Expression of TRIM22 mRNA in chronic hepatitis C patients treated with direct-acting antiviral drugs

Hepatitis C is a global public health problem, and Pakistan is the second largest country in the globe with highest prevalence rate of hepatitis C virus (HCV). Until 2014, pegylated interferon (PEG-IFN) plus ribavirin (RBV) has been the standard therapy for HCV, however, owing to its adverse side effects and very low sustained virologic response (SVR) rates therapeutics trend is shifted toward direct-acting antivirals. Tripartite motif containing 22 (TRIM22) is a dynamic antiviral protein that can inhibit multiple viruses in vivo. Expression of TRIM22 mRNA has been linked to outcome of PEG-IFN and ribavirin therapy, where its higher expression leads to rapid virus clearance. However, in terms of therapy with direct-acting antiviral (DAA) or double DAA, impact of TRIM22 expression is largely unknown. These new drugs show more than 90% of SVR rates and lesser side effects and have proven to be better than IFN therapy. Endogenous IFN system suppresses various pathogens through the induction of antiviral effectors termed as interferon-stimulating genes (ISGs). We have studied the expression levels of one of these antiviral effectors, TRIM22 in response to sofosbuvir (SOF) and daclatasvir (DAC) in combination with RBV, using quantitative PCR in the peripheral blood mononuclear cells (PBMCs) of HCV-infected patients. We have observed sustained virus clearance in more than 90% of patients treated with DAA and double DAA and have seen the expression of TRIM22 to be higher in patients who attained SVR as compared to the untreated patients. We have also observed downregulation of TRIM22 in patients who failed to attain rapid virus clearance, and upregulation in those who achieved rapid clearance of virus. Genetic factors that determine the lower TRIM22 expression in these patients are needed to be explored that may also play a role in lower response to anti-HCV therapy. Endogenous IFN system and effects of antiviral proteins in response to DAA therapy is needed to be studied in order to better understand the host response toward these drugs to make them more effective.     

Nitrate administration increases blood flow in dysfunctional but viable myocardium, leading to improved assessment of myocardial viability: A PET study.

SPECT with 99mTc-labeled agents is better able to detect viability after nitrate administration. Nitrates induce vasodilation and may increase blood flow to severely hypoperfused but viable myocardium, thereby enhancing tracer delivery and improving the detection of viability. Quantitative data on the changes in blood flow are lacking in SPECT but can be provided by PET. The aim of the present study was to use PET to evaluate whether nitrate administration increases blood flow to chronically dysfunctional but viable myocardium. METHODS: 13N-Ammonia PET was used to quantitatively assess blood flow, and 18F-FDG PET was used as the gold standard to detect viable myocardium. Twenty-five patients with chronic ischemic left ventricular dysfunction underwent 13N-ammonia PET at rest and after nitrate administration. RESULTS: A significant increase in nitrate-enhanced blood flow was observed in viable segments (from 0.55 +/- 0.15 to 0.68 +/- 0.24 mL/min/g, P < 0.05). No statistically significant change in blood flow was observed in nonviable segments (0.60 +/- 0.20 vs. 0.55 +/- 0.18 mL/min/g). A ratio of at least 1.1 for nitrate-enhanced flow to resting flow allowed optimal detection of viable myocardium, yielding a sensitivity of 82% with a specificity of 100%. CONCLUSION: 13N-Ammonia PET showed a significant increase in nitrate-enhanced blood flow in viable myocardium, whereas blood flow remained unchanged after nitrate administration in nonviable myocardium. Nitrate use during myocardial perfusion imaging will lead to improved assessment of myocardial viability.     

Vagal nerve stimulator implantation: an otolaryngologist's perspective.

OBJECTIVE: This study was conducted to compare an otolaryngologist's experience with a cohort of epilepsy patients implanted with a vagal nerve stimulator (VNS) to previously published data. METHODS: Demographics, preoperative seizure frequency, medications, and complications were retrospectively collected from patients implanted by the senior author. Postoperative medications and seizure frequency were obtained from referring neurologists. RESULTS: Seventeen patients were implanted over a 24-month period. Average age was 28.3 years. Patients presented with petit mal (n = 3), tonic-clonic (n = 6), complex partial (n = 5), and grand mal (n = 8) seizures. Mean follow-up postimplantation was 13.5 months. Most patients had at least a 50% reduction of seizure frequency, with 3 patients being seizure free. There were no postoperative infections. One patient had left vocal cord immobility. The most common side effect was voice disturbance during device activation. CONCLUSION: Otolaryngologists are well equipped to perform VNS implantation and to diagnose and treat possible laryngeal side effects. EBM rating: C-4.     

