Leishmaniasis: current status of available drugs and new potential drug targets

The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

A alpha-glycerophosphate dehydrogenase is present in Trypanosoma cruzi glycosomes

alpha-glycerophosphate dehydrogenase (alpha-GPDH-EC.1.1.1.8) has been considered absent in Trypanosoma cruzi in contradiction with all other studied trypanosomatids. After observing that the sole malate dehydrogenase can not maintain the intraglycosomal redox balance, GPDH activity was looked for and found, although in very variable levels, in epimastigotes extracts. GPDH was shown to be exclusively located in the glycosome of T. cruzi by digitonin treatment and isopycnic centrifugation. Antibody against T. brucei GPDH showed that this enzyme seemed to be present in an essentially inactive form at the beginning of the epimastigotes growth. GPDH is apparently linked to a salicylhydroxmic-sensitive glycerophosphate reoxidizing system and plays an essential role in the glycosome redox balance

Hand washing as a strategy to prevent spread of antimicrobial - Resistant Microrganism in Hospitals

Hospitals worldwide are facing a crisis due to the increasingly rapid emergence and dissemination of antimicrobial resistant organisms. Resistance to multiple antimicrobial agents; including methicillin and quinolones among Staphylococcus aureus; has been noted to be an endemic problem in Health care settings. This leaves vancomycin as the sole effective antimicrobial agent for many patients. (1). A similar problem has been noted among the coagulase negative Staphylococci (2). The situation in Uganda is quite similar; the only exception being cost availability of Vancomycin. The drug being toxic may also prove difficult to monitor. Increased use of vancomycin has exerted selective pressure on enterococci which have developed resistance to the agent. (3). Vancomycin resistant enterococci have been noted among clinical isolates in Mulago inspite of lack of use of the agent (Najjuka; personal communication). Enterobacteriaceae; pseudomanas species and other gram-negative bacilli have become increasingly resistant to most frontline antimicrobials including third generation cephalosporins; monobactams; aminoglycosides and quinolones (4;5;6). Strains of pseudomonas and serratia that elaborate extended sptectrum B-lactamases capable of inactivating the cabapenems have been recovered in Japan (7;8). Clinical isolates with similar properties have been noted recently in our set up (Najjuka; personal communication). Resistance to topical antimicrobials such as chlorhexidine gluconate and mupirocin has also been documented . Resistance is not confined to bacteria; use of triazole antifungal agents; fluconazole; has been accompanied by a dramatic increase influconazole resistance among candida species

Síndrome cerebrohepatorrenal de Zellweger: una enfermedad peroxisomal / Brain-liver-renal Zellweger syndrome: a peroxisomal disease

Se describe el caso clínico de un lactante con dismorfias craneofacilaes, hepatomegalia, quistes renales y disfunción neurológica severa. Los exámenes de rastreo para aminoacidemia, aminoaciduria, ácido láctico y amonio dieron resultados normales, pero había altas concentraciones plasmáticas de ácidos grasos de cadena muy larga, distribución subcelular anormal de la catalasa peroxisomal y fantasmas peroxisomales en fibroblastos cultivados. Estas características clínicas y de laboratorio sustentan el diagnóstico de síndrome de Zellweger

Zellweger syndrome: first reported case in Thailand and literature review.

We describe an infant boy with facial dysmorphism, profound hypotonia, psychomotor retardation, seizure and hepatomegaly. Biochemical study revealed elevation of very long chain fatty acids and pipecolic acid, consistent with peroxisomal disorder. He died at the age of 4 months. Electron microscopic study demonstrated decreased amounts of peroxisomes in liver and kidneys. The clinical characteristic, accompanied the biochemical and microscopic findings led to the diagnosis of Zellweger syndrome. The recognition of this syndrome is important since it is a fatal disease. The pattern of inheritance is autosomal recessive, hence genetic counseling is necessary. We emphasize that peroxisomal disorder should be included in the differential diagnosis in patients with infantile hypotonia. This patient is the first reported case of Zellweger syndrome in Thailand.

