Endoscopic sleeve gastroplasty plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss.

BACKGROUND AND AIMS: Endoscopic sleeve gastroplasty (ESG) has been shown to be effective for inducing weight loss. The efficacy of liraglutide, a glucagon-like peptide-1 agonist, to augment weight loss after ESG is unknown. This study aims to evaluate the efficacy of ESG and liraglutide (ESG-L) compared with ESG alone. METHODS: This was a retrospective study of prospectively collected data from patients undergoing ESG at 3 outpatient clinics in Brazil between November 2017 and July 2018. Liraglutide was offered to all patients 5 months after ESG. Patients who opted to take liraglutide (ESG-L) were matched 1:1 to patients who declined it (ESG). The primary outcome was percent total body weight loss (%TBWL), and percent excess weight loss (%EWL) 7 months after initiation of liraglutide (12 months after ESG). The secondary outcome was change in percent body fat 12 months after ESG. ESG technique and postprocedure follow-up were identical at all 3 sites. RESULTS: Propensity score matching yielded 26 matched pairs. Adjusted comparisons between the 2 groups showed that patients who opted to take liraglutide had a superior mean %TBWL 7 months after initiation of liraglutide (ESG-L) compared with those who declined it (ESG) (24.72% ± 2.12% vs 20.51% ± 1.68%, respectively; P < .001). ESG-L had a statistically greater reduction in percent body fat compared with ESG (7.85% ± 1.26% vs 10.54% ± 1.88%, respectively; P < .001) at 12 months. CONCLUSIONS: Addition of liraglutide at 5 months results in superior weight loss and improved efficacy as demonstrated by decreased body fat 12 months after ESG. Further studies are imperative to determine optimal dose, timing, and duration of liraglutide.

The Effect of the Intra-gastric Balloon on Gastric Emptying and the DeMeester Score.

BACKGROUND AND AIMS: The mechanism of weight loss with the intra-gastric balloon (IGB) is thought to be a decrease in gastric emptying (GE); however the evidence is conflicting. Nausea, abdominal pain, and gastroesophageal reflux disease (GERD) can cause intolerance resulting in early removal. This is demoralizing for the patient and costly for the healthcare system. The ability to predict which patients will have superior weight loss and tolerance is invaluable. We sought to investigate if the IGB induced weight loss by reducing GE and the effect of the IGB on the DeMeester score. METHODS: We retrospectively reviewed prospectively collected data for patients undergoing IGB placement at a single hospital. Manometry and pH studies were performed before and with the IGB in place. Weight was measured at baseline, at removal, and 6 months later. Adverse events leading to early removal were recorded. RESULTS: Twenty-four patients were evaluated. There was a statistically significant decrease in GE for solids with the IGB (117.92 ± 150.23 vs 281.48 ± 206.49 min; p = 0.0048), but not for liquids (54.44 ± 17.97 vs 56.08 ± 43.96 min; p = 0.7228). The lower esophageal sphincter (LES) pressure did not change significantly with placement of the IGB (17.76 ± 7.39 vs 14.74 ± 7.24 mmHg; p = 0.09). On multivariate analysis, increase in DeMeester score was associated with total body weight loss (p = 0.0125) and change in GE (p = 0.038) independently. CONCLUSION: The IGB delays GE for solids, but not for liquids, and increases the DeMeester score by a mechanism other than a loss of LES pressure.

Endovascular Iliocaval Stent Reconstruction for Iliocaval Thrombosis: A Multi-Institutional International Practice Pattern Survey.

