Rare Angiogenin and Ribonuclease 4 variants associated with amyotrophic lateral sclerosis exhibit loss-of-function: a comprehensive in silico study

Metabolic Brain Disease - Amyotrophic Lateral Sclerosis (ALS), a debilitating neurodegenerative disorder is related to mutations in a number of genes, and certain genes of the Ribonuclease (RNASE)...     

Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women.

Sixty-three postmenopausal women were assigned to four treatment groups and received either Premarin or percutaneous 17 beta-estradiol (Oestrogel) alone or in combination with micronized progesterone (Utrogentan). The oral administration of estrogen alone to hysterectomized women resulted in: 1) a significant increase in triglyceride levels in plasma and all major lipoprotein fractions, 2) a significant increase in very low density lipoprotein cholesterol, 3) a significant decrease in low density lipoprotein (LDL) cholesterol but not LDL apo B concentration, 4) a significant increase in all the lipid components of high density lipoprotein (HDL) as well as apo AI, 5) and a significant increase in HDL2 cholesterol. In contrast, percutaneous administration of estrogen to hysterectomized women only increased HDL2 cholesterol and the triglyceride and cholesterol content of the whole HDL fraction. These results suggest that the route of estrogen administration is important in determining effects on lipoprotein metabolism. The same two estrogens were given to women with natural menopause, along with utrogestan, a micronized progesterone. The simultaneous administration of Utrogestan reversed the HDL cholesterol elevating effect of percutaneous estrogen alone, but it had no effect on other plasma lipoproteins. On the other hand, utrogestan in combination with oral estrogen had several potential beneficial effects on plasma lipoproteins. This combination did not negate the effects of oral estrogen alone on HDL, rather it further increased the concentrations of HDL cholesterol and apo AI. It also did not negate the LDL cholesterol lowering effect of oral estrogen alone. Furthermore, utrogestan lowered the magnitude of hypertriglyceridemia induced by oral estrogen alone. These results suggest that Utrogestan has lower potency of androgenic action and has desirable effects when given in cyclic combination with estrogen.     

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 1. Structure-activity relationships and optimization of heterocyclic substituents

Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.     

Early postoperative bleeding impacts long-term survival following first-time on-pump coronary artery bypass grafting

BackgroundSignificant bleeding following cardiac surgery is a recognised complication, associated with a requirement for re-exploration and blood transfusion, both associated with increased morbidity and early mortality. The aim of this study was to examine the impact of the volume of early postoperative bleeding on long-term survival for patients undergoing coronary artery bypass grafting (CABG).MethodsA retrospective analysis was performed of patients undergoing first-time isolated CABG at a single centre between January 2003 and April 2013, conditional from 30-day survival.ResultsSix thousand two hundred and sixty-five patients were analysed, with a mean Logistic EuroSCORE of 4.9%. The mean age was 67.8 years. Median follow-up was 11.5 years. The overall 10- and 15-year survival was 70.6% and 51.9% respectively. Following surgery, 4.6% (n=291) required return to theatre for re-exploration, and 43.6% (n=2,733) received at least one red cell transfusion. In multivariable analysis, the strongest correlates of mortality were age, smoking history, BMI, COPD, renal impairment, preoperative left ventricular function and preoperative haemoglobin (Hb) level. Twelve-hour blood loss was an additional predictor of inferior long-term survival. Five-year survival was 89.6% for patients with <500 mL blood loss, 86.8% for 500–1,000 mL and 83.8% for >1,000 mL. Re-exploration and receiving blood transfusion were not associated with reduced long-term survival.ConclusionsSignificant 12-hour blood loss is associated with inferior long-term survival following CABG. This observation supports efforts aimed at improving intra-operative haemostasis and aggressive management of patients with early signs of bleeding.     

Minimally invasive techniques for lumbar decompressions and fusions

Purpose of review

The purpose of this study is to summarize the recent literature investigating the use of minimally invasive (MIS) techniques in the treatment of lumbar degenerative stenosis, spondylolisthesis, and scoliosis.

Recent findings

MIS lumbar decompression and fusion techniques for degenerative pathology are associated with reduced operative morbidity, shortened length of hospital stay, and reduced postoperative pain and narcotics utilization. Recent studies with long-term clinical follow-up have demonstrated equivalence in clinical outcomes between open and MIS surgical procedures. Radiographically, MIS procedures provide adequate postoperative correction of coronal alignment. Correction of sagittal alignment, however, is more variable based on current reports.

