Sunil K. Arora

Presumed tubercular serpiginouslike choroiditis: clinical presentations and management.

PURPOSE Choroiditis, choroidal tubercles, and tuberculomas are well known ocular manifestations of systemic tuberculosis. The present series aimed to report the occurrence of serpiginouslike choroiditis of presumed tubercular origin. DESIGN Retrospective, noncomparative, interventional case series. PARTICIPANTS Eleven eyes in seven consecutive patients with a diagnosis of choroidal tuberculosis simulating serpiginous choroiditis were studied between 1997 and 2000. TESTING AND INTERVENTION: All patients had their fundus photographs taken at the time of initial presentation as well as during follow-up. All patients underwent a Mantoux skin test and chest radiography. In addition, five patients had their aqueous or vitreous humor subjected to polymerase chain reaction (PCR) for Mycobacterium tuberculosis. Sputum examination, biopsy, or both were carried out whenever recommended by the pulmonologist. Systemic antituberculosis chemotherapy was instituted in combination with treatment for ocular inflammation. MAIN OUTCOME MEASURE Therapeutic response and visual improvement. RESULTS There were five men and two women ranging in age from 17 to 32 years. Clinical presentations included three morphologic variants; multifocal progressive choroiditis showing wavelike progression to confluent, diffuse lesions resembling serpiginous choroiditis (three eyes); diffuse choroiditis characterized by diffuse plaquelike choroiditis with an amoeboid pattern suggestive of serpiginous choroiditis at initial presentation (four eyes); and mixed variety where opposite eyes had mixed features (four eyes). All patients had strongly positive Mantoux skin test results and positive chest radiograph results. The PCR results from aqueous and vitreous humor in four samples was positive for Mycobacterium tuberculosis; one had sputum positive for acid-fast bacilli, whereas two had histopathologic evidence of tuberculosis from cervical or parahilar lymph nodes. Treatment was associated with resolution of choroidal lesions and visual improvement. Final visual acuity of 20/30 or better was achieved in five eyes. CONCLUSIONS Choroidal tuberculosis may present as multifocal progressive or diffuse choroiditis resembling serpiginous choroiditis. It is important to recognize these presentations because these eyes show good response to systemic antituberculosis chemotherapy.

Role of Anti-Tubercular Therapy in Uveitis With Latent/Manifest Tuberculosis

PURPOSE To assess the role of anti-tubercular therapy in uveitis with latent/manifest tuberculosis (TB). DESIGN Retrospective, interventional case series. METHODS A total of 360 patients from uveitis clinic with following inclusion criteria were studied: 1) complete clinical records of visual acuity, slit-lamp biomicroscopic examination, intraocular pressure, complications if any, and treatment records at the baseline and at all follow-up visits; 2) a documented positive tuberculin skin test (10 mm of induration or more) at 48 to 72 hours; 3) evidence of active uveitis, i.e., cellular reaction in the anterior chamber with or without keratic precipitates, and/or active vitreous inflammation, retinal vasculitis, choroiditis, or neuroretinitis; 4) all known causes of infectious uveitis except TB and known noninfectious uveitic syndromes ruled out; and 5) a minimum one year of follow-up from the initiation of treatment. Of these, 216 patients (Group A) received four-drug anti-tubercular therapy and corticosteroids, and 144 patients (Group B) received corticosteroids alone. The main outcome measure was recurrence of inflammation after minimum six months of initiating treatment in each group. RESULTS Recurrences reduced significantly (P < .001) in Group A (15.74%) as compared to Group B (46.53%) over a median follow-up of 24 and 31 months, respectively. The patients treated with anti-tubercular therapy with corticosteroids had decreased risk of developing recurrence of uveitis by approximately two-thirds as compared to those treated with corticosteroids alone. CONCLUSION Addition of anti-tubercular therapy to corticosteroids in uveitis patients with latent/manifest TB led to significant reduction in recurrences of uveitis.

PCR-positive tubercular retinal vasculitis: clinical characteristics and management.

Background Inflammation of retinal vessels is a known association of systemic tuberculosis. Patients with retinal vasculitis are subjected to extensive but unrewarding systemic workup. Polymerase chain reaction (PCR) is now commonly used to detect DNA of infective organisms including Mycobacterium tuberculosis. This study was undertaken to characterize the clinical characteristics of PCR-positive tubercular retinal vasculitis, so as to determine the clinical presentation, associated systemic features, management, and course of this form of vasculitis. Methods The clinical records of 13 patients seen between 1997 and 1999 with the diagnosis of PCR-positive tubercular retinal vasculitis from the aqueous or vitreous humor were reviewed. Recorded data included age, sex, race, visual acuity, anterior and posterior segment findings, and results of diagnostic evaluations. All received antituberculosis therapy with or without concomitant corticosteroids. Laser scatter photocoagulation was done in eyes with neovascularization. One eye with vitreous hemorrhage was subjected to pars plana vitrectomy. Results There were 9 (69.2%) male and 4 (30.7%) female patients with a median age of 20 years. The disease was bilateral in seven. The most consistent finding was the presence of vitritis in all the eyes followed by vitreous snowball opacities in 17 eyes (89.4%), neovascularization in 11 eyes (57.8%), retinal hemorrhages in 10 eyes (52.6%), neuroretinitis in 10 eyes (52.6%), focal choroiditis in 9 eyes (47.3%), vitreous/preretinal hemorrhage in 5 eyes (26.3%), and serous retinal detachment in 3 eyes (15.7%). Over a median follow-up of 12 months, all showed resolution of vasculitis with no recurrences. Conclusions Polymerase chain reaction–positive tubercular retinal vasculitis had varied associated fundus findings. Its recognition is important so as to order only relevant diagnostic tests.

