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Failure of antiretroviral therapy (ART) in HIV-1 infection is a critical issue for the physicians treating HIV patients. The major cause of drug failure is the development of resistance mutations in reverse transcriptase (RT) and/or protease (PR) genes. Mutations associated with drug resistance decrease drug effectiveness. This study was conducted to assess drug resistance profile of the entire PR gene in 90 HIV-1 patients consisting of 23 ART non-responsive, 32 ART responsive and 35 drug naive patients. It was observed that the majority of the sequences (94.4%) belonged to subtype C and (5.5%) to subtype A1. The ART non-responsive and responsive patients were treated with either first line of ART regimen (two NRTI and one NNRTI) or second line of ART regimen that included additional one protease inhibitor (PI). All the patients in each group except one responsive patient had various minor resistance mutations. Thus, drug failures in ART non-responsive patients may not always be due to drug resistance mutations instead other factors may also be responsible for drug failures such as non-compliance, suboptimal dose or drug interaction. The presence of minor drug resistance mutations in drug naive patients is suggestive of transmitted resistance mutations.

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INTRODUCTION: Hepatocellular carcinoma is a lethal disease worldwide and therefore the establishment of novel diagnostic biomarkers is imperative. In this study, it was hypothesized that an abnormal expression of the lysosomal-associated protein transmembrane 4 beta ( LAPTM4B) gene is crucial in the pathogenesis of hepatitis C virus-mediated hepatocellular carcinoma; hence we investigated the expression profile of LAPTM4B in hepatitis C virus-induced hepatocellular carcinoma. METHODS: A group of 189 consecutive patients (hepatitis C virus-related hepatocellular carcinoma as tumor cases; n=93, hepatitis C virus-related cirrhotics as disease controls; n=96) opting for living donor liver transplantation as a therapeutic surgical regimen were recruited with informed consent. Additionally, paired adjacent non-tumorous tissues (n=93) obtained from cases were also included. Serum LAPTM4B protein concentrations were assessed by third-generation enzyme-linked immunosorbent assay and LAPTM4B mRNA, and protein expressions at tissue level were determined by quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry techniques, respectively. RESULTS: LAPTM4B protein concentrations in sera of patients were higher ( p<0.001) in tumor cases (1.25±0.25 ng/ml) compared to disease controls (0.53±0.28 ng/ml). Our study also depicts positive clinicopathological correlations between alpha-fetoprotein titers (b=0.65; p<0.001), quantitative hepatitis C virus RNA copies (b=0.33; p<0.001), and LAPTM4B protein concentrations, all in sera of patients. In addition, qRT-PCR and immunohistochemistry analyses revealed a significantly higher ( p<0.05) tissue LAPTM4B mRNA and protein expression, respectively, in tumor cases rather than in non-tumorous tissues and disease controls. CONCLUSIONS: Together, our results illustrate the LAPTM4B gene as a diagnostic biomarker in patients with hepatocellular carcinoma having documented evidence of chronic hepatitis C virus infection.

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Drug resistance mutations in the Pol gene of human immunodeficiency virus 1 (HIV-1) are one of the critical factors associated with antiretroviral therapy (ART) failure in HIV-1 patients. The issue of resistance to reverse transcriptase inhibitors (RTIs) in HIV infection has not been adequately addressed in the Indian subcontinent. We compared HIV-1 reverse transcriptase (RT) gene sequences to identify mutations present in HIV-1 patients who were ART non-responders, ART responders and drug naive. Genotypic drug resistance testing was performed by sequencing a 655-bp region of the RT gene from 102 HIV-1 patients, consisting of 30 ART-non-responding, 35 ART-responding and 37 drug-naive patients. The Stanford HIV Resistance Database (HIVDBv 6.2), IAS-USA mutation list, ANRS_09/2012 algorithm, and Rega v8.02 algorithm were used to interpret the pattern of drug resistance. The majority of the sequences (96 %) belonged to subtype C, and a few of them (3.9 %) to subtype A1. The frequency of drug resistance mutations observed in ART-non-responding, ART-responding and drug-naive patients was 40.1 %, 10.7 % and 20.58 %, respectively. It was observed that in non-responders, multiple mutations were present in the same patient, while in responders, a single mutation was found. Some of the drug-naive patients had more than one mutation. Thymidine analogue mutations (TAMs), however, were found in non-responders and naive patients but not in responders. Although drug resistance mutations were widely distributed among ART non-responders, the presence of resistance mutations in the viruses of drug-naive patients poses a big concern in the absence of a genotyping resistance test.

