Repair of post-bariatric surgery, recurrent, and de novo hiatal hernias improves bloating, abdominal pain, regurgitation, and food intolerance.

BACKGROUND: Post-bariatric surgery hiatal hernias are associated with a cluster of symptoms, including bloating (nausea/vomiting or fullness), abdominal pain, regurgitation, and food intolerance or dysphagia (BARF). OBJECTIVES: To report the short-term outcomes of repairing post-bariatric surgery hiatal hernias in patients with BARF. SETTING: Large, multispecialty group practice with university affiliation. METHODS: We reviewed the records of all consecutive patients who underwent repair of post-bariatric surgery hiatal hernias (2012-2020). Data are shown as means ± standard deviations. RESULTS: We repaired hiatal hernias in 52 patients (age, 57 ± 10 yr), 4 ± 3 years post sleeve gastrectomy (SG; n = 27), 11 ± 6 years following Roux-en-Y gastric bypass (RYGB; n = 24), and 11 years post duodenal switch with SG (DS-SG; n = 1). Diagnoses were made by upper gastrointestinal contrast study (80%), computed tomography (70%), and/or endoscopy (56%). Hernias in patients with SG were repaired by a posterior cruroplasty after reducing the neo-stomach into the abdomen (n = 11 SG patients; n = 1 DS-SG patient) or converting the SG to RYGB (n = 16). All 24 RYGB patients underwent hernia repair similarly. At 12 ± 10 months of follow-up, dysphagia or regurgitation improved in >80% of patients; nausea, vomiting, or abdominal pain improved in 70% of patients; and heartburn persisted in 56% of patients. Subsequent recurrent hernias that required operative repair developed in 3 patients. CONCLUSIONS: Hiatal hernias containing the neo-stomach present earlier after SG than RYGB. The diagnosis can be made with a combination of imaging studies and endoscopy. Repair of post-bariatric surgery hiatal hernias markedly improves symptoms of BARF in most patients.

A Literature Review and Summary Recommendations of the Impact of Bariatric Surgery on Orthopedic Outcomes.

Many surgeons recommend weight loss in preparation for orthopedic procedures, yet the impact of surgically induced weight loss before orthopedic procedures is not clear. We undertook a literature review to assess the impact of bariatric surgery on the outcomes of total joint arthroplasty (TJA). We searched PubMed, Medline, Cochrane Library, and Google Scholar for studies (2010-2017) that evaluated the associations between obesity, bariatric surgery, and orthopedic surgery. Nine studies found that prior bariatric surgery decreased major and minor post-operative complications, operating room (OR) time, length of stay (LOS), risk of re-operation, and 90-day re-admissions after TJA. Two studies found that bariatric surgery patients had a higher reoperation rate for stiffness and infection as well as need for revision within 90 days after TJA. One meta-analysis found no statistically significant differences in wound infections, revisions, or mortality irrespective of bariatric surgery status; and another meta-analysis showed reduced medical complications, LOS, and OR time. Our review highlights many gaps in our knowledge and the need for additional studies to define the impact of the bariatric-first approach on TJA outcomes. We propose a framework from lessons learned to raise awareness of medical and surgical options of weight management before elective orthopedic operations in patients with obesity.

Management of nonalcoholic fatty liver disease and the role of bariatric surgery: a brief review for surgeons.

Nonalcoholic fatty liver disease (NAFLD) is closely linked to the metabolic syndrome and is highly prevalent in bariatric patients. The criterion standard to diagnose NAFLD is a liver biopsy specifically to detect inflammatory changes characteristic of nonalcoholic steatohepatitis. Technologic advancements will improve the accuracy of current noninvasive modalities. Modification of risk factors via food management is important to prevent the progression of NAFLD to nonalcoholic steatohepatitis and cirrhosis. Several clinical trials are underway for pharmacologic treatment of NAFLD; currently the mainstay of treatment is insulin sensitizers and vitamin E. There is strong evidence bariatric surgery improves biochemical and histologic features of NAFLD and therefore, bariatric surgery should be considered as a treatment of NAFLD in patients with obesity. Gastric bypass exhibits antilipogenic, antiinflammatory, antioxidant, and antidiabetic properties in the livers of laboratory animals; thereby, providing a unique window to study regulation of body adiposity and insulin resistance.

