Thinking beyond low-density lipoprotein cholesterol: strategies to further reduce cardiovascular risk

Several large statin trials and meta-analyses have demonstrated a reduction in low-density lipoprotein cholesterol (LDL-C) and cardiovascular morbidity and mortality. Some trials have also highlighted the significance of residual cardiovascular risk after treatment of LDL-C to target levels. This reflects the complex nature of residual cardiovascular risk. This residual risk is partially due to low HDL-C and high triglycerides (TG) despite achievement of LDL goals with statin therapy. The NCEP ATP III guidelines reported that low HDL-C is a significant and an independent risk factor for coronary heart disease (CHD) and is inversely related to CHD. Epidemiologic studies have also shown a similar inverse relationship of HDL-C with CHD. High-density lipoprotein cholesterol (HDL-C) may directly participate in the anti-atherogenic process by promoting efflux of cholesterol of the foam cells of atherogenic lesions. Many studies have demonstrated multiple anti-atherogenic actions of HDL-C and its role in promoting efflux of cholesterol from the foam cells. The residual risk by increased TG with or without low HDL-C can be assessed by calculating non–HDL-C and a reduction in TG results in decreased CHD

Fibroadenoma/benign phyllodes: a cytologic diagnostic challenge

Background: To study and compare cytomorphological features of histologically proven cases of benign phyllodes and cellular fibroadenoma.Methods: Smears of histologically-proven cases of benign phyllodes and cellular fibroadenoma in one year, were reviewed. The cellular fibroadenoma had epithelial and/or stromal hypercellularity. The stromal and epithelial components as well as the background cells were qualitatively and quantitatively analyzed.Results: Number, cellularity and type of stromal fragments varied significantly in two groups. Higher number, intermediate to large-sized and hypercellular stromal fragments were commonly seen in phyllodes. Hypercellular (3+ cellularity) fragments were seen in 100% cases of phyllodes against 11.1% cases of fibroadenoma. Large-sized stromal fragments were found in 100% of phyllodes while in only 11.1% cases of fibroadenoma. The ratio of number of epithelial to stromal fragments was significantly high (58.5:1) in fibroadenoma against phyllodes (1.3:1). The epithelial architecture, atypia, apocrine metaplasia and presence of cystic macrophages did not very much in the two groups. The cellularity of the dispersed cells in background did not reveal significant difference though the type of cells varied; the proportion of long and short spindle cells was higher in PT group while proportion of oval cells was higher in FA group.Conclusion: The number, cellularity and nature of stromal fragments, ratio of epithelial to stromal fragments, cellularity and type of background cells are helpful in distinguishing benign phyllodes from cellular fibroadenoma. The identification of these features can improve the pickup rate of phyllodes tumor, thereby assisting proper management

The interaction between clopidogrel and proton pump inhibitors (PPI): is there any clinical relevance?

The potential interaction between clopidogrel and proton pump inhibitors (PPI) in patients with acute coronary syndrome (ACS) raises serious concerns for cardiologists. However, in patients on this combination of drugs, there is no conclusive evidence of an increase in adverse cardiovascular events. From pharmacologic and pharmacodynamic perspectives, there is a real interaction between clopidogrel and PPIs because of the competitive inhibition of CYP2C19 isoenzyme which is required for biotransformation of clopidogrel to its active metabolite. The consequent decrease in the availability of this active metabolite leads to attenuation of antiplatelet efficacy of clopidogrel. In several observational trials, it was shown that decreased antiplatelet effect of clopidogrel due to PPIs may translate into poor cardiovascular outcomes. However, an incomplete RCT (COGENT) and a post hoc analysis of two large trials (PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trial) showed no significant adverse cardiovascular events with this combination. Caution is however needed in patients who are hypometabolizers of clopidogrel putting them at a higher risk of adverse coronary events. Since 3% of patients are likely to be hypometabolizers of clopidogrel, routine combination of clopidogrel and PPIs should be avoided. There is a heightened awareness of this interaction following multiple advisory warnings. At the same time, one should not withhold PPIs in patients who are at a high risk of developing gastrointestinal (GI) bleeding. In these patients, selected choices of PPI such as pantoprazole may be helpful and for low risk patients, serious consideration should be given to H2 receptor antagonists or antacids. Therefore, while not compromising the cardioprotective effect of antiplatelet agents, the gastroprotective benefit of PPI should be strongly considered in patients who need both. Health care providers should remain alert to more outcome data. Future researchers will need to demonstrate the safety of coadministration of PPIs and clopidogrel and trials should be powered to detect major adverse cardiovascular events and facilitate risk stratification based on genetic polymorphism

Ashwagandha Derived Withanone Targets TPX2-Aurora A Complex: Computational and Experimental Evidence to its Anticancer Activity

Cancer is largely marked by genetic instability. Specific inhibition of individual proteins or signalling pathways that regulate genetic stability during cell division thus hold a great potential for cancer therapy. The Aurora A kinase is a Ser/Thr kinase that plays a critical role during mitosis and cytokinesis and is found upregulated in several cancer types. It is functionally regulated by its interactions with TPX2, a candidate oncogene. Aurora A inhibitors have been proposed as anticancer drugs that work by blocking its ATP binding site. This site is common to other kinases and hence these inhibitors lack specificity for Aurora A inhibition in particular, thus advocating the need of some alternative inhibition route. Previously, we identified TPX2 as a cellular target for withanone that selectively kill cancer cells. By computational approach, we found here that withanone binds to TPX2-Aurora A complex. In experiment, withanone treatment to cancer cells indeed resulted in dissociation of TPX2-Aurora A complex and disruption of mitotic spindle apparatus proposing this as a mechanism of the anticancer activity of withanone. From docking analysis, non-formation/disruption of the active TPX2-Aurora A association complex could be discerned. Our MD simulation results suggesting the thermodynamic and structural stability of TPX2-Aurora A in complex with withanone further substantiates the binding. We report a computational rationale of the ability of naturally occurring withanone to alter the kinase signalling pathway in an ATP-independent manner and experimental evidence in which withanone cause inactivation of the TPX2-Aurora A complex. The study demonstrated that TPX2-Aurora A complex is a target of withanone, a potential natural anticancer drug

Correlates of response to olanzapine in a north Indian schizophrenia sample

Olanzapine is widely used for the treatment of schizophrenia and is considered a first line medication in India. Along with other factors, the variation in response and side effects to this agent may be accounted for by genetic differences among patients. Olanzapine was administered for 6 weeks to Indian subjects with schizophrenia or schizoaffective disorder (DSM-IV, n=130), as part of an open label study. Intent-to-treat analysis was performed, and 10 polymorphic markers from seven genes (dopamine D1, D2, D3 and D4 receptors, serotonin 2A receptor and the drug-metabolizing enzymes (CYP1A2 and CYP2D6)), together with demographic and clinical variables, were analyzed as potential predictors of response. Olanzapine was efficacious, but significant weight gain was noted. Baseline weight and a 120 bp deletion polymorphism at the dopamine receptor D4 (DRD4) gene were associated with changes in symptom scores. Predictable covariates of treatment response were also noted. These results merit replicate studies