THE ROLE OF GENETICS IN DISEASE DIAGNOSIS AND TREATMENT MITOCHONDRIAL RESPIRATORY CHAIN DYSREGULATION IN GENOMIC MEDICINE.

Although mitochondrial DNA respiration circuit abnormalities are among the most common metabolic diseases to manifest in children, identification can be difficult due to their medical variability. Given the multisystem nature of the condition and its diverse and generalized manifestations, making a final diagnosis often takes a long time. Within this summary, they give an in-depth account of the physical signs of adolescent Mitochondrial Respiratory Chain Disorders (MRCDs),analyze the available diagnostics and treatment possibilities, and emphasize current developments in this field of study. During the discovery of fresh biomarkers and the development of next generation sequencing (NGS) technology, extensive research over the years has considerably enhanced the regularity that precise diagnoses are produced. Given the intricate nature of mitochondrial DNA biology and its double genomic investments, Sequencing has made significant progress in identifying the genetic basis of Mitochondrial Respiratory Chain Disorders (MRCDs). Research studies have been created employing a variety of various methods of therapy in an effort to shift the goal on therapy that is mainly curative to possibly having a positive impact on the natural course of the trouble. That's because there is gained a greater awareness of the underlying causes of this category of ailments.

Bioinspired 5-caffeoylquinic acid capped silver nanoparticles using Coffee arabica leaf extract for high-sensitive cysteine detection.

Selection of plant extracts as bioactive phytochemical source to synthesize nanoparticles is highly demanding due to the biocompatibility, nontoxicity, and cost-effectiveness over other available physical and chemical methods. Here, for the first time, Coffee arabica leaf extracts (CAE) were used to produce highly stable silver nanoparticles (AgNPs) and the corresponding bio reduction, capping and stabilization mechanism mediated by dominant isomer 5-caffeoylquinic acid (5-CQA) is discussed. UV-Vis, FTIR, µRaman spectroscopy, TEM, DLS and Zeta potential analyzer measurements were employed to characterize these green synthesized NPs. The affinity of 5-CQA capped CAE-AgNPs to thiol moiety of amino acid is utilized for the selective as well as sensitive detection of L-cysteine (L-Cys) to a low detection limit of 0.1 nM, as obtained from its µRaman spectra. Hence, the proposed novel, simple, eco-friendly, and economically sustainable method can provide a promising nanoplatform in the field of biosensors compliant with large-scale industrial production of AgNPs without aid of further instrumentation.

Potential drug-drug interactions among hospitalised TB patients.

BACKGROUND: Hospitalised TB patients are at heightened risk for developing drug-drug interactions (DDIs) due to overlapping CYP450 enzyme and/or drug transporter biotransformation of anti-TB drugs and co-medications given for treating TB-associated comorbidities. We aimed to compare the occurrence, characterisation and determinants of database identified potential DDIs (pDDIs) associated with first-line anti-TB drugs and other co-medications using a subscription and free access drug information database.METHOD: This was a single-centre retrospective study to assess pDDIs between first-line anti-TB drugs and other medications for comorbidities among hospitalised TB patients using IBM Micromedex® and Drugs.com.RESULTS: On multivariate regression analysis, hospitalised TB patients with comorbidities such as diabetes mellitus, HIV infection and hypertension, longer hospitalisation, and patients administered with more than seven drugs during their hospital stay were associated with increased risk for the occurrence of pDDIs. Significant discrepancies were observed in the detection and severity of pDDIs between IBM Micromedex and Drugs.com.CONCLUSION: We recommend using free access drug information database to a subscription drug information database in drug interaction screening protocols in clinics for enhanced identification of pDDIs and reducing monetary burden in resource-limited settings.

Contact Force Mediated Rapid Deposition of Colloidal Microspheres Flowing over Microstructured Barriers.

Deposition of particles while flowing past constrictions is a ubiquitous phenomenon observed in diverse systems. Some common examples are jamming of salt crystals near the orifice of salt shakers, clogging of filter systems, gridlock in vehicular traffic, etc. Our work investigates the deposition events of colloidal microspheres flowing over microstructured barriers in microfluidic devices. The interplay of DLVO, contact, and hydrodynamic forces in facilitating rapid deposition of microspheres is discussed. Noticeably, a decrease in the electrostatic repulsion among microspheres leads to linear chain formations, whereas an increase in roughness results in rapid deposition.

