Aqueous Fraction of Beta vulgaris Ameliorates Hyperglycemia in Diabetic Mice due to Enhanced Glucose Stimulated Insulin Secretion,Mediated by Acetylcholine and GLP-1, and Elevated Glucose Uptake via Increased Membrane Bound GLUT4 Transporters

BackgroundThe study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris.ConclusionFindings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in the anti-hyperglycemic activity of B. Vulgaris.     

Middle East Respiratory Syndrome Coronavirus Accessory Protein 4a Is a Type I Interferon Antagonist

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory infection with as yet unclear epidemiology. We previously showed that MERS-CoV counteracts parts of the innate immune response in human bronchiolar cells. Here we analyzed accessory proteins 3, 4a, 4b, and 5 for their abilities to inhibit the type I interferon response. Accessory protein 4a was found to block interferon induction at the level of melanoma differentiation-associated protein 5 (MDA5) activation presumably by direct interaction with double-stranded RNA.     

What really matters in end-of-life discussions? Perspectives of patients in hospital with serious illness and their families

Background:

The guideline-recommended elements to include in discussions about goals of care with patients with serious illness are mostly based on expert opinion. We sought to identify which elements are most important to patients and their families.

Methods:

We used a cross-sectional study design involving patients from 9 Canadian hospitals. We asked older adult patients with serious illness and their family members about the occurrence and importance of 11 guideline-recommended elements of goals-of-care discussions. In addition, we assessed concordance between prescribed goals of care and patient preferences, and we measured patient satisfaction with goals-of-care discussions using the Canadian Health Care Evaluation Project (CANHELP) questionnaire.

Results:

Our study participants included 233 patients (mean age 81.2 yr) and 205 family members (mean age 60.2 yr). Participants reported that clinical teams had addressed individual elements of goals-of-care discussions infrequently (range 1.4%–31.7%). Patients and family members identified the same 5 elements as being the most important to address: preferences for care in the event of life-threatening illness, values, prognosis, fears or concerns, and questions about goals of care. Addressing more elements was associated with both greater concordance between patients’ preferences and prescribed goals of care, and greater patient satisfaction.

Interpretation:

We identified elements of goals-of-care discussions that are most important to older adult patients in hospital with serious illness and their family members. We found that guideline-recommended elements of goals-of-care discussions are not often addressed by health care providers. Our results can inform interventions to improve the determination of goals of care in the hospital setting.In Canada, dying is often an in-hospital, technology-laden experience.^1–4 Rates of cardiopulmonary resuscitation (CPR) before death continue to increase among older adult patients in hospital,⁵ and one-fifth of deaths in hospital occur in an intensive care unit.^1,2,6,7 These observations contrast sharply with patient-reported preferences. A recent Canadian study found that 80% of older adult patients in hospital with a serious illness prefer a less aggressive and more comfort-oriented end-of-life care plan that does not include CPR.⁸Such patients and their families have identified communication with health care providers and decision-making about goals of care as high priorites for improving end-of-life care in Canada.^9,10 We define “decision-making about goals of care” as an end-of-life communication and decision-making process that occurs between a clinician and a patient (or a substitute decision-maker if the patient is incapable) in an institutional setting to establish a plan of care. Often, this process includes deciding whether to use life-sustaining treatments.¹¹ Current guidelines recommend that health care providers address 11 key elements when discussing goals of care with patients and families (Box 1).^12–14 However, these elements are mostly based on expert opinion and lack input from patients and their families.

