Experience with direct acting anti-viral agents for treating hepatitis C virus infection in renal transplant recipients

In recent past, direct-acting anti-viral drugs (DAAs) have become the standard of care for the treatment of hepatitis C virus (HCV) infection. However, the experience with the use of these drugs in Indian renal transplant recipients is limited. We retrospectively reviewed our experience with DAA-based treatment for HCV infection in such patients. Between April 2015 and December 2016, six adults (median age 41 [range 34–52] years, male 5; GT1 2, GT3 3, and GT4 1; including three with prior failed interferon-based treatment) had received genotype-guided, DAA-based anti-HCV treatment 1 to 158 (median 15) months after renal transplantation. Of them, four completed the planned 24-week treatment without any significant adverse event. One of them had increase in serum creatinine after 16 weeks of treatment with sofosbuvir and daclatasvir, with acute interstitial nephritis on kidney biopsy; his renal function improved on stopping the drugs. The other patient had preexisting mild renal dysfunction, which worsened after 8 weeks of sofosbuvir-ledipasvir treatment; this did not reverse on stopping treatment. All the six patients achieved undetectable HCV RNA after 4 weeks of treatment and also achieved sustained virologic response, i.e. lack of detectable HCV RNA in serum 12 weeks after stopping treatment. Overall, DAA-based treatment was effective in treating HCV infection in our renal transplant recipients; however, caution and monitoring of renal function during such treatment is advisable in patients who have additional factors that predispose to renal injury.     

Evaluation of beta defensin 2 production by chicken heterophils using direct MALDI mass spectrometry

Beta defensins (BD) are cysteine rich, cationic antimicrobial peptides (AMP) produced mainly by epithelial and myeloid cells such as neutrophils. In birds, the neutrophil equivalent heterophils produce avian beta defensins (AvBD) of which AvBD2 is the major isoform. Heterophils recognize pathogens or their derived products through a series of pattern recognition receptors called toll-like receptors (TLR) leading to their antimicrobial activities. This work is the first report of TLR modulation of AvBD2 expression in chickens. To measure the effect of TLR activation on AvBD2 production, the heterophils were cultured with different TLR agonists for 6 h. Modulation of AvBD2 levels by TLR activation was measured using direct MALDI mass spectrometry without stable isotopic labeling or chromatographic separation. Chemical modification of the conditioned media was performed using reduction/alkylation with dithiothreitol/iodoacetamide to distinguish TLR treated AvBD2 (reduced/alkylated) from controls (non-reduced). Changes in corrected ion intensity ratios were assumed to reflect AvBD2 modulation in heterophils upon activation with different TLR agonists. In general, TLR agonists increased AvBD2 production with LPS showing the greatest induction and CpG-ODN showing little or no effect. These data show that the direct MALDI-MS coupled with reduction/alkylation may provide a rapid relative quantitative approach to the measurement of agonist-induced differential expression of AvBD2.     

Early heparinization decreases the incidence of left atrial thrombi detected by intracardiac echocardiography during radiofrequency ablation for atrial fibrillation

INTRODUCTION: We reviewed our experience in managing intracardiac ultrasound-detected left atrial thrombus and analyzed the impact of the timing of heparin therapy on thrombus incidence. METHODS AND RESULTS: We identified 508 patients undergoing ablation procedures for atrial fibrillation in which intracardiac ultrasound was used. All patients received unfractionated heparin during the procedure: 31 patients before the first transseptal puncture (preTS1), 257 between the first and second transseptal punctures (TS1-TS2), and 220 following both punctures (postTS2). By using intracardiac echocardiography (ICE), thrombus was detected in 30 of these 508 patients (5.9%). Of these, 29 were in the left atrium and constituted our study group. In 21 patients, the thrombi were successfully aspirated from the left atrium using strong suction through the transseptal sheath. All patients in whom thrombi were aspirated did well without neurological event or death. When patients received heparin therapy either preTS1 or TS1-TS2, there was a significant decrease in the occurrence of ICE-detected left atrial thrombus compared with those who received heparin postTS2 (0 of 31 patients (0%) preTS, 9 of 257 (3.5%) TS1-TS2, and 20 of 220 (9.1%) postTS2; (preTS1 vs postTS2, p = 0.01; preTS2 [preTS1 and TS1-TS2] vs postTS2, p < 0.001). CONCLUSION: Early administration of intravenous heparin, specifically before transseptal puncture, decreases the incidence of left atrial thrombi.     

