Frederick J. Brody

Thymosin-β4 (Tβ4) Blunts PDGF-Dependent Phosphorylation and Binding of AKT to Actin in Hepatic Stellate Cells

Hepatic stellate cell transdifferentiation is a key event in the fibrogenic cascade. Therefore, attempts to prevent and/or revert the myofibroblastic phenotype could result in novel therapeutic approaches to treat liver cirrhosis. The expression of platelet-derived growth factor (PDGF)-β receptor and the proliferative response to platelet-derived growth factor-ββ (PDGF-ββ) are hallmarks of the transdifferentiation of hepatic stellate cells (HSC). In this communication, we investigated whether thymosin-β4 (Tβ4), a chemokine expressed by HSC could prevent PDGF-BB-mediated proliferation and migration of cultured HSC. Using early passages of human HSC, we showed that Tβ4 inhibited cell proliferation and migration and prevented the expression of PDGF-β receptor (PDGF-βr), α-smooth muscle actin and α1(I) collagen mRNAs. Tβ4 also inhibited the reappearance of PDGF-βr after its PDGF-BB-dependent degradation. These PDGF-dependent events were associated with the inhibition of AKT phosphorylation at both T308 and S473 amino acid residues. The lack of AKT phosphorylation was not due to the inhibition of PDGF-βr phosphorylation, the activation of phosphoinositide 3-kinase (PI3K), pyruvate dehydrogenase kinase isozyme 1 (PDK1), and mammalian target of rapamycin (mTOR). We found that PDGF-BB induced AKT binding to actin, and that Tβ4 prevented this effect. Tβ4 also prevented the activation of freshly isolated HSC cultured in the presence of Dulbeccos modified Eagles medium or Dulbeccos minimal essential medium containing 10% fetal bovine serum. In conclusion, overall, our findings suggest that Tβ4 by sequestering actin prevents binding of AKT, thus inhibiting its phosphorylation. Therefore, Tβ4 has the potential to be an antifibrogenic agent.

Review of robotic versus conventional laparoscopic surgery.

In 2000, the robotic platform was introduced to surgeons to take advantage of the instrument’s three-dimensional visualization and articulating wrists. Today, robotic surgery is utilized across a broad array of applications. As the number and types of robotic procedures have increased, the degree of scrutiny has increased simultaneously regarding the role of robotics in the operating room. Even mainstream media articles have focused on the widespread adoption of the robotic platform. At the present time, many reports in the scientific literature document clinical outcomes utilizing robotic techniques relative to open procedures. These reports focus predominantly on the safety and feasibility of the robotic platform. However, only a limited number of reports have compared clinical outcomes of surgeries performed with robotic technologies versus conventional laparoscopy. This review provides a summary of the recent literature comparing the clinical outcomes of robot-assisted versus conventional laparoscopic surgery across an array of abdominal surgical procedures. This article also addresses the timely issues of cost, outcomes, and overall utility of the robotic platform within these disciplines. Where there is no robust comparative cost data available, it is necessarily omitted. Otherwise, relevant cost data have been included within each section.

Resistin expression correlates with steatohepatitis in morbidly obese patients.

BackgroundMorbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients.MethodsBlood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student’s t test.ResultsResistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (>4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, pxa0=xa00.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (pxa0<xa00.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (pxa0=xa00.051).ConclusionsIn morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis.

