Naji N. Abumrad

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic–pituitary–adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man

Comparisons were made between the artery and a heated superficial hand vein (HSHV) for the measurements of amino acids, lactate, glycerol, free fatty acids, insulin and glucagon and the measurements of glucose and alanine kinetics in man. Normal subjects (n = 8) were studied after an overnight fast (12–14 hr). U-14C-alanine and 3, 3H glucose were administered by a constant infusion and blood was sampled from catheters placed in a radial artery and a superficial dorsal vein of a heated hand (68°C environment), during a control period and a period of a steady state hyperaminoacidemia achieved by a constant infusion of an L-amino acid solution. The blood concentrations of all substrates and hormones measured and the concentrations of cold and radioactive glucose and alanine were comparable in the two vessels during both study periods. In contrast, measurements obtained in a deep forearm vein (DV) showed the concentrations of plasma glucose to be lower (3% in the control period and 5% during the experimental period) and those of plasma alanine to be higher (13% and 5% during control and experimental periods respectively) than the artery or the HSHV. The difference in glucose specific activity between the artery or the HSHV and the DV were however slight but non-significant, while plasma alanine specific activity was significantly lower in the DV as compared to the artery or the HSHV (32% in the control period versus 14% in the experimental period) suggesting a process of exchange of alanine and glucose occuring during the transit of blood across the forearm. As a result blood samples obtained from a DV will overestimate the derived total body glucose and alanine turnover rates. Thus the heated superficial hand vein can adequately replace the artery for the measurements of whole blood amino acids, lactate and glycerol and for plasma FFA, insulin and glucagon; its use can obviate the risks associated with arterial catheterization and can be a suitable site for the measurements of total body glucose and alanine kinetics in man.

The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies

ABSTRACT Increasing evidence has demonstrated that aggressive crystalloid-based resuscitation strategies are associated with cardiac and pulmonary complications, gastrointestinal dysmotility, coagulation disturbances, and immunological and inflammatory mediator dysfunction. As large volumes of fluids are administered, imbalances in intracellular and extracellular osmolarity occur. Disturbances in cell volume disrupt numerous regulatory mechanisms responsible for keeping the inflammatory cascade under control. Several authors have demonstrated the detrimental effects of large, crystalloid-based resuscitation strategies on pulmonary complications in specific surgical populations. Additionally, fluid-restrictive strategies have been associated with a decreased frequency of and shorter time to recovery from acute respiratory distress syndrome and trends toward shorter lengths of stay and lower mortality. Early resuscitation of hemorrhagic shock with predominately saline-based regimens has been associated with cardiac dysfunction and lower cardiac output, as well as higher mortality. Numerous investigators have evaluated potential risk factors for developing abdominal compartment syndrome and have universally noted the excessive use of crystalloids as the primary determinant. Resuscitation regimens that cause early increases in blood flow and pressure may result in greater hemorrhage and mortality than those regimens that yield comparable flow and pressure increases late in resuscitation. Future resuscitation research is likely to focus on improvements in fluid composition and adjuncts to administration of large volume of fluid.

Clinical Experience Over 48 Years With Pheochromocytoma

OBJECTIVE To analyze the presentation, localization, surgical management, pathology, and long-term outcome of a large series of patients with pheochromocytomas. SUMMARY BACKGROUND DATA There are several areas of controversy pertaining to pheochromocytomas. Although many studies report a higher rate of malignancy for extraadrenal pheochromocytomas than for adrenal pheochromocytomas, the number of patients with the former tumor are small and statistical analysis is lacking. There has also been recent debate as to whether microscopic features of the tumor may be predictive of future behavior. METHODS From 1950 to 1998, the authors observed 108 pheochromocytomas in 104 patients. The outcome of these patients has been followed prospectively. The medical records of these patients were reviewed for data on the presentation, localization, surgical management, pathology, and outcome. Patient survival was analyzed using Kaplan-Meier survival distributions. RESULTS This study included 66 female patients and 38 male patients. The average age at surgery was 42.3 years. Sporadic cases accounted for 84% of the patients; the other 16% had multiple endocrine neoplasia type 2, von Recklinghausens disease, von Hippel-Lindau disease, or Carneys syndrome. Of 64 adrenal tumors, 55 were initially considered benign, 6 had microscopic malignant features, and 3 had malignant disease. Mean patient follow-up was 12.6 years. To date, in five additional patients (none with microscopic disease) malignant disease developed (13% overall rate of malignancy). Recurrence occurred as late as 15 years after resection. Of 26 extraadrenal pheochromocytomas, 14 were initially considered benign, 8 had microscopic malignant features, and 4 had malignant disease. Thus, 46% of patients had either malignant disease or tumors with malignant features. Mean patient follow-up was 11.5 years. In one patient with benign disease and in one patient with malignant features, malignant disease developed (23% overall rate of malignancy). The difference in the rate of malignancy was not statistically significant between adrenal and extraadrenal pheochromocytomas. Patients with adrenal and extraadrenal pheochromocytomas also had similar rates of survival (p = NS). CONCLUSIONS The data suggest that patients with extraadrenal pheochromocytomas have the same risk of malignancy and the same overall survival as patients with adrenal pheochromocytomas. Lifelong follow-up of these patients is mandatory.

