Structure-based screening and validation of bioactive compounds as Zika virus methyltransferase (MTase) inhibitors through first-principle density functional theory, classical molecular simulation and QM/MM affinity estimation.

Recent Zika virus (ZIKV) outbreak and association with human diseases such as neurological disorders have raised global health concerns. However, in the absence of an approved anti-ZIKV drug has generated urgency for the drug development against ZIKV infection. Here, structure-based virtual screening of 8589 bioactive compounds, screened at the substrate-binding site of ZIKV nonstructural 5 (NS5)-based structure N-terminal methyltransferase (MTase) domain followed by ADMET (absorption, distribution, metabolism, excretion and toxicity) profiling concluded the four potential lead inhibitors, i.e. (4-acetylamino-benzenesulfonylamino)-acetic acid (F3342-0450), 3-(5-methylfuran-2-yl)-N-(4-sulfamoylphenyl)propanamide (F1736-0142), 8-(2-hydroxy-ethylamino)-1,3-dimethyl-7-(3-methyl-benzyl)-3,7-dihydro-purine-2,6-dione (F0886-0080) and N-[4-(aminosulfonyl)phenyl]-2,3-dihydro-1,4-benzodioxine-2-carboxamide (F0451-2187). Collectively, extra precision docking and Density Functional Theory(DFT) calculations studies identified the F3342-0450 molecule, having strong interactions on the active site of MTase, further supported by molecular dynamics simulation, binding affinity and hybrid QM/MM calculations, suggest a new drug molecule for the antiviral drug development against ZIKV infection. Communicated by Ramaswamy H. Sarma.

Neurocutaneous Melanosis with Bilateral Temporal Lobe Lesions without Leptomeningeal Enhancement: A Distinct Entity or Subtype.

Neurocutaneous melanosis (NCM) is a rare congenital disorder. Most of the cases described in literature for this entity have involvement of the leptomeninges and other structures of brain such as brain stem, temporal lobes, and spinal meninges and no involvement of leptomeninges and presence of lesions in bilateral temporal lobes. NCM without the involvement of leptomeninges should be considered a distinct entity as the prognosis is favorable as compared to cases with leptomeningeal involvement who develop early hydrocephalus and multiple cranial nerve palsies.

Serial brain MRI findings in a rare survivor of rabies encephalitis.

Rabies is a neurotropic viral illness, almost always fatal, that is equally dreaded by healthcare practitioners and patients due to the dismal prognosis and limited treatment options once symptoms set in. There are hardly any reports on MRI changes in the brain in survivors of rabies encephalitis. We present the clinical course and the imaging findings on serial MRI examinations in a rare patient who survived rabies infection. Initial brain MRI done 8 days after onset of symptoms revealed bilaterally symmetrical non-enhancing areas of T1 and T2 hyperintensity in the basal ganglia, thalami, mid brain, and pons along with T2 hyperintensity and restricted diffusion in fronto-parietal cortical grey matter and left hippocampus. Subsequent MRI scans at 2 months and 5 months revealed progressive brain atrophy, leukoencephalopathy, and gliosis.

Incorporation of Whole Spine Screening in Magnetic Resonance Imaging Protocols for Low Back Pain: A Valuable Addition.

STUDY DESIGN: A retrospective review of lumbar magnetic resonance imaging (MRI) studies conducted at the Department of Radiodiagnosis & Imaging of a Tertiary Care Armed Forces Hospital between May 2014 and May 2016. PURPOSE: To assess the advantages of incorporating sagittal screening of the whole spine in protocols for conventional lumbar spine MRI for patients presenting with low back pain. OVERVIEW OF LITERATURE: Advances in MRI have resulted in faster examinations, particularly for patients with low back pain. The additional detection of incidental abnormalities on MRI helps to improve patient outcomes by providing a swifter definitive diagnosis. Because low back pain is extremely common, any change to the diagnostic and treatment approach has a significant impact on health care resources. METHODS: We documented all additional incidental findings detected on sagittal screenings of the spine that were of clinical significance and would otherwise have been undiagnosed. RESULTS: A total of 1,837 patients who met our inclusion criteria underwent MRI of the lumbar spine. The mean age of the study population was 45.7 years; 66.8% were men and 33.2% women. Approximately 26.7% of the patients were diagnosed with incidental findings. These included determining the level of indeterminate vertebrae, incidental findings of space-occupying lesions of the cervicothoracic spine, myelomalacic changes, and compression fractures at cervicothoracic levels. CONCLUSIONS: We propose that T2-weighted sagittal screening of the whole spine be included as a routine sequence when imaging the lumbosacral spine for suspected degenerative pathology of the intervertebral discs.

Ultrasound Guided Percutaneous Injection of Thrombin: Effective Technique for Treatment of Iatrogenic Femoral Pseudoaneurysms.