A specific small-molecule inhibitor of protein kinase CδI activity improves metabolic dysfunction in human adipocytes from obese individuals.

The metabolic consequences and sequelae of obesity promote life-threatening morbidities. PKCδI is an important elicitor of inflammation and apoptosis in adipocytes. Here we report increased PKCδI activation via release of its catalytic domain concurrent with increased expression of proinflammatory cytokines in adipocytes from obese individuals. Using a screening strategy of dual recognition of PKCδI isozymes and a caspase-3 binding site on the PKCδI hinge domain with Schrödinger software and molecular dynamics simulations, we identified NP627, an organic small-molecule inhibitor of PKCδI. Characterization of NP627 by surface plasmon resonance (SPR) revealed that PKCδI and NP627 interact with each other with high affinity and specificity, SPR kinetics revealed that NP627 disrupts caspase-3 binding to PKCδI, and in vitro kinase assays demonstrated that NP627 specifically inhibits PKCδI activity. The SPR results also indicated that NP627 affects macromolecular interactions between protein surfaces. Of note, release of the PKCδI catalytic fragment was sufficient to induce apoptosis and inflammation in adipocytes. NP627 treatment of adipocytes from obese individuals significantly inhibited PKCδI catalytic fragment release, decreased inflammation and apoptosis, and significantly improved mitochondrial metabolism. These results indicate that PKCδI is a robust candidate for targeted interventions to manage obesity-associated chronic inflammatory diseases. We propose that NP627 may also be used in other biological systems to better understand the impact of caspase-3-mediated activation of kinase activity.

Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis.

High-level evidence of the impact of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) is lacking. We conducted a systematic review and meta-analysis according to the Cochrane guidelines to assess the resolution of NAFLD after bariatric surgery. We searched PubMed, EMBASE, Web of Science, and CENTRAL for English language publications on bariatric surgery and NAFLD. We included randomized controlled trials and observational studies of patients with NAFLD who underwent bariatric surgery and were assessed by liver biopsy or liver function tests. Duodenal switch and biliopancreatic diversion were excluded. Our primary outcome was histologic or biochemical improvement of NAFLD. Twenty-one studies (12 Roux-en-Y gastric bypass [RYGB], 3 adjustable gastric banding, 2 sleeve gastrectomy, 1 vertical banded gastroplasty, 3 multiple procedures) enrolling 2374 patients were included. The pooled proportion of patients who had improvement of steatosis was 88% (95% confidence interval [CI]: .80, .94). Steatohepatitis improved in 59% (95% CI: .38, .78) and fibrosis improved or resolved in 30% of patients (95% CI: .21, .41). Similarly, aspartate aminotransferase (AST) improved in 32% of patients (95% CI: .22, .42) and alanine aminotransferase improved in 62% of patients (95% CI: .42, .82). After RYGB, the number of patients who had improvement in NAFLD was higher than the average of all the pooled studies. Bariatric surgery improves steatosis and steatohepatitis in the majority of patients and improves or resolves liver fibrosis in 30% of patients. RYGB has a greater impact on NAFLD histology compared with other procedures. This contemporary meta-analysis strongly suggests that bariatric surgery should be considered as a treatment of NAFLD.

Stabilization of lncRNA GAS5 by a Small Molecule and Its Implications in Diabetic Adipocytes.

Long noncoding RNA (lncRNA) are regulatory RNAs >200 nt. We previously showed that lncRNA GAS5 decreases significantly in serum of type 2 diabetes mellitus (T2DM) patients. Hence, we sought to decipher the molecular mechanisms underlying the role of GAS5 in T2DM in adipose tissue. Using CHIP-RIP, we demonstrate that GAS5 binds to promoter of insulin receptor to regulate its expression, and its depletion inhibits glucose uptake and insulin signaling. Toward stabilizing GAS5 levels in T2DM, we incorporated a strategy to limit the degradation of GAS5 by blocking the interaction of GAS5 and UPF1 with a small molecule identified using OBTC screening strategy. NP-C86 binds to GAS5 with high affinity, and increases GAS5 levels and glucose uptake in diabetic patient adipocytes. As a broader impact, NP-C86 may be used as a molecular probe to investigate the intricacies of GAS5 in relevant biological systems as it offers specificity, efficient cellular uptake and is non-cytotoxic.

