Frozen section analysis of sentinel lymph nodes in patients with breast cancer does not impair the probability to detect lymph node metastases

Intra-operative frozen section analysis (FS analysis) of sentinel lymph nodes (SLNs) in patients with breast cancer can prevent a second operation for axillary lymph node dissection. In contrast, loss of tissue during FS analysis may impair the probability to detect lymph node metastases. To determine the effect of tissue loss on the probability of detection of metastases, dimensions and tissue loss resulting from intra-operative frozen section analysis were measured for 21 SLNs. In a mathematical model, the influence of tissue loss on the probability to detect metastases was calculated in relation to SLN size for various pathology protocols: an American, a widely used European, the extensive ‘Milan’ and the Dutch protocol. For median-sized SLN 11 × 8 × 5 mm (length × width × height), FS analysis led to a median loss of 680 μm (13.6%) of the height of the SLN. Irrespective of SLN size or used pathology protocol, the probability of detecting 2 mm metastases remained unchanged or even increased (0–12.8%). Moreover, the probability to detect 0.2 mm metastases increased for the majority of tested combinations of SLN size, tissue loss and used protocol. Only when combining maximum tissue loss and smallest SLN size in the Dutch protocol, or when applying the extensive Milan protocol on a median-sized SLN, the probability to detect 0.2 mm metastases decreased by 2.7% and 14.3%, respectively. Contrary to ‘common knowledge’, doing FS analysis of SLNs does not impair the probability to detect lymph node metastases

Variation in the achievement of HbA1c, blood pressure and LDL cholesterol targets in type 2 diabetes in general practice and characteristics associated with risk factor control.

Aims To identify population, general practitioner, and practice characteristics associated with the achievement of HbA1c, blood pressure and LDL cholesterol targets, and to describe variation in the achievement of risk factor control. Methods We conducted a cross‐sectional survey of 9342 people with type 2 diabetes, 281 general practitioners and 77 general practices in Norway. Missing values (7.4%) were imputed using multiple imputation by chained equations. We used three‐level logistic regression with the achievement of HbA1c, blood pressure and LDL cholesterol targets as dependent variables, and factors related to population, general practitioners, and practices as independent variables. Results Treatment targets were achieved for HbA1c in 64%, blood pressure in 50%, and LDL cholesterol in 52% of people with type 2 diabetes, and 17% met all three targets. There was substantial heterogeneity in target achievement among general practitioners and among practices; the estimated proportion of a GPs diabetes population at target was 55–73% (10–90 percentiles) for HbA1c, 36–63% for blood pressure, and 47–57% for LDL cholesterol targets. The models explained 11%, 5% and 14%, respectively, of the total variation in the achievement of HbA1c, blood pressure and LDL cholesterol targets. Use among general practitioners of a structured diabetes form was associated with 23% higher odds of achieving the HbA1c target (odds ratio 1.23, 95% confidence interval (CI) 1.02–1.47) and 17% higher odds of achieving the LDL cholesterol target (odds ratio 1.17, 95% CI 1.01–1.35). Conclusions Clinical diabetes management is difficult, and few people meet all three risk factor control targets. The proportion of people reaching target varied among general practitioners and practices. Several population, general practitioner and practice characteristics only explained a small part of the total variation. The use of a structured diabetes form is recommended.publishedVersio

Ivermectin treatment of Loa loa hyper-microfilaraemic baboons (Papio anubis): Assessment of microfilarial loads, haematological and biochemical parameters and histopathological changes following treatment.