COVID-19 lockdown: Effects on selected volatile organic compound (VOC) emissions over the major Indian metro cities.

Due to the COVID-19 pandemic, many countries across the world, including India, have imposed nationwide lockdowns to contain the spread of the virus. Many studies reported that the air quality had improved much due to the lockdown. This study examines the variation of Volatile Organic Compounds (VOCs) over the Indian metropolitan cities during the lockdown period by using ground-based and satellite observations. Ground-based BTEX (Benzene, Toluene, Ethylbenzene, and Xylenes) measurements from various metropolitan cities have shown a drastic drop of about 82% in the first phase of lockdown when compared with the pre-lockdown period. Whereas the spatial distribution of formaldehyde (HCHO), obtained from the TROPOspheric Monitoring Instrument (TROPOMI) onboard Sentinal-5P satellite, did not show any significant variation due to COVID-19 lockdown, indicating the major source of HCHO is biogenic or pyrogenic. The BTEX ratios were evaluated for a better understanding of the source and photochemical age of the air samples. The ozone forming potential of BTEX in all locations was found reduced; however, the corresponding decrease in ozone concentrations was not observed. The increase in ozone concentrations during the same period indicates alternative sources contributing to ozone formation.

Swimming statistics of cargo-loaded single bacteria.

Burgeoning interest in the area of bacteria-powered micro robotic systems prompted us to study the dynamics of cargo transport by single bacteria. In this paper, we have studied the swimming behaviour of oil-droplets attached as cargo to the cell bodies of single bacteria. The oil-droplet loaded bacteria exhibit super-diffusive motion which is characterised by a high degree of directional persistence. Interestingly, bacteria could navigate with cargo size as large as 8 µm resulting in an increased rotational drag of more than 2 orders when compared to the free bacteria. The directional change of cargo loaded bacterial trajectories seems to be enhanced by steric hindrance from other oil-droplets present in the environment.

Dataset for the reporting of carcinoma of the bladder-cystectomy, cystoprostatectomy and diverticulectomy specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a not for profit organisation whose goal is to produce standardised internationally agreed and evidence-based datasets for pathology reporting. With input from pathologists worldwide, the datasets are intended to be uniform and structured. They include all items necessary for an objective and accurate pathology report which enables clinicians to apply the best treatment for the patient. This dataset has had input from a multidisciplinary ICCR expert panel. The rationale for some items being required and others recommended is explained, based on the latest literature. The dataset incorporates data from the World Health Organization (WHO) 2016, and also from the latest (8th edition) TNM staging system of the American Joint Committee on Cancer (AJCC). Fifteen required elements and eight recommended items are described. This dataset provides all the details for a precise and valuable pathology report required for patient management and prognostication. This dataset is intended for worldwide use, and should facilitate the collection of standardised comparable data on bladder carcinoma at an international level.

Dataset for the reporting of urinary tract carcinoma-biopsy and transurethral resection specimen: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is an alliance of major pathology organisations in Australasia, Canada, Europe, United Kingdom, and United States of America that develops internationally standardised, evidence-based datasets for the pathology reporting of cancer specimens. This dataset was developed by a multidisciplinary panel of international experts based on previously published ICCR guidelines for the production of cancer datasets. It is composed of Required (core) and Recommended (noncore) elements identified on the basis of literature review and expert consensus. The document also includes an explanatory commentary explaining the rationale behind the categorization of individual data items and provides guidance on how these should be collected and reported. The dataset includes nine required and six recommended elements for the reporting of cancers of the urinary tract in biopsy and transurethral resection (TUR) specimens. The required elements include specimen site, operative procedure, histological tumor type, subtype/variant of urothelial carcinoma, tumor grade, extent of invasion, status of muscularis propria, noninvasive carcinoma, and lymphovascular invasion (LVI). The recommended elements include clinical information, block identification key, extent of T1 disease, associated epithelial lesions, coexistent pathology, and ancillary studies. The dataset provides a structured template for globally harmonized collection of pathology data required for management of patients diagnosed with cancer of the urinary tract in biopsy and TUR specimens. It is expected that this will facilitate international collaboration, reduce duplication of effort in updating current national/institutional datasets, and be particularly useful for countries that have not developed their own datasets.

Analysis of benzene air quality standards, monitoring methods and concentrations in indoor and outdoor environment.

