Mannose binding lectin gene variants and susceptibility to tuberculosis in HIV-1 infected patients of South India

Mannose binding lectin (MBL) plays an important role in innate immunity. Plasma MBL levels and MBL2 gene polymorphisms were studied in HIV-1 infected patients without tuberculosis (HIV+TB-) (n=151) and with tuberculosis (HIV+TB+) (n=109), HIV negative tuberculosis patients (HIV-TB+) (n=148) and healthy controls (n=146) by ELISA and genotyping by polymerase chain reaction based methods. MBL levels were significantly increased among HIV-TB+ and HIV+TB+ patients than controls and HIV+TB- patients (P<0.05). A significantly increased frequency of OO genotype of structural polymorphism and YY genotype of -221Y/X was observed among HIV-TB+ patients than controls. In HIV+TB+ patients, a significantly increased frequency of YA/YA diplotype (associated with very high MBL levels) was observed compared to controls (P=0.03). In HIV+TB+ patients, a significantly decreased frequency of medium MBL expression diplotypes (XA/XA and YA/YO) were noticed compared to HIV+TB- and healthy controls. The results suggest that YA/YA diplotype associated with very high MBL levels may predispose HIV-infected patients to tuberculosis while O/O genotype associated with very low MBL levels may be associated with susceptibility to tuberculosis in HIV uninfected individuals. Medium MBL expression diplotypes might protect against development of TB in HIV-infected patients.     

Potpourri of retinopathies in rare eye disease – A case series

This case series describes the ocular and retinal manifestations of rare eye diseases in systemic syndromes. This observational case series consists of five patients with varied ophthalmic manifestations and documentation of imaging in rare pediatric and adult retinopathies. Two patients had Kearns Sayre syndrome (KSS) based on the classical triad of external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age. In one patient of KSS, the mitochondrial retinopathy was seen in an asymmetric pattern, and the second patient presented with KSS after being mis-diagnosed as myasthenia gravis elsewhere. A case of Senior Loken syndrome in pediatric age is described in this series with varied ophthalmic manifestations ranging from retinitis pigmentosa to orbital abscess. This series also enlightens features of Hallervorden Spatz syndrome presenting with bull’s eye maculopathy and a case of spino-cerebellar ataxia type 7 presenting with pigmentary retinopathy.     

Haplotype analysis of HLA‐A, ‐B antigens and ‐DRB1 alleles in south Indian HIV‐1‐infected patients with and without pulmonary tuberculosis

We have shown earlier the association of human leucocyte antigen (HLA)‐A11 with resistance and HLA‐B40 and ‐DR2 with susceptibility to HIV and HIV‐TB. In the present study, we have attempted to find out the HLA‐DR2 subtypes and the possible HLA‐A/‐B/‐DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with pulmonary tuberculosis (HIV+PTB+). HLA‐DR2 subtyping was carried out by polymerase chain reaction‐based sequence‐specific oligonucleotide probe method. Overrepresentation of HLA‐DRB1*1501 in HIV‐positive PTB‐negative (HIV+PTB–) patients (P = 0.004, P_c = 0.06) and ‐DRB1*1502 in HIV‐positive PTB‐positive (HIV+PTB+) patients (P = 0.019) was observed as compared to healthy controls. Haplotype analysis revealed an increased frequency of HLA‐A2‐DRB1*1501 haplotype in HIV+PTB– patients (P = 0.008) and HLA‐A2‐DRB1*1502 among HIV+PTB+ patients (P = 0.01) compared to healthy controls. The haplotypes B40‐DRB1*1501 and B40‐DRB1*04 were found to be moderately increased in HIV+PTB– and HIV+PTB+ patients (P < 0.05). The study suggests that HLA‐A2‐DRB1*1501 haplotype may be associated with HIV infection while HLA‐A2‐DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. Moreover, HLA‐B40‐DRB1*1501 and HLA‐B40‐DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients.     

Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals: I. Alternative toxicity measures as an estimator of carcinogenic potency

Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to identify alternative toxicity measures that may be used as surrogates for carcinogenic potency. Alternative toxicity measures for carcinogenic potency currently being used in the literature include lethal dose (dose that kills 50% of a study population [LD₅₀]), lowest-observed-adverse-effect-level (LOAEL) and maximum tolerated dose (MTD). The purpose of this study was to investigate the correlation between tumor dose (TD₅₀) and three alternative toxicity measures as an estimator of carcinogenic potency. A second aim of this study was to develop a Classification and Regression Tree (CART) between TD₅₀ and estimated/experimental predictor variables to predict the carcinogenic potency of new chemicals. Rat TD₅₀s of 590 structurally diverse chemicals were obtained from the Cancer Potency Database, and the three alternative toxicity measures considered in this study were estimated using TOPKAT^®, a toxicity estimation software. Though poor correlations were obtained between carcinogenic potency and the three alternative toxicity (both experimental and TOPKAT) measures for the CPDB chemicals, a CART developed using experimental data with no missing values as predictor variables provided reasonable estimates of TD₅₀ for nine chemicals that were part of an external validation set. However, if experimental values for the three alternative measures, mutagenicity and logP are not available in the literature, then either the CART developed using missing experimental values or estimated values may be used for making a prediction.     

Less-Frequent Fusarium Species of Clinical Interest: Correlation between Morphological and Molecular Identification and Antifungal Susceptibility

Forty-eight Fusarium isolates morphologically identified as belonging to seven species of clinical interest (i.e., Fusarium chlamydosporum, Fusarium dimerum, Fusarium incarnatum, Fusarium napiforme, Fusarium nygamai, Fusarium proliferatum, and Fusarium sacchari) were characterized molecularly by the analysis of the sequences of the TUB region of the β-tubulin gene. F. chlamydosporum and F. dimerum were the most genetically heterogeneous species. A high degree of correlation between the morphological and molecular identification was shown among the isolates studied. A table with the key morphological features for the identification of these Fusarium species is provided. The antifungal susceptibilities of the Fusarium isolates to 11 antifungal drugs were tested; terbinafine was the most active drug against all the species tested with the exception of F. incarnatum, for which amphotericin B was the most active.The most frequent species causing fusariosis are Fusarium solani, Fusarium oxysporum, and Fusarium verticillioides (1, 16, 47), but several other species are also found to cause human infections, although less frequently. Some of these species are Fusarium chlamydosporum, Fusarium dimerum, Fusarium incarnatum, and the following other species that are included into the Gibberella fujikuroi species complex: Fusarium napiforme, Fusarium nygamai, Fusarium proliferatum, and Fusarium sacchari (30, 31). These species have been associated with different types of infection, in particular with keratomycoses and other ocular infections (10) and with disseminated infections in immunocompromised patients (2, 6, 17, 20, 23, 24, 26, 39, 41, 43, 44). The real incidence of these species is unknown since they are poorly known and laboratorians and clinical microbiologists are not generally aware of their possible presence in human infections.Since the species of Fusarium are generally resistant to all the available antifungal drugs (40), it could be considered that speciation of Fusarium is necessary only for epidemiological purposes. However, some in vitro data concerning particular species seem to be very promising and deserve to be investigated clinically. For instance, F. verticillioides isolates were susceptible to posaconazole and terbinafine and Fusarium thapsinum isolates to terbinafine (4). The identification of fusaria to the species level is not easy, and in numerous clinical cases the etiological agent is reported as being a Fusarium sp. However, several recent studies have demonstrated the usefulness of molecular methods for the identification of those Fusarium species that are difficult to distinguish morphologically (1, 4, 47). In recent years, the in vitro antifungal susceptibilities of the most frequent species of Fusarium have been evaluated (1, 3, 4, 40, 47), but only a few isolates of the less-common species have been studied. The objectives of our study were (i) to evaluate the correlation between the morphological and the molecular identification of less-frequent Fusarium species isolates received by our laboratory and (ii) to determine the antifungal susceptibilities of isolates representative of those less-common Fusarium species of clinical interest identified molecularly.