Carol McCloskey

Perioperative safety in the longitudinal assessment of bariatric surgery.

BACKGROUND To improve decision making in the treatment of extreme obesity, the risks of bariatric surgical procedures require further characterization. METHODS We performed a prospective, multicenter, observational study of 30-day outcomes in consecutive patients undergoing bariatric surgical procedures at 10 clinical sites in the United States from 2005 through 2007. A composite end point of 30-day major adverse outcomes (including death; venous thromboembolism; percutaneous, endoscopic, or operative reintervention; and failure to be discharged from the hospital) was evaluated among patients undergoing first-time bariatric surgery. RESULTS There were 4776 patients who had a first-time bariatric procedure (mean age, 44.5 years; 21.1% men; 10.9% nonwhite; median body-mass index [the weight in kilograms divided by the square of the height in meters], 46.5). More than half had at least two coexisting conditions. A Roux-en-Y gastric bypass was performed in 3412 patients (with 87.2% of the procedures performed laparoscopically), and laparoscopic adjustable gastric banding was performed in 1198 patients; 166 patients underwent other procedures and were not included in the analysis. The 30-day rate of death among patients who underwent a Roux-en-Y gastric bypass or laparoscopic adjustable gastric banding was 0.3%; a total of 4.3% of patients had at least one major adverse outcome. A history of deep-vein thrombosis or pulmonary embolus, a diagnosis of obstructive sleep apnea, and impaired functional status were each independently associated with an increased risk of the composite end point. Extreme values of body-mass index were significantly associated with an increased risk of the composite end point, whereas age, sex, race, ethnic group, and other coexisting conditions were not. CONCLUSIONS The overall risk of death and other adverse outcomes after bariatric surgery was low and varied considerably according to patient characteristics. In helping patients make appropriate choices, short-term safety should be considered in conjunction with both the long-term effects of bariatric surgery and the risks associated with being extremely obese. (ClinicalTrials.gov number, NCT00433810.)

Safety and Efficacy of Bariatric Surgery in Morbidly Obese Patients with Severe Systolic Heart Failure

Morbid obesity (MO) is a risk factor for congestive heart failure (CHF). The presence of MO impairs functional status and disqualifies patients for cardiac transplantation. Bariatric surgery (BAS) is a frontline, durable treatment for MO; however, the safety and efficacy of BAS in advanced CHF is unknown.

Tissue Hypoxia Activates Jnk In The Liver During Hemorrhagic Shock

The earliest signaling pathways responsible for initiating the systemic response to hemorrhagic shock (HS) remain poorly characterized. We have investigated the involvement of the mitogen-activated protein (MAP) kinase C-JUN N-terminal kinase (JNK) and its activation in the liver as an early response to tissue hypoxia soon after the initiation of hemorrhage. In the present studies, hemorrhage of mice to 25 mmHg for 30 min resulted in a significant (2.1-fold) increase in JNK phosphorylation within the liver. Results were similar in rats hemorrhaged to 40 mmHg for 1 h. Hypoxia alone, replicated by warm isolated hepatic ischemia in vivo or hepatocytes cultured under 1% oxygen, also resulted in JNK phosphorylation. Finally, preservation of tissue perfusion and oxygenation by pretreatment with a blood-soluble drag-reducing polymer (DRP) in the rat HS model prevented phosphorylation of JNK in the liver. These results identify tissue hypoxia as a key factor in activating early signaling events in the liver following hemorrhage, as measured by JNK phosphorylation.

Baseline characteristics of participants in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study

Baseline characteristics of participants in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study Steven H. Belle, Ph.D., M.Sc.Hyg.*, Paul D. Berk, M.D., William H. Chapman, M.D., Nicholas J. Christian, Ph.D., Anita P. Courcoulas, M.D., M.P.H., F.A.C.S., Greg F. Dakin, M.D., David R. Flum, M.D., M.P.H., F.A.C.S., Mary Horlick, M.D., Wendy C. King, Ph.D., Carol A. McCloskey, M.D., James E. Mitchell, M.D., Emma J. Patterson, M.D., John R. Pender, M.D., Kristine J. Steffen, Pharm.D., Ph.D., Richard C. Thirlby, M.D., Bruce M. Wolfe, M.D., F.A.C.S., Susan Z. Yanovski, M.D., for The LABS Consortium University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania Columbia University Medical Center, New York, New York East Carolina University, Greenville, North Carolina University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Weill Cornell University Medical Center, New York, New York University of Washington, Seattle, Washington National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland Neuropsychiatric Research Institute, Fargo, North Dakota Legacy Good Samaritan Hospital, Portland, Oregon Virginia Mason Medical Center, Seattle, Washington Oregon Health and Science University, Portland, Oregon Received January 23, 2013; accepted January 29, 2013

The hepatocyte as a microbial product-responsive cell.