INTRODUCTION: Arterial pseudoaneurysms are well known iatrogenic complication of percutaneous angiographic or interventional vascular procedures. In the past, the definitive treatment option was open surgical repair which is a relatively invasive procedure. In the last few years, Ultrasound (US) guided percutaneous thrombin injection has been gaining popularity as definitive treatment of pseudoaneurysms. AIM: To evaluate efficacy and safety of US guided percutaneous injection of thrombin for treatment of iatrogenic femoral pseudoanurysms at a tertiary care interventional radiological and cardiology centre. MATERIALS AND METHODS: A retrospective analysis was conducted on 38 consecutive patients, diagnosed to have iatrogenic femoral artery pseudoaneurysms by Doppler study, in the period from Jan 2013 to Jun 2016. All these patients were treated by US guided percutaneous injection of thrombin solution inside the pseudoaneurysm sac till contents became echogenic and flow inside the pseudoaneurysm stopped completely. One month further follow up in all these patients was done. RESULTS: The dose of thrombin injected varied from 200-1000 IU (mean 300 IU). Immediate thrombosis was seen in all the pseusdoaneurysms. Follow up at 24-48 hours showed complete thrombosis and regression of pseudoaneurysm in all the patients except one in whom a small residual sac was seen which thrombosed completely on second thrombin injection. Further follow up at one month showed regression of aneurysms in all the cases. No significant post procedural clinically significant complications were seen in any of the patients. CONCLUSION: US guided percutaneous thrombin injection is a highly successful and safe procedure for the treatment of iatrogenic femoral pseudoaneurysms.

A study of coronary artery variants and anomalies observed at a tertiary care armed forces hospital using 64-slice MDCT.

BACKGROUND: Isolated coronary artery anomalies are usually clinically silent and mostly detected incidentally during angiography or autopsy. However, few of them may be implicated in cases of sudden cardiac death even in the absence of additional heart abnormalities. Prior knowledge of such variants and anomalies is necessary for planning various interventional procedures. Multiple detector computed tomography coronary angiography has proved a very useful non-invasive modality in this field given its superiority over conventional coronary angiography in providing detailed coronary artery anatomy. METHODS: A retrospective review of the coronary CT angiography studies was carried out at our center between August 2014 and December 2015 with the purpose of describing the coronary artery variants and anomalies that we came across in our cohort. RESULTS: In our cohort, about 77% (n=391) of the patients had a right dominant system while left dominant and co-dominant systems were seen in 12% (n=61) and 11% (n=56) respectively. Coronary CT angiography was successful in visualizing smaller branches, such as the conus artery (96.25%, n=489), the sinus node artery (83.07%, n=422), and the septal branches (95.27%, n=484). Coronary anomalies were observed in the 10.04% of our population (n=51). Eleven anomalies of origin and course were found. CONCLUSION: Coronary CT angiography gives us a good understanding of the variations and anomalies of the anatomy of the coronary arteries. This can be of immense help to the clinician planning interventional procedures.

Obesity and insulin resistance in resistant hypertension: implications for the kidney.

There is recognition that the obesity epidemic contributes substantially to the increasing incidence of CKD and resistant hypertension (HTN). The mechanisms by which obesity promotes resistance are an area of active interest and intense investigation. It is thought that increases in visceral adiposity lead to a proinflammatory, pro-oxidative milieu that promote resistance to the metabolic actions of insulin. This resistance to insulin at the level of skeletal muscle tissue impairs glucose disposal/utilization through actions on the endothelium that include vascular rarefaction, reductions in vascular relaxation, and vascular remodeling. Insulin resistance derived from increased adipose tissue and obesity has system-wide implications for other tissue beds such as the kidney that affects blood pressure regulation. The additional autocrine and paracrine activities of adipose tissue contribute to inappropriate activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system that promote kidney microvascular remodeling, stiffness, and sodium (Na(+)) retention that in turn promote HTN and in the CKD patient, resistance. In this review, we will summarize the important mechanisms that link obesity to CKD as they relate to resistant HTN.

Lipid abnormalities in kidney disease and management strategies.

Patients with kidney diseases continue to experience significant cardiovascular disease (CVD) morbidity and mortality. Although there are many important risk factors playing a role in the pathogenesis of CVD in chronic kidney disease (CKD) patients, dyslipidemia (elevated triglycerides, elevated oxidized low-density lipoprotein and low/dysfunctional low high-density) represents one of the modifiable risk factors. Renal failure patients have unique lipid abnormalities which not only have complex role in pathogenesis of CVD but also cause relative resistance to usual interventions. Most of the randomized trials have been in hemodialysis population and data from CKD non-dialysis, peritoneal dialysis and renal transplant populations is extremely limited. Compared to general population, evidence of mortality benefit of lipid lowering medications in CKD population is scarce. Future research should be directed towards establishing long term benefits and side effects of lipid lowering medications, through randomized trials, in CKD population.

Is there a role for the incretin system in blood pressure regulation?

Incretin-based therapies are now well established for diabetes management and are among the frontline agents for control of hyperglycemia. In addition to their antihyperglycemic effects, evidence is emerging on the role of these agents on blood pressure regulation, cardioprotective and renoprotective properties. Because of the pleiotropic nature of these affects, these agents could offer significant benefits with regards to the cardiorenal metabolic complications that are part of the diabetes and obesity epidemic in the United States and worldwide. We review the various known mechanisms or pathways by which incretin based therapy exerts its regulation of blood pressure with emphasis on novel mechanisms such as inflammation/immunomodulation and oxidative stress.