The Importance of Caloric Restriction in the Early Improvements in Insulin Sensitivity After Roux-en-Y Gastric Bypass Surgery

OBJECTIVE Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB. RESEARCH METHODS AND DESIGN A mixed meal was administered to nine subjects before and after RYGB (average 4 ± 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet. RESULTS Weight loss in both groups was minimal; the RYGB subjects lost 1.4 ± 5.3 kg (P = 0.46) vs. 2.2 ± 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 ± 3.1 to 3.3 ± 2.1; P = 0.03) and caloric restriction (4.8 ± 4.1 to 3.6 ± 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 ± 67 to 65 ± 33 and 85 ± 59 to 65 ± 56 nmol · l−1 · min−1, respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 ± 8.6 to 12.2 ± 5.5 pg · l−1 · min−1; P = 0.04) and peaked higher (45.2 ± 37.3 to 84.8 ± 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction. CONCLUSIONS These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidates side effects may counterbalance its reinforcing effects.

Surgical Removal of Omental Fat Does Not Improve Insulin Sensitivity and Cardiovascular Risk Factors in Obese Adults

BACKGROUND & AIMS Visceral adipose tissue (VAT) is an important risk factor for the metabolic complications associated with obesity. Therefore, a reduction in VAT is considered an important target of obesity therapy. We evaluated whether reducing VAT mass by surgical removal of the omentum improves insulin sensitivity and metabolic function in obese patients. METHODS We conducted a 12-month randomized controlled trial to determine whether reducing VAT by omentectomy in 22 obese subjects increased their improvement following Roux-en-Y gastric bypass (RYGB) surgery in hepatic and skeletal muscle sensitivity to insulin study 1. Improvement was assessed by using the hyperinsulinemic-euglycemic clamp technique. We also performed a 3-month, longitudinal, single-arm study to determine whether laparoscopic omentectomy alone, in 7 obese subjects with type 2 diabetes mellitus (T2DM), improved insulin sensitivity study 2. Improvement was assessed by using the Frequently Sampled Intravenous Glucose Tolerance Test. RESULTS The greater omentum, which weighed 0.82 kg (95% confidence interval: 0.67-0.97), was removed from subjects who had omentectomy in both studies. In study 1, there was an approximate 2-fold increase in muscle insulin sensitivity (relative increase in glucose disposal during insulin infusion) and a 4-fold increase in hepatic insulin sensitivity 12 months after RYGB alone and RYGB plus omentectomy, compared with baseline values (P<.001). There were no significant differences between groups (P>.87) or group x time interactions (P>.36). In study 2, surgery had no effect on insulin sensitivity (P=.844) or use of diabetes medications. CONCLUSIONS These results demonstrate that decreasing VAT through omentectomy, alone or in combination with RYGB surgery, does not improve metabolic function in obese patients.

Thermogenesis in humans during overfeeding with medium-chain triglycerides

To test whether excess dietary energy as medium-chain triglycerides (MCT) affects thermogenesis differently from excess dietary energy as long chain triglycerides (LCT), ten male volunteers (ages 22 to 44) were overfed (150% of estimated energy requirement) liquid formula diets containing 40% of fat as either MCT or LCT. Each patient was studied for one week on each diet in a double-blind, crossover design. Resting metabolic rate (RMR) did not change during either week of overfeeding. The thermic response to food (TEF) was greater on day 1 following a meal (1,000 kcal) containing MCT than following an isocaloric meal containing LCT (8 +/- .8% v 5.8 +/- .8% of ingested energy; P less than .05). Moreover, the TEF observed after a 1,000 kcal meal containing MCT increased significantly to 12% (+/- 1.3%) overfeeding. The TEF of the 1,000 kcal meal containing LCT was unchanged by five days of LCT overfeeding (6.6 +/- 1.0% of ingested energy). Energy expenditure during a 20-hour continuous enteral infusion of the diet on day 7 was also significantly higher with the MCT diet than with the LCT diet (15.7 +/- 1.7% v 7.3 +/- .9% of ingested energy; P less than .05). Our results demonstrate that excess dietary energy as MCT stimulates thermogenesis to a greater degree than does excess energy as LCT. This increased energy expenditure, most likely due to lipogenesis in the liver, provides evidence that excess energy derived from MCT is stored with a lesser efficiency than is excess energy derived from dietary LCT.

Resident Work Hour Limits and Patient Safety

Objective:This study evaluates the effect of resident physician work hour limits on surgical patient safety. Background:Resident work hour limits have been enforced in New York State since 1998 and nationwide from 2003. A primary assumption of these limits is that these changes will improve patient safety. We examined effects of this policy in New York on standardized surgical Patient Safety Indicators (PSIs). Methods:An interrupted time series analysis was performed using 1995 to 2001 Nationwide Inpatient Sample data. The intervention studied was resident work hour limit enforcement in New York teaching hospitals. PSIs included rates of accidental puncture or laceration (APL), postoperative pulmonary embolus or deep venous thrombosis (PEDVT), foreign body left during procedure (FB), iatrogenic pneumothorax (PTX), and postoperative wound dehiscence (WD). PSI trends were compared pre- versus postintervention in New York teaching hospitals and in 2 control groups: New York nonteaching hospitals and California teaching hospitals. Results:A mean of 2.6 million New York discharges per year wereanalyzed with cumulative events of 33,756 (APL), 36,970 (PEDVT), 1,447 (FB), 10,727 (PTX), and 2,520 (WD). Increased rates over time (expressed per 1000 discharges each quarter) were observed in both APL (0.15, 95% confidence interval, 0.09–0.20, P<0.05) and PEDVT (0.43, 95% confidence interval, 0.03–0.83, P<0.05) after policy enforcement in New York teaching hospitals. No changes were observed in either control group for these events or New York teaching hospital rates of FB, PTX, or WD. Conclusions:Resident work hour limits in New York teaching hospitals were not associated with improvements in surgical patient safety measures, with worsening trends observed in APL and PEDVT corresponding with enforcement.

Is Roux-en-Y gastric bypass surgery the most effective treatment for type 2 diabetes mellitus in morbidly obese patients?

Type 2 diabetes mellitus (T2DM) has a very strong association with obesity. The aim of our study was to analyze the effects of Roux-en-Y gastric bypass (RYGB) surgery on the glucose metabolism in morbidly obese patients with T2DM. Morbidly obese patients (n = 117) with T2DM underwent measurements of fasting serum glucose and glycosylated hemoglobin (HbA1C) at baseline, 6 months, and 12 months after laparoscopic RYGB surgery. Logistic regression was used in both univariate and multivariate modeling to identify independent variables associated with complete resolution of T2DM. Twelve months after surgery, fasting plasma glucose decreased from a preoperative mean of 164 ± 55 mg/dL to 101 ± 38 mg/dL (P = .001) and HbA1C decreased from a preoperative mean of 7.7% ±1.5% to 6.0% ± 1.1% (P = .001). Resolution of T2DM was achieved in 72 patients (74%). All of the remaining 25 patients decreased the daily medication requirements. On univariate analysis, preoperative variables associated with resolution of T2DM were waist circumference, HbA1C, and absence of insulin treatment. Waist circumference (odds ratio 2.4; 95% confidence interval 1.4- 4.1; P = .001) and treatment without insulin (odds ratio 42.2; 95% confidence interval 4.3-417.3; P = .002) remained significant predictors of T2DM resolution in the multivariate logistic regression model after adjusting for covariates. Laparoscopic RYGBP resulted in significant resolution of T2DM. Peripheral fat distribution (smaller waist circumference) and absence of insulin treatment were independent and significant predictors of complete resolution of T2DM.