrospective chart review of 62 patients, admitted to the Intensive Care Unit (ICU) with OP poisoning between 2000 and 2012. RESULTS Of the 62 patients studied, 40 (65%) were male, 45 (73%) were suicide attempts, 59 (95%) ingested the OP compounds, and three patients (5%) (two patients with suicide and 1 with accidental exposure) died in the ICU. There were statistically significant differences between survivors and nonsurvivors for Glasgow Coma Scale (GCS) on admission (P = 0.034), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (P = 0.003), Sequential Organ Failure Assessment (SOFA) score (P = 0.024), time to initiation of treatment (P = 0.034) and serum lactate dehydrogenase (LDH) levels (P = 0.007). CONCLUSIONS Organophosphate poisoning is a life-threatening condition that requires immediate diagnosis and management. GCS, APACHE II score, SOFA score, and time to admission to the emergency department and LDH levels can provide prognostic information and predict outcomes.

Outcomes of percutaneous endoscopic gastrostomy in hospitalized patients at a tertiary care center in Turkey

Background/objectives:The aim of this study was to perform a retrospective analysis characterizing patients receiving tube feeding following percutaneous endoscopic gastrostomy (PEG) tube placement between 2004 and 2012 at Erciyes University Hospital in Turkey.Subjects/Methods:Patients above the age of 18 years who required long-term enteral tube feeding were studied. All PEGs were performed using the pull-through technique by one experienced endoscopist. Demographic, clinical outcomes and PEG-related complication data were collected.Results:Of the 128 subjects studied, 91 were men (71%) and 37 were women (29%). The mean age of this patient population was 54±19 years. The most common reason for PEG tube insertion was the inability to consume oral diet due to complications of cerebrovascular disease (27%), while cerebral hypoxia, occuring after nonneurological medical disorders, was the second most common indication (23%). A total of 70 patients (55%) had chronic comorbidities, with hypertension being the most common (20%). The most common procedure-related complication was insertion-site bleeding, which occurred in 4% of patients. Long-term complications during 1 year were insertion-site cellulitis, gastric contents leakage and peristomal ulceration, which occurred in 14%, 5% and 0.5% of patients, respectively. There were no PEG insertion-related mortalities; 1-year mortality was unrelated to the indication for PEG tube insertion.Conclusions:PEG tube insertion was a safe method to provide enteral access for nutrition support in this hospitalized patient population.