Much research has focused on the responses to microbial products of immune cells such as monocytes, macrophages, and neutrophils. Although the liver is a primary response organ in various infections, relatively little is known about the antimicrobial responses of its major cell type, the hepatocyte. It is now known that the recognition of bacteria occurs via cell-surface proteins that are members of the Toll-like receptor (TLR) family. In addition, lipopolysaccharide (LPS) is bound by circulating LPS-binding protein (LBP) and presented to cell-surface CD14, which in turn interacts with TLR and transduces an intracellular signal. We investigated the CD14 and TLR2 responses of whole liver and isolated hepatocytes, and demonstrated that these cells can be induced to express the molecules necessary for responses to both Gram-positive and Gram-negative bacteria. Our findings may have clinical implications for pathological states such as sepsis.

Overexpression of mutated IκBα inhibits vascular smooth muscle cell proliferation and intimal hyperplasia formation

Abstract Purpose Vascular injury and inflammation are associated with elaboration of a number of cytokines that signal through multiple pathways to act as smooth muscle cell (SMC) mitogens. Activation of the nuclear factor–kappa B (NF-κB) transcription factor is essential for SMC proliferation in vitro and is activated by vascular injury in vivo. Activation of NF-κB is controlled by several upstream regulators, including the inhibitors of kappa B (IκB). These proteins bind to and keep NF-κB inactivated. The purpose of this study was to determine whether adenoviral gene transfer of a mutated IκBα super-repressor (AdIκBα SR ) could inhibit development of intimal hyperplasia in vivo and to investigate how over-expression of this construct influences in vitro SMC proliferation and cell cycle regulatory proteins. Methods A rat carotid injury model was used to study prevention of intimal hyperplasia. Arteries were assayed 14 days after injury and infection with AdIκBαSR or adenoviral β-galactosidase (AdLacZ). Untreated SMC or SMC infected with AdLacZ or AdIκBαSR were stimulated with 10% fetal bovine serum, interleukin-1β, or tumor necrosis factor-α. Electrophoretic mobility shift assays were used to assay for NF-κB activation. Protein levels of IκBα and cyclin-dependent kinase inhibitors p21 Cip1/Waf1 and p27 Kip1 were determined with Western blot analysis. Proliferation was measured with 3 H-thymidine incorporation assays. Results AdIκBαSR inhibited the development of intimal hyperplasia by 49% ( P Cip1/Waf1 and p27 Kip1 protein levels. Conclusions Gene transfer of IκBα super-repressor inhibited development of intimal hyperplasia in vivo and SMC proliferation in vitro. The antiproliferative activity may be related to cell cycle arrest through upregulation of the cyclin-dependent kinase inhibitors p21 and p27. Overexpression of IκBα may be a future therapeutic option in treatment of vascular diseases.

The Effect of Gastric Bypass on the Pharmacokinetics of Serotonin Reuptake Inhibitors

OBJECTIVE Morbidly obese patients frequently present with mood and anxiety disorders, which are often treated with serotonin reuptake inhibitors (SRIs). Having observed that patients treated with SRIs frequently relapse after Roux-en-Y gastric bypass surgery, the authors sought to assess whether SRI bioavailability is reduced postoperatively. METHOD Twelve gastric bypass candidates treated with an SRI for primary mood or anxiety disorders were studied prospectively. Timed blood samples for SRI plasma levels were drawn for pharmacokinetic studies before surgery and 1, 6, and 12 months afterward. Maximum concentration, time to maximum concentration, and area under the concentration/time curve (AUC) were determined. RESULTS In eight of the 12 patients, AUC values 1 month after surgery dropped to an average of 54% (SD=18) of preoperative levels (range=36%-80%); in six of these patients, AUC values returned to baseline levels (or greater) by 6 months. Four patients had an exacerbation of depressive symptoms, which resolved by 12 months in three of them. Three of the four patients had a reduced AUC level at 1 month and either gained weight or failed to lose weight between 6 and 12 months. Normalization of the AUC was associated with improvement in symptom scores. CONCLUSIONS Patients taking SRIs in this study were at risk for reduced drug bioavailability 1 month after Roux-en-Y gastric bypass. The authors recommend close psychiatric monitoring after surgery.

Preoperative weight loss in high-risk superobese bariatric patients: a computed tomography-based analysis.

