Combination therapy: A new strategy to manage diabetes and its complications

Diabetes mellitus is the most common metabolic disorder. The major cause of mortality and morbidity here is due to the complications caused by increased glucose concentrations. All the available commercial antidiabetic drugs are associated with side effects. The combination therapy could be a new and highly effective therapeutic strategy to manage hyperglycemia. Combination of commercial drugs with phytochemicals may reduce the side effects caused by these synthetic drugs. Herbal products have been thought to be inherently safe, because of their natural origin and traditional use rather than based on systemic studies. New formulation and cocrystallisation strategies need to be adopted to match the bioavailability of the drug and the phytochemical. This review describes in detail, the observed synergy and mechanism of action between phytochemicals and synthetic drugs in effectively combating. The mode of action of combination differs significantly than that of the drugs alone; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries.     

SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets

Combinatorial therapies have been recently proposed to improve the efficacy of anticancer treatment. The Synergy Finder R package is a software used to analyze pre-clinical drug combination datasets. Here, we report the major updates to the Synergy Finder R package for improved interpretation and annotation of drug combination screening results. Unlike the existing implementations, the updated Synergy Finder R package includes five main innovations. 1) We extend the mathematical models to higher...     

A Method for the Assessment of Reports of Drug Trials

A stepwise method for the assessment of reports of drug trials was used to determine the validity of drug reports published in The Canadian Medical Association Journal during the five-year period, January 1, 1956, to December 31, 1960. The method is simple and consists of applying four criteria: (1) the presence of adequate controls; (2) randomization of treatments; (3) objective assessment of drug effects; and (4) statistical analysis of results. If these criteria were absent, the assessment was stopped, and the report was felt to be invalid. A total of 203 articles were reviewed and 11 were found to fulfil these criteria. During the same period of time there were 93 additional case reports of drug effects, 39 of which described the effectiveness of a drug without there being adequate controls. The remainder of the case reports described drug toxicities.     

A latent contingency table approach to dose finding for combinations of two agents

Summary .  Two-agent combination trials have recently attracted enormous attention in oncology research. There are several strong motivations for combining different agents in a treatment: to induce the synergistic treatment effect, to increase the dose intensity with nonoverlapping toxicities, and to target different tumor cell susceptibilities. To accommodate this growing trend in clinical trials, we propose a Bayesian adaptive design for dose finding based on latent 2 × 2 tables. In the search for the maximum tolerated dose combination, we continuously update the posterior estimates for the unknown parameters associated with marginal probabilities and the correlation parameter based on the data from successive patients. By reordering the dose toxicity probabilities in the two-dimensional space, we assign each coming cohort of patients to the most appropriate dose combination. We conduct extensive simulation studies to examine the operating characteristics of the proposed method under various practical scenarios. Finally, we illustrate our dose-finding procedure with a clinical trial of agent combinations at M. D. Anderson Cancer Center.     

Design and analysis of drug combination experiments

In this paper we present and discuss a novel, simple and easy to implement parametric modeling approach to assess synergy. An extended three parameter log-logistic model is used to analyse the data and calculate confidence intervals of the interaction indices. In addition the model corrects for the bias due to plate-location effects. The analysis is performed with PROC NLMIXED and SAS-code is provided. The approach is illustrated using data coming from an oncology study in which the inhibition effect of a combination of two compounds is studied using 96-well plates and a fixed-ratio design.     

Anthropometric Indices and the Incidence of Hypertension: A Comparative Analysis

Objective: To investigate the association between several anthropometric measurements of obesity with the incidence of hypertension. Research Methods and Procedures: Participants were 592 individuals free of hypertension, selected at random from the community. In the baseline evaluation, they were submitted to completed measures of demographics, anthropometrics, blood pressure, and other risk factors for hypertension. Incident hypertension was defined by blood pressure equal or higher than 140/90 mm Hg or use of blood pressure‐lowering drugs. Results: During a mean follow‐up time of 5.6 ± 1.1 years, 127 developed hypertension. The hazard ratios for the development of hypertension, adjusted for age, baseline blood pressure, gender, and alcohol consumption, were 1.042 (p = 0.091) for BMI, 1.023 (p = 0.028) for waist circumference, 1.042 (p = 0.013) for waist‐to‐height ratio, 1.061 (p = 0.014) for waist‐to‐height² index, 1.079 (p = 0.022) for waist‐to‐height³ index, and 1.033 (p = 0.006) for the waist‐to‐hip ratio. Discussion: The correction of the circumference of waist for stature or hip circumference improves its performance in the prediction of the incidence of hypertension.     

