Bioanalytical Method Development and Validation: A Review

For various types of drug approval processes like INDs, NDAs, ANDAs, veterinary drug approval, the data related to bioanalytical method development and validation is needed to sponsors. Various agencies namely US FDA, American association of pharmaceutical scientists (AAPS), Health protection Branch (HPB), Association of analytical chemists (AOAC), Center for Veterinary Medicine (CVM), U.S. Department of Health and Human Services Food and drug Administration, Center for Drug Evaluation and Research (CDER), European Medicine Agency (EMA), China Food and Drug administration(CFDA), European Bioanalytical Forum (EBF), Global CRO council (GCC), ANVISA (Brazil), Japan Bioanalytical Forum (JBF) had done collective efforts at different timings to regulate and harmonize bioanalytical method development and validation

Rare case of primary esophageal synovial sarcoma with (x;18) translocation presenting as dysphagia

Synovial sarcoma (SS) in young adult mainly involves periarticular region of the extremities. Synovial sarcomas are exceedingly rare neoplasms of the digestive tract. In this report, we describe a very rare occurrence of primary SS of the esophagus in a 30-year-old female. Patient presented with dysphagia. Endoscopy showed submucosal esophageal polyp. Piecemeal polypectomy was done. Histologically, the tumor demonstrated biphasic morphology with epithelial and mesnchymal component. Tumor cells expressed pancytokeratin, bcl-2 and CD99 antigens. Differential diagnosis of synovial sarcoma and epithelial mesenchymal biphasic tumor was made. Cytogenetics was done to confirm the diagnosis of SS. It showed translocation (x;18). Synovial sarcomas are very rare tumor entities, particularly in the gastrointestinal tract and are likely to be mistaken with other more common tumors such as gastrointestinal stromal tumors

Drug-induced cutaneous adverse drug reactions in dermatology in Dr. B.R. Ambedkar Medical College

Background: Cutaneous adverse drug reactions (ADRs) affect 2-3% of hospitalized patients. The severity varies from mild itching to life-threatening Stevens-Johnson syndrome (SJS). Hence, this study was undertaken to emphasize the need to report ADRs.Methods: The study was carried out in the Department of Dermatology in Dr. B.R Ambedkar Medical College Hospital from June to December 2012. Naranjo’s algorithm was used to determine the causality of an ADR. Informed consent was obtained from each patient, and thorough clinical examination was conducted. All the information was carefully recorded in a pre-designed proforma. To establish the etiologic agent for a particular type of reaction, attention was paid to the drug history, temporal correlation with the drug, duration of the reaction, morphology of the reaction, associated mucosal or systemic involvement, improvement of lesions on withdrawal of the drug.Results: In the present study, all the age groups were affected with cutaneous ADRs, with a higher incidence in age group between 31 and 40 years, non-steroidal anti-inflammatory drugs (NSAIDs) (41.66%) were most commonly observed drug, followed by anti-microbials (25%) and anti-convulsants (21.66%). Fixed drug eruptions (FDE) (46.66%) most commonly observed cutaneous reaction, followed by SJS (16.66%), erythema multiformae (16.66%) most commonly observed ADRs.Conclusions: ADRs are potentially avoidable causes for seeking medical care. FDE was most common ADR and NSAIDs were most common causative agents in our study. ADRs can be prevented by avoiding polypharmacy, obtaining history of any previous skin reaction and the causative agent

Effective flow and transport properties of heterogeneous unsaturated soils

The heterogeneity of field scale soils poses a challenge to predictive large scale flow and transport modeling. The theory of effective macroscale parameters holds good and is applicable in dealing with such problems. But the va- lidity of the analytic stochastic solutions obtained for randomly heterogeneous soils is debatable, as the test cases under which they are validated are of limited scope due to linearization and perturbation approximations. In this study, samples of heterogeneous soils are generated using sets of spatially correlated random field parameters that are either geometrically isotropic, or else, geometrically anisotropic with either horizontal or vertical stratifi- cation (perfect or imperfect). Several combinations of ratios of correlation length and capillary dispersion lengths are considered. Numerical simulations of unsaturated flow are performed on each randomly heterogeneous soil sample. The principal components ̂K ii (Ψ) of the macroscale effective unsaturated conductivity are then obtained as a function of the mean suction Ψof the sample. They are compared to stochastic spectral perturbation theory, and to a probabilistic semi-empirical Power Average Model (PAM). They are also compared with arithmetic, geo- metric and harmonic mean conductivity-suction curves. The numerically upscaled principal conductivity curves match quite well the PAM, better than the classical means (Arithmetic, Geometric, Harmonic), and also some- what better than the curves obtained from stochastic spectral perturbation theory. It is observed that the upscaled principal components K ii ( ????), obtained numerically and with the PAM along directions “i ”orthogonal/parallel to perfect stratification coincide with the harmonic/arithmetic mean curves at low suctions (i.e., near saturation), but deviate from it and come closer to the geometric mean at higher suctions. The PAM appears suitable for generation of approximate upscaled conductivity curves, e.g., for obtaining the mesh-scale or block-scale con- ductivity curves in large scale simulation codes. Transient solute transport simulations are then performed on the detailed random velocity fields obtained from the steady state simulations of unsaturated flow in the randomly heterogeneous soil samples. Snapshots of solute concentration C(x,z,t) are taken at different times. The temporal evolution of spatial moments of concentration is analyzed in order to characterize the macroscale advection and dispersion of the unsaturated concentration plume, and in particular, its macro-dispersion coefficient (D) and dis- persivity length scale (A). For the synthetic soil samples considered in this study, the macro-dispersive spreading of the solute is stronger for flow parallel to vertical stratification, compared to flow perpendicular to horizontal stratification, and also, compared to flow in statistically isotropic non-stratified soil