Individuals with high intensity of Loa loa are at risk of developing serious adverse events (SAEs) post treatment with ivermectin. These SAEs have remained unclear and a programmatic impediment to the advancement of community directed treatment with ivermectin. The pathogenesis of these SAEs following ivermectin has never been investigated experimentally. The Loa/baboon (Papio anubis) model can be used to investigate the pathogenesis of Loa-associated encephalopathy following ivermectin treatment in humans. 12 baboons with microfilarial loads > 8,000mf/mL of blood were randomised into four groups: Group 1 (control group receiving no drug), Group 2 receiving ivermectin (IVM) alone, Group 3 receiving ivermectin plus aspirin (IVM + ASA), and Group 4 receiving ivermectin plus prednisone (IVM + PSE). Blood samples collected before treatment and at Day 5, 7 or 10 post treatment, were analysed for parasitological, hematological and biochemical parameters using standard techniques. Clinical monitoring of animals for side effects took place every 6 hours post treatment until autopsy. At autopsy free fluids and a large number of standard organs were collected, examined and tissues fixed in 10% buffered formalin and processed for standard haematoxylin-eosin staining and specific immunocytochemical staining. Mf counts dropped significantly (p0.05). All animals became withdrawn 48 hours after IVM administration. All treated animals recorded clinical manifestations including rashes, itching, diarrhoea, conjunctival haemorrhages, lymph node enlargement, pinkish ears, swollen face and restlessness; one animal died 5 hours after IVM administration. Macroscopic changes in post-mortem tissues observed comprised haemorrhages in the brain, lungs, heart, which seen in all groups given ivermectin but not in the untreated animals. Microscopically, the major cellular changes seen, which were present in all the ivermectin treated animals included microfilariae in varying degrees of degeneration in small vessels. These were frequently associated with fibrin deposition, endothelial changes including damage to the integrity of the blood vessel and the presence of extravascular erythrocytes (haemorrhages). There was an increased presence of eosinophils and other chronic inflammatory types in certain tissues and organs, often in large numbers and associated with microfilarial destruction. Highly vascularized organs like the brain, heart, lungs and kidneys were observed to have more microfilariae in tissue sections. The number of mf seen in the brain and kidneys of animals administered IVM alone tripled that of control animals. Co-administration of IVM + PSE caused a greater increase in mf in the brain and kidneys while the reverse was noticed with the co-administration of IVM + ASA. The treatment of Loa hyper-microfilaraemic individuals with ivermectin produces a clinical spectrum that parallels that seen in Loa hyper-microfilaraemic humans treated with ivermectin. The utilization of this experimental model can contribute to the improved management of the adverse responses in humans

The multiplex bead array approach to identifying serum biomarkers associated with breast cancer

Introduction Breast cancer is the most common type of cancer seen in women in western countries. Thus, diagnostic modalities sensitive to early-stage breast cancer are needed. Antibody-based array platforms of a data-driven type, which are expected to facilitate more rapid and sensitive detection of novel biomarkers, have emerged as a direct, rapid means for profiling cancer-specific signatures using small samples. In line with this concept, our group constructed an antibody bead array panel for 35 analytes that were selected during the discovery step. This study was aimed at testing the performance of this 35-plex array panel in profiling signatures specific for primary non-metastatic breast cancer and validating its diagnostic utility in this independent population. Methods Thirty-five analytes were selected from more than 50 markers through screening steps using a serum bank consisting of 4,500 samples from various types of cancer. An antibody-bead array of 35 markers was constructed using the Luminex (TM) bead array platform. A study population consisting of 98 breast cancer patients and 96 normal subjects was analysed using this panel. Multivariate classification algorithms were used to find discriminating biomarkers and validated with another independent population of 90 breast cancer and 79 healthy controls. Results Serum concentrations of epidermal growth factor, soluble CD40-ligand and proapolipoprotein A1 were increased in breast cancer patients. High-molecular-weight-kininogen, apolipoprotein A1, soluble vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, vitamin-D binding protein and vitronectin were decreased in the cancer group. Multivariate classification algorithms distinguished breast cancer patients from the normal population with high accuracy (91.8% with random forest, 91.5% with support vector machine, 87.6% with linear discriminant analysis). Combinatorial markers also detected breast cancer at an early stage with greater sensitivity. Conclusions The current study demonstrated the usefulness of the antibody-bead array approach in finding signatures specific for primary non-metastatic breast cancer and illustrated the potential for early, high sensitivity detection of breast cancer. 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Left ventricular speckle tracking-derived cardiac strain and cardiac twist mechanics in athletes: a systematic review and meta-analysis of controlled studies

