Dissociation Between Long-term Weight Loss Intervention and Blood Pressure: an 18-month Randomized Controlled Trial

BackgroundObesity is associated with elevated blood pressure (BP). In patients with obesity and hypertension, weight loss lowers BP, but the long-term effect of weight loss on BP is less clear.ObjectiveWe aimed to assess the effect of long-term weight loss intervention on BP in normotensive and hypertensive subjects.DesignRandomized controlled trial.ParticipantsTwo hundred seventy-eight subjects (mean age 47.9 ± 9.3 years, 89% male, 56% hypertensive) with abdominal obesity or elevated serum triglycerides and low high-density lipoprotein cholesterol were recruited.InterventionEighteen-month weight loss intervention.Main MeasuresBody weight and BP were measured at baseline, after 6 and 18 months.ResultsAfter 6 months of intervention, in the weight loss phase, body mass index (BMI) decreased by an average of −2.2±1.5 kg/m² (p<0.001) and both diastolic BP (DBP) and systolic BP (SBP) decreased by −2.1±8.8 mmHg and −2.3±12.9 mmHg, respectively (p<0.01 for both). The change in BMI was similar in normotensive and hypertensive subjects (−2.0±1.6 and −2.3±1.5, p = 0.246). However, DBP and SBP decreased significantly (−5.2±7.1 mmHg and −6.2±12.5 mmHg, respectively, p<0.001 for both) in hypertensive subjects, and increased in normotensive subjects (1.8±9.3 mmHg, p = 0.041 and 2.7±11.7 mmHg, p = 0.017, respectively). After 18 months, in the weight maintenance phase, BMI slightly increased (0.9±1.3 kg/m², p<0.001) but remained significantly lower than at baseline (p<0.0001). Unlike BMI, DBP and SBP increased significantly in hypertensive subjects (p<0.001) and returned almost to baseline levels.ConclusionWeight-loss intervention reduced BP in hypertensive patients, but this was not maintained in the long run.Clinical Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01530724","term_id":"NCT01530724"}}NCT01530724KEY WORDS: blood pressure, weight loss, body mass index, hypertension, randomized controlled trial     

Liposomal Simvastatin Attenuates Neointimal Hyperplasia in Rats

Monocytes, macrophages, and inflammation play a key role in the process of neointimal proliferation and restenosis. The present study evaluated whether systemic and transient depletion of monocytes could be obtained by a single intravenous (IV) injection of simvastatin liposomes, for the inhibition of neointima formation. Balloon-injured carotid artery rats (n = 30) were randomly assigned to treatment groups of free simvastatin, simvastatin in liposomes (3 mg/kg), and saline (control). Stenosis and neointima to media ratio (N/M) were determined 14 days following single IV injection at the time of injury by morphometric analysis. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Inhibition of RAW264.7, J774, and THP-1 proliferation by simvastatin-loaded liposomes and free simvastatin was determined by the 3-(4, 5-dimethylthiazolyl-2)-2, 5- diphenyltetrazolium bromide assay. Simvastatin liposomes were successfully formulated and were found to be 1.5-2 times more potent than the free drug in suppressing the proliferation of monocytes/macrophages in cell cultures of RAW 264.7, J774, and THP-1. IV injection of liposomal simvastatin to carotid-injured rats (3 mg/kg, n = 4) resulted in a transient depletion of circulating monocytes, significantly more prolonged than that observed following treatment with free simvastatin. Administration to balloon-injured rats suppressed neointimal growth. N/M at 14 days was 1.56 ± 0.16 and 0.90 ± 0.12, control and simvastatin liposomes, respectively. One single systemic administration of liposomal simvastatin at the time of injury significantly suppresses neointimal formation in the rat model of restenosis, mediated via a partial and transient depletion of circulating monocytes.Key words: drug delivery systems, liposomes, monocytes, restenosis, statins     

Enterococcal bacteraemia: epidemiological, microbiological, clinical and prognostic characteristics, and the impact of high level gentamicin resistance

