Genotoxic effect of monocrotophos to sentinel species using comet assay.

Monocrotophos is the single largest selling agrochemical in India. Sensitive biomarkers to study the genotoxic effects caused by monocrotophos in aquatic organisms, especially fish, are lacking. The fish used in this study are Tilapia mossambica, which are edible, commercially valuable and distributed all over India. The objective of this study was to study DNA strand breaks induced by monocrotophos in T. mossambica in vivo using single-cell micro gel electrophoresis/comet assay. Tilapia were treated orally with 0.313, 0.625, 1.25, 1.875, 2.5, 3.125, 3.75 and 4.375 ppm of monocrotophos and the assay was performed on nucleated erythrocytes after 24, 48, 72 and 96 h. A significant increase in mean comet tail-length (5.21-7.46 microM), indicating DNA damage, was observed at all the doses with monocrotophos when compared to controls (3.36 microM). The mean tail-length showed a dose-related increase and time-dependent decrease. The maximum increase in mean comet tail-length was observed at 24 h. Relative to these effects, reductions in mean comet tail-length were seen at 48 and 72 h. By 96 h, values had returned to control levels at all doses, indicating repair of the damaged DNA and/or loss of heavily damaged cells. The study reveals that the comet assay is a sensitive and rapid method to detect genotoxicity of monocrotophos and other environmental pollutants in sentinel species.     

Unraveling enhanced brain delivery of paliperidone-loaded lipid nanoconstructs: pharmacokinetic,behavioral, biochemical,and histological aspects

Antipsychotics are accompanied by extrapyramidal side effects that deter treatment adherence and patient compliance. Paliperidone (PPD), an atypical (second-generation) antipsychotic recommended for managing schizophrenia presents biopharmaceutical challenges and pharmacological constraints which dissuade it from crossing the brain barrier. The present research aimed to assess paliperidone-loaded lipid nanoconstruct (PPD-LNC) for an improved antipsychotic activity for managing schizophrenia. High % cell viability in Neuro-2a cells (70–98%) exhibited the safety of PPD-LNC. The pharmacokinetic data showed a 3.46-fold improvement in the relative bioavailability in the brain for PPD-LNC compared to a drug suspension. The pharmacodynamic evaluation demonstrated a significant (p < .05) reduction in cataleptic behavior, attenuated escape latency, and prolonged stay in the open arm with PPD-LNC, thus showing its effectiveness in reducing extrapyramidal symptoms. The histopathological images further validated the safety of the formulation. Reduction in NF-κB levels as identified by immunohistochemical analysis exhibited the anti-inflammatory effect of PPD-LNC. The formulation demonstrated significant (p < .01) improvement in the activity of oxidative stress parameters and attenuation of neuroinflammatory markers. Based on the study findings, it was observed that formulating LNC of PPD would surmount the pharmacological constraints, improve the in vivo performance, and diminish the associated side effects.     

Genetic variant of IL28B rs12979860, as predictive marker of interferon‐based therapy in Pakistani population

Hepatitis C virus (HCV) genotypes and genetic variants of interleukin 28B (IL28B) are significantly associated with interferon plus ribavirin treatment of HCV infection. We investigated the distribution of HCV genotypes and single‐nucleotide polymorphisms (SNPs) of IL28B (rs12979860 and rs8099917) in Pakistani population. IL28B genotyping was performed by allele‐specific PCR and restriction fragment length polymorphism PCR in 140 chronic hepatitis C patients (CHC) and 120 healthy controls. HCV genotype 3 (HCVG3) was the most prevalent genotype, 71.4% (n = 100/140) and with the highest treatment response of 90% (n = 90/100). The overall treatment response of all the HCV genotypes was 82% (n = 115/140). The distribution of IL28B rs12979860CC genotype in treatment responder and non‐responder groups was 40.8% (n = 47/115) and 16% (n = 4/25) respectively. IL28B rs12979860CC genotype demonstrated a significant correlation (p = 0.019) with interferon‐based therapy of HCV infection. However, there was no observed association of IL28B rs8099917 polymorphism with treatment response in CHC patients (p = 0.264). In conclusion, HCV genotypes and IL28B rs12979860 are predictive markers for the efficiency of interferon plus ribavirin combinational therapy of HCV infection. We recommend the inclusion of testing for these markers in the clinical criteria for decision making for HCV therapy in Pakistani population.     