BACKGROUND: Limited guidelines for the treatment and management of acute and chronic iliocaval thrombosis are published in the literature. The purpose of this report is to present global iliocaval stent reconstruction practices by interventionalists. METHODS: A 45-question survey focusing on iliocaval stent reconstruction evaluation was distributed through the Open Forum and Venous Disease Service Line of the Society of Interventional Radiology Connect website from June 20, 2017 until September 7, 2017 and the Cardiovascular and Interventional Radiological Society of Europe electronic newsletter on August 11, 2017. RESULTS: One hundred seven complete responses were received from interventional radiologists in the United States, 2 from South America, and 2 from Central America. 92.5% performed iliocaval reconstruction, and 79.8% performed the procedure for both acute and chronic iliocaval thrombosis. 82.8% completed a standardized physician assessment tool, and 91.9% obtained computed tomography (CT) venography before the procedure. 64.6% used intravascular ultrasound to guide reconstruction. 41.4% found blunt recanalization successful for >75% of patients. 63.6% used sharp recanalization for <25% of patients. 97.0% and 90.9% used uncovered and self-expanding stents, respectively. Wallstents were used most commonly. Most common stent diameters were 24-mm in the inferior vena cava, 14-mm in the common iliac vein, and 12-mm in the external iliac vein. 48.5% and 21.2% prescribed 2 and 3 anticoagulants after stent placement, respectively. 62.6% found iliocaval reconstruction provided symptomatic clinical improvement for iliocaval thrombosis in >75% of patients. 72.7% estimated their 1-year primary stent patency to be >75%. CONCLUSIONS: Iliocaval reconstruction is performed by many interventionalists; however, there are global inconsistencies in practices, suggesting a need for further research and guideline development.

Improvements in Patient and Health System Outcomes Using an Integrated Oncology and Palliative Medicine Approach on a Solid Tumor Inpatient Service.

PURPOSE: Early palliative care (PC) improves outcomes for outpatients with advanced cancer. Its effect on hospitalized patients with cancer is unknown. Herein, we report on the influence of a novel, fully integrated inpatient medical oncology and PC partnership at a tertiary medical center during its first year of implementation. METHODS: We conducted a retrospective, longitudinal, pre- and postintervention cohort study at Duke University Hospital. Pre- and postintervention cohorts were defined as all patients admitted to the solid tumor inpatient service from September 1, 2009, to June 30, 2010, and September 1, 2011 to June 30, 2012, respectively. We extracted patient data, including demographics, cancer diagnosis, disease status, length of stay, intensive care unit transfer rate, discharge disposition, time to emergency department return, time to readmission, and 7- and 30-day emergency department return and readmission rates. Nursing and physician surveys assessed satisfaction. Descriptive statistics, and Kruskal-Wallis and Χ2 tests were used to describe and compare cohorts. A generalized estimating equation accounted for repeated measures. RESULTS: Pre- and postintervention analysis cohorts included 731 and 783 patients, respectively, representing a total of 1,514 patients and 2,353 encounters. Cohorts were similar in baseline characteristics. Statistically significant lower odds in 7-day readmission rates were observed in the postintervention cohort (adjusted odds ratio, 0.76; 95% CI, 0.58 to 1.00; P = .0482). Patients in the postintervention group had a decrease in mean length of stay (-0.30 days; 95% CI, -0.62 to 0.02); P = .0651). We observed a trend for increasing hospice referrals ( P = .0837) and a 15% decrease in intensive care unit transfers ( P = .61). Physicians and nurses universally favored the model. CONCLUSION: A fully integrated inpatient partnership between PC and medical oncology is associated with significant and clinically meaningful improvements in key health system-related outcomes and indicators of quality cancer care.

SWI/SNF-independent nuclease hypersensitivity and an increased level of histone acetylation at the P1 promoter accompany active transcription of the bone master gene Runx2.

The Runx2 transcription factor is essential for skeletal development as it regulates expression of several key bone-related genes. Multiple lines of evidence indicate that expression of the Runx2/p57 isoform in osteoblasts is controlled by the distal P1 promoter. Alterations of chromatin structure are often associated with transcription and can be mediated by members of the SWI/SNF family of chromatin remodeling complexes, or by transcriptional coactivators that possess enzymatic activities that covalently modify structural components of the chromatin. Here, we report that a specific chromatin remodeling process at the proximal region (residues -400 to 35) of the Runx2 gene P1 promoter accompanies transcriptional activity in osteoblasts. This altered chromatin organization is reflected by the presence of two DNase I hypersensitive sites that span key regulatory elements for Runx2/p57 transcription. Chromatin remodeling and transcription of the Runx2 gene are associated with elevated levels of histone acetylation at the P1 promoter region and binding of active RNA polymerase II and are independent of the activity of the SWI/SNF chromatin remodeling complex. Changes in chromatin organization at the P1 promoter are stimulated during differentiation of C2C12 mesenchymal cells to the osteoblastic lineage by treatment with BMP2. Together, our results support a model in which changes in chromatin organization occur at very early stages of mesenchymal differentiation to facilitate subsequent expression of the Runx2/p57 isoform in osteoblastic cells.