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OBJECTIVES: To assess the feasibility and safety of transulnar approach whenever transradial access fails. BACKGROUND: Radial access for coronary procedures has gained sound recognition. However, the method is not always successful. METHODS: Between January 2010 and June 2013, diagnostic with or without percutaneous coronary intervention (PCI) was attempted in 2804 patients via the radial approach. Transradial approach was unsuccessful in 173 patients (6.2%) requiring crossover to either femoral (128 patients, 4.6%) or ulnar approach (45 patients, 1.6%). Patients who had undergone ulnar approach constituted our study population. Selective forearm angiography was performed after ulnar sheath placement. We documented procedural characteristics and major adverse cardio-cerebrovascular events. RESULTS: Radial artery spasm was the most common cause of crossover to the ulnar approach (64.4%) followed by failure to puncture the radial artery (33.4%). Out of 45 patients (82.2%), 37 underwent successful ulnar approach. The eight failed cases (17.8%) were mainly due to absent or weak ulnar pulse (75%). PCI was performed in 17 cases (37.8%), of which 8 patients underwent emergency interventions. Complications included transient numbness, non-significant hematoma, ulnar artery perforation, and minor stroke in 15.5%, 13.3%, 2.2% and 2.2%, respectively. No major cardiac-cerebrovascular events or hand ischemia were noted. CONCLUSION: Ulnar approach for coronary diagnostic or intervention procedures is a feasible alternative whenever radial route fails. It circumvents crossover to the femoral approach. Our study confirms satisfactory success rate of ulnar access in the presence of adequate ulnar pulse intensity and within acceptable rates of complications.

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Genetic heterogeneity in the nef genes from human immunodeficiency virus type 1 (HIV-1)-infected rapid progressors (RPs) and long-term nonprogressors (LTNPs) was analyzed to identify various amino acid substitutions responsible for the discernible difference in disease progression. It was found that the majority of the strains characterized belonged to subtype C, followed by several BC recombinants and subtype A1. Complete nef subtype C sequences from 33 RPs and seven LTNPs were compared, and it was observed that, in the majority of the sequences from both groups, highly conserved functional motifs showed subtle changes. However, drastic changes were observed in two isolates from LTNPs where the arginine cluster was deleted, while in one of them, additionally, acidic residues were replaced by basic residues (EEEEE→RK(R)KKE). The deletion of the arginine cluster and the mutation of acidic residues to basic residues are predicted to delay disease development by abolishing CD4 downmodulation and causing diminution of major histocompatibility complex class I (MHC-I) downregulation, respectively. Nonetheless, this is an exclusive finding in these LTNPs, which necessitates their analysis at the functional level. The synonymous-to-nonsynonymous substitution ratio was greater than one in both of the groups, suggesting amino acid sequence conservation and functional robustness. Interpatient nucleotide distance within the group and between the two groups showed very little variation, confirming genetic relatedness among isolates.

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Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in many developing countries including India. Among the various etiological factors being implicated in the cause of HCC, the most important cause, however, is hepatitis B virus (HBV) infection. Among all HBV genes, HBx is the most critical carcinogenic component, the molecular mechanisms of which have not been completely elucidated. Despite its clinical significance, there exists a very elemental understanding of the molecular, cellular, and environmental mechanisms that drive disease pathogenesis in HCC infected with HBV. Furthermore, there are only limited therapeutic options, the clinical benefits of which are insignificant. Therefore, the quest for novel and effective therapeutic regimen against HBV-related HCC is of paramount importance. This review attempts to epitomize the current state of knowledge of this most common and dreaded liver neoplasm, highlighting the putative treatment avenues and therapeutic research strategies that need to be implemented with immediate effect for tackling HBV-related HCC that has plagued the medical and scientific fraternity for decades. Additionally, this review proposes a novel "five-point" management algorithm for HBV-related HCC apart from portraying the unmet needs, principal challenges, and scientific perspectives that are relevant to controlling this accelerating global health crisis.

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