Pattern of ocular injuries in stone pelters in Kashmir valley

PurposeTo describe the pattern and types of ocular injuries in stone pelters in Kashmir valley during recent turmoil.DesignCross sectional study.MethodsSixty patients with different types of eye injuries were assessed between June–September 2010 and initial visual acuity was recorded. The injuries were classified according to Systems for Classifying Ocular Injuries (OTCS) and Ocular Trauma Score (OTS) was calculated in order to estimate the probability of follow-up visual acuity range.ResultsMost of the victims (75%) were young boys between 16–26 years with a mean age of 20.95, 95% of cases were males. The main cause of injury was stones (48.3%) and pellets (30%) besides rubber bullets, sling shots and tear gas shells.Most of the open-globe injuries due to stones were of Type B and A, Grade E, Zone II and III with Afferent Pupillary Defect (APD) in 30% of the cases. Closed-globe injuries were mostly of Type A, Grade C and D and Zone II and III.Most of the open-globe injuries due to pellets were of Type D, Grade D, Zone II and APD in 33.3%. Pellets Intra Ocular Foreign Body (IOFB) was in 41.6%. Most of the closed-globe injuries were of Type A, Grade D and E and of Zone III.Overall OTS of 1 was calculated in 16.6% and 3 in 53.3% of the cases.ConclusionIn stone pelting demonstrations eye injuries can result in visually significant trauma. Injuries due to pellets are mostly perforating and pellet IOFB, and both tend to have a very poor prognosis. OTS can be used to estimate visual prognosis.     

Incidence,Diagnosis, and Treatment of Cardiac Toxicity From Trastuzumab in Patients With Breast Cancer

Purpose of Review

Treatment with trastuzumab is a cornerstone of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer treatment, but carries an unfortunate risk of toxicity to the cardiovascular system. Here, we review recent findings on trastuzumab-associated cardiotoxicity, focusing on its incidence, diagnosis, and treatment.

Recent Findings

Screening with multigated acquisition scan (MUGA) or echocardiogram (ECHO) is recommended to assess cardiac function prior to and during trastuzumab therapy. Because trastuzumab-induced cardiotoxicity is typically reversible, cessation of trastuzumab and/or administration of first-line heart failure agents effectively restores cardiac function in most cases. Severe trastuzumab-induced cardiotoxicity is rare enough that the risk-benefit ratio still weighs in favor of its use in the vast majority of patients with HER2+ breast cancer.

Summary

An improved understanding of the pathophysiology underlying trastuzumab-induced cardiotoxicity and the identification of patients at highest risk will allow us to continue to safely administer trastuzumab in patients with breast cancer.

     

Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats

Bisphenol A (BPA), an estrogenic and endocrine disrupting agent, is widely used in manufacturing of polycarbonate plastics and epoxy resins. BPA and other endocrine disrupting chemicals (EDCs) act via multiple mechanisms including interference with mitochondrial functions. Mitochondria are the hub of cellular energy pool and hence are the target of many EDCs. We studied perturbation of activities of mitochondrial enzymes by BPA and its possible role in hepatotoxicity in Wistar rats. Rats were exposed to BPA (150 mg/kg, 250 mg/kg, 500 mg/kg per os, for 14 days) and activities of enzymes of mitochondrial electron transport chain (ETC) were measured. Besides, other biochemical parameters such as superoxide generation, protein oxidation, and lipid peroxidation (LPO) were also measured. Our results indicated a significant decrease in the activities of enzymes of mitochondrial ETC complexes, i.e., complex I, II, III, IV, and V along with significant increase in LPO and protein oxidation. Additionally, a significant increase in mitochondrial superoxide generation was also observed. All these findings could be attributed to enhanced oxidative stress, decrease in reduced glutathione level, and decrease in the activity of superoxide dismutase in rat liver mitochondria isolated from BPA‐treated rats. BPA treatment also caused a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase indicating its potential hepatotoxicity. Furthermore, histopathological findings revealed marked edema formation, hepatocellular degeneration, and necrosis of liver tissue in BPA‐exposed rats. In conclusion, this study provides an evidence of impaired mitochondrial bioenergetics and liver toxicity after high‐dose BPA exposure in rats. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1922–1934, 2016.     

Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy

DNA is under constant assault from genotoxic agents which creates different kinds of DNA damage. The precise replication of the genome and the continuous surveillance of its integrity are critical for survival and the avoidance of carcinogenesis. Cells have evolved an arsenal of repair pathways and cell cycle checkpoints to detect and repair DNA damage. When repair fails, typically cell cycle progression is halted and apoptosis is initiated. Here, we review the different sources and types of DNA damage including DNA replication stress and oxidative stress, the repair pathways that cells utilize to repair damaged DNA, and discuss their biological significance, especially with reference to cancer induction and cancer therapy. We also describe the main methodologies currently used for the detection of DNA damage with their strengths and limitations. We conclude with an outline as to how this information can be used to identify novel pharmacological targets for DNA repair pathways or enhancers of DNA damage to develop improved treatment strategies that will benefit cancer patients.     

Characterization of an outer membrane protein of Salmonella enterica serovar typhimurium that confers protection against typhoid

Typhoid caused by Salmonella enterica serovar Typhi remains a major health concern worldwide. The emergence of multidrug-resistant strains of Salmonella with increased virulence, communicability, and survivability leading to increased morbidity and mortality has further complicated its management. Currently available vaccines for typhoid have less-than-desired efficacy and certain unacceptable side effects, making it pertinent to search for new immunogens suitable for vaccine formulation. The outer membrane proteins (OMPs) of Salmonella have been considered possible candidates for conferring protection against typhoid. OMPs interface the cell with the environment, thus representing important virulence factors with a significant role in the pathobiology of gram-negative bacteria and bacterial adaptation. An OMP of Salmonella enterica serovar Typhimurium with an apparent molecular mass of 49 kDa that is highly immunogenic, evokes humoral and cell-mediated immune responses, and confers 100% protection to immunized rats against challenge with very high doses (up to 100 times the 50% lethal dose) of Salmonella enterica serovar Typhimurium has been identified. Further, very efficient clearance of bacteria from the reticuloendothelial systems of immunized animals was seen. This protein is recognized by the antibodies present in serum of typhoid patients. When sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel-eluted protein was further analyzed by high-performance liquid chromatography (HPLC) and two-dimensional electrophoresis, two polypeptides with the same molecular weight were resolved. These have different isoelectric points and gave two peaks with different retention times in reverse-phase HPLC. However, only one of the two bands interacted with patient serum. The immunogenicity studies (enzyme-linked immunosorbent assay and delayed-type hypersensitivity [DTH]) indicated that the immunoreactive protein evoked a strong immune response in rats. The N-terminal sequencing and analysis of the homology of this protein with sequences in the protein database of Salmonella resulted in a match with the N-terminal sequences of a protein in Salmonella enterica serovar Typhi (CT18 and Ty2 strains). The homology search further revealed it to be a hypothetical protein, whose gene had unidentified open reading frames in Salmonella serovar Typhi encoding 447 amino acid residues, corresponding to a molecular mass of 49 kDa. The nucleotide sequence of the encoding gene was deduced, and the gene was amplified by PCR using appropriate primers. An amplified 1.3-kb band was purified and sequenced to confirm its identity. These OMPs provide promising targets for the development of a candidate vaccine against typhoid.     

Molecular markers for cancer prognosis and treatment: Have we struck gold?

The last decade has witnessed an emerging role for molecular or biochemical markers indicating a specific cellular mechanism or tissue function, often called 'biomarkers'. Biomarkers such as altered DNA, proteins and inflammatory cytokines are critical in cancer research and strategizing treatment in the clinic. In this review we look at the application of biological indicators to cancer research and highlight their roles in cancer detection and treatment. With technological advances in gene expression, genomic and proteomic analysis, biomarker discovery is expanding fast. We focus on some of the predominantly used markers in different types of malignancies, their advantages, and their limitations. Finally we conclude by looking at the future of biomarkers, their utility in the tumorigenic studies, and the progress towards personalized treatment strategies.     

Epigenetic inactivation of DNA repair in breast cancer

The study of epigenetic mechanisms in cancer, such as DNA methylation and histone modifications, has revealed a plethora of events that contribute to cancer through stable changes in the expression of genes critical to transformation pathways. In this mini review we look at the different epigenetic modifications prevalent in this neoplastic phenotype, focusing on breast cancer. Most encouragingly, research in epigenetics has led to improved survival of patients with certain forms of lymphoma and leukemia through the use of drugs that alter DNA methylation and histone acetylation. Thus, we look at the clinical utility of targeting epigenetic pathways. In addition, we explore numerous other clinical applications of epigenetics, in areas such as cancer screening and early detection, prevention, classification for epidemiology and prognostic purposes, and predicting outcomes after standard therapy.