Enterococci are increasingly common nosocomial pathogens that can cause serious infections and often acquire antibiotic resistance. This study focused on the epidemiological, microbiological and clinical characteristics of enterococcal bacteraemia with special attention to the impact of high level gentamicin resistance (HLGR) on prognosis. 117 cases of enterococcal bacteraemia constituted 8% of all bacteraemic episodes during the y 2002. The most common source of infection was the urinary tract, more than half of the episodes were polymicrobial and the vast majority of cases was healthcare-associated. 50 of 117 isolates (43%) were resistant to gentamicin. Infection-related mortality (22 of 117, 19%) was associated with 2 independent variables in multivariate analysis: severity-of-illness score (OR=39.6, p<0.00001) and HLGR (OR=6.4, p=0.006). It was concluded that HLGR adversely affects the outcome of bacteraemic enterococcal infection.     

Skin microbiota analysis in human 3D skin models—“Free your mice”

In the May issue of Experimental Dermatology 2018, we published a review article focusing on human 3D skin models in the context of microbiota research. The principal intention was to provide an overview of present and future concepts to use skin models in microbiota analyses. With the present viewpoint, we would like to draw the reader's attention again to the use of human skin models in microbiota research with the aim to highlight the benefits and necessity of human skin models to analyse the human skin-microbiota interaction. This is accompanied by a critical view on mice models that often are not suitable to analyse the functional impact of the human skin microbiota. In addition, we present novel and future concepts highlighting the benefits of human 3D skin models in microbiota research.     

Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells

Neurodegenerative diseases differ in etiology but are propagated similarly. We show that neuronal loss caused by intraocular injection of aggregated beta-amyloid was significantly greater in immunodeficient mice than in normal mice. The neurodegeneration was attenuated or augmented by elimination or addition, respectively, of naturally occurring CD4(+)CD25(+) regulatory T cells (Treg). Vaccination with retina-derived antigens or with the synthetic copolymer glatiramer acetate (Copolymer-1, Cop-1), but not with beta-amyloid, reduced the ocular neuronal loss. In mouse hippocampal slices, microglia encountering activated T cells overcame the cytotoxicity of aggregated beta-amyloid. These findings support the concept of "protective autoimmunity", show that a given T cell-based vaccination is protective at a particular site irrespective of toxicity type, and suggest that locally activated T cells induce a microglial phenotype that helps neurons withstand the insult. Alzheimer's and other neurodegenerative diseases might be arrested or retarded by vaccination with Cop-1 or related compounds or by treatment with compounds that weaken Treg suppression.     

Colorimetric Polymer Films for Predicting Lipid Interactions and Percutaneous Adsorption of Pharmaceutical Formulations

Purpose  To develop and demonstrate a rapid and simple colorimetric film assay for evaluating lipid interactions of pharmaceutical compounds and gel formulations. Methods  The colorimetric assay comprises glass-supported films of phospholipids and polydiacetylene, which undergo visible and quantifiable blue–red transformations induced by interactions with amphiphilic molecules applied in very small volumes on the film surface. The color transitions are recorded by scanning of the films, and quantified through a simple image analysis algorithm. Results  We show that pharmaceutical molecules and gel formulations induce blue–red transformations after short incubation with the lipid/polydiacetylene (PDA) films. Colorimetric dose–response curves exhibit dependence upon the lipid affinity and extent of membrane binding of the pharmaceutical compounds examined. The colorimetric lipid/PDA film assay was employed for distinguishing the contributions of individual molecular components within gel formulations. Conclusions  The colorimetric data yield insight into the degree of lipid binding of the molecules tested. The film assay is particularly advantageous for analysis of semi-solid (gel or lotion) formulations, elucidating the lipid interaction characteristics of specific molecular components within the mixtures. The new colorimetric film assay constitutes a generic, rapid, and easily applicable platform for predicting and screening interactions of pharmaceutical compounds and complex formulations with lipid barriers. Izek Ben-Shlush and Roman Volinsky contributed equally.     