Fuentes intracelulares de especies oxidantes en condiciones normales y patológicas / Intracellular fountain of oxidant species in pathologic and normal conditions

La generación de especies oxidantes es un proceso inevitable que ocurre como consecuencia de la adaptación de organismos a la vida en aerobiosis. La protección natural contra estos oxidantes es limitada y puede ser sobrepasada, en diferentes condiciones, llevando a lesiones y llevar, eventualmente, a la muerte celular

Adrenoleucodistrofia ligada al cromosoma X: informe de dos casos clínicos / Adrenoleukodystrophy linked with chromosome X. Report of two clinical cases

La adrenoleucodistrofia infantil es un trastorno peroxisomal caracterizado por una falla en la función de la lignoceroil CoA sintetasa, se transmite en forma reseciva ligada al cromosoma X, con localización el locus 28 (q28). La deficiencia enximática condiciona una degradación imcompleta de los ácidos grasos de cadena larga, acumulándose en consecuencia en el tejido cerebral y adrenal. El motivo del presente trabajo es identificar los hallazgos clínicos encontrados en estos casos donde incluímos la presencia del asma bronquial, manifestaciones endocrinológicas y neurológicas. Los pacientes fueron tratados en el servicio a partir de 1990. Se describen los métodos utilizados para el diagnóstico, desde las alteraciones tempranas de los potenciales evocados de tallo, hasta las imágenes de tomografía computarizada de cráneo con doble cantidad de medio de contraste, y cortes tardíos

Peroxisomes and the hepatic pathology of childhood malnutrition

Liver specimens obtained immediately after death from eight severly malnourished children were examined by electron microscopy, and compared with seven liver biopsy specimens from children who recovered from malnutrition. The liver cells from the fatal cases showed mitochondrial swelling, with coarse densities in the matrix, cholestasis, depletion of the endoplasmic reticulum and Golgi apparatus, diminished glycogen stores, prominent lipid deposits and focal cytoplasmic degradation. The nucleoli were enlarged. There was marked reducation in peroxisomes. In contrast, the biopsies from recovering children showed good cellular organisation, and a normal frequency of peroxisomes. Multiple factors, including sepsis, may lead to depletion of peroxisomes. Loss of peroximes may interrupt beta-oxidation of long-chain fatty acids and accentuate the accumulation of lipid. Moreover, a reduction in the concentration of catalase may remove one avenue for the detoxification of free radicals. As the concentration of other anti-oxidants, notably glutathione, is also reduced, free radical damage may occur, leading to lipid peroxidation of membranes, mitochondrial damage, pump failure and influx of water and electrolyted into the cell.

Zellweger (cerebro-hepato-renal) syndrome: first brazilian case with confirmed peroxisomal defect

A síndrome de Zellweger (ZS) é uma doença recessiva causada por uma deficiência generalizada das funçöes peroxissônicas, sendo um exemplo ilustrativo de uma doença metabólica herdada que usualmente chama a atençäo já no período neonatal pelo seu quadro dismórfico típico. Embora a suspeita de ZS seja freqüentemente levantada nas unidades neonatais, o diagnóstico é raramente confirmado uma vez que ele exige procedimentos bioquímicos sofisticados. Neste artigo é descrito um paciente com ZS que, tanto quanto estejamos informados, é o primeiro caso brasileiro no qual o defeito peroxissômico foi confirmado bioquimicamente. Os autores ressaltam a importância da confirmaçäo bioquímica do diagnóstico de ZS, uma vez que ela permite näo apenas um melhor delineamento do fenótipo da síndrome mas principalmente porque permite a prevençäo de casos adicionais através do aconselhamento genético e do diagnóstico pré-natal

Microbodies in methanol assimilating yeast pichia pastoris CBS [704]

The effect of culturing methods on the occurrence of microbodies in the cells of Pichia pastoris CBS 704 was studied. It was found that microbodies were highly affected by culturing methods used for yeast propagation. Growth in shake flasks and fermenter as a batch culture showed smell organelles as well as low numbers of microbodies. Their number and size highly increased when the organism was grown in continuous culture at 0.054h[-1] dilution rate