Marty Zdichavsky

Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes

Objective Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO), opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion. Methods In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro. Results Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, −15% and −40%, respectively; p < 0.01 both), reduced adiponectin expression (−20%; p < 0.05), markedly reduced adiponectin release (−60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release. Conclusions The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.

Metabolic Signatures of Cultured Human Adipocytes from Metabolically Healthy versus Unhealthy Obese Individuals

Background and Aims Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO) can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO. Methods 10 insulin-resistant (IR) vs. 10 insulin-sensitive (IS) non-diabetic morbidly obese (BMI >40 kg/m2) Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma. Results/Interpretation Among others, aspartate was reduced intracellularly to one third (p = 0.0039) in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHOs and MHOs adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs) were lower in MUHOs extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA) metabolism was found: 15(S)-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014), AA (1.5-fold; p = 0.0055) and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033) were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO. Conclusion/Interpretation We identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO.

Impact of risk factors for prolonged operative time in laparoscopic cholecystectomy.

Objective Laparoscopic cholecystectomy (LC) remains one of the most frequent surgical therapies for symptomatic gallstone disorders. Prolonged operative time is frequently associated with increased complication rates. The aim of this study was to identify the risk factors for prolonged operative times to minimize perioperative morbidity and optimize clinical management. Methods A total of 677 consecutive patients underwent LC. The exclusion criteria were conversion to an open procedure, intraoperative cholangiography, and liver cirrhosis (n=81). Data were analyzed retrospectively with respect to age, sex, BMI, ASA score, previous abdominal surgery, preoperative endoscopic retrograde cholangiopancreatography, acute cholecystitis, and surgeon’s experience. Univariate and multivariate analyses were performed. Results A total of 596 patients, mean (±SD) age of 52.2±16.7 years, were analyzed. In all, 29% of the patients were obese (BMI≥30 kg/m2); 11% had ASA III. Five percent of patients had undergone previous upper abdominal surgery. Overall, 105/596 patients had an acute cholecystitis. Residents of general surgery performed 58% of all operations. The median operative time was 80 min (range, 15–281 min). No statistical significance was found between intraoperative and postoperative complications by surgeon’s experience. Statistically, independent preoperative predictors for prolonged operative time as identified through multivariate analysis were acute cholecystitis, obesity, previous upper abdominal surgery, male sex, and low degree of surgical expertise. Conclusion The risk for prolonged operative times in LC can be assessed on the basis of patients’ characteristics. Assessment of these factors not only helps to optimize the individual outcome for each patient but also improves the decision process toward operative training for junior surgeons.

Circadian Expression of Clock- and Tumor Suppressor Genes in Human Oral Mucosa

Purpose: Circadian rhythms are daily oscillations of multiple biological processes driven by endogenous clocks. Imbalance of these rhythms has been associated with cancerogenesis in humans. To further elucidate the role circadian clocks have in cellular growth control, tumor suppression and cancer treatment, it is revealing to know how clock genes and clock-controlled genes are regulated in healthy humans. Materials and Methods: Therefore comparative microarray analyses were conducted investigating the relative mRNA expression of clock genes throughout a 24-hour period in cell samples obtained from oral mucosa of eight healthy diurnally active male study participants. Differentially expressed selected genes of interest were additionally evaluated using qRT-PCR. Results: Microarray analysis revealed 33 significant differentially regulated clock genes and clock- controlled genes, throughout a one day period (6.00h, 12.00h, 18.00h, 24.00h). Hereof were 16 clock genes and 17 clock- controlled genes including tumor suppressor- and oncogenes. qRT-PCR of selected genes of interest, such as hPER2, hCRY1, hBMAL1, hCCRN4L and hSMAD5 revealed significant circadian regulations. Conclusion: Our study revealed a proper circadian regulation profile of several clock- and tumor suppressor genes at defined points in time in the participants studied. These findings could provide important information regarding genes displaying the same expression profile in the gastrointestinal tract amounting to a physiological expression profile of healthy humans. In the future asynchronous regulations of those genes might be an additional assistant method to detect derivations distinguishing normal from malignant tissue or assessing risk factors for cancer.

Three-dimensional laparoscopy and thoracoscopy in children and adults: A prospective clinical trial

Abstract Background: Laparoscopic procedures for children and adults already provide many advantages in two-dimensional (2D) vision. Only limited experiences exist for laparoscopic three-dimensional (3D) procedures in vivo. The aim of this prospective trial was to identify indications and limitations of the 3D-system in laparoscopic minimally invasive procedures in children and adults. Material and methods: In a prospective quality assurance for laparoscopic 3D evaluation in children and adults, a total of 53 consecutive patients (22 children, 31 adults) were included. Laparoscopic transabdominal, retroperitoneal and thoracoscopic procedures were performed. For laparoscopic 3D imaging a Camera Control Unit (CCU), 3D monitor and 3D-TIPCAM® were used. Patient data, operative procedures and image quality of the 3D system were assessed. Results: Of 53 patients, 22/53 were children and 31/53 adults with a mean age of 7.6 years (range, 10 months to 15 years) and 51.5 years (range, 18 to 79 years), respectively. 8/22 children were two years old or younger. No relevant difficulties occurred with nausea, fatigue, vertigo, eye blurring or double vision, burning eyes, visual fatigue, inconvenience of visual adaptation of 3D to 2D, or medical discomforts for the surgeons in both children and adults. Difficulties were mainly addressed to the small distance of the video endoscope and the organ tissue in small children and affected mainly image definition, resolution and eye focusing. Conclusions: Advantages of 3D over 2D were mainly considered to be of relevant benefit in adults. Subjective advantages were seen in children and adults for stereoscopic depth perception, better visualization of anatomical structures and understanding of the anatomy, as well as for complex maneuvers such as suturing.

