Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex.

Heme Regulated Inhibitor (HRI) is known to get activated in various stresses such as heme deficiency, heat shock, heavy metal toxicity etc. Heat shock protein 90 (Hsp90), a ubiquitous cytoplasmic protein interacts with HRI in order to regulate protein synthesis. However, it still remains to establish this interaction of HRI and Hsp90 at cellular levels and how this modulation of HRI activity is mediated by Hsp90 during stress. In the present report, using co-immunoprecipitation analysis we show that HRI interacts with Hsp90 and this association is independent of other co-chaperones in in vitro conditions. Further, analysis using truncated domains of HRI revealed that the K1 subdomain is essential for HRI - Hsp90 complex formation. Our in silico protein - protein interaction studies also indicated interaction of Hsp90 with K1 subdomain of HRI. Mammalian two hybrid assay validated this HRI - Hsp90 interaction at cellular levels. When the in vitro kinase assay was carried out with the co-immunoprecipitated complex of HRI - Hsp90, an increase in the kinase activity was observed resulting elevated levels of eIF2α phosphorylation upon heavy metal stress and heat shock. Thus, our results clearly indicate modulation of HRI kinase activity with simultaneous Hsp90 association under stress conditions.

The Leishmania donovani IMPACT-like protein possesses non-specific nuclease activity.

IMPACT (Imprinted and Ancient)-like proteins are known to be regulators of GCN2 (General control non-derepressible 2) kinases involved in translation regulation. Here, we report on cloning and characterization of an IMPACT-like protein, LdIMPACT from Leishmania donovani which harbours two domains. 'RWD domain' at the N-terminal end that mediates GCN2 regulation, while a conserved 'ancient domain' lies at the C-terminal end whose function remains elusive. Interestingly, our observations indicated that LdIMPACT has a novel non-specific nuclease activity. In silico analysis further revealed the resemblance of ancient domain of LdIMPACT to RNase PH domain (known to bind to nucleic acids). The recombinant LdIMPACT exhibited a Mg2+-dependent nuclease activity. Moreover, thermostability and pH stability assays of the protein suggest it to be a stress-responsive protein. Circular dichroism studies elucidated the conformational transitions of the enzyme in response to various temperature and pH conditions which correlated well with the activity profiles. Thus, the current study highlights the structural and functional characteristics of LdIMPACT which interestingly also possesses a novel nuclease activity. With its physiological relevance unresolved, the multifaceted LdIMPACT might therefore lie in a hitherto unknown network, whose perturbation could be an attractive therapeutic approach for treating leishmaniasis.

Pathologic lesions in children with acquired immunodeficiency syndrome an autopsy study of 11 cases from Mumbai, India.

BACKGROUND: Human immunodeficiency virus (HIV) infection in India has now been prevalent over three decades, and an increasing number of children are being affected with HIV. The spectrum of pathologic lesions in children with acquired immunodeficiency syndrome (AIDS) in India has not been well described. MATERIALS AND METHODS: A review of systematically conducted autopsies of 11 (10 boys and 1 girl) children with AIDS is presented. RESULTS: The mode of HIV transmission in 6 children was vertical; in one it was blood transfusion and in 4 children route was presumably vertical as these were children of orphanage. The clinical manifestations were failure to thrive; 9 children, persistent gastroenteritis; 8, recurrent fever; 5, bacterial infections; 5, hepatosplenomegaly; 5, candidiasis; 1, scabies; 1, skin rash; 2, tuberculous (TB) meningitis; 1 and paraplegia; in 1 child. The spectrum of pathologic lesions observed were precocious involution in thymus in 3 and dysinvolution in 2 cases. Infectious diseases comprised of TB; 4 cases, cytomegalovirus infection (CMV) 4; bacterial pneumonia and meningitis; 7, and esophageal candidiasis in 2 cases. Dual or multiple infections were observed in 9 (82%) cases; these comprised of two lesions in 2, three lesions in 2, four lesions in 4, and five lesions in 1 case. TB, bacterial pneumonia, meningitis, and CMV infection are the most frequent causes of death in children with AIDS. Vascular lesions showing features of arteriopathy were observed in 5 cases and brain in one case showed non-Hodgkin's lymphoma. CONCLUSIONS: This study provides a better insight into the spectrum of pathologic lesions in children with AIDS in India. TB and CMV infection has been found to be the most prevalent infection in our children.

Cystic Hygroma in an Adult Male: A Diagnostic Challenge.

Cystic Hygroma is a well-recognized lesion in paediatric patients but it is very rare in adults. We report here a case of Cervical Cystic Hygroma in a 45 yr old male. The reasons to present this case are 1) Its rarity in adults 2) Unusual age of presentation 3) Simulates various benign and malignant lesions at this site 4) Is a diagnostic challenge and 5) Role of histology for definitive postoperative diagnosis.

Cutaneous myxoma: an important clue to Carney complex.

A 22-year-old male became unconscious and was found to have left-sided weakness and facial asymmetry. Previously, he had up to 35 excisions for subcutaneous swellings all over the body, commencing at age 6 years. Examination revealed small nodular skin lesions on the neck, the eyelid and hard palate. Two-dimensional echocardiography showed two left atrial masses. Histopathological examination of the subcutaneous lesions showed cutaneous myxomas with a prominent epithelial component. The left atrial masses were also myxomas. The case attempts to highlight the importance of histopathological examination of subcutaneous swellings. Cutaneous and subcutaneous manifestations, including cutaneous myxomas, are among the earliest presentations in Carney's complex and may herald potentially fatal cardiac myxoma. The prominent epithelial component in cutaneous myxomas may be confusing and cause diagnostic difficulties.

Childhood actinic keratosis in an albino transforming into squamous cell carcinoma.

Actinic keratosis is a scaly, cutaneous lesion that is often seen in elderly patients. It is almost never seen in children and young adults. It develops on areas such as the face, ears and dorsa of the hands with chronic sun exposure. Actinic keratosis is a premalignant lesion, since histological changes in the epidermis may progress to squamous cell carcinoma if left untreated. There are roughly 70,000 people with albinism in India. These patients are prone to develop actinic keratosis which may undergo spontaneous remission or develop into invasive squamous cell carcinoma, basal cell carcinoma and malignant melanoma.We present an unusual case of a 35 year old albino who developed actinic keratosis at the age 15 years which progressed to squamous cell carcinoma.

Solitary intramuscular cysticercosis-A report of two cases.

Cysticercosis, infestation with the encysted larval stage of Taenia solium, is a major health problem in most countries of Latin America, Asia, and Africa. It involves mainly the central nervous system. Muscle involvement is also seen, although it usually remains asymptomatic. Solitary intramuscular cysticercosis, without involvement of central nervous system is a rare entity. We present two cases of solitary intramuscular cysticercosis, without any systemic or neurologic manifestations.