Bariatric surgery and its impact on pseudotumor cerebri: A case report.

PURPOSE: Pseudotumor cerebri is a debilitating condition that causes severe headaches and progressive visual field loss. In this report, we present a patient with Class III obesity, with pseudotumor cerebri who failed medical management and attempted weight loss via diet and exercise. OBSERVATIONS: After undergoing bariatric surgery, the patient had significant weight loss and improvement of visual field defects. CONCLUSION AND IMPORTANCE: These results suggest that bariatric surgery may be an effective option for patients with rapidly progressing visual loss due to pseudotumor cerebri.

Bariatric Surgery as a Bridge to Renal Transplantation in Patients with End-Stage Renal Disease.

BACKGROUND: Obesity is a relative contraindication to organ transplantation. Preliminary reports suggest that bariatric surgery may be used as a bridge to transplantation in patients who are not eligible for transplantation because of morbid obesity. SETTING: The Bariatric Center at Tampa General Hospital, University of South Florida, Tampa, Florida. METHODS: We reviewed the outcomes of 16 consecutive patients on hemodialysis for end-stage renal disease (ESRD) who underwent bariatric surgery from 1998 to 2016. Demographics, comorbidities, weight loss, as well as transplant status were reported. Data is mean ± SD. RESULTS: Six men and ten women aged 43-66 years (median = 54 years) underwent laparoscopic Roux-en-Y gastric bypass (LRYGB, n = 12), laparoscopic adjustable gastric banding (LAGB, n = 3), or laparoscopic sleeve gastrectomy (LSG, n = 1). Preoperative BMI was 48 ± 8 kg/m2. Follow-up to date was 1-10 years (median = 2.8 years); postoperative BMI was 31 ± 7 kg/m2; %EBWL was 62 ± 24. Four patients underwent renal transplantation (25%) between 2.5-5 years after bariatric surgery. Five patients are currently listed for transplantation. Five patients were not listed for transplantation due to persistent comorbidities; two of these patients died as a consequence of their comorbidities (12.5%) more than 1 year after bariatric surgery. Two patients were lost to follow-up (12.5%). CONCLUSION: Bariatric surgery is effective in patients with ESRD and improves access to renal transplantation. Bariatric surgery offers a safe approach to weight loss and improvement in comorbidities in the majority of patients. Referrals of transplant candidates with obesity for bariatric surgery should be considered early in the course of ESRD.

Roux-en-Y gastric bypass improves glucose homeostasis, reduces oxidative stress and inflammation in livers of obese rats and in Kupffer cells via an AMPK-dependent pathway.

BACKGROUND: Oxidative stress and inflammation are implicated in the pathogenesis of steatohepatitis. We hypothesize that Roux-en-Y gastric bypass reduces oxidative stress and inflammation in the liver of obese rats via activation of AMPK-α. METHODS: Obese Sprague-Dawley male rats underwent either sham operation or Roux-en-Y gastric bypass. Hepatic TNF-α, NF-κB, IRS-2, PI3 kinase, PKC-ζ, NOX2, and AMPK-α were measured. Mechanistic studies were done in a rat Kupffer cell line (RKC1) that was treated with free fatty acids to mimic lipotoxicity and then transfected with AMPK-α siRNA. Reactive oxygen species, TNF-α, NF-κB, AMPK-α, p-AMPK-α, PPAR-γ, and NOX2 were measured. A t test was used. RESULTS: Roux-en-Y gastric bypass lowered nonfasting serum glucose, improved the glucose tolerance test, and induced IRS2/PI3 kinase interaction. Additionally, Roux-en-Y gastric bypass decreased hepatic NOX2, PKC-ζ, TNF-α expression and activation of NF-κB. Free fatty acids increased reactive oxygen species, TNF-α protein, NOX2 protein, and activated NF-κB. Rosiglitazone attenuated the free fatty acids-induced increase in reactive oxygen species, TNF-α, NOX2, and NF-κB; blocking AMPK-α by siRNA abolished the effects of rosiglitazone. CONCLUSION: Roux-en-Y gastric bypass exhibits antidiabetic properties and is associated with downregulation of proinflammation genes and oxidative stress in the liver and within Kupffer cells via activation of AMPK-α.