Changes in GIP gene expression following bariatric surgery

BackgroundAfter bariatric surgery, there is a significant improvement in type 2 diabetes (T2D). T2D has been linked to incretins, including glucose-dependent insulinotropic polypeptide (GIP). Analysis of bariatric surgery patients may help to understand the link between GIP and T2D.MethodsTwenty-three morbidly obese patients underwent Roux-en-Y gastric bypass (RYGB) or gastric banding. Overall, there were 12 RYGB (5 T2D; 7 nondiabetic) patients and 11 gastric band (7 T2D; 4 nondiabetic) patients. Preoperative and postoperative blood samples were collected. Total RNA was extracted, cDNA synthesized, and real-time quantitative PCR were used to quantify gene expression. Student’s t test was used for statistical analysis.ResultsPostoperatively, T2D resolved or improved in 83.3xa0% (10/12) of the diabetic patients. Six (4 RYGB, 2 bands) patients discontinued hypoglycemic medications and four (3 RYGB, 1 band) patients discontinued the majority of their hypoglycemic agents. The remaining two diabetic patients (bands) showed no improvement. Postoperative GIP gene expression increased 4.36-fold (pxa0=xa00.02) in diabetic RYGB patients, whereas diabetic band patients increased 1.4-fold (pxa0=xa00.25). All diabetic patients with either resolution or improvement of T2D, had a 3.4-fold increase (pxa0=xa00.01) but nonresponders decreased 0.69-fold (pxa0=xa00.41). Nondiabetic RYGB patients increased 2.21-fold (pxa0=xa00.07) versus a 0.81-fold (pxa0=xa00.37) decrease of nondiabetic band patients.ConclusionsThis is one of the initial studies that show a significant increase in GIP gene expression following a RYGB. This increase correlates with the clinical resolution of T2D. The anatomical changes after RYGB may account for these changes. Based on this data, GIP may be a key peptide in the “foregut hypothesis” for resolution of T2D.

Celiac artery compression after a gastric bypass.

Median arcuate ligament (MAL) syndrome or celiac artery compression occurs secondary to diaphragmatic compression of the celiac artery and the corresponding neural structures of the celiac plexus. Typically, patients present with postprandial abdominal pain, nausea, vomiting, and weight loss. Diagnostically, various radiologic studies are used to document impingement of the celiac artery including ultrasound, computed tomography, aortograms, and magnetic resonance imaging. Historically, open approaches to the aorta and the celiac artery are performed to release the MAL and relieve compression of the celiac artery and the plexus. Laparoscopic approaches are now utilized to divide the MAL. This study describes a patient who underwent a successful laparoscopic Roux-en-Y gastric bypass and lost 100 lbs over a 2-year postoperative period. Subsequently, the patient developed postprandial abdominal pain associated with nausea. She underwent a computed tomogram that diagnosed celiac compression and then a dynamic ultrasound that showed elevated velocities with deep expiration. Ultimately, a laparoscopic MAL release with division of the celiac plexus was performed. At 10 months postoperatively, the patient remains asymptomatic. To our knowledge, this report documents a rare case of CAC after Roux-en-Y gastric bypass. On the basis of this report, CAC should be considered in the differential diagnosis of postprandial abdominal pain in patients after bariatric surgery.

Median arcuate ligament release

PT Harjola performed the first median arcuate ligament (MAL) release in 1963. In 1965, Dunbar published a larger series of 15 patients after an MAL release. Over the ensuing 5 decades, numerous articles have appeared that discuss various topics regarding MAL syndrome including diagnostic modalities, outcomes, and surgical techniques. However, the overwhelming majority of these reports entail small case series with limited follow-up. Few series document large cohorts with follow-up beyond a few months. Radiologically, compression of the celiac artery secondary to the MAL may be found as a normal variant in more than 20% of patients. Based on these findings, MAL syndrome may be a normal variant in a patient with abdominal pain. Therefore, a definitive diagnosis of MAL compression requires evidence of radiologic compression and clinical symptoms. These symptoms may include postprandial pain, nausea, vomiting, and weight loss. Presently, there are few studies that provide any preoperative factors or tests that accurately predict the impact of surgical intervention with clinical outcomes. After establishing a diagnosis of MAL syndrome, surgical intervention includes endovascular treatments with angioplasty or stent placement, MAL releases, arterial bypasses, or some type of hybrid mixture of these procedures. Historically, a MAL release has been performed through an open incision, but now laparoscopic approaches are used. To date, 38 patients have undergone a laparoscopic MAL release at our institution. The diagnostic workup and laparoscopic technique for a MAL release at our institution are presented. An overview of the clinical outcomes is provided as well.