Translation and Validation of the Breast Cancer Awareness Measurement Tool in Malaysia (B-CAM-M)

Background: Breast cancer is the most common cancer among women in Malaysia, and the incidence of 31.1 per 100,000 population is comparatively higher than other Southeast Asian countries. Diagnosis tends to occur at later stages which may be due, partly, to inadequate knowledge about warning signs and symptoms. Therefore, this study investigated the validity and reliability of a UK-developed measure in the context of assessing women’s awareness of breast cancer in Malaysia. Aims: This study aimed to translate, adapt and validate the internationally recognised Breast Cancer Awareness Measure (B-CAM) into the Malay language. Methods: The original B-CAM (Cancer Research UK) was forward and backward translated and content validation was ascertained. Face validity (n=30), test-retest reliability (n=50) and the internal consistency of the B-CAM-M (M for Malay language) were assessed in a community sample of adults (n=251) in 2018. Results: The translated B-CAM-M was validated by an expert panel. The Item-Content Validity Index ranged from .83 to 1.00. The results from the survey (n=251) indicated that the B-CAM-M was well received by Malay-speaking women across the main ethnic groups (85 Malay, 84 Chinese and 82 Indian adults). Cronbach alpha scores for the knowledge about breast cancer symptoms (0.83) and the barriers to healthcare seeking items (0.75) were high. Test-retest reliability (separated by 2-week-interval) with 50 randomly selected participants from the community survey produced intra-class correlations ranging from 0.39 to 0.69. Conclusion: The Malay-version, the B-CAM-M, is a culturally acceptable, valid and reliable assessment tool with which to measure breast cancer awareness among Malay-speaking women.     

The role of sex-differentiated variations in stress hormones,antioxidants, and neuroimmune responses in relation to social interaction impairment in a rodent model of autism

Males are more likely to develop autism as a neurodevelopmental disorder than females, but the mechanisms underlying male susceptibility are not fully understood. In this paper, we used a well-characterized propionic acid (PPA) rodent model of autism to study sex differences in stress hormones, antioxidants’ status, and the neuroimmune response that may contribute to the preponderance of autism in males. Sprague Dawley rats of both sexes were divided into a saline-treated group as controls and PPA-treated groups, receiving 250 mg/kg of PPA per day for three days. Animals’ social behavior was examined using the three-chamber social test. Hormones (ACTH, corticosterone, melatonin, and oxytocin), oxidative stress biomarkers (glutathione, glutathione-S-transferase, and ascorbic acid), and cytokines (IL-6, IL-1α, IL-10, and IFNγ) were measured in the brain tissue of all the animals. The results showed a sex dimorphic social response to PPA treatment, where males were more susceptible to the PPA treatment and exhibited a significant reduction in social behavior with no effects observed in females. Also, sex differences were observed in the levels of hormones, antioxidants, and cytokines. Female rats showed significantly higher corticosterone and lower oxytocin, antioxidants, and cytokine levels than males. The PPA treatment later modulated these baseline differences. Our study indicates that the behavioral manifestation of autism in PPA-treated males and not females could be linked to neural biochemical differences between the sexes at baseline, which might play a protective role in females. Our results can contribute to early intervention strategies and treatments used to control autism, an increasingly prevalent disorder.

     

Hepatitis B virus therapy:What's the future holding for us?

