Clinicoradiological Profile of Cerebral Venous Sinus Thrombosis with Prognostic Evaluation Using MR Sequences.

Acute Stroke Is One Of The Major Cause Of Morbidity And Mortality. It Can Be Arterial Or Venous In Origin. Venous Infarction, Compared To Arterial Stroke, Is Less Common, Potentially Treatable And So Has A Good Prognosis. Cerebral Venous Thrombosis Is Not An Uncommon Disease. The Presenting Signs And Symptoms Of Cerebral Venous Sinus Thrombosis Is So Vague And Diverse That It Is Referred To As `The Great Masquerador Of Diseases'. Without CT Or MRI Many Cases Would Be Missed Since The Clinician Is Unsuspected Of This Disease. With The Widespread Availability Of CT And MRI, And The Awareness Of This Pathology Among General Physicians And Obstetricians, The Rate Of Diagnosis Of This Disease Has Increased Manifold During The Last Two Decades. Many A Times Cerebral Venous Thrombosis Is Unsuspected By The Treating Clinician That The Disease Is First Diagnosed By The Radiologists. It Is Important On The Part Of The Radiologist To Promptly Diagnose Cerebral Venous Thrombosis Since With Early Treatment The Pathology Is Almost Completely Reversible And So Has A Very Good Prognosis. Catheter Angiography Is The Gold Standard For Diagnosing Venous Thrombosis. But The Preferred Modalities Are CT And MRI Since They Are Noninvasive, Cheap And With Little Risk To The Patient. Conventional CT, With And Without Contrast, Is A Good First Investigation For Patients With Any CNS Signs And Symptoms. More Than 80% Of Cerebral Venous Thrombosis Can Be Diagnosed With This. It Is Also Useful In Ruling Out Intracranial Tumors And Infections. MRI And MRV Are More Sensitive Than CT In Diagnosing Cerebral Venous Thrombosis. It Can Also Map The Extent Of Thrombosis And Parenchymal Lesions. With Certain Criteria MRI Can Also Give A Prognostic Valuation Of The Disease

Chandrayaan-3 Alternate Landing Site: Pre-Landing Characterisation

India's third Moon mission Chandrayaan 3 will deploy a lander and a rover at a high latitude location of the Moon enabling us to carry out first ever in-situ science investigations of such a pristine location that will potentially improve our understanding on primary crust formation and subsequent modification processes. The primary landing site (PLS), is situated at 69.367621 degS, 32.348126 degE. As a contingency, an alternate landing site (ALS) was also selected at nearly the same latitude but nearly 450 km west to PLS. In this work, a detailed study of the geomorphology, composition, and temperature characteristics of ALS has been carried out using the best-ever high resolution Chandrayaan 2 OHRC DEMs and Ortho images, datasets obtained from Chandrayaan 1 and on-going Lunar Reconnaissance Orbiter. For understanding the thermophysical behaviour, we used a well-established thermophysical model. We found that the Chandrayaan 3 ALS is characterised by a smooth topography with an elevated central part. The ALS is a scientifically interesting site with a high possibility of sampling ejecta materials from Tycho and Moretus. Based on the spectral and elemental analysis of the site, Fe is found to be near approx. 4.8 wt.%, with Mg approx. 5 wt.%, and Ca approx. 11 wt.%. Compositionally, ALS is similar to PLS with a highland soil composition. Spatial and diurnal variability of around 40 K and 175 K has been observed in the surface temperatures at ALS. Although belonging to similar location like PLS, ALS showed reduced daytime temperatures and enhanced night-time temperatures compared to PLS, indicating a terrain of distinctive thermophysical characteristics. Like PLS, ALS is also seems to be an interesting site for science investigations and Chandrayaan 3 is expected to provide new insights into the understanding of lunar science even if it happens to land in the alternate landing site.Comment: 13 pages, 7 figure

Pharmacokinetic profile of a 24-hour controlled-release OROS(® )formulation of hydromorphone in the presence and absence of food

BACKGROUND: The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS(® )hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated. METHODS: In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS(® )hydromorphone under fasting conditions, 16 mg OROS(® )hydromorphone under fed conditions, or 16 mg OROS(® )hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%. RESULTS: The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC(0-t); AUC(0-∞)) were within 20%. Confidence intervals were within 80% to 125% for AUC(0-t )and AUC(0-∞ )but were slightly higher for C(max )(105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone C(max )increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in T(max), AUC(0-t )or AUC(0-∞). CONCLUSION: Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS(® )hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption. TRIAL REGISTRATION: Clinical Trials.gov NCT0039929

The Androgen Receptor Does Not Directly Regulate the Transcription of DNA Damage Response Genes

UNLABELLED: The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in prostate cancer cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at a steady state in asynchronously growing prostate cancer cells. IMPLICATIONS: Our data indicate that the clinical benefit of combining ADT with RT is not due to direct AR regulation of DDR gene transcription, and that the field needs to consider alternative mechanisms for this clinical benefit

An open-label, 1-year extension study of the long-term safety and efficacy of once-daily OROS® hydromorphone in patients with chronic cancer pain

