Ashim Malhotra

An Organ System Approach to Explore the Antioxidative, Anti-Inflammatory, and Cytoprotective Actions of Resveratrol.

Resveratrol is a phenolic phytochemical, with a stilbene backbone, derived from edible plants such as grape and peanut. It is a bioactive molecule with physiological effects on multiple organ systems. Its effects range from the neuroprotective to the nephroprotective, including cardiovascular, neuronal, and antineoplastic responses as a part of its broad spectrum of action. In this review, we examine the effects of resveratrol on the following organ systems: the central nervous system, including neurological pathology such as Parkinsons and Alzheimers disease; the cardiovascular system, including disorders such as atherosclerosis, ischemia-reperfusion injury, and cardiomyocyte hypertrophy; the kidneys, including primary and secondary nephropathies and nephrolithiasis; multiple forms of cancer; and metabolic syndromes including diabetes. We emphasize commonalities in extracellular matrix protein alterations and intracellular signal transduction system induction following resveratrol treatment. We summarize the known anti-inflammatory, antioxidative, and cytoprotective effects of resveratrol across disparate organ systems. Additionally, we analyze the available literature regarding the pharmacokinetics of resveratrol formulations used in these studies. Finally, we critically examine select clinical trials documenting a lack of effect following resveratrol treatment.

Pharmacogenomic Considerations in the Treatment of the Pediatric Cardiomyopathy Called Barth Syndrome

Barth syndrome (BTHS) is a genetic, X-linked, rare but often fatal, pediatric skeletal- and cardiomyopathy occurring due to mutations in the tafazzin gene (TAZ). TAZ encodes a transacylase involved in phospholipid biosynthesis, also called tafazzin, which is responsible for remodeling the inner mitochondrial membrane phospholipid, cardiolipin (CL). Tafazzin mutations lead to compositional alterations in CL molecular species, causing extensive mitochondrial aberrations and ultrastructural muscle damage. There are no specific treatments or cure for BTHS. Current therapy is largely palliative and aimed at treatment of organ-specific complications during disease progression. Polypharmacy frequently occurs during treatment and may lead to severe adverse events. Adverse reactions may originate from exogenous factors such as the inadvertent co-administration of contraindicated drugs. Theoretically, endogenous factors such as polymorphic variations in genes encoding drug metabolizing enzymes may also precipitate fatal toxicity. Investigation of the consequences of pharmacogenomic variations on BTHS therapy is lacking. To our knowledge, this review presents the first examination of the possible sources of pharmacogenomic variations that may affect BTHS therapy. We also explore BTHSspecific patents for possible treatment options. The patents discussed suggest innovative strategies for treatment, including feeding linoleic acid to patients to overcome compositional CL deficiency; or the use of 2S,4R ketoconazole formulations to augment CL levels; or the delivery of mitochondrial stabilizing cargo. Future research directions are also discussed.

Impact of standardization of antimicrobial prophylaxis duration in pediatric cardiac surgery

OBJECTIVESnThe optimal duration of antimicrobial prophylaxis following pediatric cardiac surgery is still debated. Adult studies suggest that shorter durations are adequate, but there is a paucity of data on pediatric patients.nnnMETHODSnThis quasi-experimental study reviewed the charts of patients 18xa0years and younger who underwent cardiac surgery from April 2011 to November 2014 at a single institution. Starting in April 2013, a protocol was implemented to limit antimicrobial prophylaxis to 48xa0hours following sternal closure. Two analyses were performed: (1) identification of risk factors for surgical site infections from the entire cohort, and (2) comparison of surgical site infection incidence in the pre- and postprotocol groups.nnnRESULTSnIn the entire cohort, delayed sternal closure (adjusted odds ratio [OR], 5.7; 95% confidence interval [CI], 1.8-17.9) and younger age (adjusted OR, 2.1; 95% CI, 1.1-3.8) were associated with incidence of surgical site infection. Following the protocol change, duration of antimicrobial prophylaxis decreased from 4.2xa0±xa02.7 to 1.9xa0±xa01.3xa0days (Pxa0<xa0.0001). After adjusting for age and delayed sternal closure, the postprotocol group had an adjusted OR of 0.98 (95% CI, 0.32-3.00) for occurrence of surgical site infection. Other outcomes were not altered following the protocol change.nnnCONCLUSIONSnRestricting antimicrobial prophylaxis to 48xa0hours following pediatric cardiac surgery did not increase the incidence of surgical site infection at our institution. Further study is needed to validate this finding and to identify practices that reduce surgical site infections in those with delayed sternal closure.

