StomaphyX vs a sham procedure for revisional surgery to reduce regained weight in Roux-en-Y gastric bypass patients : a randomized clinical trial.

IMPORTANCE: Revisional laparoscopic surgery after Roux-en-Y gastric bypass (RYGB) has been linked to substantial complications and morbidity. OBJECTIVE: To investigate the safety and effectiveness of endoscopic gastric plication with the StomaphyX device vs a sham procedure for revisional surgery in RYGB patients to reduce regained weight. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center, randomized, single-blinded study from July 2009 through February 2011, evaluating revisional surgery using StomaphyX was conducted in patients with initial weight loss after RYGB performed at least 2 years earlier. We planned for 120 patients to be randomized 2:1 to multiple full-thickness plications within the gastric pouch and stoma using the StomaphyX device with SerosFuse fasteners or a sham endoscopic procedure and followed up for 1 year. The primary efficacy end point was reduction in pre-RYGB excess weight by 15% or more excess body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) loss and BMI less than 35 at 12 months after the procedure. Adverse events were recorded. RESULTS: Enrollment was closed prematurely because preliminary results indicated failure to achieve the primary efficacy end point in at least 50% of StomaphyX-treated patients. One-year follow-up was completed by 45 patients treated with StomaphyX and 29 patients in the sham treatment group. Primary efficacy outcome was achieved by 22.2% (10) with StomaphyX vs 3.4% (1) with the sham procedure (P < .01). Patients undergoing StomaphyX treatment experienced significantly greater reduction in weight and BMI at 3, 6, and 12 months (P ≤ .05). There was one causally related adverse event with StomaphyX, that required laparoscopic exploration and repair. CONCLUSIONS AND RELEVANCE: StomaphyX treatment failed to achieve the primary efficacy target and resulted in early termination of the study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00939055.

Bariatric surgery: a safe and effective conduit to cardiac transplantation.

BACKGROUND: Obesity and obesity-related co-morbidities, including advanced heart failure, are epidemic. Some of these patients will progress to require cardiac allografts as the only means of long-term survival. Unfortunately, without adequate weight loss, they may never be deemed acceptable transplant candidates. Often surgical weight loss may be the only effective and durable option for these complex patients. The objective of this study was to assess whether bariatric surgery is feasible and safe in patients with severe heart failure, which in turn, after adequate weight loss, would allow these patients to be listed for a heart transplant. METHODS: Four patients who underwent bariatric procedures, such as laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (SG), for the purpose of attaining adequate weight loss with the goal to improve their eligibility for orthotopic heart transplants are presented. RESULTS: All patients did well around the time of surgery, and 3 of the 4 progressed to receiving a heart transplant. The fourth patient will be listed pending attaining adequate weight loss. CONCLUSION: Bariatric surgery may be an important bridge to transplantation for morbidly obese patients with severe heart failure. With the appropriate infrastructure, bariatric surgery is a feasible and effective weight loss method in this population.

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.

Laparoscopic colorectal surgery is safe in the high-risk patient: a NSQIP risk-adjusted analysis.

BACKGROUND: Laparoscopic colectomy was considered initially to be contraindicated in patients at high risk for operative morbidity and mortality. We hypothesized that this procedure is safe to perform in high-risk patients, stratifying this risk using National VA Surgical Quality Improvement Program (NSQIP) algorithms. METHODS: A case-matched, comparative study was performed for high-risk veteran patients who underwent colectomy during the period October 2002-September 2004. Consecutive patients undergoing laparoscopic colectomy were matched to patients who underwent open colectomy during the same period for age, body mass index (BMI), procedure, and NSQIP-predicted risk. The groups were compared for risk-stratified, 30-day morbidity/mortality, length of stay (LOS), and operating time. RESULTS: Forty-five patients (23 laparoscopic and 22 open cases) were defined as at high risk for complications (predicted complication >0.15). The rate of major complications was significantly less in the laparoscopic group. There were 4 (18%) cases of postoperative respiratory failure in the open group and none in the laparoscopic group. There was no surgically related mortality in the laparoscopic group, compared with 2 deaths in the open group (P = .5). Median LOS was less in the laparoscopic group (5 days) compared with open (8 days) (P = .001). There were no significant differences in operating time or the number of minor complications. CONCLUSIONS: Our results suggest that the laparoscopic approach to colorectal diseases is safe in the population of patients at high risk for operative morbidity and mortality. Rather, this approach may represent a safer alternative to open access.

Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes.

