Leprosy & gangrene: A rare association; role of anti phospholipid antibodies

BACKGROUND: Leprosy still remains an important public health problem for many parts of the world. An association of gangrene with leprosy is a rare one & can have a number of causative mechanisms. We present a case with Leprosy & gangrene with positive anti phopholipid antibody titers. CASE PRESENTATION: A 50-year-old non-diabetic, non-hypertensive lady presented with 2 months history of progressive gangrene of bilateral toes. She was found to have madarosis & hypopigmented, hypoaesthetic macular lesions on the upper limb & thighs. Bilateral ulnar & popliteal nerves were thickened. A skin biopsy of the lesions revealed borderline tuberculoid leprosy, slit skin smears revealed a bacteriological index of 1+. She did not have any evidence of thromboembolic episode or atherosclerosis. ACLA was positive at presentation & also on another occasion 6 weeks later. ACLAs were of the IgM type on both occasions. Lupus Anticoagulant & β2 GPI antibody were negative. DOPPLER of the lower limb arteries did not reveal any abnormality. Patient was successfully treated with multi-drug antileprotics & anticoagulants. CONCLUSION: Infectious APLAs should be recognized as a cause of thrombosis in Leprosy. Appropriate anticoagulation can salvage limb function

Farmacogen\ue9tica de la Tuberculosis: Nuevo modelo de predicci\uf3n de hepatotoxicidad inducida por f\ue1rmacos antituberculosis

Introducci\uf3n: La hepatotoxicidad inducida por f\ue1rmacos antituberculosis (HIFA) es una reacci\uf3n adversa grave y potencialmente fatal del tratamiento de la tuberculosis (TB). Tres de los cuatro f\ue1rmacos utilizados como terapia de primera l\uednea (isoniacida, rifampicina, pirazinamida), han sido asociados a HIFA. Estudios sobre farmacogen\ue9tica de la TB han asociado el desarrollo de HIFA con variaciones en genes de enzimas que metabolizan estos f\ue1rmacos. Objetivos: Debido a que en Argentina la TB es una enfermedad re-emergente y a la elevada prevalencia de HIFA encontrada en pacientes internados, nos propusimos evaluar la posible asociaci\uf3n de factores ambientales y variantes gen\ue9ticas en enzimas que metabolizan f\ue1rmacos anti-TB con el desarrollo de HIFA. Tambi\ue9n, investigar las posibles interacciones gen-gen y gen-ambiente y su asociaci\uf3n con el desarrollo de HIFA, en una poblaci\uf3n de pacientes con TB hospitalizados de la Ciudad de Buenos Aires. M\ue9todos: Se estudiaron 345 pacientes con TB tratados con f\ue1rmacos anti-TB (96 con HIFA). Se analizaron variables cl\uednicas y demogr\ue1ficas tomadas en fichas de datos. Las variaciones gen\ue9ticas en las enzimas N-acetiltransferasa 2 (NAT2), citocromo P450 2E1 (CYP2E1), glutathione S-transferasa theta 1 (GSTT1) y glutathione S-transferasa mu 1 fueron detectadas por reacci\uf3n en cadena de polimerasa (PCR), secuenciaci\uf3n o PCR-RFLP. Para comparar las posibles variables predictoras entre pacientes con y sin HIFA se utiliz\uf3 un an\ue1lisis de regresi\uf3n log\uedstica binaria. Para estudiar las interacciones gen\ue9ticas y ambientales en asociaci\uf3n con HIFA se utiliz\uf3 el m\ue9todo de reducci\uf3n de la dimensionalidad multifactorial (MDR). Resultados: Este estudio mustra que ser acetilador lento (AL) de NAT-2 [OR (IC95%) = 3,02 (1,82-5,00); p<0,001], ser portador de la variante c2 [OR (IC95%) = 2,16 (1,33-3,51); p = 0,002] o ser portador de la variante A4 de CYP2E1 [OR (IC95%) = 2,13 (1,06-4,29); p = 0,049], y ser mujer [OR (IC95%) = 1,94 (1,20 - 3,14); p = 0,006] resultaron variables predictoras independientes para HIFA. Aquellos pacientes AL que adem\ue1s eran portadores de la variante c2 de CYP2E1 tienen un riesgo mayor [OR (IC95%) = 7.07 (3.34-14.95); p <0,001]. Por primera vez, se identific\uf3 una interacci\uf3n sin\ue9rgica (epistasis) entre GSTT1 y CYP2E1 con mayor riesgo de HIFA. A su vez, se describe por primera vez una significativa interacci\uf3n gen (NAT2 y CYP2E1) - ambiente (sexo) con riesgo aumentado de HIFA [TBA = 0,675, (p = 0,001) y CVC = 10/10]. Es decir que el mejor modelo de predicci\uf3n (67,5%) de HIFA contempla las variables NAT2, CYP2E1 y sexo. Conclusiones: HIFA es una reacci\uf3n adversa potencialmente fatal y prevalente (11% de los pacientes tratados) que conduce a la interrupci\uf3n del f\ue1rmaco. En nuestro estudio, se obtuvo un modelo de predicci\uf3n que clasifica adecuadamente al 67,5% de los pacientes con TB en su riesgo de desarrollar HIFA. Dado el n\ufamero considerable de TB en nuestro pa\ueds, las pruebas farmacogen\ue9ticas y una historia cl\uednica completa podr\uedan ser \ufatiles para reconocer a los pacientes con alto riesgo de sufrir hepatotoxicidad. Estos representan datos nacionales e internacionales in\ue9ditos relacionados a HIFA

Evolutionary approaches for the reverse-engineering of gene regulatory networks: A study on a biologically realistic dataset

<p>Abstract</p> <p>Background</p> <p>Inferring gene regulatory networks from data requires the development of algorithms devoted to structure extraction. When only static data are available, gene interactions may be modelled by a Bayesian Network (BN) that represents the presence of direct interactions from regulators to regulees by conditional probability distributions. We used enhanced evolutionary algorithms to stochastically evolve a set of candidate BN structures and found the model that best fits data without prior knowledge.</p> <p>Results</p> <p>We proposed various evolutionary strategies suitable for the task and tested our choices using simulated data drawn from a given bio-realistic network of 35 nodes, the so-called insulin network, which has been used in the literature for benchmarking. We assessed the inferred models against this reference to obtain statistical performance results. We then compared performances of evolutionary algorithms using two kinds of recombination operators that operate at different scales in the graphs. We introduced a niching strategy that reinforces diversity through the population and avoided trapping of the algorithm in one local minimum in the early steps of learning. We show the limited effect of the mutation operator when niching is applied. Finally, we compared our best evolutionary approach with various well known learning algorithms (MCMC, K2, greedy search, TPDA, MMHC) devoted to BN structure learning.</p> <p>Conclusion</p> <p>We studied the behaviour of an evolutionary approach enhanced by niching for the learning of gene regulatory networks with BN. We show that this approach outperforms classical structure learning methods in elucidating the original model. These results were obtained for the learning of a bio-realistic network and, more importantly, on various small datasets. This is a suitable approach for learning transcriptional regulatory networks from real datasets without prior knowledge.</p

IL-10 Mediated by Herpes Simplex Virus Vector Reduces Neuropathic Pain Induced by HIV gp120 Combined with ddC in Rats

BACKGROUND: HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state. RESULTS: Neuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2′,3′-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks. CONCLUSION: The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy