PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population.

OBJECTIVES: Cytokines and related molecules in immune-response pathways seem important in deciding the outcome of the host-pathogen interactions towards different polar forms in leprosy. We studied the role of significant and functionally important single-nucleotide polymorphisms (SNPs) in these genes, published independently from our research group, through combined interaction with an additional analysis of the in silico network outcome, to understand how these impact the susceptibility towards the disease, leprosy. DESIGN: The study was designed to assess an overall combined contribution of significantly associated individual SNPs to reflect on epistatic interactions and their outcome in the form of the disease, leprosy. Furthermore, in silico approach was adopted to carry out protein-protein interaction study between PARK2 and proinflammatory/anti-inflammatory cytokines. SETTING: Population-based case-control study involved the data of North India. Protein-protein interaction networks were constructed using cytoscape. PARTICIPANTS: Study included the data available from 2305 Northern Indians samples (829 patients with leprosy; 1476 healthy controls), generated by our research group. PRIMARY AND SECONDARY OUTCOME MEASURES: For genotype interaction analysis, all possible genotype combinations between selected SNPs were used as an independent variable, using binary logistic regression with the forward likelihood ratio method, keeping the gender as a covariate. RESULTS: Interaction analysis between PARK2 and significant SNPs of anti-inflammatory/proinflammatory cytokine genes, including BAT1 to BTNL2-DR spanning the HLA (6p21.3) region in a case-control comparison, showed that the combined analysis of: (1) PARK2, tumour necrosis factor (TNF), BTNL2-DR, interleukin (IL)-10, IL-6 and TGFBR2 increased the risk towards leprosy (OR=2.54); (2) PARK2, BAT1, NFKBIL1, LTA, TNF-LTB, IL12B and IL10RB provided increased protection (OR=0.26) in comparison with their individual contribution. CONCLUSIONS: Epistatic SNP-SNP interactions involving PARK2 and cytokine genes provide an additive risk towards leprosy susceptibility. Furthermore, in silico protein-protein interaction of PARK2 and important proinflammatory/anti-inflammatory molecules indicate that PARK2 is central to immune regulation, regulating the production of different cytokines on infection.

Acitretin in dermatology.

Acitretin, a synthetic retinoid has gradually replaced etretinate in today's dermatologic practice because of its more favorable pharmacokinetics. Acitretin over the past 20 years has proven useful in a number of difficult-to-treat hyperkeratotic and inflammatory dermatoses and nonmelanoma skin cancers. It is effective both as monotherapy and in combination with other drugs for hyperkeratotic disorders. It is considered to be an established second line treatment for psoriasis and exerts its effect mainly due to its antikeratinizing, antiinflammatory, and antiproliferative effect. Its antineoplastic properties make it a useful agent for cancer prophylaxis. Evidence-based efficacy, side-effect profile, and approach to the use of acitretin would be discussed in this review. In addition to its approved uses, the various off label uses will also be highlighted in this section. Since its use is limited by its teratogenic potential and other adverse effects, including mucocutaneous effects and hepatotoxicity, this review would summarize the contraindications and precautions to be exercised before prescribing acitretin.

Mapping of PARK2 and PACRG overlapping regulatory region reveals LD structure and functional variants in association with leprosy in unrelated indian population groups.

Leprosy is a chronic infectious disease caused by Mycobacterium Leprae, where the host genetic background plays an important role toward the disease pathogenesis. Various studies have identified a number of human genes in association with leprosy or its clinical forms. However, non-replication of results has hinted at the heterogeneity among associations between different population groups, which could be due to differently evolved LD structures and differential frequencies of SNPs within the studied regions of the genome. A need for systematic and saturated mapping of the associated regions with the disease is warranted to unravel the observed heterogeneity in different populations. Mapping of the PARK2 and PACRG gene regulatory region with 96 SNPs, with a resolution of 1 SNP per 1 Kb for PARK2 gene regulatory region in a North Indian population, showed an involvement of 11 SNPs in determining the susceptibility towards leprosy. The association was replicated in a geographically distinct and unrelated population from Orissa in eastern India. In vitro reporter assays revealed that the two significantly associated SNPs, located 63.8 kb upstream of PARK2 gene and represented in a single BIN of 8 SNPs, influenced the gene expression. A comparison of BINs between Indian and Vietnamese populations revealed differences in the BIN structures, explaining the heterogeneity and also the reason for non-replication of the associated genomic region in different populations.

A rare presentation of mammary Paget's disease involving the entire breast in the absence of any underlying ductal malignancy.

Paget's disease of the breast is an uncommon form of breast cancer presenting as an eczematous eruption over the nipple and/or areola. The diagnosis remains elusive with varied presentations, mimicking many benign skin diseases, the awareness of which is indispensable for diagnosis and minimizing morbidity. Most of the cases have an associated malignancy of the underlying breast tissue. There have been very few reports wherein the disease has occurred independent of any underlying malignancy. Since, the initial presentation is limited to skin; it is the dermatologist who plays a key role in making a diagnosis, thus, facilitating proper management. We report a rare presentation of mammary Paget's disease with a wide cutaneous spread probably attributed to a significantly delayed diagnosis without any associated underlying malignancy.

Newer and upcoming therapies for melasma.

