Differential effects of bariatric surgery and caloric restriction on hepatic one-carbon and fatty acid metabolism.

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to ad-libitum (AL)-fed controls. Analysis of liver and blood metabolome and transcriptome revealed distinct and sometimes contrasting metabolic effects between the two interventions. SG primarily influenced one-carbon metabolic pathways, whereas IF-CR increased de novo lipogenesis and glycogen storage. These findings suggest that the unique metabolic pathways affected by SG and IF-CR contribute to their distinct clinical benefits, with bariatric surgery potentially influencing long-lasting changes through its effect on one-carbon metabolism.

Sleeve Gastrectomy Reduces Glycemia but Does Not Affect Cognitive Impairment in Lean 5xFAD Mice.

Obesity and hyperglycemia are risk factors for cognitive decline and for the development of Alzheimer's Disease (AD). Bariatric surgery is an effective treatment for obesity that was shown to improve cognitive decline in obese patients. Bariatric surgery was shown to exert weight loss independent effects on metabolic diseases such as type 2 diabetes. We tested whether sleeve gastrectomy (SG), a common bariatric surgery, can affect the cognitive impairment in lean, normoglycemic female 5xFAD mice, a genetic model for AD. 5xFAD mice and wild-type (WT) littermates underwent SG or sham surgery at the age of 5 months and were tested for metabolic, behavioral, and molecular phenotypes 90 days later. SG led to a reduction in blood glucose levels and total plasma cholesterol levels in 5xFAD mice without inducing weight loss. However, the surgery did not affect the outcomes of long-term spatial memory tests in these mice. Analysis of ß-Amyloid plaques corroborated the behavioral studies in showing no effect of surgery on the molecular phenotype of 5xFAD mice. In conclusion, SG leads to an improved metabolic profile in lean female 5xFAD mice without inducing weight loss but does not affect the brain pathology or behavioral phenotype. Our results suggest that the positive effects of bariatric surgery on cognitive decline in obese patients are likely attributed to weight loss and improvement in obesity sequelae, and not to weight loss independent effects of surgery.

Maternal antagonism of Glp1 reverses the adverse outcomes of sleeve gastrectomy on mouse offspring.

Mothers that underwent bariatric surgery are at higher risk for delivering a small-for-gestational age (SGA) infant. This phenomenon is attributed to malabsorption and rapid weight loss following surgery. We compared pregnancy outcomes in lean mice that underwent sham surgery or sleeve gastrectomy (SG). SG led to a reduction in glucose levels and an increase in postprandial levels of glucagon-like peptide 1 (Glp1) without affecting mice weight during pregnancy. Pups of SG-operated mice (SG pups) were born SGA. The placenta and pancreas of the pups were not affected by SG, although a high-fat diet caused hepatic steatosis and glucose intolerance in male SG pups. Treatment with a Glp1 receptor antagonist during pregnancy normalized the birth weight of SG pups and diminished the adverse response to a high-fat diet without affecting glucose levels of pregnant mice. The antagonist did not affect the birth weight of pups of sham-operated mice. Our findings link elevated Glp1 signaling, rather than weight loss, to the increased prevalence of SGA births following bariatric surgery with metabolic consequences for the offspring. The long-term effects of bariatric surgery on the metabolic health of offspring of patients require further investigation.

Generation and characterization of a mouse model for one anastomosis gastric bypass surgery.

One anastomosis gastric bypass (OAGB) surgery became a common bariatric procedure in recent years. In this surgery, the distal stomach, duodenum, and proximal jejunum are bypassed, leading to weight loss, improvement in metabolic parameters, and a change in hormonal secretion. We sought to generate and characterize a mouse model for OAGB. Mice fed for 26 wk on a high-fat diet were assigned to OAGB, sham surgery, or caloric restriction and were followed for 50 more days on a high-fat diet. Physiological and histological parameters of the mice were compared during and at the end of the experiment. OAGB-operated mice lost weight and displayed low levels of plasma lipids, high insulin sensitivity, and rapid glucose metabolism compared with sham-operated mice. OAGB-operated mice had higher energy expenditure, higher levels of glucagon-like peptide (GLP-1), and lower albumin than weight-matched calorie-restricted mice. There was no difference in the histology of the endocrine pancreas. The livers of OAGB mice had little hepatic steatosis yet presented with a large number of phagocytic cells. The OAGB mouse model recapitulates many of the phenotypes described in patients that underwent OAGB and enables molecular and physiological studies on the outcome of this surgery.NEW & NOTEWORTHY A mouse model for one anastomosis gastric bypass (OAGB) surgery displays similar outcomes to clinical reports and enables to study the weight loss-dependent and -independent effects of this bariatric surgery.

Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight Loss.

Bariatric operations induce weight loss, which is associated with an improvement in hepatic steatosis and a reduction in hepatic glucose production. It is not clear whether these outcomes are entirely due to weight loss, or whether the new anatomy imposed by the surgery contributes to the improvement in the metabolic function of the liver. We performed vertical sleeve gastrectomy (VSG) on obese mice provided with a high-fat high-sucrose diet and compared them to diet and weight-matched sham-operated mice (WMS). At 40 days after surgery, VSG-operated mice displayed less hepatic steatosis compared with WMS. By measuring the fasting glucose and insulin levels in the blood vessels feeding and draining the liver, we showed directly that hepatic glucose production was suppressed after VSG. Insulin levels were elevated in the portal vein, and hepatic insulin clearance was elevated in VSG-operated mice. The hepatic expression of genes associated with insulin clearance was upregulated. We repeated the experiment in lean mice and observed that portal insulin and glucagon are elevated, but only insulin clearance is increased in VSG-operated mice. In conclusion, direct measurement of glucose and insulin in the blood entering and leaving the liver shows that VSG affects glucose and insulin metabolism through mechanisms independent of weight loss and diet.

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca2+) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Sleeve Gastrectomy Improves Glycemia Independent of Weight Loss by Restoring Hepatic Insulin Sensitivity.

Bariatric surgery dramatically improves glycemic control, yet the underlying molecular mechanisms remain controversial because of confounding weight loss. We performed sleeve gastrectomy (SG) on obese and diabetic leptin receptor-deficient mice (db/db). One week postsurgery, mice weighed 5% less and displayed improved glycemia compared with sham-operated controls, and islets from SG mice displayed reduced expression of diabetes markers. One month postsurgery SG mice weighed more than preoperatively but remained near-euglycemic and displayed reduced hepatic lipid droplets. Pair feeding of SG and sham db/db mice showed that surgery rather than weight loss was responsible for reduced glycemia after SG. Although insulin secretion profiles from islets of sham and SG mice were indistinguishable, clamp studies revealed that SG causes a dramatic improvement in muscle and hepatic insulin sensitivity accompanied by hepatic regulation of hepatocyte nuclear factor-α and peroxisome proliferator-activated receptor-α targets. We conclude that long-term weight loss after SG requires leptin signaling. Nevertheless, SG elicits a remarkable improvement in glycemia through insulin sensitization independent of reduced feeding and weight loss.

Mapping of the Lassa virus LAMP1 binding site reveals unique determinants not shared by other old world arenaviruses.

Cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and pH-induced membrane fusion. A previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: Ebola and Lassa viruses. Our recent studies revealed the functional role of receptor switching to LAMP1 for triggering membrane fusion by Lassa virus and showed the involvement of conserved histidines in this switching, suggesting that other viruses from this family may also switch to LAMP1. However, when we investigated viruses that are genetically close to Lassa virus, we discovered that they cannot bind LAMP1. A crystal structure of the receptor-binding module from Morogoro virus revealed structural differences that allowed mapping of the LAMP1 binding site to a unique set of Lassa residues not shared by other viruses in its family, illustrating a key difference in the cell-entry mechanism of Lassa virus that may contribute to its pathogenicity.

Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus.

To effectively infect cells, Lassa virus needs to switch in an endosomal compartment from its primary receptor, α-dystroglycan, to a protein termed LAMP1. A unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of Lassa virus is important for LAMP1 binding. Here we investigate mutated spikes that have an impaired ability to interact with LAMP1 and show that although LAMP1 is important for efficient infectivity, it is not required for spike-mediated membrane fusion per se Our studies reveal important regulatory roles for histidines from the triad in sensing acidic pH and preventing premature spike triggering. We further show that LAMP1 requires a positively charged His230 residue to engage with the spike complex and that LAMP1 binding promotes membrane fusion. These results elucidate the molecular role of LAMP1 binding during Lassa virus cell entry and provide new insights into how pH is sensed by the spike. IMPORTANCE: Lassa virus is a devastating disease-causing agent in West Africa, with a significant yearly death toll and severe long-term complications associated with its infection in survivors. In recent years, we learned that Lassa virus needs to switch receptors in a pH-dependent manner to efficiently infect cells, but neither the molecular mechanisms that allow switching nor the actual effects of switching were known. Here we investigate the activity of the viral spike complex after abrogation of its ability to switch receptors. These studies inform us about the role of switching receptors and provide new insights into how the spike senses acidic pH.

