Elucidating hippocampal proteome dynamics in moderate hepatic encephalopathy rats: insights from high-resolution mass spectrometry.

Hepatic encephalopathy (HE) is a debilitating neurological disorder associated with liver failure and characterized by impaired brain function. Decade-long studies have led to significant advances in our understanding of HE; however, effective therapeutic management of HE is lacking, and HE continues to be a significant cause of morbidity and mortality in patients, underscoring the need for continued research into its pathophysiology and treatment. Accordingly, the present study provides a comprehensive overview aimed at elucidating the molecular underpinnings of HE and identifying potential therapeutic targets. A moderate-grade HE model was induced in rats using thioacetamide, which simulates the liver damage observed in patients, and its impact on cognitive function, neuronal arborization, and cellular morphology was also evaluated. We employed label-free LC-MS/MS proteomics to quantitatively profile hippocampal proteins to explore the molecular mechanism of HE pathogenesis; 2175 proteins were identified, 47 of which exhibited significant alterations in moderate-grade HE. The expression of several significantly upregulated proteins, such as FAK1, CD9 and Tspan2, was further validated at the transcript and protein levels, confirming the mass spectrometry results. These proteins have not been previously reported in HE. Utilizing Metascape, a tool for gene annotation and analysis, we further studied the biological pathways integral to brain function, including gliogenesis, the role of erythrocytes in maintaining blood-brain barrier integrity, the modulation of chemical synaptic transmission, astrocyte differentiation, the regulation of organ growth, the response to cAMP, myelination, and synaptic function, which were disrupted during HE. The STRING database further elucidated the protein‒protein interaction patterns among the differentially expressed proteins. This study provides novel insights into the molecular mechanisms driving HE and paves the way for identifying novel therapeutic targets for improved disease management.

Prospective study of immunomodulation in osteoarticular tuberculosis non responsive to anti tubercular therapy.

BACKGROUND: Tuberculosis is one of the common disease of Indian subcontinent. India has the highest TB burden, accounting for one fifth of the global incidence. Previous studies have shown positive response of immunomodulation in patients of ostearticular tuberculosis We did this prospective study to assess the role of immunomodulation in the cases of osteoarticular tuberculosis who were not responding to anti tubercular therapy. MATERIALS AND METHOD: This study was conducted in our institute. New patients presenting to OPD who were diagnosed with tuberculosis with no previous history of taking anti tubercular treatment were enrolled. Total of 109 patients were diagnosed clinicoradiologically. Four patients, where diagnosis was not confirmed, histopathological examination of tissue was done and the diagnosis was confirmed as tubercular in origin. Newly diagnosed patients were put on anti tubercular therapy(ATT) after documenting there blood parameters (complete hemogram,ESR, serum proteins, CD4 & CD8 counts). After 3 months patients were re-evaluated and favourably responding patients were labelled group A. Those who did not respond to therapy were put on immunomodulation along with continuation of ATT. These were designated as group B and blood parameters were compared with pre immunomodulation values. RESULTS: Out of total 109 patients registered, 73 patients were enlisted in group A, while 30 patients were found to be non-responsive to ATT and were included in non-responder group B (six lost to follow up). In group B the blood parameters after one month of completion of immunomodulation showed statistically significant increase in CD4 & CD8 counts (p = 0.04). Mean CD4 count increased from 488/mm3 to 747/mm3 while CD8 count showed increment from 494/mm3 to 617/mm3. Mean haemoglobin values increased along with decrease in ESR and total leucocyte count. In group A mean CD4 and CD8 counts increased with ATT though the results were not significant statistically. CONCLUSION: Treatment: of tuberculosis has been a great success after introduction of chemotherapy specifically targeting Mycobacterium tuberculosis. In this study relationship between the increase in the peripheral T-cell count and a favourable clinical outcome was further associated with concomitant increase in the haemoglobin level as well as by a decrease in the ESR, total leucocyte count. In our study immunomodulation has shown a good promise to be of adjunctive use in patients on ATT with non-responsiveness.

Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria from three highly malarious states in India.

BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states. This study investigates the therapeutic efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in three malaria-endemic states in India. The data generated through this study will benefit the immediate implementation of second-line ACT as and when required. METHODS: This was a one-arm prospective evaluation of clinical and parasitological responses for uncomplicated falciparum malaria using WHO protocol. Patients diagnosed with uncomplicated mono P. falciparum infection were administered six-dose regimen of AL over 3 days and subsequent follow-up was carried out up to 28 days. Molecular markers msp-1 and msp-2 were used to differentiate recrudescence and re-infection and K13 propeller gene was amplified and sequenced covering the codon 450-680. RESULTS: A total of 402 eligible patients were enrolled in the study from all four sites. Overall, adequate clinical and parasitological response (ACPR) was 98 % without PCR correction and 99 % with PCR correction. At three study sites, ACPR rates were 100 %, while at Bastar, cure rate was 92.5 % on day 28. No early treatment failure was found. The PCR-corrected endpoint finding confirmed that one late clinical failure (LCF) and two late parasitological failures (LPF) were recrudescences. The PCR corrected cure rate was 96.5 %. The mean fever clearance time was 27.2 h ± 8.2 (24-48 h) and the mean parasite clearance time was 30.1 h ± 11.0 (24-72 h). Additionally, no adverse event was recorded. Analysis of total 186 samples revealed a mutation in the k13 gene along with non-synonymous mutation at codon M579T in three (1.6 %) samples. CONCLUSION: AL is an efficacious drug for the treatment of uncomplicated falciparum malaria. However, regular monitoring of AL is required in view of malaria elimination initiatives, which will be largely dependent on therapeutic interventions, regular surveillance and targeted vector control.

Comparative evaluation of 201Tl SPECT and CT in the follow-up of irradiated brain tumors.

BACKGROUND: Radiation-induced changes in post-irradiated brain tumors may produce morphological alterations similar to those of tumor recurrence on computed tomography (CT). However, 201Tl single-photon-emission computed tomography (SPECT), with its ability to image metabolic changes, may differentiate post-irradiated gliotic changes from metabolically active congregations of viable tumor cells. This study was carried out to compare these two imaging modalities for the follow-up evaluation of post-irradiated brain tumors. METHODS: Thirty-five patients with previously irradiated primary brain tumors were evaluated for this study. 201Tl SPECT and CT were carried out during follow-up, which ranged from 3 to 125 months (median, 18 months). These findings were compared with the clinical outcome, as observed during the subsequent follow-up. RESULTS: Sensitivity, specificity, and the overall accuracy of 201Tl SPECT were 82.7%, 83.3%, and 82.8%, compared to 58.6%, 66.6%, and 58.3%, respectively, for CT. Post-scan progression-free survival (PFS) was significantly different for those patients having positive and those having negative evidence of tumor recurrence based on the imaging studies during follow-up. However, PFS was better correlated with 201Tl SPECT results than with the CT results. With 201Tl SPECT, median PFS was 4 months for those with positive reports, versus 33 months for those with negative reports (P = 0.003), compared to a corresponding median PFS of 3 months versus 14 months (P = 0.025), respectively, with CT. On multivariate analysis, age and 201Tl SPECT were the only significant variables for predicting post-scan PFS. CONCLUSION: 201Tl SPECT, with its ability to be taken up by viable tumor tissues, is superior to CT for the follow-up evaluation of post-irradiated brain tumors.