Worsening renal function in patients with baseline renal impairment treated with intravenous voriconazole: A systematic review

The objective of this paper was to review the risk of worsening renal function in patients with pre-existing renal impairment receiving intravenous voriconazole (IVV). Controversy exists regarding the cause and risk of renal dysfunction in patients treated with IVV. Whilst some studies implicate renally excreted cyclodextrin, a pharmaceutical formulation stabiliser, as the cause of renal dysfunction following voriconazole administration, others provide contradicting evidence. Here we analyse the available literature to gain an insight into the significance of renal toxicity in patients treated with IVV. PubMed was searched for relevant studies to December 2014. To account for publication bias, abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, the Infectious Diseases Society of America/ID Week, and the European Congress of Clinical Microbiology and Infectious Diseases from 2008-2014 were reviewed. Bibliographies of all identified articles were reviewed and cross-referenced for additional sources. Seven retrospective studies were identified for inclusion in the review; no prospective studies were identified. Based on the available evidence, we conclude that there is no strong evidence suggesting an increased incidence of worsening renal function with IVV use. No study thus far has provided direct conclusive evidence for cellular and physiological renal toxicity due to IVV at clinically prevalent doses.

Thienopyrimidine derivatives exert their anticancer efficacy via apoptosis induction, oxidative stress and mitotic catastrophe

In this study, a series of 13 structural variants of thieno[2,3d]pyrimidine derivatives (6a-6m) were synthesized and screened for cytotoxicity in a panel of colorectal, ovarian, and brain cancer cell lines. The selectivity of the compounds was assessed by determining the cytotoxicity in normal epithelial cell line (CHO). The most potent compound, 6j, was efficacious (with IC50 range of 0.6-1.2xa0μM) in colon (HCT116 and HCT15), brain (LN-229 and GBM-10) and ovarian (A2780 and OV2008) cancer cell lines. In contrast, in the normal cell line (CHO), the IC50 values for 6j were 14xa0±xa01.3xa0μM. Compound 6j significantly inhibited the clonogenic potential of HCT116, OV2008 and A2780xa0cell lines in concentration - dependent (0.5-4xa0μM) manner. Also, 6j induced 1) formation of reactive oxygen species; 2) apoptosis and 3) mitotic catastrophe in HCT116 and OV2008xa0cells (IC50xa0=xa00.5-2xa0μM). Furthermore, apoptosis was the predominant mechanism of death in A2780xa0cells. The cytotoxicity of 6j in wild type HCT116xa0cells was similar to that in HCT116xa0cells lacking the apoptotic genes for Bax, Bak, or Bak and Bax, indicating that 6j induces mitotic catastrophe as alternative mechanism of death when when certain apoptotic proteins are absent. In summary, this study has identified a lead molecule, 6j, that selectively induces oxidative stress, apoptosis and mitotic catastrophe in specific cancer (colon and ovarian) cell lines.

Forecasting academic success through implementation of an online prerequisite review tutorials program for first year pharmacy students

OBJECTIVEnOnline prerequisite review (OPR) tutorials were designed and implemented to reinforce foundational scientific material in order to protect in-class time, foster self-directed learning, and ensure all students have similar baseline knowledge.nnnMETHODSnTwenty-one tutorials covering undergraduate prerequisite material were developed by faculty and organized into six core modules, comprising basic biology, chemistry, and physiology topics. A quiz on this material was given on the first day of each course. This score was correlated with the final exam score at course completion. Additional student and faculty feedback was collected through surveys.nnnRESULTSn2372 quiz-exam pairings were collected over three consecutive fall semesters. A one point increase in the quiz score was associated with a 3.6 point (95% confidence interval 3.1-4.0) higher exam score, as well as a greater probability of passing the exam (P<0.0001). Furthermore, simple linear regression revealed a positive correlation between quiz and exam scores (P<0.0001). Three full years of student survey data revealed an overwhelmingly positive perception of the OPR tutorials, and surveyed faculty reported better use of class time and improved student competency and participation.nnnCONCLUSIONSnImplementation of OPR tutorials may give faculty more efficient use of class time, and their associated quizzes serve as an early indicator for students at-risk of not passing who are candidates for early interventions. Furthermore, the OPR tutorial design gives it great transferability to biomedical post-graduate programs.