BACKGROUND Superobesity, through organomegaly, excessive adiposity, and associated severe co-morbidities, is a recognized risk factor for bariatric surgery. Our study examined the utility of preoperative weight loss with a liquid low-calorie diet (LCD) as a method of risk reduction. METHODS All patients with a body mass index (BMI) >50 kg/m(2) were instructed to consume a LCD (800 kcal/d) with the goal of losing ≥10% of their body weight. The co-morbidities were monitored. The abdominal wall depth and cross-sectional areas of subcutaneous adipose tissue (SAT) at 12 and 20 cm below the costal margin, visceral adipose tissue (VAT), and liver volume were measured, using computed tomography, at baseline and after completion of the LCD. Laparoscopic gastric bypass was performed in all patients. RESULTS The study included 30 patients (27 men and 3 women) with a mean age of 53 years (range 34-53). The mean BMI was reduced from 56 kg/m(2) (range 50-69) at baseline to 49 kg/m(2) (range 43-60) after an average of 9 weeks of the LCD. The VAT decreased from a mean of 388 cm(2) to 342 cm(2). The abdominal wall depth decreased from 3.6 to 3.2 cm at 12 cm below the costal margin and from 3.7 to 3.4 cm at 20 cm. The mean SAT at both 12 and 20 cm below the costal margin had decreased from 577 cm(2) and 687 cm(2) to 509 cm(2) and 614 cm(2), respectively. The liver volume was reduced by 18%. All co-morbidities were well controlled at LCD completion. No patient died, and 2 minor complications occurred postoperatively. CONCLUSION The results of our study have shown that preoperative LCD is a safe and effective tool leading to a significant decrease in liver volume and abdominal wall depth, as well as a reduction in both VAT and SAT. Its use might contribute to improved short-term surgical outcomes in high-risk superobese patients.

Type 2 Diabetes Remission Rates After Laparoscopic Gastric Bypass and Gastric Banding: Results of the Longitudinal Assessment of Bariatric Surgery Study

OBJECTIVE The goals of this study were to determine baseline and postbariatric surgical characteristics associated with type 2 diabetes remission and if, after controlling for differences in weight loss, diabetes remission was greater after Roux-en-Y gastric bypass (RYGBP) than laparoscopic gastric banding (LAGB). RESEARCH DESIGN AND METHODS An observational cohort of obese participants was studied using generalized linear mixed models to examine the associations of bariatric surgery type and diabetes remission rates for up to 3 years. Of 2,458 obese participants enrolled, 1,868 (76%) had complete data to assess diabetes status at both baseline and at least one follow-up visit. Of these, 627 participants (34%) were classified with diabetes: 466 underwent RYGBP and 140 underwent LAGB. RESULTS After 3 years, 68.7% of RYGBP and 30.2% of LAGB participants were in diabetes remission. Baseline factors associated with diabetes remission included a lower weight for LAGB, greater fasting C-peptide, lower leptin-to-fat mass ratio for RYGBP, and a lower hemoglobin A1c without need for insulin for both procedures. After both procedures, greater postsurgical weight loss was associated with remission. However, even after controlling for differences in amount of weight lost, relative diabetes remission rates remained nearly twofold higher after RYGBP than LAGB. CONCLUSIONS Diabetes remission up to 3 years after RYGBP and LAGB was proportionally higher with increasing postsurgical weight loss. However, the nearly twofold greater weight loss–adjusted likelihood of diabetes remission in subjects undergoing RYGBP than LAGB suggests unique mechanisms contributing to improved glucose metabolism beyond weight loss after RYGBP.

The role of hepatic type 1 plasminogen activator inhibitor (PAI‐1) during murine hemorrhagic shock

Hemorrhagic shock (HS) followed by resuscitation (HS‐R) is characterized by profound physiological changes. Even if the patient survives the initial blood loss, these poorly understood changes can lead to morbidity. One of the tissues most often affected is liver. We sought to recognize specific hepatic changes induced by this stressor to identify targets for therapeutic intervention. Gene array analyses using mouse liver mRNAs were used to identify candidate genes that contribute to hepatic damage. To verify the role of one of the genes identified using the arrays, mice were subjected to HS‐R, and multiple parameters were analyzed. A profound increase in plasminogen activator inhibitor type 1 (PAI‐1) mRNA was observed using hepatic mRNAs from C57Bl/6 mice after HS, both with and without resuscitation. Constitutive loss of PAI‐1 resulted in notable tissue preservation and lower (P < .05) alanine aminotransferase (ALT) levels. Fibrin degradation products (FDPs) and interleukins 6 and 10 (IL‐6 and IL‐10) were unaffected by loss of PAI‐1; however, enhanced urokinase activity, an elevation of active hepatocyte growth factor (HGF), an increase in unprocessed transforming growth factor‐β1 (TGF‐β1), and retention of ERK phosphorylation after HS‐R were associated with improved hepatic function. In conclusion, PAI‐1 protein is a negative effector of hepatic damage after HS‐R through its influence on classic regulators of hepatic growth, as opposed to its role in fibrinolysis. (HEPATOLOGY 2005;42:390–399.)