A First Exploration of Health Impact Assessment of Chemical Exposure: Assigning Weights to Subclinical Effects Based on Animal Studies

Health impact assessments (HIA) have become an important tool for applying evidence-based policy. Recently, the concept of HIA has been introduced in the field of chemical substances. Two main issues are encountered, i.e., the focus of risk assessment is deriving safe levels and on first signs of adverse effects. These adverse effects, often at a subclinical level, fall outside the scope of a HIA. However, the number of subjects with subclinical effects can be extensive, thus relevant to consider in HIA and subsequent risk management policies and socioeconomic analyses (e.g., under REACH). The approach to include subclinical effects in a HIA relies on the dose–response relationship for toxicological endpoints, which are indicative for subclinical and clinical effects. Assessment of (sub)clinical effect sizes requires expertise from toxicologists, pathologists, and risk assessors. The clinical effect is appraised by a disability weight in the disability adjusted life year (DALY) concept. Subsequently, a derivative thereof, the severity weight, is assigned to parameter value changes in the range of subclinical effect sizes to appraise subclinical effects. Ultimately, if the approach is repeated for many substances, severity weights may be assigned based on changes in endpoints alone, making it a valuable tool for health impact assessors of chemical substances.     

生物组织折射率的概念与测量方法评述

折射率作为描述介质光学特性的一个重要物理参量,它在组织光学理论中起着非常重要的作用.随着组织光学研究的深入,生物组织折射率的概念也在不断地完善和发展.本文将主要介绍生物组织折射率的基本概念和测量手段的研究进展情况,明确了生物组织折射率的概念,评述了现有测量方法的优缺点,希望为生物组织折射率问题的进一步研究提供有益参考.     

Notes on Estimation of the General Odds Ratio and the General Risk Difference for Paired‐Sample Data

Under the matched‐pair design, this paper discusses estimation of the general odds ratio OR_G for ordinal exposure in case‐control studies and the general risk difference RD_G for ordinal outcomes in cross‐sectional or cohort studies. To illustrate the practical usefulness of interval estimators of OR_G and RD_G developed here, this paper uses the data from a case‐control study investigating the effect of the number of beverages drunk at “burning hot” temperature on the risk of possessing esophageal cancer, and the data from a cross‐sectional study comparing the grade distributions of unaided distance vision between two eyes. Finally, this paper notes that using the commonly‐used statistics related to odds ratio for dichotomous data by collapsing the ordinal exposure into two categories: the exposure versus the non‐exposure, tends to be less efficient than using the statistics related to OR_G proposed herein.     

Molecular Identification of Melanised Non-Sporulating Moulds: A Useful Tool for Studying the Epidemiology of Phaeohyphomycosis

Subcutaneous infections caused by melanised fungi have been increasingly reported among transplant patients, and these infections have the potential for blood and visceral dissemination. Some moulds, such as Mycelia sterilia, cannot grow and sporulate on different media, making their identification impossible by conventional methods. The fast and accurate identification of melanised fungi at the species level is important because species may have tropism to different organs and different susceptibilities to antifungal agents. Molecular tools have been reported to be helpful for the species identification of non-sporulating moulds. Our goal was to identify the species of M. sterilia isolates obtained from clinical samples of transplant patients using sequences of ITS and the D1/D2 regions of rDNA. Clinical samples were obtained from eight kidney transplant recipients who developed subcutaneous fungal infections. The diagnosis was confirmed by histopathology and conventional culture. Histopathology showed septated, melanised hyphae, and the cultures identified non-sporulating fungi. Therefore, the DNA from the M. sterilia isolates was subjected to PCR amplification and sequencing of the ITS and D1/D2 regions. Genus/species identification was obtained by comparison with gene banks. We obtained the following identifications: Alternaria sp. (2), Cochliobolus lunatus/Curvularia lunata (2), Cochliobolus hawaiiensis/Bipolaris hawaiiensis (1), Ochroconis sp. (1), Medicocopsis romeroi/Pyrenochaeta romeroi (1) and Nigrograna mackinnonii/Pyrenochaeta mackinnonii (1).     