Ribosomal Antibiotics: Contemporary Challenges.

Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of "pathogen-specific antibiotics," in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification.

Q-Switched Nd:YAG Laser Removal of Facial Amateur Tattoos in Patients With Fitzpatrick Type VI: Case Series.

INTRODUCTION: Q-switched neodymium:YAG (Nd:YAG) lasers are reported to be gold standard for laser tattoo removal. In particular, the Q-switched Nd:YAG laser at 1064 nm is widely recognized for the removal of blue/black amateur tattoos. However, treatment modalities in Fitzpatrick Type VI skin carry a greater risk of complications including alterations in pigmentation compared to fairer skin (Fitzpatrick Type I-IV skin). Therefore, the aim of this case series was to describe with the use of the Q-Switched Nd:YAG laser, the removal of carbon-based amateur tattoos on patients with Fitzpatrick Type VI skin as an effective and safe method. METHODS: Twenty- five patients with Fitzpatrick type VI skin, from Ethiopian origins, with facial tribal tattoos, were treated with the Q- Switched Nd:YAG laser at 1064 nm. Digital images were taken upon every treatment and the clearance rates of the tattoo was evalu- ated by imaging software. RESULTS: We observed an average tattoo clearance rate of 95% among the 45 facial tattoos in 25 patients presented in the case series with minimal pigmentary and textual changes evident. DISCUSSION: These positive aesthetic results have a signi cant psychosocial impact on the lives of those with Fitzpatrick Type VI skin, in particular the Ethiopian Jewish population. J Drugs Dermatol. 2016;15(11):1448-1452..

Molecular Mechanism for LAMP1 Recognition by Lassa Virus.

UNLABELLED: Lassa virus is a notorious human pathogen that infects many thousands of people each year in West Africa, causing severe viral hemorrhagic fevers and significant mortality. The surface glycoprotein of Lassa virus mediates receptor recognition through its GP1 subunit. Here we report the crystal structure of GP1 from Lassa virus, which is the first representative GP1 structure for Old World arenaviruses. We identify a unique triad of histidines that forms a binding site for LAMP1, a known lysosomal protein recently discovered to be a critical receptor for internalized Lassa virus at acidic pH. We demonstrate that mutation of this histidine triad, which is highly conserved among Old World arenaviruses, impairs LAMP1 recognition. Our biochemical and structural data further suggest that GP1 from Lassa virus may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Together with a variable region that we identify on the surface of GP1, those could be two distinct mechanisms that Lassa virus utilizes to avoid antibody-based immune response. IMPORTANCE: Structural data at atomic resolution for viral proteins is key for understanding their function at the molecular level and can facilitate novel avenues for combating viral infections. Here we used X-ray protein crystallography to decipher the crystal structure of the receptor-binding domain (GP1) from Lassa virus. This is a pathogenic virus that causes significant illness and mortality in West Africa. This structure reveals the overall architecture of GP1 domains from the group of viruses known as the Old World arenaviruses. Using this structural information, we elucidated the mechanisms for pH switch and binding of Lassa virus to LAMP1, a recently identified host receptor that is critical for successful infection. Lastly, our structural analysis suggests two novel immune evasion mechanisms that Lassa virus may utilize to escape antibody-based immune response.

Treatment of the skin manifestations of hereditary hemorrhagic telangiectasia with pulsed dye laser.

Hereditary hemorrhagic telangiectasia (HHT) is a familial disorder, in which variably sized arteriovenous malformations develop in the skin, respiratory tract, central nervous system, and gastrointestinal and urogenital tracts. Bleeding is a major problem in the abnormal vessels, primarily in the nose and internal lesions. Skin lesions, in contrast, do not generally bleed spontaneously but pose a significant cosmetic concern. The lesions are characteristically small caliber vessels located in the dermis. As such, they are ideal targets for vascular lesions. Eight patients with cutaneous facial lesions of HHT were treated by pulsed dye laser. All patients exhibited excellent (75-100%) clearance after a mean of 2.6 treatments (range 1-8). In comparison, a control group of patients with non-HHT facial telangiectasia required a mean of 1.9 (range 1-5; p < 0.05) treatments. No adverse events were reported in either group. The study confirms the safety and efficacy of PDL in the management of the cutaneous lesions of HHT.