A novel single agent for nutritional supplementation following roux-en-Y gastric bypass

BACKGROUNDnDuodenal bypass and intestinal malabsorption from Roux-en-Y gastric bypass (RYGB) can exacerbate known nutritional deficiencies of morbidly obese patients and worsen symptoms. Preventatively, most bariatric patients use postoperative nutritional supplementation. This study evaluated Nuvista(®) (Nutricia North America, Rockville, MD) and its potential as an adequate single nutritional supplement.nnnSUBJECTS AND METHODSnFrom October 2009 to June 2010, 25 patients enrolled in a prospective, consecutive pilot study. Each underwent laparoscopic RYGB. The study group consumed two packs of Nuvista daily. The control group received standard nutritional supplements. Both groups had the same postoperative diet. Laboratory and demographics were compared at baseline and 12 months. Statistical analysis included paired t test, and a value of P<.05 was significant.nnnRESULTSnThe study and control groups (16 and 9 patients, respectively) had statistically similar demographic profiles. Both groups had preoperative elevations of hemoglobin A1c (HbA1c) (6.2% and 6.2%, respectively), low-density lipoprotein (LDL) (108.2u2009mg/dL and 199.2u2009mg/dL, respectively), and high-density lipoprotein (HDL) (55.1u2009mg/dL and 48.0u2009mg/dL, respectively) and deficiencies in vitamin D with respective mean values of 20.6u2009ng/mL and 22.7u2009ng/mL (normal range, 30-100u2009ng/mL). Postoperatively, the study group had significant increases in phosphorus (P=.02), iron (P=.03), vitamin D (P=.05), zinc (P=.01), and HDL (P≤.01) and significant decreases in body mass index (BMI) (P≤.01), creatinine (P=.02), HbA1c (P=.01), triglycerides (P≤.01), and LDL (P≤.01). The control group had a significant increase in HDL (P=.01) and significant decreases in BMI (P≤.01), hemoglobin (P=.01), creatinine (P≤.01), albumin (P=.05), HbA1c (P=.05), zinc (P≤.01), triglycerides (P=.03), and LDL (P=.01). No change in mean parathyroid hormone value was seen.nnnCONCLUSIONSnNuvista can provide adequate supplementation to bariatric patients 12 months after RYGB. Lifelong biochemical follow-up is necessary to personalize the diet and nutritional supplementation to compensate for the pathophysiologic changes of the gastric bypass.

Laparoscopic bilateral cortical-sparing adrenalectomy for pheochromocytoma.