Summary

MIS techniques are both safe and effective in the treatment of lumbar degenerative pathologies. While some studies have reported on long-term outcomes and costs associated with MIS procedures, more investigation into these topics is still necessary. Additionally, further work is required to analyze the training requirements and learning curves of MIS procedures to better promote adoption amongst surgeons.

     

Reduced Patient Radiation Exposure during Neurodiagnostic and Interventional X-Ray Angiography with a New Imaging Platform

BACKGROUND AND PURPOSE:Advancements in medical device and imaging technology as well as accruing clinical evidence have accelerated the growth of the endovascular treatment of cerebrovascular diseases. However, the augmented role of these procedures raises concerns about the radiation dose to patients and operators. We evaluated patient doses from an x-ray imaging platform with radiation dose–reduction technology, which combined image noise reduction, motion correction, and contrast-dependent temporal averaging with optimized x-ray exposure settings.MATERIALS AND METHODS:In this single-center, retrospective study, cumulative dose-area product inclusive of fluoroscopy, angiography, and 3D acquisitions for all neurovascular procedures performed during a 2-year period on the dose-reduction platform were compared with a reference platform. Key study features were the following: The neurointerventional radiologist could select the targeted dose reduction for each patient with the dose-reduction platform, and the statistical analyses included patient characteristics and the neurointerventional radiologist as covariates. The analyzed outcome measures were cumulative dose (kerma)-area product, fluoroscopy duration, and administered contrast volume.RESULTS:A total of 1238 neurointerventional cases were included, of which 914 and 324 were performed on the reference and dose-reduction platforms, respectively. Over all diagnostic and neurointerventional procedures, the cumulative dose-area product was significantly reduced by 53.2% (mean reduction, 160.3 Gy × cm²; P < .0001), fluoroscopy duration was marginally significantly increased (mean increase, 5.2 minutes; P = .0491), and contrast volume was nonsignificantly increased (mean increase, 15.3 mL; P = .1616) with the dose-reduction platform.CONCLUSIONS:A significant reduction in patient radiation dose is achievable during neurovascular procedures by using dose-reduction technology with a minimal impact on workflow.

The advancement of neurointerventional practice offers increasingly safe and minimally invasive treatment for a variety of neurovascular diseases. In most cases, the benefits of neurointerventional treatment afforded by fluoroscopic image guidance clearly outweigh the associated radiation risks to patients, especially in comparison with invasive surgical alternatives.¹ However, the growing use of diagnostic procedures and complex fluoroscopy-guided interventions² has led to heightened concerns over ionizing radiation exposure to patients and staff.^3,4To address these concerns, a new commercially available angiographic imaging platform has been developed.⁵ Its dose-reduction strategy applies to digital fluoroscopy and digital subtraction angiography, which accounts for approximately 70%–80% of the total patient radiation dose in vascular angiographic procedures.^6,7 At the core of the system is an image postprocessing chain intended to yield diagnostic-quality DSA images at a lower radiation dose to the patient.⁷ Key features of this image-processing chain are multiscale implementations of real-time motion correction, image contrast-dependent temporal averaging, and image noise reduction.⁷ Lower dose acquisitions further allow the use of a smaller focal spot size, reducing magnification-dependent focal spot blur.⁷ Additional hardware optimization includes the use of Cu beam filtration, depending on x-ray tube loading and a narrower x-ray pulse width.⁸ Herein, these noise reduction algorithms and optimized exposure settings⁷ will be collectively referred to as “dose-reduction technology,” which is implemented on the dose-reduction x-ray imaging platform (IP_DRT).Procedural dose reductions and the noninferiority of image quality by using IP_DRT have been described for iliac^9,10 and coronary angiography in adults^8,11–13 and in children.¹³ For neuroangiographic procedures, a randomized, blinded review of consecutive DSA runs with dose-reduction technology targeting one-fourth of the standard radiation dose showed the ability to maintain diagnostic image quality.⁷ A larger European study in 614 patients provided further evidence of significant reductions in total dose-area products of 62% and 65% for diagnostic and interventional procedures, respectively, while not significantly affecting fluoroscopy time, procedure duration, and the number of acquired images.⁵A unique aspect of this study was that the neurointerventional radiologist with the dose-reduction platform had the flexibility to select, per case and per acquisition, a targeted dose reduction of 0%, 50%, or 75% as preferred, rather than using a protocol with a prespecified dose-reduction target.⁵ This paradigm was investigated so that any equivocal image finding may be better visualized at different settings. Our study investigated the dose-reduction achieved in cumulative dose (kerma)-area product (CP_KA) by using such a flexible protocol for common interventional treatments and diagnostic examinations based on a retrospective review of all such procedures during a 2-year period in a North American academic practice. In addition, a key feature of this study that distinguishes it from prior studies was the inclusion of the neurointerventional radiologist (operator) and patient-specific factors as covariates in the statistical analyses.     

