Case Report A Case Study of Severe Esophageal Dysmotility following Laparoscopic Sleeve Gastrectomy

Following bariatric surgery, a proportion of patients have been observed to experience reflux, dysphagia, and/or odynophagia. The etiology of this constellation of symptoms has not been systematically studied to date. This case describes a 36-year-old female with severe esophageal dysmotility following LSG. Many treatments had been used over a course of 3 years, and while calcium channel blockers reversed the esophageal dysmotility seen on manometry, significant symptoms of dysphagia persisted. Subsequently, the patient underwent a gastric bypass, which seemed to partially relieve her symptoms. Her dysphagia was no longer considered to be associated with a structural cause but attributed to a "sleeve dysmotility syndrome." Considering the difficulties with managing sleeve dysmotility syndrome, it is reasonable to consider the need for preoperative testing. The question is whether motility studies should be required for all patients planning to undergo a LSG to rule out preexisting esophageal dysmotility and whether conversion to gastric bypass is the preferred method for managing esophageal dysmotility after LSG

The Economic Impact of Weight Regain

Background. Obesity is well known for being associated with significant economic repercussions. Bariatric surgery is the only evidence-based solution to this problem as well as a cost-effective method of addressing the concern. Numerous authors have calculated the cost effectiveness and cost savings of bariatric surgery; however, to date the economic impact of weight regain as a component of overall cost has not been addressed. Methods. The literature search was conducted to elucidate the direct costs of obesity and primary bariatric surgery, the rate of weight recidivism and surgical revision, and any costs therein. Results. The quoted cost of obesity in Canada was $2.0 billion-$6.7 billion in 2013 CAD. The median percentage of bariatric procedures that fail due to weight gain or insufficient weight loss is 20% (average: 21.1% ± 10.1%, range: 5.2-39, = 10). Revision of primary surgeries on average ranges from 2.5% to 18.4%, and depending on the procedure accounts for an additional cost between $14,000 and$50,000 USD per patient. Discussion. There was a significant deficit of the literature pertaining to the cost of revision surgery as compared with primary bariatric surgery. As such, the cycle of weight recidivism and bariatric revisions has not as of yet been introduced into any previous cost analysis of bariatric surgery

The Economic Impact of Weight Regain

Background. Obesity is well known for being associated with significant economic repercussions. Bariatric surgery is the only evidence-based solution to this problem as well as a cost-effective method of addressing the concern. Numerous authors have calculated the cost effectiveness and cost savings of bariatric surgery; however, to date the economic impact of weight regain as a component of overall cost has not been addressed. Methods. The literature search was conducted to elucidate the direct costs of obesity and primary bariatric surgery, the rate of weight recidivism and surgical revision, and any costs therein. Results. The quoted cost of obesity in Canada was $2.0 billion–$6.7 billion in 2013 CAD. The median percentage of bariatric procedures that fail due to weight gain or insufficient weight loss is 20% (average: 21.1%±10.1%, range: 5.2–39, n=10). Revision of primary surgeries on average ranges from 2.5% to 18.4%, and depending on the procedure accounts for an additional cost between $14,000 and$50,000 USD per patient. Discussion. There was a significant deficit of the literature pertaining to the cost of revision surgery as compared with primary bariatric surgery. As such, the cycle of weight recidivism and bariatric revisions has not as of yet been introduced into any previous cost analysis of bariatric surgery

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome

IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo

Interferons (IFN) exert antiviral, immunomodulatory and cytostatic activities. IFN-α/β (type I IFN) and IFN-λ (type III IFN) bind distinct receptors, but regulate similar sets of genes and exhibit strikingly similar biological activities. We analyzed to what extent the IFN-α/β and IFN-λ systems overlap in vivo in terms of expression and response. We observed a certain degree of tissue specificity in the production of IFN-λ. In the brain, IFN-α/β was readily produced after infection with various RNA viruses, whereas expression of IFN-λ was low in this organ. In the liver, virus infection induced the expression of both IFN-α/β and IFN-λ genes. Plasmid electrotransfer-mediated in vivo expression of individual IFN genes allowed the tissue and cell specificities of the responses to systemic IFN-α/β and IFN-λ to be compared. The response to IFN-λ correlated with expression of the α subunit of the IFN-λ receptor (IL-28Rα). The IFN-λ response was prominent in the stomach, intestine and lungs, but very low in the central nervous system and spleen. At the cellular level, the response to IFN-λ in kidney and brain was restricted to epithelial cells. In contrast, the response to IFN-α/β was observed in various cell types in these organs, and was most prominent in endothelial cells. Thus, the IFN-λ system probably evolved to specifically protect epithelia. IFN-λ might contribute to the prevention of viral invasion through skin and mucosal surfaces

Effects of Blood Products on Inflammatory Response in Endothelial Cells In Vitro

BACKGROUND: Transfusing blood products may induce inflammatory reactions within the vascular compartment potentially leading to a systemic inflammatory response. Experiments were designed to assess the inflammatory potential of different blood products in an endothelial cell-based in vitro model and to compare baseline levels of potentially activating substances in transfusion products. METHODS: The inflammatory response from pre-activated (endotoxin-stimulated) and non-activated endothelial cells as well as neutrophil endothelial transmigration in response to packed red blood cells (PRBC), platelet concentrates (PC) and fresh frozen plasma (FFP) was determined. Baseline inflammatory mediator and lipid concentrations in blood products were evaluated. RESULTS: Following incubation with all blood products, an increased inflammatory mediator release from endothelial cells was observed. Platelet concentrates, and to a lesser extent also FFP, caused the most pronounced response, which was accentuated in already pre-stimulated endothelial cells. Inflammatory response of endothelial cells as well as blood product-induced migration of neutrophils through the endothelium was in good agreement with the lipid content of the according blood product. CONCLUSION: Within the group of different blood transfusion products both PC and FFP have a high inflammatory potential with regard to activation of endothelial cells. Inflammation upon blood product exposure is strongly accentuated when endothelial cells are pre-injured. High lipid contents in the respective blood products goes along with an accentuated inflammatory reaction from endothelial cells

Childhood IQ and survival to 79: Follow-up of 94% of the Scottish Mental Survey 1947.

Objective To extend previous literature that suggests higher IQ in youth is associated with living longer. Previous studies have been unable to assess reliably whether the effect differs across sexes and ages of death, and whether the effect is graded across different levels of IQ. Methods We test IQ-survival associations in 94% of the near-entire population born in Scotland in 1936 who took an IQ test at age 11 (n = 70,805) and were traced in a 68-year follow-up. Results Higher IQ at age 11 years was associated with a lower risk of death (HR = 0.80, 95% CI = 0.79, 0.81). The decline in risk across categories of IQ scores was graded across the full range with the effect slightly stronger in women (HR = 0.79, 95% CI = 0.77, 0.80) than in men (HR = 0.82, 95% CI = 0.81, 0.84). Higher IQ had a significantly stronger association with death before and including age 65 (HR = 0.76, 95% CI = 0.74, 0.77) than in those participants who died at an older age (HR = 0.79, 95% CI = 0.78, 0.80). Conclusions Higher childhood IQ is associated with lower risk of all-cause mortality in both men and women. This is the only near-entire population study to date that examines the association between childhood IQ and mortality across most of the human life course

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease