Bariatric surgery in morbidly obese patients improves the atherogenic qualitative properties of the plasma lipoproteins

Objective

The purpose of this study was to evaluate the effect of weight loss induced in morbidly obese subjects by Roux-en-Y gastric bypass bariatric surgery on the atherogenic features of their plasma lipoproteins.

Methods

Twenty-one morbidly obese subjects undergoing bariatric surgery were followed up for up to 1 year after surgery. Plasma and lipoproteins were assayed for chemical composition and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. Lipoprotein size was assessed by non-denaturing polyacrylamide gradient gel electrophoresis, and oxidised LDL by ELISA. Liver samples were assayed for mRNA abundance of oxidative markers.

Results

Lipid profile analysis revealed a reduction in the plasma concentrations of cholesterol and triglycerides, which were mainly associated with a significant reduction in the plasma concentration of circulating apoB-containing lipoproteins rather than with changes in their relative chemical composition. All patients displayed a pattern A phenotype of LDL subfractions and a relative increase in the antiatherogenic plasma HDL-2 subfraction (>2-fold; P < 0.001). The switch towards predominantly larger HDL particles was due to an increase in their relative cholesteryl ester content. Excess weight loss also led to a significant decrease in the plasma concentration of oxidised LDL (∼−25%; P < 0.01) and in the total Lp-PLA2 activity. Interestingly, the decrease in plasma Lp-PLA2 was mainly attributed to a decrease in the apoB-containing lipoprotein-bound Lp-PLA2.

Conclusion

Our data indicate that the weight loss induced by bariatric surgery ameliorates the atherogenicity of plasma lipoproteins by reducing the apoB-containing Lp-PLA2 activity and oxidised LDL, as well as increasing the HDL-2 subfraction.     

From the Cover: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.Inherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancer. Among female mutation carriers, presymptomatic surgical measures significantly reduce morbidity and mortality (1, 2). In particular, risk-reducing salpingo-oophorectomy (i.e., the removal of ovaries and fallopian tubes from a woman without ovarian cancer) reduces risk both of breast cancer and of ovarian cancer, as well as overall mortality (1). However, for many mutation carriers identified following their first cancer diagnosis, genetic testing was not previously indicated because family history did not suggest inherited cancer predisposition (3–5, 6). From a prevention perspective, it is a missed opportunity to identify a woman as a BRCA1 or BRCA2 mutation carrier only after she develops cancer.Among Ashkenazi (European) Jews (AJ), three mutations, BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, account for the great majority of inherited cancer risk due to BRCA1 and BRCA2 (7). In the AJ population, 2.5% of persons carry one of these three mutations (8), and the mutations account for 11% of breast cancer (3) and 40% of ovarian cancer (9, 10). These observations suggest that genetic testing in the AJ population for these mutations fulfills WHO criteria for population screening (11, 12): The disease is an important public health burden to the target population; prevalence and attributable risk of disease due to the mutations are known; and effective interventions exist. However, one necessary piece of information remains unknown: What is the disease risk to mutation carriers ascertained from the general population, rather than carriers identified based on family history (13)?Previous studies assessing cancer risks due to mutations in BRCA1 and BRCA2 ascertained carriers through high-incidence families (14), through a single index case with breast or ovarian cancer (3, 15) or through both affected and unaffected carriers (16). In a 1997 study of AJ volunteers, most index cases had no previous cancer diagnosis, but the percentage of index cases with a family history of breast cancer was approximately double that of unselected AJs (17). In principle, these strategies could have yielded risk estimates different from those of carriers ascertained from the local host population, if cancer risk in BRCA1 or BRCA2 carriers were influenced by familial factors other than the BRCA1 or BRCA2 mutation, such as modifier genes or shared environment (18). In addition, in almost all of these studies, risk estimates were based on imputing carrier status, rather than on direct genetic testing of BRCA1 and BRCA2. This year, the Recommendation Statement on BRCA Testing from the US Preventive Services Task Force recommended against population screening for BRCA1 and BRCA2 mutations, because cancer risk to mutation carriers in the general population was not yet known (19). To address this gap, in this study we assessed breast and ovarian cancer risks in confirmed carriers of BRCA1 and BRCA2 mutations ascertained from the general population. The study was undertaken in the AJ population, because screening for only three founder mutations is sufficient to capture nearly all inherited cancer risk in this population due to BRCA1 and BRCA2 (7).     