Chromatin remodeling by SWI/SNF results in nucleosome mobilization to preferential positions in the rat osteocalcin gene promoter.

Changes in local chromatin structure accompany transcriptional activation of eukaryotic genes. In vivo these changes in chromatin organization can be catalyzed by ATP-dependent chromatin-remodeling complexes, such as SWI/SNF. These complexes alter the tight wrapping of DNA in the nucleosomes and can facilitate the mobilization of the histone octamer to adjacent DNA segments, leaving promoter regulatory elements exposed for transcription factor binding. To gain understanding of how the activity of SWI/SNF complexes may be modulated by the different DNA sequences within a natural promoter, we have reconstituted nucleosomes containing promoter segments of the transcriptionally active cell type-specific osteocalcin (OC) gene and determined how they affect the directional movements of the nucleosomes. Our results indicate that SWI/SNF complexes induce octamer sliding to preferential positions in the OC promoter, leading to a nucleosomal organization that resembles that described in intact cells expressing the OC gene. Our studies demonstrate that the position of the histone octamer is primarily determined by sequences within the OC promoter that include or exclude nucleosomes. We propose that these sequences are critical components of the regulatory mechanisms that mediate expression of this tissue-specific gene.

Structure of Leishmania mexicana phosphomannomutase highlights similarities with human isoforms.

Phosphomannomutase (PMM) catalyses the conversion of mannose-6-phosphate to mannose-1-phosphate, an essential step in mannose activation and the biosynthesis of glycoconjugates in all eukaryotes. Deletion of PMM from Leishmania mexicana results in loss of virulence, suggesting that PMM is a promising drug target for the development of anti-leishmanial inhibitors. We report the crystallization and structure determination to 2.1 A of L. mexicana PMM alone and in complex with glucose-1,6-bisphosphate to 2.9 A. PMM is a member of the haloacid dehalogenase (HAD) family, but has a novel dimeric structure and a distinct cap domain of unique topology. Although the structure is novel within the HAD family, the leishmanial enzyme shows a high degree of similarity with its human isoforms. We have generated L. major PMM knockouts, which are avirulent. We expressed the human pmm2 gene in the Leishmania PMM knockout, but despite the similarity between Leishmania and human PMM, expression of the human gene did not restore virulence. Similarities in the structure of the parasite enzyme and its human isoforms suggest that the development of parasite-selective inhibitors will not be an easy task.

Chromatin remodeling and transcriptional activity of the bone-specific osteocalcin gene require CCAAT/enhancer-binding protein beta-dependent recruitment of SWI/SNF activity.

Tissue-specific activation of the osteocalcin (OC) gene is associated with changes in chromatin structure at the promoter region. Two nuclease-hypersensitive sites span the key regulatory elements that control basal tissue-specific and vitamin D3-enhanced OC gene transcription. To gain understanding of the molecular mechanisms involved in chromatin remodeling of the OC gene, we have examined the requirement for SWI/SNF activity. We inducibly expressed an ATPase-defective BRG1 catalytic subunit that forms inactive SWI/SNF complexes that bind to the OC promoter. This interaction results in inhibition of both basal and vitamin D3-enhanced OC gene transcription and a marked decrease in nuclease hypersensitivity. We find that SWI/SNF is recruited to the OC promoter via the transcription factor CCAAT/enhancer-binding protein beta, which together with Runx2 forms a stable complex to facilitate RNA polymerase II binding and activation of OC gene transcription. Together, our results indicate that the SWI/SNF complex is a key regulator of the chromatin-remodeling events that promote tissue-specific transcription in osteoblasts.

Properties of GDP-mannose pyrophosphorylase, a critical enzyme and drug target in Leishmania mexicana.