Anterior T-Wave Inversion in Young White Athletes and Nonathletes: Prevalence and Significance

Background

Anterior T-wave inversion (ATWI) on electrocardiography (ECG) in young white adults raises the possibility of cardiomyopathy, specifically arrhythmogenic right ventricular cardiomyopathy (ARVC). Whereas the 2010 European consensus recommendations for ECG interpretation in young athletes state that ATWI beyond lead V₁ warrants further investigation, the prevalence and significance of ATWI have never been reported in a large population of asymptomatic whites.

Design, synthesis and characterization of some bioactive conjugates of curcumin with glycine, glutamic acid, valine and demethylenated piperic acid and study of their antimicrobial and antiproliferative properties

The monoesters of curcumin, a symmetric diphenol with valine and glycine have been prepared by a novel solid phase synthesis and its diesters with valine, glutamic acid and demethylenated piperic acid have been prepared by solution phase method. The assessment of their antimicrobial and anticancer (antiproliferative) activities suggested that diesters of curcumin are relatively more active than curcumin itself due to their increased solubility, slow metabolism and better cellular uptake. Furthermore, significant observation was that monoesters of curcumin have even better antimicrobial activity than their corresponding diesters, emphasizing the role of free phenolic group. The conjugate of curcumin with demethylenated piperic acid in which methylenedioxy ring was open also shows enhanced activity than the corresponding piperic acid conjugate, emphasizing the role of free phenolics in the transport or in the binding processes.     

Evaluation of miR-711 as Novel Biomarker in Prostate Cancer Progression

Objective: MicroRNAs (miRs) are class of small non-coding regulatory RNA aberrantly expressed in various types of malignancies including prostate cancer and serves as potential targets to develop new diagnostic and therapeutic strategies. In this quiet we investigated miRNAs expression profile in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissue samples and correlated their expression with clinicopathological parameters. Methodology: The miRNAs expression profile as well as their validation has been done by using Microarray and RT-PCR, respectively. Additionally, we also tried to speculate microRNA-mRNA regulatory module through computational target predictions by using Targetscan, Miranda and MirWalk and obtained results were analysed through DAVID software. Result: We observed that miR-711 is significantly deregulated in BPH and PCa, compared to controls. The lower expression of miR-711 was found to be significantly associated with high Gleason score and metastatic disease. Furthermore, the computational target prediction analysis explored miR-711 association to various cancer cells signalling cascade key molecules associated with cancer cell survival.Conclusion: From our observations we suggest that miR-711 may play a critical role in PCa progression, regulation of various cancer cell survival signalling cascades and that it may be a valuable biomarker for prediction of metastatic disease and poor prognosis in PCa.     

Neurotic manifestations in adolescents with thalassemia major

Objective To study the neurotic manifestations in thalassemic adolescents as a consequence of long-term illness. Methods From July 2003, thirty six thalassemic adolescents and forty normal adolescents were selected with age ranging from 13 to 18, and with same socio economic status and family, background. Middlesex Hospital Questionnaire by Crown and Crisp [1996] was administered and Mann Whiteny ‘U’ test was employed to measure free-floating anxiety, phobia, somatic anxiety, obsession, depression, hysteria and total neuroticism score. An interview was conducted along with the questionnaire to detect the problems in depth. Parents of thalassemic adolescents were interviewed subsequently to realize the behavioral problems existing along with neuroticism. Results Thirty-six of thalassemic and all forty normal adolescents returned the questionnaires. The responses suggest a marked difference in total neuroticism score and all other variables except that of hysteria. The interview on parents of thalassemic adolescents exposed various behavioral problems in these adolescents. Conclusions Thalassemic adolescents were having higher scores in neuroticism. Some behavioral problems are also found to exist along with neurotic manifestations. There remains a need, to improve the management of thalassemia in terms of psychological aspects in order to improve the mental health of this group.