Background: The athlete’s heart is associated with physiological remodeling as a consequence of repetitive cardiac loading. The effect of exercise training on left ventricular (LV) cardiac strain and twist mechanics are equivocal, and no meta-analysis has been conducted to date. Objective: The objective of this systematic review and meta-analysis was to review the literature pertaining to the effect of different forms of athletic training on cardiac strain and twist mechanics and determine the influence of traditional and contemporary sporting classifications on cardiac strain and twist mechanics. Methods: We searched PubMed/MEDLINE, Web of Science, and ScienceDirect for controlled studies of aged-matched male participants aged 18–45 years that used two-dimensional (2D) speckle tracking with a defined athlete sporting discipline and a control group not engaged in training programs. Data were extracted independently by two reviewers. Random-effects meta-analyses, subgroup analyses, and meta-regressions were conducted. Results: Our review included 13 studies with 945 participants (controls n = 355; athletes n = 590). Meta-analyses showed no athlete–control differences in LV strain or twist mechanics. However, moderator analyses showed greater LV twist in high-static low-dynamic athletes (d = –0.76, 95% confidence interval [CI] –1.32 to –0.20; p < 0.01) than in controls. Peak untwisting velocity (PUV) was greater in high-static low-dynamic athletes (d = –0.43, 95% CI –0.84 to –0.03; p < 0.05) but less than controls in high-static high-dynamic athletes (d = 0.79, 95% CI 0.002–1.58; p = 0.05). Elite endurance athletes had significantly less twist and apical rotation than controls (d = 0.68, 95% CI 0.19–1.16, p < 0.01; d = 0.64, 95% CI 0.27–1.00, p = 0.001, respectively) but no differences in basal rotation. Meta-regressions showed LV mass index was positively associated with global longitudinal (b = 0.01, 95% CI 0.002–0.02; p < 0.05), whereas systolic blood pressure was negatively associated with PUV (b = –0.06, 95% CI –0.13 to –0.001; p = 0.05). Conclusion: Echocardiographic 2D speckle tracking can identify subtle physiological differences in adaptations to cardiac strain and twist mechanics between athletes and healthy controls. Differences in speckle tracking echocardiography-derived parameters can be identified using suitable sporting categorizations

(+)-Rutamarin as a Dual Inducer of Both GLUT4 Translocation and Expression Efficiently Ameliorates Glucose Homeostasis in Insulin-Resistant Mice

Glucose transporter 4 (GLUT4) is a principal glucose transporter in response to insulin, and impaired translocation or decreased expression of GLUT4 is believed to be one of the major pathological features of type 2 diabetes mellitus (T2DM). Therefore, induction of GLUT4 translocation or/and expression is a promising strategy for anti-T2DM drug discovery. Here we report that the natural product (+)-Rutamarin (Rut) functions as an efficient dual inducer on both insulin-induced GLUT4 translocation and expression. Rut-treated 3T3-L1 adipocytes exhibit efficiently enhanced insulin-induced glucose uptake, while diet-induced obese (DIO) mice based assays further confirm the Rut-induced improvement of glucose homeostasis and insulin sensitivity in vivo. Subsequent investigation of Rut acting targets indicates that as a specific protein tyrosine phosphatase 1B (PTP1B) inhibitor Rut induces basal GLUT4 translocation to some extent and largely enhances insulin-induced GLUT4 translocation through PI3 kinase-AKT/PKB pathway, while as an agonist of retinoid X receptor α (RXRα), Rut potently increases GLUT4 expression. Furthermore, by using molecular modeling and crystallographic approaches, the possible binding modes of Rut to these two targets have been also determined at atomic levels. All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration

Open questions in utility theory

Throughout this paper, our main idea is to explore different classical questions arising in Utility Theory, with a particular attention to those that lean on numerical representations of preference orderings. We intend to present a survey of open questions in that discipline, also showing the state-of-art of the corresponding literature.This work is partially supported by the research projects ECO2015-65031-R, MTM2015-63608-P (MINECO/ AEI-FEDER, UE), and TIN2016-77356-P (MINECO/ AEI-FEDER, UE)