Box 1:

Key elements of goals-of-care discussions with patients in hospital with serious illness^12–14

• Ask about previous discussions or written documentation about the use of life-sustaining treatments
• Offer a time to meet to discuss goals of care
• Provide information about advance care planning to review before conversations with the physician
• Disclose prognosis
• Ask about patients’ values (i.e., what is important to them when considering health care decisions)
• Provide information about outcomes, benefits and risks of life-sustaining treatments
• Provide information about outcomes, benefits and risks of comfort measures
• Prompt for additional questions about goals of care
• Provide an opportunity to express fears or concerns
• Ask about preferences for care in the event of a life-threatening illness
• Facilitate access to legal documents to record patients’ wishes

Our primary objective was to determine which of these elements are most important to patients and their families. In addition, we examined whether these discussions were associated with concordance between patients’ (or family members’) preferences and prescribed goals of care, and with satisfaction with end-of-life communication and decision-making.     

TP53 Mutational Status Is a Potential Marker for Risk Stratification in Wilms Tumour with Diffuse Anaplasia

Purpose

The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information.

Patients and Methods

We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling.

Results

From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26–16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36–31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes.

Conclusion

This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.     

Excipient Stability in Oral Solid Dosage Forms: A Review

The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Therefore, several studies have been performed to evaluate the effect of drug-excipient interactions on the overall formulation. This article reviews the information available on the physical and chemical instabilities of excipients and their incompatibilities with the active pharmaceutical ingredient in solid oral dosage forms, during various drug-manufacturing processes. The impact of these interactions on the drug formulation process has been discussed in detail. Examples of various excipients used in solid oral dosage forms have been included to elaborate on different drug-excipient interactions.     

<Emphasis Type="Italic">In Planta</Emphasis> transformation for conferring salt tolerance to a tissue-culture unresponsive indica rice (<Emphasis Type="Italic">Oryza sativa</Emphasis> L.) cultivar

Many farmer-popular indica rice (Oryza sativa L.) cultivars are recalcitrant to Agrobacterium-mediated transformation through tissue culture and regeneration. In planta transformation using Agrobacterium could therefore be a useful alternative for indica rice. A simple and reproducible in planta protocol with higher transformation efficiencies than earlier reports was established for a recalcitrant indica rice genotype. Agrobacterium tumefaciens containing the salt tolerance-enhancing Pea DNA Helicase45 (PDH45) gene, with the reporter and selectable marker genes, gus-INT (β-glucuronidase with intron) and hygromycin phosphotransferase (hpt), respectively, were used. Overnight-soaked mature embryos were infected and allowed to germinate, flower, and set T₁ seeds. T₀ plants were considered positive for the transgene if the spikelets of one or more of their panicles were positive for gus. Thereafter, selection at T₁ was done by germination in hygromycin and transgenic status re-confirmation by subjecting plantlet DNA/RNA to gene-specific PCR, Southern and semi-quantitative RT-PCR. Additionally, physiological screening under saline stress was done at the T₂ generation. Transformation efficiency was found to be 30–32% at the T₀ generation. Two lines of the in planta transformed seedlings of the recalcitrant rice genotype were shown to be saline tolerant having lower electrolyte leakage, lower Na⁺/K⁺, minimal leaf damage, and higher chlorophyll content under stress, compared to the WT at the T₂ generation.     

Sexual size dimorphism and morphometric sexing in a North African population of Laughing Doves Spilopelia senegalensis

Like the majority of Columbiformes, the Laughing Dove Spilopelia senegalensis is sexually monomorphic in plumage, but seems to be slightly dimorphic in size. However, due to the lack of studies little is known about the sexual size dimorphism in this species. In this work, we used morphometric data on a sample of 61 Laughing Doves from southern Tunisia, and sexed using a DNA-based method, to assess size differences between males and females and to determine a discriminant function useful for sex identification. The results showed that wing length was the most dimorphic trait, which could be due to the effects of sexual selection. The best function for the discrimination between sexes included wing length and head length, which is comparable with findings on other dove species. This discriminant function accurately classified 89% of birds, providing a rapid and accurate tool for sex identification in the studied population. Further data from different populations are needed for firmer conclusions about the extent of sexual size dimorphism and the reliability of the morphometric sexing approach in this dove species.     

DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk

Identification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1 locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02–1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1 locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75–0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1 locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.