A prospective randomised open labelled comparative study of anti inflammatory effects of topical 5% benzoyl peroxide gel vs topical 4% nicotinamide gel for grade I-II acne in a tertiary care hospital

Background: Acne vulgaris is a dermatological disorder characterised by formation of comedones and inflammatory lesions. The treatment of acne basically involves reduction of lesions. Benzoyl peroxide, in concentrations of 5%, 10%, and 20%, has been used effectively in the treatment of acne for more than 20 years. Nicotinamide/ Niacinamide is a newly-approved anti-acne drug with a potent anti-inflammatory effect. The present study assessed the efficacy of 5% Benzoyl peroxide gel in comparison to 4% Nicotinamide gel for topical treatment of mild to moderate acne vulgaris.Methods: In this study, the patients with mild to moderate acne vulgaris with inflammation were divided into two groups, group I was treated with topical 5% Benzoyl peroxide gel whereas topical Nicotinamide gel was given to the group II. Assessment of efficacy was done by total lesion counting according acne global severity index, the results were compared at the end of 2 weeks and 4 weeks with the baseline values.Results: At the end of this study, it was found that the reduction of inflammatory and total percentage of decrease in counts of lesions from baseline were highly significant in both the groups (p<0.001), between the groups, differences were statistically significant (p<0.001), therefore 5% Benzoyl peroxide gel has better efficacy than 4% Nicotinamide gel.Conclusions: Benzoyl peroxide is more efficacious than 4 % Nicotinamide gel in mild to moderate acne

ReP-ETD: A Repetitive Preprocessing technique for Embedded Text Detection from images in spam emails

Email service proves to be a convenient and powerful communication tool. As internet continues to grow, the type of information available to user has shifted from text only to multimedia enriched. Embedded text in multimedia content is one of the prevalent means for delivering messages to content viewers. With the increasing importance of emails and the incursions of internet marketers, spam has become a major problem and has given rise to unwanted mails. Spammers are continuously adopting new techniques to evade detection. Image spam is one such technique where in embedded text within images carries the main information of the spam message instead of text based spam. Currently, image spam is evaluated to be roughly 50% of all spam traffic and is still on the rise, thus a serious research issue. Filtering mails is one of the popular approaches used to block spam mails. This work proposes new model ReP-ETD (Repetitive Pre-processing technique for Embedded Text Detection) for efficiently and accurately detecting spam in email images. The performance of the proposed ReP-ETD model has been evaluated across the identified parameters and compared with other existing models. The simulation results demonstrate the effectiveness of the proposed model

The natural history of primary sclerosing cholangitis in 781 children. A multicenter, international collaboration

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes

Characterization and monitoring of deltamethrin-resistance in Anopheles culicifacies in the presence of a long-lasting insecticide-treated net intervention.

BACKGROUND: Deltamethrin-impregnated, long-lasting insecticidal nets (LLINs) were distributed in the study area from November 2014 to January 2015 to evaluate their impact on malaria transmission in the presence of insecticide-resistant vectors. Studies were carried out in 16 selected clusters in Keshkal sub-district, Chhattisgarh State, India to monitor and characterize deltamethrin resistance in Anopheles culicifacies sensu lato. RESULTS: Deltamethrin susceptibility of An. culicifacies decreased in a post-LLIN survey compared to a pre-LLIN survey and was not significant (p > 0.05) while, the knockdown values showed significant increase (p < 0.05). Pre-exposure to piperonyl butoxide, triphenyl phosphate showed synergism against deltamethrin (p < 0.001). Biochemical assays showed significantly (p < 0.05) elevated monooxygenases in 3 of 5 clusters in post-LLIN survey-I that increased to 10 of 11 clusters in post-LLIN survey-II, while esterases were found significantly elevated in all clusters and both enzymes were involved in conferring pyrethroid resistance, not discounting the involvement of kdr (L1014L/S) gene that was heterozygous and at low frequency (4-5%). CONCLUSION: This field study, in a tribal district of India, after distribution of deltamethrin-impregnated LLINs showed decrease in deltamethrin susceptibility in An. culicifacies, a major vector of malaria in this study area and in India. Results indicated development of resistance as imminent with the increase in insecticide selection pressure. There is an urgent need to develop new vector control tools, with insecticide classes having novel mechanisms of resistance, to avoid or delay the onset of resistance. Regular insecticide resistance monitoring and mechanistic studies should be the priority for the malaria control programmes to suggest strategies for insecticide resistance management. The global commitment to eliminate malaria by 2030 needs various efforts that include development of combination vector control products and interventions and few are becoming available

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis : Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course

Objective To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. Study design We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level >= 50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level Results We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. Conclusions Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.Peer reviewe