MALAT1 in Human Adipose Stem Cells Modulates Survival and Alternative Splicing of PKCδII in HT22 Cells.

Brain injury may be caused by trauma or may occur in stroke and neurodegenerative diseases. Because the central nervous system is unable to regenerate efficiently, there is utmost interest in the use of stem cells to promote neuronal survival. Of interest here are human adipose-derived stem cells (hASCs), which secrete factors that enhance regeneration and survival of neurons in sites of injury. We evaluated the effect of hASC secretome on immortalized mouse hippocampal cell line (HT22) after injury. Protein kinase C δ (PKCδ) activates survival and proliferation in neurons and is implicated in memory. We previously showed that alternatively spliced PKCδII enhances neuronal survival via B-cell lymphoma 2 Bcl2 in HT22 neuronal cells. Our results demonstrate that following injury, treatment with exosomes from the hASC secretome increases expression of PKCδII in HT22 cells and increases neuronal survival and proliferation. Specifically, we demonstrate that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA contained in the hASC exosomes mediates PKCδII splicing, thereby increasing neuronal survival. Using antisense oligonucleotides for MALAT1 and RNA immunoprecipitation assays, we demonstrate that MALAT1 recruits splice factor serine-arginine-rich splice factor 2 (SRSF2) to promote alternative splicing of PKCδII. Finally, we evaluated the role of insulin in enhancing hASC-mediated neuronal survival and demonstrated that insulin treatment dramatically increases the association of MALAT1 and SRSF2 and substantially increases survival and proliferation after injury in HT22 cells. In conclusion, we demonstrate the mechanism of action of hASC exosomes in increasing neuronal survival. This effect of hASC exosomes to promote wound healing can be further enhanced by insulin treatment in HT22 cells.

Adipose-derived stem cells from lean and obese humans show depot specific differences in their stem cell markers, exosome contents and senescence: role of protein kinase C delta (PKCδ) in adipose stem cell niche.

BACKGROUND: Adipose-derived stem cells (ASC) and its exosomes are gaining utmost importance in the field of regenerative medicine. The ASCs tested for their potential in wound healing are predominantly derived from the subcutaneous depot of lean donors. However, it is important to characterize the ASC derived from different adipose depots as these depots have clinically distinct roles. METHODS: We characterized the ASC derived from subcutaneous and omental depots from a lean donor (sc-ASCn and om-ASCn) and compared it to the ASC derived from an obese donor (sc-ASCo and om-ASCo) using flow cytometry and real time qPCR. RESULTS: We show that stem cell markers Oct4, Sal4, Sox15, KLF4 and BMI1 have distinct expression patterns in each ASC. We evaluated the secretome of the ASC and characterized their secreted exosomes. We show long noncoding RNAs (lncRNAs) are secreted by ASC and their expression varied between the ASC's derived from different depots. Protein kinase C delta (PKCδ) regulates the mitogenic signals in stem cells. We evaluated the effect of silencing PKCδ in sc-ASCn, om-ASCn, sc-ASCo and om-ASCo. Using ß-galactosidase staining, we evaluated the percentage of senescent cells in sc-ASCn, om-ASCn, sc-ASCo and om-ASCo. Our results also indicated that silencing PKCδ increases the percentage of senescent cells. CONCLUSIONS: Our case-specific study demonstrates a role of PKCδ in maintaining the adipose stem cell niche and importantly demonstrates depot-specific differences in adipose stem cells and their exosome content.