Leishmania parasites synthesize a range of mannose-containing glycoconjugates thought to be essential for virulence in the mammalian host and sandfly vector. A prerequisite for the synthesis of these molecules is the availability of the activated mannose donor, GDP-Man, the product of the catalysis of mannose-1-phosphate and GTP by GDP-mannose pyrophosphorylase (GDP-MP). In contrast to the lethal phenotype in fungi, the deletion of the gene in Leishmania mexicana did not affect parasite viability but led to a total loss of virulence, making GDP-MP an ideal target for anti-Leishmania drug development. We show by immunofluorescence and subcellular fractionation that GDP-MP is a cytoplasmic protein, and we describe a colorimetric activity assay suitable for the high throughput screening of small molecule inhibitors. We expressed recombinant GDP-MP as a fusion with maltose-binding protein and separated the enzyme from maltose-binding protein by thrombin cleavage, ion-exchange, and size exclusion chromatography. Size exclusion chromatography and analytical ultracentrifugation studies demonstrate that GDP-MP self-associates to form an enzymatically active and stable hexamer. However, sedimentation studies show that the GDP-MP hexamer dissociates to trimers and monomers in a time-dependent manner, at low protein concentrations, at low ionic strength, and at alkaline pH. Circular dichroism spectroscopy reveals that GDP-MP is comprised of mixed alpha/beta structure, similar to its closest related homologue, N-acetyl-glucoseamine-1-phosphate uridyltransferase (Glmu) from Streptococcus pneumoniae. Our studies provide insight into the structure of a novel target for the development of anti-Leishmania drugs.

What are the long-term results of endoscopic pancreatic sphincterotomy for pancreatitis?

Endoscopic pancreatic sphincterotomy (EPS) has been touted as effective therapy for several disorders including chronic pancreatitis and unexplained abdominal pain associated with pancreatic sphincter dysfunction (pSOD). Although short-term data are encouraging, there are no reports on how these patients fare beyond the first few months after EPS. The data on all patients who had EPS performed at the Johns Hopkins Hospital over a 4 year period between August 1992 and November 1996 were reviewed. Patients were then contacted by a physician other than the original endoscopist and asked to rate their pain using the linear pain scale score (0-10 where 10 is the worst possible pain). Patients were asked to score their pain before EPS and also at follow-up. Clinical improvement was defined as a >50 percent reduction in the pain score. The data on 55 patients were available for review. There were 17 men and 38 women age (yrs) ñSD: 43.6 ñ 16.7. Indications for EPS included 1) chronic pancreatitis (n=40); 2) unexplained abdominal pain with pSOD (n=15). EPS was associated with pancreatitis in 5 patients (9 percent), bleeding in 2 (3.6 percent) and early stent occlusion in 5 (9 percent). 7 patients had surgical sphincteroplasty after EPS. No patient died from EPS. After a median follow-up of 16 months (longest, 52 months) 60 percent of all patients improved, with an overall improvement in pain scores (mean ñ SD) from 8.8 ñ 1.8 pre-EPS to 3.6 ñ 3.4 post-EPS (p<0.0001). The response rate was even more impressive in the pSOD group with 73 percent of the patients reporting improvement and a reduction in pain scores from 9.0 ñ 1.6 to 2.9 ñ 3.3 after sphincter ablation (p<0.001). In a subgroup of patients with pancreatic disease and pancreatic sphincter dysfunction, EPS results in sustained significant clinical improvement.(AU)

Jamaican vomiting sickness: a theoretical investigation

Jamaican vomiting sickness has been investigated for over sixty years, and yet this acute disease remains an epidemiological mystery. In this article, we have critically examined the toxin hypotheses emphasized in the literature - particularly the ackee and yam theories of causation. Because of the inadequacies of the conventional toxin hypotheses, we suggest that more attention should be given to a malnutrition hypothesis and a psychogenic hypothesis. Jamaican vomiting sickness (JVS), a reportedly culture bound syndrome, may very well have multiple causation. That is, toxin, malnutrition, and psychogenic etiologies may be operative independently and sometimes jointly in the epidemics and family outbreaks of acute and often fatal Jamaican vomiting sickness. (AU)