Lysophosphatidic acid pretreatment prevents micromolar atorvastatin-induced endothelial cell death and ensures the beneficial effects of high-concentration statin therapy on endothelial gene expression

Because of the pleiotropic effects of statins, it may potentially be used as a locoregional adjuvant in vascular revascularization, tissue engineering, and regenerative procedures. Electron probe X-ray microanalyses and oligonucleotide microarrays were used to identify the global effects of micromolar concentrations of atorvastatin on the gene expression and cell viability of endothelial cells in different states of lysophosphatidic acid (LPA)-induced activation. Treatment with 1-μM atorvastatin for 24 hours significantly reduced the viability of human vascular endothelial cells (HUVECs). However, the same treatment of LPA-preactivated HUVECs produced elevated cell viability levels and an optimal vascular gene expression profile, including endothelial nitric oxide synthase overexpression, endothelin-1 repression, an anti-inflammatory genetic pattern, and upregulation of molecules involved in maintaining the endothelial barrier (vascular endothelial cadherin, claudin 5, tight junction protein 1, integrin β4). The atorvastatin treatment also produced a repression of microRNA 21 and genes involved in cell proliferation and neointimal formation (vascular endothelial growth factor [VEGF] A, VEGF receptor 1, VEGFC). Results obtained suggest that micromolar atorvastatin therapy can enhance global endothelial function, but its effects on cell viability vary according to the baseline state of cell activation (preactivated, postactivated, or not activated). Preactivation with LPA protects HUVECs against atorvastatin-induced apoptosis and delivers optimal levels of cell viability and functionality.     

Pancreatic adenocarcinoma: Outstanding problems

Pancreatic adenocarcinoma remains the fourth leading cause of cancer-related death and is one of the most aggressive malignant tumors with an overall 5-year survival rate of less than 4%.Surgical resection remains the only potentially curative treatment but is only possible for 15%-20% of patients with pancreatic adenocarcinoma.About 40% of patients have locally advanced nonresectable disease.In the past,determination of pancreatic cancer resectability was made at surgical exploration.The development of modern imaging techniques has allowed preoperative staging of patients.Institutions disagree about the criteria used to classify patients.Vascular invasion in pancreatic cancers plays a very important role in determining treatment and prognosis.There is no evidence-based consensus on the optimal preoperative imaging assessment of patients with suspected pancreatic cancer and a unified definition ofborderline resectable pancreatic cancer is also lacking.Thus,there is much room for improvement in all aspects of treatment for pancreatic cancer.Multi-detector computed tomography has been widely accepted as the imaging technique of choice for diagnosing and staging pancreatic cancer.With improved surgical techniques and advanced perioperative management,vascular resection and reconstruction are performed more frequently;patients thought once to be unresectable are undergoing radical surgery.However,when attempting heroic surgery,a realistic approach concerning the patient’s age and health status,probability of recovery after surgery,perioperative morbidity and mortality and life quality after tumor resection is necessary.     

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1^–/y). Generation of Mtm1^–/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle–specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.     

New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells

From in vivo observations, a majority of M. tuberculosis cells in latently infected individuals are in a dormant and probably nonculturable state, display little metabolic activity, and are phenotypically resistant to antibiotics. Despite many attempts, no specific antimicrobials effective against latent tuberculosis have yet been found, partly because of a lack of reliable and adequate in vitro models for screening of drug candidates. We propose here a novel in vitro model of M. tuberculosis dormancy that meets the important criteria of latency, namely, nonculturability of cells, considerable reduction of metabolic activity, and significant phenotypic resistance to the first-line antibiotics rifampin and isoniazid. Using this model, we found a new group of 2-thiopyridine derivatives that had potent antibacterial activity against both actively growing and dormant M. tuberculosis cells. By means of the model of M. tuberculosis nonculturability, several new 2-thiopyridine derivatives were found to have potent antitubercular activity. The compounds are effective against both active and dormant M. tuberculosis cells. The bactericidal effects of compounds against dormant M. tuberculosis was confirmed by using three different in vitro models of tuberculosis dormancy. The model of nonculturability could be used as a reliable tool for screening drug candidates, and 2-thiopyridine derivatives may be regarded as prominent compounds for further development of new drugs for curing latent M. tuberculosis infection.     

Promoting cardiovascular health post‐transplant through early diagnosis and adequate management of hypertension and dyslipidemia

Despite correction of underlying solid organ failure by transplantation, pediatric transplant recipients still have increased mortality rates compared to the general pediatric population, in part due to increased cardiovascular risk. In particular, pediatric kidney and non‐kidney transplant recipients with chronic kidney disease have significant cardiovascular risk that worsens with declining kidney function. Biomarkers associated with future cardiovascular risk such as casual and ambulatory hypertension, dyslipidemia, vascular stiffness and calcification, and left ventricular hypertrophy can be detected throughout the post‐transplant period and in patients with stable kidney function. Among these, hypertension and dyslipidemia are two potentially modifiable cardiovascular risk factors that are highly prevalent in kidney and non‐kidney pediatric transplant recipients. Standardized approaches to appropriate BP measurement and lipid monitoring are needed to detect and address these risk factors in a timely fashion. To achieve sustained improvement in cardiovascular health, clinicians should partner with patients and their caregivers to address these and other risk factors with a combined approach that integrates pharmacologic with non‐pharmacologic approaches. This review outlines the scope and impact of hypertension and dyslipidemia in pediatric transplant recipients, with a particular focus on pediatric kidney transplantation given the high burden of chronic kidney disease‐associated cardiovascular risk. We also review the current published guidelines for monitoring and managing abnormalities in blood pressure and lipids, highlighting the important role of therapeutic lifestyle changes in concert with antihypertensive and lipid‐lowering medications.     