Examining disaster planning models for large scale burn incidents--a theoretical plane crash into a high rise building.

BACKGROUND: The escalation of global terrorist attacks has resulted in a rise of traumatic injuries. Planning for mass casualty incidents (MCIs) is critical to decrease the morbidity and mortality that ensues after large-scale terrorist attacks. This study provides criteria for the management of burn victims following large-scale disasters. METHODS: Mass casualty outcomes from three disasters involving commercial aircraft crashes were analyzed. The three events included the El-Al cargo Aircraft crash near the Amsterdam Schiphol Airport in 1992, the World Trade Center attacks in New York and the attack against the Pentagon in Washington, DC on 9/11/01. RESULTS: Using the data obtained from these events, the severity of injuries in patients were determined. The result is a general template that may be customized with locally or regionally specific data, in order to evaluate the preparedness of a specific burn alignment for such a scenario. CONCLUSION: Recommendations based on the analysis of previous MCI's were put forth. Based on the needs recognized during these past events, suggestions were made to enhance the preparedness of burn units, hospitals and national agencies as well as municipal authorities.

The temporal suspension flap for malar defects: a novel technique.

Close opposition of full-thickness skin grafts to the recipient wound bed is felt to be critical for graft survival. This is usually accomplished by bolster dressings, basting sutures, or both. Herein, we describe a facile and rapid technique for placing quilting sutures in full-thickness grafts on the ear using a plain gut suture with a short, straight needle. This technique is especially valuable in facilitating precise approximation of grafts within the fossae of the anterior ear. In our experience, this approach promotes graft survival and produces excellent cosmetic results.

Delay techniques for local flaps in dermatologic surgery.

Local flaps may be required to reconstruct defects on the face, neck, and scalp. Occasionally, delay techniques are indicated to reduce the risk for flap ischemia and subsequent necrosis. Delay may be employed before the flap is raised, as done to improve blood supply to a random flap when length to breadth proportions are not ideal, or after the flap is raised and before separation of the pedicle in the final reconstructive step to improve vascularity in the distal end of an interpolation flap. We present our techniques and results of delay procedures for interpolation and similar flaps.

Reconstruction of a lower eyelid defect with a V to Y island flap.

Repair of full thickness defects in the lower eyelid following extirpation of malignant tumors presents a challenge to the reconstructive surgeon. There are several techniques to choose from, depending on the defect's size and location.

Complex forehead defects: a novel reconstructive technique and review of available methods.

Complex forehead defects may result from excision of tumors or trauma. The reconstructive challenge is determined by the extent of tissue loss, the quality of the remaining tissue, possibly comprised vascular supply to the affected region, and special considerations (eg, exposed bone or injury to underlying structures). This paper describes a novel reconstructive approach to correct a complex forehead defect with exposed bone and discusses the armamentarium of reconstructive options for such cases.

Defying consensus: correct sizing of full-thickness skin grafts.

BACKGROUND: Full-Thickness skin grafts are routinely used to reconstruct defects throughout the body. When planning the size of the graft, the surgeon usually copies a template from the defect and measures the graft to fit its full dimensions. This may lead to an oversized graft, resulting an unaesthetic outcome. OBJECTIVE: To evaluate discrepancy in size between the excised full-thickness skin and the excision (donor) site. METHODS: Data from 20 cases of full-thickness excisions was reviewed and analyzed. RESULTS: There was a considerable difference in length of both the short and long axes between the excised full-thickness skin and the excision site. CONCLUSIONS: The initial size of a full-thickness skin graft should be smaller than the defect it is planned to cover.

Nasal ala reconstruction with a crus helix composite graft: a stepladder approach.

BACKGROUND: Defects of the nasal ala present a complex reconstructive challenge. Composite grafts comprise all layers required to successfully reconstruct these full thickness deformities making them the ideal reconstructive method, yet they are usually avoided because of unjustified disreputable failure rates. OBJECTIVE: The authors introduce a stepladder approach for alar reconstruction with a crus of helix composite graft according to the severity and complexity of the defect. METHODS: Data from 25 patients who underwent correction of full thickness alar defects with composite grafts was collected and reviewed. RESULTS: There were no complete graft failures in any of the cases. Ten patients (40%) had partial graft necrosis ranging from 5 to 50% (average 18%); two of them (20%) were heavy smokers. CONCLUSIONS: Composite grafts should be considered for reconstruction of full thickness nasal ala defects, given the correct surgical technique is implemented.