Single-port live donor nephrectomy using a novel Curved Radius r2 Surgical System in an in vivo model.

Abstract Objective: Single-port laparoscopic donor nephrectomy provides low morbidity and satisfactory cosmetic results for patients. The aim of this animal study was to establish a surgical technique of single-site (LESS) living donor nephrectomy using novel curved r2 CURVE manipulators specially designed for single-port access. Material and methods: A total of six LESS nephrectomies were performed in three female pigs. r2 CURVE-instruments (Tuebingen Scientific Medical GmbH) were used providing a curved rotatable shaft, endless tip rotation, as well as 90° tip deflection. A 10 mm 30° extra long laparoscope, r2-curved Grasper, Maryland dissector and bipolar scissors were used for mobilization and dissection. Results: All LESS nephrectomies were performed successfully. Average operative time was 80 min (range, 42–149 min). No technical problems were observed. Insertion and extraction of the instruments through the single-port were easy to conduct. The diameter of the used single-port was sufficient for safe manual organ harvesting. Potential conflict between the laparoscope and the instrument handles was avoided by using an extra long laparoscope. Conclusions: The new curved and deflectable instruments showed that single-port nephrectomy using the R2 manipulators is feasible. Single-port laparoscopic nephrectomy might be more patient-friendly and improve the willingness of potential donors to donate live organs.

Large proportion of low frequency microsatellite-instability and loss of heterozygosity in pheochromocytoma and endocrine tumors detected with an extended marker panel

PurposePheochromocytoma (PCC) is a usually benign tumor originated in the majority of patients from the adrenal medulla. Regarding sporadic forms of PCC, mechanisms of pathogenesis are largely unknown. Recently, microsatellite-instability (MSI) was discussed as genetic factor contributing to PCC development. Since microsatellite markers used for MSI detection have only been recommended for colorectal carcinoma (CRC), we established an extended marker set for MSI detection in PCC.MethodsTwenty-two PCC patients were analyzed applying 11 microsatellite markers. Our marker set comprised the reference panel for CRC and six additional markers, which have already been described to detect MSI in tumors other than CRC. Moreover, 23 endocrine tumors with gastrointestinal origin were examined in order to test the applicability of this marker panel.ResultsMicrosatellite-instability was detected in 41% of PCCs. Twenty-seven percent showed loss of heterozygosity (LOH) events affecting different chromosomal regions. Among the 23 patients with endocrine tumors, only three (one pancreatic endocrine tumor, one duodenal neuro-endocrine tumor, one hepatic metastasis of a primary tumor with unknown origin) demonstrated MSI.ConclusionsThe extended microsatellite panel is qualified to detect MSI in PCC. Nine percent of MSI-positive cases would have not been noticed by the use of the reference panel alone. PCCs are characterized by low frequency MSI pointing to failures in factors involved in DNA replication.

Laparoscopic Rectosigmoid Resection for Acute Sigmoid Diverticulitis

Laparoscopic sigmoid colectomy has been widely accepted as elective approach but is, however, still discussed controversially for acute cases. Patients receiving a laparoscopic early single-stage procedure benefit from an early postoperative convalescence with a minimum of disability. As more surgeons gain expertise in minimally invasive surgery of the rectosigmoid, this video highlights the main steps of a rectosigmoid resection for acute complicated diverticulitis.

Laparoscopic pelvic mesh placement with closure of pelvic floor entrance to prevent small intestine radiation trauma - A retrospective cohort analysis.

BACKGROUND In most pelvic malignancies radiation therapy is a main part of the treatment concept. The main dose limiting organ is the small intestine. Different mechanical methods to prevent radiation damage to the small intestine have been described. We herein report a retrospective study of laparoscopic placement of an absorbable vicryl mesh in patients requiring pelvic radiotherapy displacing the bowel out of the radiation field. PATIENTS/METHODS The study included 6 consecutive patients requiring definitive radiotherapy due to locally advanced prostate cancer. All patients had small intestine within the radiation fields despite the use of non-invasive displacement methods. RESULTS All patients underwent laparoscopic small bowel displacement from the pelvis and closure of the pelvic floor entrance using vicryl mesh placement. Peri- or postoperative complications were not seen. Postoperative radiotherapy planning CT scans confirmed displacement of the small intestine allowing all patients to receive the planned radiotherapy volume. CONCLUSION Laparoscopic mesh placement represents a safe and efficient procedure in patients requiring high-dose pelvic radiation, presenting with unacceptable small intestine volume in the radiation field. As an alternate to native tissue, the vicryl mesh is a safe, effective substitute for small bowel exclusion from external-beam radiation therapy.

Laparoscopic resection of a lymphangiomatous cyst of the colon: a case report

IntroductionLymphangiomatous cysts are submucosal masses that are rarely found in the gastrointestinal tract and more often in the neck, oral cavity, and skin. These cysts are benign tumors and mostly clinically silent. Symptoms include abdominal pain, diarrhea, and rectal bleeding. Their pathogenesis remains unclear.Case presentationDuring a routine ultrasound examination of a Caucasian 25-year-old woman, a structure that raised our suspicions of an ovarian cyst was found. MRI showed a 4.5 cm cystic lesion in the cecal region. Laparoscopic exploration revealed unexpected contact with the ascending colon. The cyst, including its base and of portion of the colon, was resected laparoscopically. The histological examination revealed cystic lymphangioma.ConclusionLymphangiomatous cysts of the colon are very rare lesions. Although their pathology is benign, the recommended treatment is resection, which can be performed with minimal invasiveness.