The Effect of Weight-Loss Interventions on Cervical and Chin Subcutaneous Fat Depots; the CENTRAL Randomized Controlled Trial

Accumulation of cervical and chin subcutaneous adipose tissues (SAT) represent known phenotypes of obesity. We aimed to evaluate the sensitivity of these fat storages to long-term weight-loss directed lifestyle-intervention and to assess their relations to bodily-adiposity, insulin-resistance, and cardiometabolic risk; We randomly assigned 278 participants with abdominal-obesity/dyslipidemia to low-fat or Mediterranean/low-carbohydrate diets +/− physical-activity. All participants underwent an 18 month whole-body magnetic resonance imaging follow-up, from which we assessed cervical and chin SAT-areas; Participants (age = 48 years; 90% men; body-mass-index = 30.9 kg/m²) had an 18-month adherence-rate of 86%. Cervical-SAT and chin-SAT decreased after 6-months (−13.1% and −5.3%, respectively, p < 0.001). After 18-months only cervical-SAT remained decreased compared to baseline (−5%, p < 0.001). Cervical and chin-SAT 18-month changes were associated with changes in weight (r = 0.70, r = 0.66 respectively; <0.001 for both) and visceral-adipose-tissue (VAT; r = 0.35, r = 0.42 respectively; <0.001 for both). After adjustment to VAT, waist-circumference, or weight-changes, chin-SAT 18-month reduction was associated with favorable changes in fasting-glucose (β = 0.10; p = 0.05), HbA1c (β = 0.12; p = 0.03), and homeostasis-model-assessment-of-insulin-resistance (β = 0.12; p = 0.03). Cervical-SAT 18-month reduction was associated with decreased triglycerides (β = 0.16; p = 0.02) and leptin (β = 0.19; p = 0.01) independent of VAT; Cervical and chin-SATs are dynamic fat depots that correspond with weight-loss and are associated with changes in cardiometabolic profile. In long-term, chin-SAT displays a larger rebound compared with cervical-SAT. Chin-SAT accumulation is associated with in insulin-resistance, independent of central obesity. (ClinicalTrials identifier {"type":"clinical-trial","attrs":{"text":"NCT01530724","term_id":"NCT01530724"}}NCT01530724)     

Infant Formula with Added Bovine Milk Fat Globule Membrane and Modified Iron Supports Growth and Normal Iron Status at One Year of Age: A Randomized Controlled Trial

Inclusion of bovine-derived milk fat globule membrane (bMFGM) or bMFGM components in infant formulas (IFs) may support healthy brain development. This double-blind, prospective trial evaluated growth, tolerance, and iron status in infants receiving added bMFGM and modified protein, iron, and arachidonic acid (ARA) concentrations in IF. Healthy term infants were randomized to: control (marketed, routine cow’s milk-based IF/100 kcal: 2.1 g protein, 1.8 mg iron, 34 mg ARA) or INV-MFGM (investigational cow’s milk-based IF/100 kcal: 1.9 g protein, 1.2 mg iron, 25 mg ARA and whey protein-lipid concentrate, 5 g/L (source of bMFGM)). Anthropometrics, stool characteristics, fussiness, and gassiness through day 365 and blood markers of iron status at day 365 were evaluated. The primary outcome was rate of weight gain from 14–120 days of age. Of 373 infants enrolled (control: 191, INV-MFGM: 182), 275 completed the study (control: 141; INV-MFGM: 134). No group differences in growth rate (g/day) from day 14–120 or study discontinuation were detected. Few group differences in growth or parent-reported fussiness, gassiness, or stool characteristics were detected. No group differences were detected in hemoglobin, hematocrit, or incidence of anemia. In healthy term infants, bMFGM and modified protein, iron, and ARA concentrations in a cow’s milk-based IF were well-tolerated, associated with adequate growth throughout the first year of life, and supported normal iron status at one year of age.     

Treatment patterns and clinical outcomes in high‐risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi‐center retrospective study

Del17p is a genomic imbalance occurring in ～7%‐10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib‐based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M‐Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M‐Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.