Benzene is a proven carcinogen. Its synergistic action with other pollutants can damage different components of the biosphere. Literature comparing the air quality standards of benzene, its monitoring methods and global concentrations are sparse. This study compiles the worldwide available air quality standards for benzene and highlights the importance of strict and uniform standards all over the world. It was found that out of the 193 United Nation member states, only 53 countries, including the European Union member states, have ambient air quality standard for benzene. Even where standards were available, in most cases, they were not protective of public health. An extensive literature review was conducted to compile the available monitoring and analysis methods for benzene, and found that the most preferred method, i.e, analyzing by Gas Chromatography and Mass spectroscopy is not cost effective and not suitable for real-time continuous monitoring. The study compared the concentrations of benzene in the indoor and outdoor air reported from different countries. Though the higher concentrations of benzene noticed in the survey were mostly from Asian countries, both in the case of indoor and outdoor air, the concentrations were not statistically different across the various continents. Based on the analyzed data, the average benzene level in the ambient air of Asian countries (371 µg/m3) was approximately 3.5 times higher than the indoor benzene levels (111 µg/m3). Similarly, the outdoor to the indoor ratio of benzene level in European and North American Countries were found to be 1.2 and 7.7, respectively. This compilation will help the policymakers to include/revise the standards for benzene in future air quality guideline amendments.

An Experience of Optimizing A Community-Based Micro-Insurance Model to Bridge the Gap between Treatment Cost and Ability to pay at BPKIHS.

In the year 2001 the leaders of BPKIHS started a micro social insurance scheme; Social Health Insurance (SHI) for prospective research. It is a method of financing and managing health care using compulsory contributions from employers, employees and may be from the government. Household members from organized groups in catchment areas enrolled voluntarily. Photographed service cards were issued entitled for free IPD/OPD consultations, investigations and bed charges excluding CT scans and specialty treatment. Institute bore operation and medicine costs up to 10000 and 3500 respectively for IPD yearly. Premium was fixed after a research through focus group discussion in villages of Morang, Sunsari and Biratnagar. A flat rate premium of 15 and 50 NRS/adult/month for villagers, city dwellers and half for children was fixed. Marginalized community and handicapped paid 33% of premium, 33% by Institute and 33% by concerned VDC. As the client number increased from 2383 to 7392 in second and to 15779 in third year, Premium: Expenditure ratio moved from 225:222 to 198:391. Average cost sharing of premium to expenditure came to 226:332 showing a negative 3alance. This scheme completed its fourth year till this research in 2005 A.D. But it was closed due to deficit. As reinsured population occasionally concealed information by not incorporating all family members. They defaulted in subsequent year after utilizing the benefits of SHI and misused the card for uninsured ones. It may, in its optimized form, become a model to be widely adopted to bridge the gap between the cost of treatment and the ability to pay in developing countries.

Prevalence of TEM, SHV, and CTX-M Beta-Lactamase genes in the urinary isolates of a tertiary care hospital.

INTRODUCTION: Extended-spectrum beta-lactamases (ESBLs) are the major cause of resistance to beta-lactam antibiotics such as penicillins, cephalosporins, and monobactams. They are derived from the narrow-spectrum beta-lactamases (TEM-1, TEM-2, or SHV-1) by mutations that alter the amino acid configuration around the enzyme active site. AIM: To determine the prevalence of ESBL (blaTEM, blaCTX-M, and blaSHV) genes among the members of Enterobacteriaceae. METHODOLOGY: The present prospective study was carried out from January 2015 to June 2015 in the Department of Microbiology and Molecular Medicine of a Teaching Tertiary Care Hospital. A total of 526 urine samples were studied. Seventy-eight isolates were subjected to polymerase chain reaction for detection of ESBL genes. RESULTS: In our study, ESBL genes were detected among 18 (45%) phenotypically confirmed ESBL producers and 20 (52.5%) phenotypically confirmed non-ESBL producers. The gene that predominated was blaTEM (48.7%), followed by blaCTX-M (7.6%) and blaSHV (5.1%). CONCLUSION: Definitive identification of ESBL genes is only possible by molecular detection methods. Phenotypic tests need to be evaluated periodically as their performance may change with the introduction of new enzymes.

Transporter-Mediated Hepatic Uptake Plays an Important Role in the Pharmacokinetics and Drug-Drug Interactions of Montelukast.

Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems. Single-dose rifampicin, an OATP inhibitor, decreased montelukast clearance in rats and monkeys. Clinical DDIs of montelukast were evaluated using physiologically based pharmacokinetic modeling; and simulation of the interactions with gemfibrozil-CYP2C8 and OATP1B1/1B3 inhibitor, clarithromycin-CYP3A and OATP1B1/1B3 inhibitor, and itraconazole-CYP3A inhibitor, implicated OATPs-CYP2C8-CYP2C8 interplay as the primary determinant of montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions.

Quantitative Prediction of Drug-Drug Interactions Involving Inhibitory Metabolites in Drug Development: How Can Physiologically Based Pharmacokinetic Modeling Help?

This subteam under the Drug Metabolism Leadership Group (Innovation and Quality Consortium) investigated the quantitative role of circulating inhibitory metabolites in drug-drug interactions using physiologically based pharmacokinetic (PBPK) modeling. Three drugs with major circulating inhibitory metabolites (amiodarone, gemfibrozil, and sertraline) were systematically evaluated in addition to the literature review of recent examples. The application of PBPK modeling in drug interactions by inhibitory parent-metabolite pairs is described and guidance on strategic application is provided.

An anatomical evaluation of the serratus anterior plane block.

The serratus anterior plane block has been described for analgesia of the hemithorax. This study was conducted to determine the spread of injectate and investigate the anatomical basis of the block. Ultrasound-guided serratus anterior plane block was performed on six soft-fix embalmed cadavers. All cadavers received bilateral injections, on one side performed with 20 ml latex and on the other with 20 ml methylene blue. Subsequent dissection explored the extent of spread and nerve involvement. Photographs were taken throughout dissection. The intercostal nerves were involved on three occasions with dye, but not with latex. The lateral cutaneous branches of the intercostal nerve contained dye and latex on all occasions. The serratus plane block appears to be mediated through blockade of the lateral cutaneous branches of the intercostal nerves. Anatomically, serratus plane block does not appear to be equivalent to paravertebral block for rib fracture analgesia.

[Intraductal carcinoma of the prostate]. / Intraduktales Karzinom der Prostata.

For many tumor entities, especially in breast cancer, an intraductal carcinoma is generally perceived as a precursor lesion, which precedes the emergence of invasive carcinoma. Therefore, in addition to parameters of the invasive carcinoma, histological parameters of the intraductal component have always played an important role in therapy planning of breast cancer. This is different in prostate cancer and although the term "intraductal carcinoma" has long been propagated by some authors, its routine use remains rare and inconsistent. This is certainly not only due to the far simpler therapy options of prostate cancer, in which focal and organ-preserving therapies still play a subordinate role, but also due to substantial interobserver variation and our inconsistent perception of intraductal carcinomas. This article gives a brief overview of currently available literature on this topic and explains why intraductal carcinoma of the prostate deserves our attention. In contrast to breast cancer, intraductal carcinoma of the prostate usually represents a post-invasive lesion, in which an aggressive tumor exhibits spread into pre-existing ducts; however, in rare cases, intraductal carcinoma may represent a true precursor lesion.

Faecal incontinence in men referred for specialty care: a cross-sectional study.

AIM: Little is known about men with faecal incontinence. We compared clinical findings and quality of life in a large cohort of men and women with faecal incontinence to guide its evaluation and treatment in men. METHOD: We analysed men and women presenting to a tertiary referral centre with faecal incontinence between 2005 and 2013. Demographics, physical examination, anorectal physiology testing, symptom severity (Fecal Incontinence Severity Index) and quality of life (Fecal Incontinence Quality of Life Scale) were recorded. We determined differences between men and women and analysed the association between gender and quality of life. RESULTS: Data were obtained from 144 men and 897 women. Men with faecal incontinence were slightly younger than women (55.3 vs 57.6 years, P = 0.001), more likely to report coexisting constipation (P = 0.004) and more likely to have normal internal and external sphincter function on physical examination (both P < 0.001). Anorectal physiology testing revealed fewer sphincter defects (P < 0.05) and less pudendal neuropathy (P < 0.05) in men compared with women. Although symptom severity and overall quality of life were similar, men had improved coping and less embarrassment compared with women after we adjusted for important clinical factors. CONCLUSION: Men with faecal incontinence presenting to a tertiary referral centre are more likely than women to have a mixed presentation characterized by constipation and less sphincter dysfunction. They exhibited better coping and less embarrassment than women. These findings should be taken into consideration when evaluating and treating men with faecal incontinence.