External Quality Assessment for Tuberculosis Diagnosis and Drug Resistance in the European Union: A Five Year Multicentre Implementation Study

BackgroundExternal quality assurance (EQA) systems are essential to ensure accurate diagnosis of TB and drug-resistant TB. The implementation of EQA through organising regular EQA rounds and identification of training needs is one of the key activities of the European TB reference laboratory network (ERLTB-Net). The aim of this study was to analyse the results of the EQA rounds in a systematic manner and to identify potential benefits as well as common problems encountered by the participants.MethodsThe ERLTB-Net developed seven EQA modules to test laboratories’ proficiency for TB detection and drug susceptibility testing using both conventional and rapid molecular tools. All National TB Reference laboratories in the European Union and European Economic Area (EU/EEA) Member States were invited to participate in the EQA scheme.ResultsA total of 32 National TB Reference laboratories participated in six EQA rounds conducted in 2010–2014. The participation rate ranged from 52.9% - 94.1% over different modules and rounds. Overall, laboratories demonstrated very good proficiency proving their ability to diagnose TB and drug-resistant TB with high accuracy in a timely manner. A small number of laboratories encountered problems with identification of specific Non-tuberculous Mycobacteria (NTMs) (N = 5) and drug susceptibility testing to Pyrazinamide, Amikacin, Capreomycin, and Ethambutol (N = 4).ConclusionsThe European TB Reference laboratories showed a steady and high level of performance in the six EQA rounds. A network such as ERLTB-Net can be instrumental in developing and implementing EQA and in establishing collaboration between laboratories to improve the diagnosis of TB in the EU/EEA.     

Recommendation for the minimum number of steps to analyze when performing the uncontrolled manifold analysis on walking data

The uncontrolled manifold (UCM) analysis quantifies the extent to which co-variation among a set of variables facilitates consistent performance by partitioning variance in those variables into two components then calculating their normalized difference (i.e., the synergy index). Although UCM-derived measures are thought to depend on the number of data points analyzed, the minimum number needed to reasonably approximate true values of these measures is unknown. For each of two performance variables related to mechanical stability of gait, we evaluated changes in UCM-derived measures when increasing the number of analyzed points, here steps. Fourteen older adults walked on a treadmill while motion capture tracked movement. For each subject, n steps (where n = 2–99) were randomly sampled from the first 100, then used to calculate UCM-derived variables. For each subject, variables were expressed as a percent of the subject-specific value with n = 100 and averaged across 50 simulations. For each n, 95% confidence intervals (CIs) were calculated from group data. The minimum number of steps to “reasonably approximate” a variables was defined as the value of n for which the lower CI was >90% of the value with n = 100. Regardless of performance variable, reasonable approximations of the synergy index were attained with n = 16 steps, whereas n = 50 steps were needed for each of the variance components However, the differences between using 16 steps and 50 steps were small. Collecting 15–20 steps is recommended for a reasonable approximation of the synergy indices considered herein, particularly when data collection is constrained to a limited number of steps.     

Cadmium Exposure in the South Korean Population: Implications of Input Assumptions for Deterministic Dietary Assessment

Dietary exposure to Cadmium (Cd) is of increasing interest globally because of the adverse health effects of Cd arising from multiple sources. The assumptions used when undertaking deterministic assessment of Cd in global or regional diets have implications when applied to specific national cases representing local variation in food composition and consumption patterns different from global or regional norms. We have conducted deterministic dietary Cd exposure assessments for the South Korean population using a variety of schemes for point estimation. Consumption data from the Korean Nutrition Survey (2001 to 2003) and monitoring data from the Korea Food and Drug Administration were used as the basis for the exposure estimates. The average daily per capita Cd exposure was 14 μ g for the South Korean population, representing about 27% of tolerable daily intake (TDI) and is similar to that reported in other countries. The hazard index (HI, the ratio of total Cd exposure to the TDI) typically ranged from 0.3 to 0.9 depending on assumptions used in deterministic estimates of dietary exposure. Even though the current exposure of the South Korean population at large is found to be safe on the basis of these estimates, consideration of high-end patterns of Cd level and consumption suggests the need for continued vigilance in dietary Cd monitoring.     