Load-induced proteoglycan orientation in bone tissuein vivo andin vitro

Summary Previous studies of Alcian blue-induced birefringence in adult avian cortical bone showed that a short period of intermittent loading rapidly produces an increased level of orientation of proteoglycans within the bone tissue. In the absence of further loading, this persists for over 24 hours. We have proposed that this phenomenon could provide a means for “capturing” the effects of transient strains, and so provide a persistent, constantly updated strain-related influence on osteocyte populations related to the bones' averaged recent strain history, in effect, a “strain memory” in bone tissue. In our present study, we use the Alcian blue-induced birefringence technique to demonstrate that proteoglycan orientation also occurs after intermittent loading of both cortical and cancellous mammalian bonein vivo andin vitro. We also show that the change in birefringence is proportional to the magnitude of the applied strain, and that the reorientation occurs rapidly, reaching a maximal value after only 50 loading cycles. Examination of electron micrographs of bone tissue after staining with cupromeronic blue allows direct visualization and quantification of the change in proteoglycan orientation produced by loading. This shows that intermittent loading is associated with a realignment of the proteoglycan protein cores, bringing them some 5 degrees closer to the direction of collagen fibrils in the bone matrix.     

Effect of euphylline and no-shpa on cerebrovascular resistance and the survivability of animals after cerebral ischemia

In acute experiments on anesthetized cats with total ischemia of the brain (15-minute arrest of blood autoperfusion of the cerebral vessels by a stable blood volume) it was shown that euphylline and no-shpa administered before ischemia or in the early period after ischemia inhibit or prevent the development of the postischemic phenomenon of non-recovery of the cerebral blood flow. The two drugs contributed to survival of albino rats following the brain ischemia produced by ligation of both carotid arteries.     

The cytochromes P-450 concentrations in microsomes of liver, kidney and duodenal mucosa of the camel, sheep and goat

The concentration of microsomal cytochromes P-450, and of protein in the homogenate, cytosol and microsomes were measured in the liver, kidney and duodenal mucosa of healthy well-fed male and female camels, sheep and goats. For comparison, data from the liver of male and female rats were also obtained. The protein concentrations in the tissues of adult animals were broadly similar in the four species. The concentration of cytochromes P-450 was highest in the liver, followed by the kidney, then the duodenal mucosa in all the species. No cytochromes P-450 were detected in the tissues of immature (less than 1 mo) male goats, whereas the female goat had the highest concentrations of these enzymes in the liver and kidney when compared with the respective tissues in the other species studied. Males had higher activity of cytochromes P-450 than females in the three tissues, except in the duodenal mucosa of sheep, where males had lower activity than females. In camel liver and sheep kidney, the amount of cytochromes P-450 were similar in the two sexes. The present results suggest that the mature female goat is the species best equipped to handle xenobiotics which are detoxified by the cytochromes P-450 and other drug metabolizing enzymes in diseased or malnourished animals is suggested as these two conditions are known to modify drug metabolizing enzymes.     

Oxybutynin versus propantheline in patients with multiple sclerosis and detrusor hyperreflexia

Hyperreflexia is the most common urological finding in patients with multiple sclerosis. A prospective randomized study was done to compare the effectiveness of 2 commonly used drugs, oxybutynin and propantheline. Of the 34 patients entered into the trial 19 were treated with oxybutynin and 15 with propantheline. The urological symptoms (frequency, nocturia, hesitancy, urgency and urge incontinence) were graded according to severity from 0 to 3. Patients with urinary infection were excluded. Urodynamic examination, consisting of cystometrography and electromyography, was performed in all patients before treatment. Both groups of patients had comparable neurological, urological and urodynamic status before treatment. In 4 patients (21 per cent) treated with oxybutynin and in 4 (27 per cent) treated with propantheline side effects were so severe that the treatment had to be discontinued. Symptomatic response to oxybutynin was good in 10 patients (67 per cent), fair in 2 (13 per cent) and poor in 3 (20 per cent). Propantheline produced good symptomatic results in 4 patients (36 per cent), fair in 1 (9 per cent) and poor in 6 (55 per cent). The mean increase in maximum cystometric capacity on cystometrography was significantly larger in the oxybutynin group than in the propantheline group (144 +/- 115 versus 35 +/- 101). Our results indicate that oxybutynin is more effective than propantheline in the treatment of detrusor hyperreflexia in patients with multiple sclerosis.