Inhibition of Mycobacterial Growth In Vitro following Primary but Not Secondary Vaccination with Mycobacterium bovis BCG

Despite the widespread use of the Mycobacterium bovis BCG vaccine, there are more than 9 million new cases of tuberculosis (TB) every year, and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific gamma interferon (IFN-γ) response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 United Kingdom adults who were followed for 6 months to evaluate the abilities of both a whole-blood- and a novel peripheral blood mononuclear cell (PBMC)-based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMCs, we observed a significant improvement in mycobacterial growth inhibition following primary vaccination but no improvement in growth inhibition following revaccination with BCG (P < 0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with purified protein derivative (PPD) antigen-specific IFN-γ enzyme-linked immunospot (ELISPOT) responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization, but not revaccination, with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in vaccine responses by comparing both primary and secondary BCG vaccinations, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than the assays currently used for the assessment of candidate TB vaccines.     

Comparison of current guidelines for primary prevention of coronary heart disease

OBJECTIVE: In primary prevention of atherosclerotic disease, it is difficult to decide when medical treatment should be initiated. The main goal of the study was to compare different guidelines for coronary heart disease (CHD) risk assessment and initiation of lipid-lowering therapy. DESIGN: Cross-sectional evaluation. SETTING: An outpatient lipid and diabetes clinic in a university hospital. PARTICIPANTS/METHODS: Risk factor data obtained on 100 consecutive patients (58 men and 42 women) without clinical evidence of cardiovascular disease were used to compare the Framingham risk equation, the U.S. National Cholesterol Education Program (Adult Treatment Panel III) (NCEP ATP III) guidelines, the joint European Societies guidelines, the joint British guidelines, the revised Sheffield table, and the Munster Heart Study calculator (PROCAM) CHD risk assessment and lipid-lowering therapy. RESULTS: Guidelines could be applied to different subsets of the cohort, ranging from 22% (PROCAM) to 95% of the cohort (revised Sheffield table). All guidelines (except PROCAM) could be applied to a total of 62 patients. Guidelines predicted > or =20% risk for developing CHD over 10 years in 53% (NCEP ATP III), 26% (European) and 32% (British), while Framingham predicted this risk level in 34%. CHD risk was estimated to be > or =3%/year in 5% according to Sheffield, while Framingham predicted this risk in 13%. Lipid-lowering drug therapy is recommended in 52% by NCEP ATP III, while European, British, and Sheffield guidelines recommend this in 26%, 35%, and 5%, respectively. CONCLUSIONS: Guidelines for assessing CHD risk and lipid-lowering therapy differ greatly. Therefore, these algorithms must be used with caution.     

Subcutaneous Electrical Nerve Stimulation: A Feasible and New Method for the Treatment of Patients With Refractory Angina

Introduction: Patients suffering from chronic angina pectoris, insufficiently controllable with medication and revascularization, are an increasing medical and psychosocial problem. Although spinal cord stimulation (SCS) is proven to employ, safe, long‐term anti‐angina, and anti‐ischemic effects for these patients, the use of SCS in this group remains limited. The reason for this restricted use is largely unknown. However, among other reasons, it may be related to the difficulties in positioning an electrode in the epidural space. We studied the feasibility and efficacy of subcutaneous implantation of an entire system. Methods: Seven male patients, mean age 67 ± 3.6 years, received complete subcutaneously implanted electrical nerve stimulation (SENS) systems, with one or more leads fixed in parallel with the sternum, covering the angina area. At baseline and 2 months follow‐up patients performed exercise and quality of life tests (Seattle Angina Questionnaire and diaries number angina attacks and glyceryl trinitrate use). Results: All patients showed clinical relevant improvement (baseline vs. follow‐up), in exercise (63%) and quality of life (Seattle Angina Questionnaire 59%). The number of angina attacks dropped 82% and the number of glyceryl trinitrate use decreased by 90%. No major adverse events were observed. Conclusion: This small feasibility study demonstrates SENS to be an effective and safe method to treat patients suffering from refractory angina. Furthermore, SENS is less invasive and appears to have less lead migrations compared with SCS.     

Interstitial fluid physiology as it relates to glucose monitoring technologies: symposium introduction

Nearly all commercially available glucose sensors share the subcutaneous interstitial fluid (ISF) compartment as their preferred implantation site. However, ISF physiology as it relates to glucose sensors is not well understood. This special symposium titled "Interstitial Fluid Physiology as It Relates to Glucose Monitoring Technologies" is intended to help to bridge the gap in our understanding. This symposium is intended to foster a greater understanding of biological factors that impact the success of implantable glucose monitors and to inspire additional research in the area of ISF physiology as it relates to glucose sensing. Recognition that sensor designers need to have an intimate understanding of the biological environment in which their sensor will reside is emphasized. The symposium is published in two parts, with part I published in September 2010 and part II published in May 2011. All articles published in this symposium are summarized herein.     

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. Methods. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m², HbA_1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. Results. Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol•min^–1•m^–2•mM^–1 and 55 [IQR, 39] pmol•min^–1•m^–2•mM^–1 vs. 44 [IQR, 32] pmol•min^–1•m^–2•mM^–1, P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. Conclusions. In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov {"type":"clinical-trial","attrs":{"text":"NCT01248364","term_id":"NCT01248364"}}NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.     

Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins

Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are "HDL animals" and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor-deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (ELS149A); unexpectedly, expression of ELS149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive ELS149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.     

PD-L1 – inhibitors in neuroendocrine neoplasia: Results from a real-life study

Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.     

The word frequency effect for open- and closed-class items

A previous attempt (Segui, Mehler, Frauenfelder,&Morton, 1982) to assess in French the putative computational asymmetry between open- and closed-class words failed to reveal a difference in frequency sensitivity for these two types of words. In the present paper, two further lexical decision experiments are presented. The experimental conditions were chosen to maximise the chances of finding differences in frequency sensitivity between the two word classes (speeded responses and stimulus masking). Both experiments revealed strong frequency effects for open- and closed-class items and thus no asymmetry in frequency sensitivity. The implications of these results for both normal and aphasic populations are discussed.