Melasma is one of the most common and distressing pigmentary disorders presenting to dermatology clinics. The precise cause of melasma remains unknown; however, there are many possible contributing factors. It is notably difficult to treat and has a tendency to relapse. The existing and most tried topical therapy is hydroquinone and the triple combination with tretinoin and corticosteroids, which is considered the gold standard for melasma. Besides that, azelaic acid, kojic acid, arbutin, ascorbic acid, glycolic acid and salicylic peels have also been tried with limited success. However, multiple novel topical agents are being investigated for their potential as hypopigmenting agents with unique mode of action. But, further trials are required to study their efficacy and safety before they can be further recommended. The article highlights these newer formulations and also briefly mentions about the newer chemical peels and the much hyped lasers in treating this difficult and frustrating condition.

Association of variants in BAT1-LTA-TNF-BTNL2 genes within 6p21.3 region show graded risk to leprosy in unrelated cohorts of Indian population.

Host immune response against Mycobacterium leprae plays an important role in providing resistance to infection and disease progression. Genome-wide linkage and association studies suggest the possibility of multiple risk loci within HLA (6p21.3) region. Any systematic study of relevance within the histocompatibility complex of importance in host immune response would be pertinent because of non-replication of the known loci and unavailable information on some of the unexplored genes and regions. A systematic scan was performed of the selected region involving LTA-TNF-LTB genes within 6p21.3 with a resolution of 1SNP/127 bp; and the SNPs in flanking BAT1, NFKBIL and BTNL2-DRA genes on the basis of their tag status or their presence in promoter/exonic regions with MAF of >5%. Nine SNPs located in BAT1, LTA, TNF genes and BTNL2-DRA interval showed strong association with leprosy susceptibility in two independent sets of North Indian population which was replicated in a geographically distinct East Indian population. Conditional logistic regression showed at least one functional SNP remaining significant in each gene, suggesting an independent role of each of the disease associated SNPs. In vitro reporter assay revealed that two SNPs located at BAT1 promoter and 13 kb upstream to LTA gene affected the transcription factor binding site, hence the gene expression. We unravel the role of unexplored immunologically important genes, BAT1 and BTNL2, in addition to known LTA and TNF genes, and the haplotypes of the significantly associated SNPs therein, to understand susceptibility to the disease, leprosy and its differential severity.

Multifocal cutaneous melanoacanthoma with ulceration: a case report with review of literature.

We report a case of a 58-year-old female patient who presented with multiple, asymptomatic, slowly-growing, raised pigmented lesions all over her body for the past 10 years with ulceration in one of the lesions on the trunk for the past five months. Histopathology of the lesion revealed features consistent with melanoacanthoma. Here, we report the first case of cutaneous melanoacanthoma presenting with an ulcerated plaque and the third case of cutaneous melanoacanthoma with multiple lesions. To the best of our knowledge, ulceration has not yet been reported as a feature of cutaneous melanoacanthoma in the medical literature.

Genetic variations and interactions in anti-inflammatory cytokine pathway genes in the outcome of leprosy: a study conducted on a MassARRAY platform.

BACKGROUND: Mycobacterium leprae is the etiologic pathogen that causes leprosy. The outcome of disease is dependent on the host genetic background. METHODS: We investigated the association of 51 single-nucelotide polymorphisms (SNPs) in anti-inflammatory cytokines (IL-10, TGFB1, IL-6, IL-4, and IL-13) and receptors (IL-10RA, IL-10RB, TGFBR1, TGFBR2, IL-6R, IL-4R, IL-5RA, IL-5RB, and IL-13RA1) with susceptibility to leprosy in a case-control study from New Delhi in northern India. This was followed by replication testing of associated SNPs in a geographically distinct and unrelated population from Orissa in eastern India. The functional potential of SNPs was established with in vitro reporter assays. RESULTS: Significant associations (P < .05) were observed for 8 polymorphisms (rs1800871, rs1800872, and rs1554286 of IL-10; rs3171425 and rs7281762 of IL-10RB; rs2228048 and rs744751 of TGFBR2; and rs1800797 of IL-6) with leprosy. This association was replicated for 4 SNPs (rs1554286 of IL-10, rs7281762 of IL-10RB, rs2228048 of TGFBR2, and rs1800797 of IL-6). The interaction study revealed a significantly greater association with leprosy risk than was obtained for any SNP individually. CONCLUSIONS: This study provides an interesting insight on the cumulative polygenic host component that regulates leprosy pathogenesis.

Leprosy and the adaptation of human toll-like receptor 1.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.

Efficacy of low-dose isotretinoin in acne vulgaris.

Low-dose isotretinoin (0.5 mg/kg/day) is a mode of therapy for mild to moderate grades of acne. We analyzed the various trials of this mode of therapy with or without combination with topical agents. We also statistically analyzed the results, efficacy and relapse rates of standard therapy in comparison with the low-dose therapy. Our analysis of the data revealed that the efficacy and relapse rates of low-dose isotretinoin in mild to moderate grades of acne is comparable with the standard regimen (1 mg/kg/day), which is given in the severe grade of acne vulgaris. Thus, the grade of acne vulgaris should dictate the dose of administration of isotretinoin and the standard dose of 1 mg/kg/day is an unnecessary overtreatment for mild to moderate grades of acne.