Predictive genetic testing in maturity-onset diabetes of the young (MODY).

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance of young-onset non-insulin-dependent diabetes. It accounts for approximately 1% of Type 2 diabetes (approximately 20 000 people in the UK). Diagnostic and predictive genetic tests are now possible for 80% of MODY families. Diagnostic tests can be helpful as the diagnosis can be confirmed and the subtype defined which has implications for treatment and prognosis. However predictive genetic testing, particularly in children, raises many scientific, ethical and practical questions. METHODS: This is a case report of a family with diabetes resulting from an hepatic nuclear factor (HNF)1alpha mutation, who request a predictive test in their 5-year-old daughter. The scientific issues arising from molecular genetic testing in MODY are discussed, along with the process of genetic counselling. The views of the family and the clinical genetics team involved are presented. RESULTS: The implications of positive and negative predictive test results and the possibility of postponing the test were among many issues discussed during genetic counselling. The family remained convinced the test was appropriate for their daughter and the clinical genetics team fully supported this decision. The family, motivated by their family history of diabetes and personal experiences of the disease, wished to reduce uncertainty about their daughter's future irrespective of the result. CONCLUSIONS: This case emphasizes that decisions on predictive testing are very personal and require appropriate counselling.     

Role of nitric oxide and prostaglandin systems in lithium modulation of acetylcholine vasodilation

The mechanism of lithium action, an effective treatment for bipolar disease, is still unknown. The present study examined the role of nitric oxide (NO) and prostaglandin systems in lithium modulation of acetylcholine in mesenteric vascular bed of rats by cannulating superior mesenteric artery. Acetylcholine (ACh) or sodium nitroprusside was injected under constant controlled flow induced by phenylephrine; therefore, changes in perfusion pressure reflect changes in resistance. Although 0.5 mM or 1 mM lithium-pretreatment of vascular bed causes reduction in ACh-response, 1.5 mM lithium induced no changes and 2 and 2.5 mM lithium potentiated ACh-induced mesenteric vascular bed relaxation compared to control group. Pretreatment of vascular bed with L-NAME or indomethacin decreased ACh-induced relaxation in 2 concentrations of 0.5 and 2 mM of lithium. The vasorelaxation response to sodium nitroprusside, the NO donor, was not different among lithium groups (0.5 and 2 mM) and controls. In conclusion, there is a dual modulation of endothelium-dependent relaxation, including an inhibitory effect at lower dose and a stimulating effect at higher dose of lithium in rat mesenteric vascular bed. NO synthesis or cyclooxygenase inhibition decreased vasorelaxation in both lower and higher doses of lithium, suggesting a role for NO and prostaglandin in this effect.     

Is miR‐34a a Well‐equipped Swordsman to Conquer Temple of Molecular Oncology?

Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA‐based (locked nucleic acid) antisense molecule against miR‐122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench‐top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to ‘final frontier’. MRX34, a liposome‐formulated mimic of miR‐34 for treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has also entered in clinical trial. There is a successive increase in the research work related to miR‐34 biology and miRNA regulation of modulators of intracellular signaling cascades. We partition this review into how miR‐34a is regulated by different proteins and how Wnt‐ and TGF‐induced intracellular signaling cascades are modulated by miR‐34a. In this review, we bring to limelight how miR‐34a regulates its target genes to induce apoptosis and inhibit cell proliferation as evidenced by in vitro and in vivo analysis. We also discuss miR‐34 regulation of PDGFR and c‐MET and recent advancements in nanotechnologically delivered miR‐34a. Spotlight is also set on modulation of chemotherapeutic sensitivity by miR‐34a in cancer cells using reconstruction studies. Clinical trial of miR‐34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.     

Characteristics,sources, and health risks of atmospheric PM10-bound heavy metals in a populated middle eastern city

ABSTRACT

This study reports on the characteristics, sources, and health risks of atmospheric PM₁₀-bound heavy metals (HMs) on citizenship living in different regions of Ahvaz, Southwest of Iran were investigated during 2016–2017. A total of 84 samples were analyzed from different regions: (S1) industrial, (S2) high traffic, and (S3) residential. Blood samples were collected from people who came to the east health center of Ahvaz. High volume air samplers, equipped with quartz fiber filters (8?×?10) were utilized for sampling in this study. Inductively coupled plasma optical emission spectroscopy (ICP-OES) was also used for HMs. Risk assessment and hazard index of these pollutants were estimated, using USEPA’s exposure parameters. Based on the results, the highest and the lowest concentration of HM were observed in industrial and residential areas. Blood’s HMs concentration for chromium (Cr), nickel (Ni), lead (Pb), and zinc (Zn) were 2.932, 4.199, 8.425, and 71.2?μg/dL, respectively. In conclusion, increasing exposure concentration of HMs would have a significant potential for increased cancer and risk of diseases. The results of this study show that increasing exposure concentration to HM in the studied scenarios have a significant potential for generating different health endpoints, although exposing to HMs led to generating diseases in individuals particularly in polluted and populated districts; so, environmental measures should be considered by urban air authorities to mitigate the concentration of these pollutants in ambient air.     

Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C‐terminal domain

Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non‐24‐hour sleep‐wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT₁ and MT₂, belonging to the G protein‐coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT₁ and MT₂. Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT₁ and MT₂ by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT₁ or MT₂. None of the mABs cross‐reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR‐KO mice as control. MT₂ expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta‐cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies.     

Breast Cancer Risk From Modifiable and Non-Modifiable Risk Factors among Palestinian Women: A Systematic Review and Meta-Analysis

Objective: Breast cancer (BC) is known as one of the deadliest forms of cancer, and it is increasing globally. Identifying risk factors for BC is a key point in developing preventive strategies to reduce its occurrence. Herein, we aimed to conduct a systematic review and meta-analysis focus on the risk factors for BC in Palestine. Material and Methods: We performed a systematic search via PubMed, MEDLINE, SCOPUS, Science Direct, Cochrane library, Emerald Insight, and Google scholar for identifying studies published on BC risk factors up to March 2021. Pooled odds ratios (OR) are calculated using fixed and random-effect models. Data were processed using Review Manager 5.4 (RevMan 5.4). Results: From a total of 73 articles, seven case-control studies met the criteria for systematic review. Meta-analysis results showed that of the known modifiable risk factors for BC, diabetes mellitus (DM) had the highest odds ratio (OR = 4.97, 95% CI 3.00- 8.25) followed by hypertension (OR = 3.21, 95% CI 1.96-5.23), obesity (BMI >30 Kg/m2) (OR = 2.90, 95% CI 2.00- 4.21), and passive smoking (OR = 1.50, 95% CI 1.12- 2.02). Controversially, breastfeeding (OR = 0.37, 95% CI 0.23- 0.61) was protective factor in BC. Of non-modifiable risk factors for BC has reached menopause had the highest odds ratio (OR = 3.74, 95% CI 2.64- 5.29), followed by family history of BC (OR = 2.63, 95% CI 1.07-6.44) and age (≥ 40 years) (OR = 2.49, 95% CI 1.43-4.34). Conclusions: The most significant predictors of BC in Palestine were DM, hypertension, passive smokers, age (>40), reached menopause, and family history of BC. Almost all these risk factors are consistent with known risk factors for breast cancer in other parts of the world.     

GJB2 mutations: passage through Iran

Hereditary hearing loss (HHL) is a very common disorder. When inherited in an autosomal recessive manner, it typically presents as an isolated finding. Interestingly and unexpectedly, in spite of extreme heterogeneity, mutations in one gene, GJB2, are the most common cause of congenital severe-to-profound deafness in many different populations. In this study, we assessed the contributions made by GJB2 mutations and chromosome 13 g.1777179_2085947del (the deletion more commonly known as del (GJB6-D13S1830) that includes a portion of GJB6 and is hereafter called Delta(GJB6-D13S1830)) to the autosomal recessive non-syndromic deafness (ARNSD) genetic load in Iran. Probands from 664 different nuclear families were investigated. GJB2-related deafness was found in 111 families (16.7%). The carrier frequency of the 35delG mutation showed a geographic variation that is supported by studies in neighboring countries. Delta(GJB6-D13S1830) was not found. Our prevalence data for GJB2-related deafness reveal a geographic pattern that mirrors the south-to-north European gradient and supports a founder effect in southeastern Europe.     

Effect of sinapic acid on aripiprazole pharmacokinetics in rats: Possible food drug interaction

Dietary supplements and foods can interact with various drugs, leading to possible clinical concerns. This study aimed to investigate the effect of orally administered sinapic acid (SA) on the pharmacokinetics of aripiprazole (APZ) in rats and its possible modulatory effects on hepatic cytochrome P450 (CYP3A2 and CYP2D6) expression in the liver tissues. Single dose and multiple dose parallel groups of wistar rats were categorized into six groups (n = 6 each) which abstained from food for 12 h prior to the experiment, while water was allowed ad libitum. The investigation was carried out for single dose: Group I was treated with normal saline orally for 15 days (normal control). Group II was administered normal saline orally for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group III received SA (20 mg/kg p.o.) for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group IV was treated with SA (20 mg/kg p.o.) for 15 days. For the multiple dose study, Group I was treated with normal saline orally for 15 days (normal control); Group II received APZ (3 mg/kg p.o.) daily for 15 days; Group III was administered with SA (20 mg/kg p.o.) and APZ (3 mg/kg p.o.) for 15 days and Group IV received SA (20 mg/kg p.o.) for 15 days. The group I and IV were kept common in single and multiple dose groups. After last APZ dose, plasma samples were collected and APZ concentrations were determined using an UPLC-MS/MS technique. The pharmacokinetic parameters were calculated using a non-compartmental analysis. The concomitant administration of APZ with SA (as single or multiple dose) resulted in an increase in APZ absorption and a decrease on its systemic clearance. This was associated with a reduction in CYP3A2 and CYP2D6 protein expressions by 33–43% and -71–68% after the single and multiple co-administration, which are two enzymes responsible of the metabolism of APZ. Therefore, a reduction in the metabolic clearance appears to be the mechanism underlying the drug interaction of dietary supplement containing SA with APZ. Therefore, the concomitant administration of SA and APZ should be carefully viewed. Further investigations are required to assess the clinical significance of such observations in humans.