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.     

Ischemic Stroke in the Setting of Tuberculous Meningitis

The clinical syndrome of tuberculous (TB) meningitis leading to ischemic strokes is rarely seen today in immunocompetent adults native to North America. This entity is also notoriously difficult to diagnose because the presenting symptoms are often nonspecific. The authors describe a case of a man with TB meningitis which progressed to recurrent ischemic cerebral infarcts.     

Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.     

Delayed Reduction of Irreducible Chronic Posterolateral Dislocation of the Knee with Buttonholing of the Medial Femoral Condyle

Abstract Traumatic knee dislocations are relatively rare and almost always respond to closed reduction; however, a small percentage of knee dislocations are irreducible and in these cases open reduction is frequently required. A 65-year-old man with an unreduced posterolateral knee dislocation with laterally dislocated patella was seen 3 weeks after a motor vehicle accident. Medial femoral condyle was found buttonholed through the medial capsule together with the medial collateral ligament and lying in the medial joint space that allowed posterior rotary dislocation of the joint. Both cruciate ligaments and medial meniscus were torn. There was no evidence of any vascular or nerve injury. Reduction was accomplished by removal of the capsuloligamentous structures which were incarcerated in the trochlea and intercondylar notch and by excision of meniscal tear. Following posterior cruciate ligament reconstruction with patellar tendon autograft, lateral patellar release, vastus medialis advancement, and gracilis transfer were done.     

Ofloxacin plus Rifampicin versus Doxycycline plus Rifampicin in the treatment of brucellosis: a randomized clinical trial [ISRCTN11871179]

Background  

The combination therapies recommended by the World Health Organization for treatment of brucellosis are doxycycline plus rifampicin or doxycycline plus streptomycin. Although highly successful results have been obtained with these two regimens, relapse rates as high as 14.4%. The most effective and the least toxic chemotherapy for human brucellosis is still undetermined. The aim of the present study was to investigate the efficacy, adverse effects and cost of ofloxacin plus rifampicin therapy, and doxycycline plus rifampicin therapy and evaluate in the treatment of brucellosis.     

Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with parkinson's disease

This study investigated whether domperidone could improve gastrointestinal symptoms in patients with Parkinson's disease who were receiving levodopa therapy. A total of 11 patients were studied. Following a baseline gastric emptying test, patients were treated with a starting dose of domperidone 20 mg p.o. q.i.d. A follow-up gastric emptying test was repeated at least 4 months after starting domperidone therapy. At the beginning and at each 3-month follow-up visit, symptoms of nausea, vomiting, anorexia, abdominal bloating, heartburn, regurgitation, dysphagia, and constipation were evaluated and scored on a scale of 0–3. The overall mean follow-up period was 3 years. Compared with their baseline evaluation, patients experienced a significant improvement in all symptoms (p < 0.05) except dysphagia and constipation. Gastric emptying of an isotope-labeled solid meal was significantly faster, with a baseline result of 60.2 ± 6.4% retention of isotope 2 h after the meal compared with 37.0 ± 2.2% retention during domperidone therapy (p < 0.05). Patients' global assessment of Parkinson's disease remained stable or improved. Serum prolactin was elevated in all patients after domperidone therapy (p < 0.05). Domperidone therapy significantly reduces upper gastrointestinal symptoms and accelerates gastric emptying of a solid meal, but does not interfere with response to antiparkinsonism treatment.     

Multiple primary malignant neoplasms in urologic patients

Methods: Second primary cancers constitute approximately 9–10% of malignancies diagnosed in the United States. We aimed to show the risk and incidance of second primary tumor occuring associated to urologic tumors and show the distrubution of tumors in Tracia region. We retrospectively examined the patients' files with the diagnosis of malignant disease between the years 1985–2000. Hazard function analysis was performed to estimate the relative risk of secondary malignancy occuring. Age, sex and tumor number were examined to find out if they affect on mortality rate. Results: A total number of 25 MPMNs were diagnosed. In 52 percent of the cases the second primary neoplasm developed within six months. The relative risk of development of a second neoplasm is found as increasing 1.111 times per month. The incidence of secondary malignancy occuring in the patients with one tumor was found as 6.31%. Age (p < 0.001) and tumor number (p < 0.001) are found as statistically effective predictor on mortality rate where the sex is not. Conclusions: In the patients with a primary tumor not only the metastasis must be investigated but also second primary tumors should be taken in to consideration. This revised version was published online in August 2006 with corrections to the Cover Date.     

Effect of tissue inhomogeneity on beta dose distribution of 32P

In a homogeneous medium of soft tissue the radiation dose distribution due to a nonuniformly distributed beta source can be calculated by convolution of the beta dose point kernel of the nuclide with the source distribution. A possible extension of the technique to the calculation of the dose distribution in heterogeneous media involving relatively simple geometric interfaces requires the knowledge of the resulting perturbation to the beta point kernels in individual media. We simulated a soft-tissue-bone planar interface by a polystyrene (PST)-aluminum junction and measured the change in beta dose from the dose value in homogeneous PST due to a point source of 32P using 7LiF thermoluminescent dosimeters. With the point source at the interface, the dose rates at 0-31, 125-156, and 283-314 mg/cm2 separations from the interface were increased by (12 +/- 3)%, (8 +/- 2)%, and (3 +/- 2)%, respectively, compared with homogeneous PST. With the point source at a PST-air planar interface to simulate a soft-tissue-air junction, the dose rates at 0-31, 139-170, and 283-314 mg/cm2 from the interface were decreased by (25 +/- 4)%, (11 +/- 7)%, and (5 +/- 2)%, respectively. The changes in dose rates for these two interfaces have also been measured with degraded spectra of 32P. Comparison of the experimental data with Monte Carlo calculation for a point source and the two-group method of calculation for a plane source is also presented.     

Behavioural strategies used by the hookworms Necator americanus and Ancylostoma duodenale to find, recognize and invade the human host

The infective third-stage larvae of the hookworms Necator americanus and Ancylostoma duodenale infect their human hosts by active skin invasion, but A. duodenale is in addition capable of oral infection. The behaviour of the larvae when crawling on surfaces has already been described. Here we analyse in various in vitro systems the other behavioural invasion phases: activation, penetration, and orientation within the host. The larvae normally remained in a motionless, energy-saving, resting posture. An activation to sinusoidal locomotion was stimulated in both species by similar cues such as touch, vibration, water currents, heat, light, and chemicals. Human breath in addition stimulated searching and waving (nictating) behaviour, which facilitates a change-over to the host. Activating cues in air streams were warmth and moisture; CO₂ activated only in combination with warmth and/or moisture. Penetration behaviour in both species was stimulated by warmth and skin extracts. The stimulating components of skin extracts were fatty acids, but their stimulating characteristics differed from those inducing schistosome cercarial skin penetration. After penetration into agar substrates, both species showed thermo-orientation, but only A. duodenale followed gradients of serum. The directing serum cues were not amino acids and glucose (the supposed cues for schistosome blood vessel localization), but Ringers solution attracted the larvae. The host-finding and host-invasion behaviour of both hookworm species is well adapted to the invasion of the human skin, and there seems to be no particular adaptation of A. duodenale behaviour to the oral infection mode. Hookworm host-finding behaviour is not as complex as that of schistosome cercariae but seems well adapted to the ecological conditions in the transmission sites.