Self-assembly of the general membrane-remodeling protein PVAP into sevenfold virus-associated pyramids

Viruses have developed a wide range of strategies to escape from the host cells in which they replicate. For egress some archaeal viruses use a pyramidal structure with sevenfold rotational symmetry. Virus-associated pyramids (VAPs) assemble in the host cell membrane from the virus-encoded protein PVAP and open at the end of the infection cycle. We characterize this unusual supramolecular assembly using a combination of genetic, biochemical, and electron microscopic techniques. By whole-cell electron cryotomography, we monitored morphological changes in virus-infected host cells. Subtomogram averaging reveals the VAP structure. By heterologous expression of PVAP in cells from all three domains of life, we demonstrate that the protein integrates indiscriminately into virtually any biological membrane, where it forms sevenfold pyramids. We identify the protein domains essential for VAP formation in PVAP truncation mutants by their ability to remodel the cell membrane. Self-assembly of PVAP into pyramids requires at least two different, in-plane and out-of-plane, protein interactions. Our findings allow us to propose a model describing how PVAP arranges to form sevenfold pyramids and suggest how this small, robust protein may be used as a general membrane-remodeling system.Release of virus particles from infected cells is the last essential step of the viral replication cycle. In the course of this process, virions face the challenging task of crossing the cell envelope. Viruses have developed an arsenal of diverse strategies to overcome this problem. Most bacterial viruses are lytic and induce lysis of the infected cell with help of the holin-endolysin system (1), whereas others disrupt the host cell envelope via inhibition of the murein biosynthesis pathway (2). The morphological and genomic properties of archaeal viruses (3) suggested that their egress from host cells may have unusual traits that are different from those of bacterial viruses. Indeed, although most archaeal viruses exit cells without lysis, some, in particular the Sulfolobus islandicus rod-shaped virus 2 (SIRV2) and Sulfolobus turreted icosahedral virus (STIV), are lytic and exploit a special mechanism of virion egress (4–8). During the infection cycle of these viruses, pyramidal protrusions with sevenfold rotational symmetry form in the host cell membrane. As the final step of the infection cycle the virus-associated pyramids (VAPs) open outwards along the seams of their seven facets, creating ∼100-nm apertures through which the newly formed virions escape from the host cell (4, 7). VAPs consist of multiple copies of an ∼10-kDa virus-encoded protein, which we term “PVAP” (Protein forming Virus-Associated Pyramids/SIRV2_P98) (7–9). Surprisingly, PVAP assembles into membrane pyramids even when expressed heterologously in archaeal and bacterial expression systems, demonstrating that no other viral proteins are required for VAP formation (7). The mechanism by which VAPs self-assembles in the membrane remains unknown.In the present study we used electron cryotomography to investigate morphological features of SIRV2 replication and the formation of VAPs at different time points after infection. By subtomogram averaging, we determined a 3D map of the VAP. This map, in combination with secondary structure predictions of PVAP and the expression of wild-type (WT) PVAP or a variety of truncation mutants in archaeal, bacterial and eukaryotic cells allows us to propose a model showing how PVAP arranges to form the sevenfold pyramids. These insights are fundamental for understanding how this mechanism can be exploited as a universal tool to engineer the formation and controlled opening of large pores in biological or artificial lipid bilayers.     

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH)

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34⁺ selection, CD3⁺CD19⁺ depletion, TCRαβ⁺CD19⁺ depletion or CD45RA⁺ depletion, added to CD34⁺ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.     

Physical activity behaviour in children and adolescents before,during and after cancer treatment

Purpose

Childhood cancer survivors show reduced physical activity (PA) levels which may considerably impact child development, quality of life, social participation and sequelae such as functional and cardiovascular health. This study aims to evaluate different aspects of PA behaviour in patients with childhood cancer (PaC) before (bT), during (dT) and after (aT) cancer treatment.

Methods

In this cross-sectional, multicentre study, 114 PaC and 37 healthy controls between 4 and 20 years of age were enrolled. PA behaviour was assessed using an adapted questionnaire which included items asking about PA level, PA intensity and domains of PA.

Results

Patients reported lower PA levels and less minutes of PA at moderate-intensity dT than aT and bT (P?≤?0.05). Healthy controls reported higher PA levels than patients aT (P?≤?0.05). At school, 41.7% of PaC did not participate in physical education aT or bT. Lastly, 45.6% of PaC who were engaged in sport club activities bT did no more participate in sport club activities aT.

Conclusion

Patients reported different PA behaviours dT and aT than bT. Therefore, monitoring of PA should be considered to increase PA levels in PaC. Future studies also need to examine how PA behaviour can be influenced in a positive way in PaC.

     

The use of tocilizumab in the treatment of refractory eosinophilic fasciitis: a case-based review

Clinical Rheumatology - Eosinophilic fasciitis (EF) is a rare disorder involving chronic inflammation of the fascia and connective tissue of unknown aetiology and poorly understood pathogenesis. We...     

18F-FDG PET/CT in bone sarcoidosis: an observational study

Clinical Rheumatology - Bone sarcoidosis is usually rare. Imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) can reveal bone...