Sensory evoked potentials in SIV-infected monkeys with rapidly and slowly progressing disease

Human immunodeficiency virus (HIV-1) infects the central nervous system (CNS) early in the course of disease progression and leads to some form of neurological disease in 40-60% of cases. Both symptomatic and asymptomatic HIV-infected subjects also show abnormalities in evoked potentials. As part of an effort to further validate an animal model of the neurological disease associated with lentiviral infection, we recorded multimodal sensory evoked potentials (EPs) from nine rhesus macaques infected with passaged strains of SIVmac (R71/E17), prior to and at 1 month intervals following inoculation. The latencies of forelimb and hindlimb somatosensory evoked potentials (SEP) and flash visual evoked potentials (VEP) were measured. Within 14 weeks of inoculation, all but two animals had progressed to end-stage disease (rapid progressors). The two animals with slowly progressing disease (AQ15 and AQ94) had postinoculation life spans of 109 and 87 weeks, respectively. No significant changes were observed in evoked potentials recorded during the control period or at any time in the animals with slowly progressing disease. However, all of the monkeys with rapidly progressing disease exhibited increases in latency for at least one evoked potential type. The overall mean increases in somatosensory and visual evoked potential peak latencies for the rapid progressors were 22.4 and 25.3%, respectively. For comparison, the changes in slow progressors were not significant (1.8 and -1.9%, respectively). These results, coupled with our previous finding of slowed motor evoked potentials in the same cohort of macaques (Raymond et al.: J Neurovirol 1999;5:217-231), demonstrate a broad and somewhat variable pattern of viral injury to both sensory and motor system structures, resembling the findings in HIV-infected humans. These results coupled with our earlier work demonstrating cognitive and motor behavioral impairments in the same monkeys support the use of the SIVmac-infected rhesus macaque as a model of AIDS-related neurological disease.     

Fecal Steroid 21-Dehydroxylase, a Potential Marker for Colorectal Cancer

Eubacterium lentum and phenotypically similar organisms synthesize a steroid 21-dehydroxylase which converts biliary tetrahydrodeoxycorticosterone to pregnanolone. Tetrahydrodeoxycorticosterone, in contrast to pregnanolone, is carcinogenic for hamster embryonic cells (HECT test). In patients with recently diagnosed, untreated sigmoidal or rectal cancer the fecal concentration of 21-dehydroxylating organisms is reduced by more than 99% as compared with age-matched controls. The lack of fecal 21-dehydroxylating organisms, therefore, is a potential marker for the disorder. The role of steroid 21-dehydroxylase in the pathogenesis of colorectal cancer is unknown.     

Establishment of a Maternal Newborn Health Registry in the Belgaum District of Karnataka,India

Background

Pregnancy-related vital registration is important to inform policy to reduce maternal, fetal and newborn mortality, yet few systems for capturing accurate data are available in low-middle income countries where the majority of the mortality occurs. Furthermore, methods to effectively implement high-quality registration systems have not been described. The goal of creating the registry described in this paper was to inform public health policy makers about pregnancy outcomes in our district so that appropriate interventions to improve these outcomes could be undertaken and to position the district to be a leader in pregnancy-related public health research.

Methods

We created a prospective maternal and newborn health registry in Belgaum, Karnataka State, India. To initiate this registry, we worked with the Ministry of Health to first establish estimated birth rates and define the catchment areas of the clusters, working within the existing health system and primary health centers. We also undertook household surveys to identify women likely to become pregnant. We then implemented monitoring measures to ensure high quality and completeness of the maternal newborn health registry. All pregnant women in the catchment area were identified, consented and enrolled during pregnancy, with follow-up visits to ascertain pregnancy outcomes and mother/infant status at 42-days postpartum.

Results

From 2008 through 2014, we demonstrated continued improvements in both the coverage for enrollment and accuracy of reporting pregnancy outcomes within the defined catchment area in Belgaum, India. Nearly 100% of women enrolled had follow-up at birth and 99% had 42-day follow-up. Furthermore, we facilitated earlier enrollment of women during pregnancy while achieving more timely follow-up and decreased time of reporting from the date of the pregnancy event.

Conclusions

We created a pregnancy-related registry which includes demographic data, risk factors, and outcomes allowing for high rates of ascertainment and follow-up while working within the existing health system. Understanding the elements of the system used to create the registry is important to improve the quality of the results. Tracking of pregnancies and their outcomes is an important step toward reducing maternal and perinatal mortality.