IntroductionSince laparoscopic adrenalectomy for pheochromocytoma was reported in 1992, the laparoscopic technique has largely replaced the open approach [4]. Numerous studies have demonstrated that the laparoscopic approach is associated with decreased blood loss, shorter hospitalization, faster recovery, and lower cost [1]. Conversion rates are reported at less than 5.5xa0%, yet concern still exists that intraoperative hypertensive crisis may be more severe with laparoscopy due to increased intraabdominal pressure [3]. Bilateral pheochromocytomas are common in patients with multiple endocrine neoplasia type 2 (MEN 2) or von Hippel-Lindau (VHL) disease. Total adrenalectomy commits the patient to lifelong steroid hormone replacement and the risk of Addisonian crisis after bilateral adrenalectomy [5]; [8]. The risk of malignant pheochromocytomas in patients with or without MEN 2 or VHL is low. The current literature supports cortical-sparing adrenalectomy in patients with bilateral pheochromocytomas [2, 7, 10]. This video presents a patient with bilateral pheochromocytomas who underwent bilateral laparoscopic cortical-sparing adrenalectomies.MethodsA 40-year-old female presented to her primary care physician with a history of a hypertensive crisis that required an emergent cesarean section. Her workup revealed elevated urinary metanephrines, and a CT scan showed a left adrenal lesion measuring 3.9xa0cm and a right adrenal lesion measuring 2.7xa0cm. After undergoing alpha blockade, she was consented for bilateral partial adrenalectomies. A left partial adrenalectomy was performed first using four ports. The ports were then closed and the patient was repositioned in a left lateral decubitus position for a subsequent right partial adrenalectomy.ResultsThe patient had an uncomplicated hospital course and was discharged home on postoperative day 4. She returned for follow-up at 2xa0weeks and 1xa0month and had returned to her normal activities. Testing for MEN and von Hippel-Lindau was both negative. Her electrolyte and cortisol levels normalized, and she was weaned off her postoperative steroids by week five. At 1-year follow-up, she remains off steroids and no longer requires anti-hypertensive medications.ConclusionLaparoscopic adrenalectomy is the gold standard for removal of benign lesions of the adrenal gland. Bilateral pheochromocytomas are more common in the presence of hereditary conditions such as MEN and von Hippel-Lindau and should be ruled out [8, 10]. The risk of Addisonian crisis and lifelong steroid replacement should prompt cortical preservation with bilateral disease [9]. Laparoscopic bilateral partial adrenalectomies should be considered in patients with bilateral pheochromocytomas [6]. Finally, all patients undergoing pheochromocytoma excision require lifelong follow-up to monitor for recurrence.

Laparoscopic Puestow: lateral pancreaticojejunostomy.

IntroductionChronic pancreatitis is a painful inflammatory disease that leads to progressive and irreversible destruction of pancreatic parenchyma [1]. A lateral pancreaticojejunostomy, also known as the Puestow procedure, is performed for symptomatic chronic pancreatitis associated with a dilated pancreatic duct secondary to calcifications or strictures [4]. An open approach is used traditionally due to the complexity of the case, and there have only been a handful of laparoscopic case reports [2]. This video depicts a laparoscopic lateral pancreaticojejunostomy for chronic pancreatitis.MethodsA 45-year-old gentleman with a 20-year history of chronic alcohol abuse presented with diffuse abdominal pain. His pain was worse postprandially and associated with loose stools. A computed tomography scan revealed multiple calcified deposits within the body and tail of the pancreas, and a dilated pancreatic duct measuring 1.4xa0cm with a proximal obstructing calcified stone. A 5-port foregut technique was used, and a 15-cm pancreatic ductotomy was performed with an ultrasonic scalpel. Calcified stones were cleared from the duct, and a roux-en-y pancreaticojejunostomy was performed using a hand-sewn technique.ResultsThe patient had a relatively uncomplicated hospital course with return of bowel function on postoperative day 4. His patient-controlled analgesic device was discontinued on post operative day 3. He was ambulating, tolerating a regular diet and discharged home on postoperative day 5. At 12- and 26-month follow-up, he remains off narcotics, but still requires 1–2 tabs of pancreatic enzyme replacement per meal. Most importantly, he has not had any alcohol for over 2xa0years.ConclusionThe two primary goals in treating chronic pancreatitis include long-term pain relief and improvements in quality of life [3]. For patients with chronic pancreatitis and a dilated pancreatic duct, a laparoscopic lateral pancreaticojejunostomy may be an effective approach to decrease pain and improve quality of life.

Minimally invasive repair of a late stricture in a reversed gastric tube

Ingestion of caustic agents may result in severe scarring and stricture formation of the esophagus. Reversed gastric tube esophagoplasty is an option for definitive surgical management of severe esophageal stricture refractory to medical treatment. Delayed complications from this procedure have rarely been reported. We present a case involving a patient who developed a delayed gastric stricture three decades after receiving a reversed gastric tube esophagoplasty. A historical review of the reversed gastroplasty is presented as well.