Hepatitis B is one of the leading causes of liver cancer worldwide and unfortunately the number of people affected with hepatitis B virus (HBV) infection is still on the rise. Although the HBV has been known to cause fatal illness since decades but the population effected by this lethal virus have still only a few options for its management. The major treatment strategies include interferons and nucleos(t)ide analogues. These agents have so far produced unsatisfactory results in terms of complete virus eradication. Interferons cannot be used for long term therapy because of their potential side effects. Prolong treatment with nucleos(t)ide analogues has also been reported to cause serious side effects besides the increasing resistance by the virus. The need for new innovative solutions for treatment of HBV has been realized by global research institutes and pharmaceutical industry. Present review focuses in detail on the new ideas that are being transformed into therapeutic tools for use as future therapies in HBV infection. Modern drug designing and screening methods have made the drug discovery process shorter and more reliable. HBV therapeutics will take a new turn in coming years owing to these intelligent drug designing and screening methods. Future therapy of HBV is aiming to include the use of vaccines (both prophylactic and therapeutic), immunomodulators such as antibodies, non-nucleoside antivirals such as RNAi and inhibitors of viral life cycle.     

A review of imaging modalities for detecting early keratoconus

ObjectivesEarly identification of keratoconus is imperative for preventing iatrogenic corneal ectasia and allowing for early corneal collagen cross-linking treatments to potentially halt progression and decrease transplant burden. However, early diagnosis of keratoconus is currently a diagnostic challenge as there is no uniform screening criteria. We performed a review of the current literature to assess imaging modalities that can be used to help identify subclinical keratoconus.MethodsA Pubmed database search was conducted. We included primary and empirical studies for evaluating different modalities of screening for subclinical keratoconus.ResultsA combination of multiple imaging tools, including corneal topography, tomography, Scheimpflug imaging, anterior segment optical coherence tomography, and in vivo confocal microscopy will allow for enhanced determination of subclinical keratoconus. In patients who are diagnostically borderline using a single screening criteria, use of additional imaging techniques can assist in diagnosis. Modalities that show promise but need further research include polarization-sensitive optical coherence tomography, Brillouin microscopy, and atomic force microscopy.ConclusionsRecognition of early keratoconus can reduce risk of post-refractive ectasia and reduce transplantation burden. Though there are no current uniform screening criterion, multiple imaging modalities have shown promise in assisting with the early detection of keratoconus.Subject terms: Tomography, Corneal diseases     

Comparison of PD-L1 Expression in Oral Squamous Cell Carcinoma and Premalignant Lesions of Oral Cavity

Objective: Objectives of this study were to compare  expression of Programmed Death-Ligand 1(PD-L1) protein in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorder (OPMD) cases; and to compare the PD-L1 protein expression in histological grades of OSCC and also in OPMD’s with Dysplasia and without Dysplasia. Materials & Methods: In this study,  25 cases of Oral squamous cell carcinoms, 25 cases of Oral Potentially Malignant Disorders and 10 cases of non-neoplastic oral mucosa (control) cases were included. FFPE blocks of OSCC and OPMD cases were contributed by Department of Pathology, Histopathology Division,Pakistan Institute of Medical Sciences, Islamabad. Immunohistochemical staining of cases with PD-L1 monoclonal antibody (1:100; Dako) was carried out at Histopathology division , PMC Labs,  Peshawar Medical College,Peshawar, Riphah International University, Islamabad . Epithelial cells (membranous and cytoplasmic) positivity was observed for PD-L1 Antibody. Data was analyzed in SPSS version20. For qualitative variables frequencies and percentages were calculated whereas for quantitative variables means and standard deviations were recorded. The Chi-square test was applied to evaluate the significant difference in categorical variables . p-value of ≤0.05 was taken as significant. Results: PD-L1 expression in OSCC cases turned out to be 48% (n=12/25) as compared to 8% of OPMD cases (n=2/25) with a significant p value of 0.002 and all non-neoplastic oral mucosa cases were negative. PD-L1 expression in high grade OSCC cases was quite high (61% n=11/18) as compared to low grade OSCC (14% n=1/7) cases with a significant p value of 0.035. Conclusion: A statistically significant increased PD-L1 expression was noted in  OSCC as compared to OPMD. Expression of PD-L1 was more intense in high grade OSCC cases. The relation of PD-L1 expression to age ,gender or location of OSCC and OPMD cases , and presence of dysplasia in OPMD cases was statistically not significant.