The earliest events after the induction of hemorrhagic shock (HS) are complex and poorly understood. We have recently demonstrated that decreased tissue perfusion and hypoxia during HS lead to an increased phosphorylation of c-Jun N-terminal kinase (JNK) in vivo. The purpose of these investigations was to test the hypothesis that hypoxia activates JNK via Rac1-dependent reactive oxygen species (ROS) signaling. Mice subjected to HS and resuscitated with Ringer's ethyl pyruvate solution (REPS) or N-acetylcysteine (NAC), two scavengers of ROS, demonstrated decreased levels of phosphorylated JNK. Exposure of primary mouse hepatocytes in culture to 1% oxygen led to increased production of ROS and phosphorylation of JNK. The duration of hypoxia correlated with the level of generation of ROS and JNK activation. The phosphorylation of JNK was attenuated in the presence of ROS scavengers or the nicotinamide adenosine dinucleotide phosphate [NDA(P)H] oxidase inhibitor, diphenyleneiodonium (DPI). In addition, hypoxia increased activation of Rac1. Inhibition of Rac1 activation by adenoviral gene transfer of dominant-negative Rac1 (AdRac1) attenuated both ROS formation and JNK activation. Together, these data suggest that ROS generation during hypoxia in the liver directly leads to JNK activation in a Rac1-dependent process.

Carbon monoxide prevents multiple organ injury in a model of hemorrhagic shock and resuscitation.

The insult from severe hemorrhage is a multifactorial injury involving ischemia/reperfusion with inflammatory dysfunction. Our laboratories and others have demonstrated that the administration of exogenous carbon monoxide (CO) at low concentrations provides cytoprotection in vivo and in vitro. The purpose of these investigations was to test the hypothesis that CO protects against hemorrhagic shock- and resuscitation-induced systemic inflammation and end-organ damage. C57BL/6 mice underwent anesthesia and arterial cannulation. Mice were bled to reach a mean arterial pressure (MAP) of 25 mmHg and were maintained at this pressure for 2.5 h. Mice were then resuscitated with shed blood plus two times the volume of shed blood with Ringer's lactate. Sham animals were not bled. Additionally, mice were maintained in room air or in an environment of CO (250 parts per million). Primary mouse hepatocytes were harvested and used for in vitro cell viability and ATP measurement. These data demonstrate that delivery of a low concentration of inhaled CO protects against the development of end-organ injury decreases serum levels of inflammatory cytokines and increases serum levels of the anti-inflammatory cytokine IL-10. Additionally, CO paradoxically abrogates hemorrhage-induced hepatic cellular hypoxia. Furthermore, CO protected mouse hepatocytes from hypoxia-induced death while maintaining normal ATP levels. CO protects against systemic effects of hemorrhagic shock and resuscitation. The precise cellular mechanisms involved require further elucidation. CO may prove to be an adjunctive therapy that could be instituted rapidly and with ease as an out-of-hospital therapeutic modality for severe blood loss after trauma.

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.

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

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-kappaB) transcription factor is essential for SMC proliferation in vitro and is activated by vascular injury in vivo. Activation of NF-kappaB is controlled by several upstream regulators, including the inhibitors of kappa B (IkappaB). These proteins bind to and keep NF-kappaB inactivated. The purpose of this study was to determine whether adenoviral gene transfer of a mutated IkappaBalpha super-repressor (AdIkappaBalphaSR) 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 AdIkappaBalphaSR or adenoviral beta-galactosidase (AdLacZ). Untreated SMC or SMC infected with AdLacZ or AdIkappaBalphaSR were stimulated with 10% fetal bovine serum, interleukin-1beta, or tumor necrosis factor-alpha. Electrophoretic mobility shift assays were used to assay for NF-kappaB activation. Protein levels of IkappaBalpha 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: AdIkappaBalphaSR inhibited the development of intimal hyperplasia by 49% (P <.05). Infection with AdIkappaBalphaSR significantly suppressed in vitro SMC proliferation when stimulated with serum, interleukin 1, or tumor necrosis factor alpha, and did not result in cell death. Inhibition of proliferation was associated with increased p21(Cip1/Waf1) and p27(Kip1) protein levels. CONCLUSIONS: Gene transfer of IkappaBalpha 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 IkappaBalpha may be a future therapeutic option in treatment of vascular diseases.

A role for angiotensin II in the activation of extracellular signal-regulated kinases in the liver during hemorrhagic shock.

Hemorrhagic shock (HS) is a complex process that initiates a global stress response. However, the earliest signaling pathways responsible for initiating this response remain unidentified. We have investigated the involvement of the extracellular signal-regulated kinases (ERK 1/2; also known as p42/44) and their activation in the liver by angiotensin II in the early signal transduction after HS. Hemorrhage of mice to 25 mmHg for 30 min was associated with the activation of ERK 1/2 in the liver, and this was accompanied by a 6.7-fold elevation of circulating angiotensin II levels. Similar results were obtained in rats. Both the angiotensin II levels and ERK 1/2 phosphorylation were suppressed by administration of an angiotensin-converting enzyme inhibitor peptide. Plasma from shocked rats, but not shocked rats treated with the angiotensin-converting enzyme inhibitor, increased ERK 1/2 phosphorylation in cultured hepatocytes. Together, these data suggest that angiotensin II is an important stimulus for ERK 1/2 activation in the liver during HS.