Genetic Variability of Adult Body Mass Index: A Longitudinal Assessment in Framingham Families

Objective: To explore the contribution of genetics to the mean, SD, maximum value, maximum less the mean, and change over time in body mass index (BMI) and the residual of body weight after adjustment for height. BMI is frequently used as a general indicator of obesity because of its ease and reliability in ascertainment. Cross‐sectional twin and family studies have shown a moderate‐to‐substantial genetic component for BMI. However, the contribution of genetics to the long‐term average, variability, or change over time in BMI is less clear. Research Methods and Procedures: Longitudinal data from the Framingham heart study were used to create pedigrees of age‐matched individuals. Heritability estimates were derived using variance‐decomposition methods on a total of 1051 individuals from 380 extended pedigrees followed for a period of 20 years. All subjects were followed from approximately age 35 to 55 years. Results: Moderate heritability estimates were found for the mean BMI (h² = 0.37), maximum BMI (h² = 0.40), and the mean residual of body weight (h² = 0.36). Low heritability estimates (h² ? 0.20) were found for the maximum less the mean in BMI and the SDs of BMI and residual of body weight. No additive genetic contribution was found for the average change over time in BMI or the residual of body weight. Discussion: These findings suggest that there is a significant genetic component for the magnitude of BMI throughout an individual's middle‐adult years; however, little evidence was found for a genetic contribution to the variability or rate of change in an individual's BMI.     

Cut-loading: A Useful Tool for Examining the Extent of Gap Junction Tracer Coupling Between Retinal Neurons

In addition to chemical synaptic transmission, neurons that are connected by gap junctions can also communicate rapidly via electrical synaptic transmission. Increasing evidence indicates that gap junctions not only permit electrical current flow and synchronous activity between interconnected or coupled cells, but that the strength or effectiveness of electrical communication between coupled cells can be modulated to a great extent^1,2. In addition, the large internal diameter (~1.2 nm) of many gap junction channels permits not only electric current flow, but also the diffusion of intracellular signaling molecules and small metabolites between interconnected cells, so that gap junctions may also mediate metabolic and chemical communication. The strength of gap junctional communication between neurons and its modulation by neurotransmitters and other factors can be studied by simultaneously electrically recording from coupled cells and by determining the extent of diffusion of tracer molecules, which are gap junction permeable, but not membrane permeable, following iontophoretic injection into single cells. However, these procedures can be extremely difficult to perform on neurons with small somata in intact neural tissue.Numerous studies on electrical synapses and the modulation of electrical communication have been conducted in the vertebrate retina, since each of the five retinal neuron types is electrically connected by gap junctions^3,4. Increasing evidence has shown that the circadian (24-hour) clock in the retina and changes in light stimulation regulate gap junction coupling^3-8. For example, recent work has demonstrated that the retinal circadian clock decreases gap junction coupling between rod and cone photoreceptor cells during the day by increasing dopamine D2 receptor activation, and dramatically increases rod-cone coupling at night by reducing D2 receptor activation^7,8. However, not only are these studies extremely difficult to perform on neurons with small somata in intact neural retinal tissue, but it can be difficult to adequately control the illumination conditions during the electrophysiological study of single retinal neurons to avoid light-induced changes in gap junction conductance.Here, we present a straightforward method of determining the extent of gap junction tracer coupling between retinal neurons under different illumination conditions and at different times of the day and night. This cut-loading technique is a modification of scrape loading^9-12, which is based on dye loading and diffusion through open gap junction channels. Scrape loading works well in cultured cells, but not in thick slices such as intact retinas. The cut-loading technique has been used to study photoreceptor coupling in intact fish and mammalian retinas^{7, 8,13}, and can be used to study coupling between other retinal neurons, as described here.