<p>Abstract</p> <p>Background</p> <p>Opioid analgesics have proven efficacy in the short-term management of chronic cancer pain, but data on their long-term use is more limited. OROS^®hydromorphone is a controlled-release formulation of oral hydromorphone that may be particularly well suited to long-term management of chronic cancer pain because it provides stable plasma concentrations and consistent analgesia with convenient once-daily dosing. The objective of this study (DO-118X) was to characterise the pain control achieved with long-term repeated dosing of OROS^®hydromorphone in patients with chronic cancer pain.</p> <p>Methods</p> <p>In this multicentre, phase III, open-label, single treatment, 1-year extension study, OROS^®hydromorphone was administered to 68 patients with moderate-to-severe chronic cancer pain, who had successfully completed a short-term equivalence study, and whose pain was controlled with a stable dose of medication (≥ 8 mg OROS^®hydromorphone or equivalent controlled-release morphine). Patients were started on the dose of OROS^®hydromorphone equivalent to the opioid dose on which they achieved dose-stable pain control in the equivalence study; dose adjustments were made as necessary and breakthrough pain medication was permitted. Efficacy was assessed with the Brief Pain Inventory (BPI) and patient and investigator global evaluations of treatment effectiveness. No formal statistical analysis was done.</p> <p>Results</p> <p>The mean (standard deviation) duration of exposure to study medication was 139 (129.9) days and the mean (standard deviation) average daily consumption of OROS^®hydromorphone was 43.7 (28.14) mg/day. All scores were maintained at a mild to moderate severity throughout the study; however, BPI scores for pain at its worst, pain at its least, pain on average, pain right now, and pain relief were slightly worsened at end point compared with baseline. Mean BPI pain interference with daily activities and patient and investigator global evaluation scores also remained generally stable. Treatment effectiveness was rated as fair to good throughout the study. The most frequently reported adverse events were nausea (n = 24, 35.3%), constipation (n = 22, 32.4%), and vomiting (n = 15, 22.1%).</p> <p>Conclusion</p> <p>The results of this extension study suggest that long-term repeated dosing with once-daily OROS^®hydromorphone can be beneficial in the continuing management of persistent, moderate-to-severe cancer pain.</p

A randomized, double-blind comparison of OROS® hydromorphone and controlled-release morphine for the control of chronic cancer pain

<p>Abstract</p> <p>Background</p> <p>Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS^®hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations. The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain.</p> <p>Methods</p> <p>200 patients with cancer pain (requiring ≤ 540 mg/d of oral morphine) participated in this double-blind, parallel-group trial. Patients were randomized to receive hydromorphone or morphine (immediate-release for 2–9 days, sustained-release for 10–15 days). Efficacy was assessed with the Brief Pain Inventory (BPI), investigator and patient global evaluations, Eastern Cooperative Oncology Group performance status, and the Mini-Mental State Examination. The primary endpoint was the 'worst pain in the past 24 hours' item of the BPI, in both the immediate-release and sustained-release study phases, with treatments deemed equivalent if the 95% confidence intervals (CI) of the between-group differences at endpoint were between -1.5 and 1.5. No equivalence limits were defined for secondary endpoints.</p> <p>Results</p> <p>Least-squares mean differences (95% CI) between groups were 0.2 (-0.4, 0.9) in the immediate-release phase and -0.8 (-1.6, -0.01) in the sustained-release phase (intent-to-treat population), indicating that the immediate-release formulations met the pre-specified equivalence criteria, but that the lower limit of the 95% CI (-1.6) was outside the boundary (-1.5) for the sustained-release formulations. BPI 'pain now PM' was significantly lower with OROS^®hydromorphone compared with controlled-release morphine (least-squares mean difference [95% CI], -0.77 [-1.49, -0.05]; <it>p </it>= 0.0372). Scores for other secondary efficacy variables were similar between the two sustained-release treatments. At endpoint, > 70% of investigators and patients rated both treatments as good to excellent. The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics.</p> <p>Conclusion</p> <p>Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROS^®hydromorphone and controlled-release morphine. The direction of the mean difference between the treatments (-0.8) and the out-of-range lower limit of the 95% CI (-1.6) were in favor of OROS^®hydromorphone.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: NCT0041054</p

A novel mechanical cleavage method for synthesizing few-layer graphenes

A novel method to synthesize few layer graphene from bulk graphite by mechanical cleavage is presented here. The method involves the use of an ultrasharp single crystal diamond wedge to cleave a highly ordered pyrolytic graphite sample to generate the graphene layers. Cleaving is aided by the use of ultrasonic oscillations along the wedge. Characterization of the obtained layers shows that the process is able to synthesize graphene layers with an area of a few micrometers. Application of oscillation enhances the quality of the layers produced with the layers having a reduced crystallite size as determined from the Raman spectrum. Interesting edge structures are observed that needs further investigation

The Mitochondrial Genome Is a “Genetic Sanctuary” during the Oncogenic Process

Since Otto Warburg linked mitochondrial physiology and oncogenesis in the 1930s, a number of studies have focused on the analysis of the genetic basis for the presence of aerobic glycolysis in cancer cells. However, little or no evidence exists today to indicate that mtDNA mutations are directly responsible for the initiation of tumor onset. Based on a model of gliomagenesis in the mouse, we aimed to explore whether or not mtDNA mutations are associated with the initiation of tumor formation, maintenance and aggressiveness. We reproduced the different molecular events that lead from tumor initiation to progression in the mouse glioma. In human gliomas, most of the genetic alterations that have been previously identified result in the aberrant activation of different signaling pathways and deregulation of the cell cycle. Our data indicates that mitochondrial dysfunction is associated with reactive oxygen species (ROS) generation, leading to increased nuclear DNA (nDNA) mutagenesis, but maintaining the integrity of the mitochondrial genome. In addition, mutational stability has been observed in entire mtDNA of human gliomas; this is in full agreement with the results obtained in the cancer mouse model. We use this model as a paradigm of oncogenic transformation due to the fact that mutations commonly found in gliomas appear to be the most common molecular alterations leading to tumor development in most types of human cancer. Our results indicate that the mtDNA genome is kept by the cell as a “genetic sanctuary” during tumor development in the mouse and humans. This is compatible with the hypothesis that the mtDNA molecule plays an essential role in the control of the cellular adaptive survival response to tumor-induced oxidative stress. The integrity of mtDNA seems to be a necessary element for responding to the increased ROS production associated with the oncogenic process