PREDIRCAM eHealth Platform for Individualized Telemedical Assistance for Lifestyle Modification in the treatment of Obesity,Diabetes, and Cardiometabolic Risk Prevention: A Pilot Study (PREDIRCAM 1)

Background

Healthy diet and regular physical activity are powerful tools in reducing diabetes and cardiometabolic risk. Various international scientific and health organizations have advocated the use of new technologies to solve these problems. The PREDIRCAM project explores the contribution that a technological system could offer for the continuous monitoring of lifestyle habits and individualized treatment of obesity as well as cardiometabolic risk prevention.

Methods

PREDIRCAM is a technological platform for patients and professionals designed to improve the effectiveness of lifestyle behavior modifications through the intensive use of the latest information and communication technologies. The platform consists of a web-based application providing communication interface with monitoring devices of physiological variables, application for monitoring dietary intake, ad hoc electronic medical records, different communication channels, and an intelligent notification system. A 2-week feasibility study was conducted in 15 volunteers to assess the viability of the platform.

Results

The website received 244 visits (average time/session: 17 min 45 s). A total of 435 dietary intakes were recorded (average time for each intake registration, 4 min 42 s ± 2 min 30 s), 59 exercises were recorded in 20 heart rate monitor downloads, 43 topics were discussed through a forum, and 11 of the 15 volunteers expressed a favorable opinion toward the platform. Food intake recording was reported as the most laborious task. Ten of the volunteers considered long-term use of the platform to be feasible.

Conclusions

The PREDIRCAM platform is technically ready for clinical evaluation. Training is required to use the platform and, in particular, for registration of dietary food intake.     

No Cytomegalovirus-related Deaths After Non-ablative Stem Cell Allografts

Cytomegalovirus (CMV)-related deaths and data of clinically evident CMV disease were assessed in a group of 47 individuals given allogeneic non-myeloablative hematopoietic stem cell transplants (NST). IgG anti-CMV antibodies were found in 56% of the donors and 76% of the receptors. Prophylactic ganciclovir was given to only 12 of the recipients during 100 days after the graft. There were no CMV-related deaths and clinically overt CMV disease was not found in any individual. The follow up post-transplant period of the patients, ranges between 30 and 810 days (median 242 days), the actuarial median survival (SV) is above 810 days and has not been reached, whereas the 810-days SV is 60%. Eighteen patients (38%) died 30-480 days after the transplant; four failed to engraft and died because of progressive disease; three died as a consequence of graft versus host disease (GVHD), whereas eleven individuals had a relapse of the malignancy and died. It is possible that the reduced bone marrow damage during NST, the prompt recovery of both the hematopoiesis and immune function in this type of allografts and the use of peripheral blood hematopoietic stem cell (HSC) is responsible for the absence of CMV-related deaths and clinical disease despite a high prevalence of CMV infection in these individuals.     

Sexual Risk, Serostatus and Intimate Partner Violence Among Couples During Pregnancy in Rural South Africa

The aim of this study was to describe sexual risk behavior among 239 couples during pregnancy and to examine the relationship of sexual risk behavior with HIV serostatus and intimate partner violence. One-third (31.8 %) of pregnant women and 20.9 % of male partners were HIV positive. HIV risk factors included lack of knowledge of partners’ HIV serostatus, unprotected sexual intercourse and multiple sexual partners. Among men, multivariate logistic regression identified awareness of HIV negative partner status, multiple sexual partners and low levels of partner violence and among women Zulu or Swati ethnicity were associated with unprotected intercourse. HIV positive concordance was associated with protected sex and in multilevel analysis of couples HIV positive status and awareness of the partner’s HIV positive status were associated with protected sex. High levels of HIV risk behaviour was found among couples during pregnancy calling for HIV risk reduction interventions.     

Cascade plasma filtration during the first year after CABG in patients with hyperlipidemia refractory to statins

ObjectiveTo evaluate the effect of a 12-month course of weekly lipid apheresis on vein graft patency after coronary artery bypass grafting (CABG) in patients with hyperlipidemia refractory to statins.MethodsIn a 12-month prospective controlled clinical trial we enrolled 34 male patients (mean age 57 ± 8 years) who passed through successful CABG and low-density lipoprotein cholesterol (LDL-C) level >2.6 mmol/L prior to the operation despite statin treatment. Patients were allocated into 2 groups: active (n = 17, weekly apheresis by cascade plasma filtration (CPF) plus atorvastatin), and control (n = 17, atorvastatin alone). Graft patency was evaluated by multislice computed tomography at 3 months and by angiography at 12 months after an operation.ResultsBoth groups were comparable in clinical and biochemical characteristics. During each CPF procedure, LDL-C level decreased by 64 ± 9%, apoB – by 65 ± 8%, Lp(a) – by 52 ± 15%,; these changes were significant compared to baseline and the control group. Mean net difference in LDL-C level between apheresis and control groups was 1.1 ± 0.3 mmol/L. Vein graft patency at study end was 88.2% (45 of 51) in the apheresis group versus 72.7% (40 of 55) in the control group (p = 0.05). Use of apheresis was associated with decreased vein graft occlusions by 46%: relative risk 0.54; 95% confidence interval 0.27 to 1.02; p = 0.05.ConclusionOur data suggest that the use of lipoprotein apheresis with CPF results in a better vein graft patency during the first year after CABG in patients with hyperlipidemia refractory to statins.