Intratumoral FOXP3 expression in infiltrating breast carcinoma: Its association with clinicopathologic parameters and angiogenesis.

The activity of T regulatory cells (Tregs) is known to be closely associated with the expression of forkhead/winged helix transcription factor, FOXP3. To determine, whether accumulation and activation of intratumoral Tregs help in the progression of breast carcinoma, we have analyzed the intratumoral expression of FOXP3 in invasive breast carcinoma and compared it with its level in ductal carcinoma in situ (DCIS) and adjacent normal tissue with the main aim of using this factor as marker of tumor progression. Intratumoral FOXP3 levels were correlated with the levels of transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF, an invasogenic and angiogenic growth factor) and intratumoral microvessel density (IMD, a prognostic marker for angiogenesis). We also analyzed whether FOXP3 gene expression correlated with other clinicopathological variables like age, tumor stage, histological grade and lymph node metastasis. Infiltrating cancers had higher FOXP3 transcription (7.43±3.44) than did ductal carcinoma in situ (4.27±1.97, p<0.05) and normal tissues (3.51±1.22, p<0.001). Intratumoral FOXP3 expression was significantly higher in patients with stage III disease (TNM classification) compared to patients who had stage II disease (p=0.037). In infiltrating carcinoma, a significant positive correlation between FOXP3 expression and TGF-β1 expression was noted (p<0.001). Furthermore, a positive correlation between FOXP3 expression with VEGF expression and IMD values was also detected, however, statistically that was non-significant. A linear association of intratumoral FOXP3 expression with invasion, size and vascularity suggests a utility of FOXP3, an indicator of Treg activity as a marker of tumor progression and metastasis in breast carcinoma.

Immune responses in patients with HIV infection after vaccination with recombinant Hepatitis B virus vaccine

BackgroundPatients with HIV infection are at risk of co-infection with HBV, as the routes of transmission are shared and thus immunization with HBV vaccine could be protective in them. The aim of the present study was to assess the efficacy of recombinant vaccine in treatment-naive HIV positive patients and healthy controls, and to dissect out differences if any, in different limbs of immune response.MethodsForty HIV positive patients and 20 HIV negative controls, negative for HBsAg, HBsAbs and HBcAbs were vaccinated with three doses of 40μg and 20μg of vaccine respectively. Patients were divided into high CD4 and low CD4 group based on CD4+ lymphocytes of 200 and < 200/mm3 respectively. Group II consisted of healthy controls. Detection of phenotypic markers was done by flowcytometry. Cytokine estimation was done by sandwich ELISA. HBsAbs were estimated in serum by ELISA.ResultsAfter vaccination, CD4+, CD8+ and CD3+ cells increased significantly in all the groups. There was no increase in NK cell activity in patients with high CD4+ lymphocytes and only a marginal increase in patients with low CD4+ lymphocytes (170 to 293/mm3) whereas a marked increase was observed in controls (252 to 490/mm3). After vaccination, although an increase in memory cells was observed in HIV positive patients, yet HBsAb levels were significantly lower than controls (P < 0.05) indicating a functional defect of memory cells in HIV/AIDS patients. Basal IFN-γ levels were also significantly lower in HIV/AIDS patients (P < 0.01). Although the levels increased after vaccination, the peak level remained lower than in controls. HBsAb titers were much lower in HIV positive patients compared to controls. (High CD4+ group: 8834 mIU/ml, low CD4+ group: 462 mIU/ml Vs. Controls: 16,906 mIU/ml). IL-4 and IL-10 were low in patients.ConclusionDespite a double dose in patients, IL-4 and IL-10, which regulate antibody response, were also lower in patients, and this together with low CD4+ counts and lack of T help, accounted for low HBsAb levels. Vaccination in patients with CD4+ lymphocytes < 50/mm3 was ineffective. Thus early immunization is advocated in all HIV positive patients at a stage when they are still capable of mounting an adequate immune response

Successful Management of Tubercular Subretinal Granulomas

Purpose: To report the successful management of 12 eyes of 11 patients with tubercular subretinal granulomas. Methods: Eleven consecutive patients with a presumed or confirmed diagnosis of tubercular subretinal granulomas were treated with four-drug anti-tuberculosis chemotherapy with concomitant oral corticosteroids. Two patients underwent pars plana vitrectomy. Results: The study included seven males and four women with a median age of 30.5 years. Ten eyes responded well to medical management and a final visual acuity of 20/80 or better was achieved in eight of them. The eyes subjected to pars plana vitrectomy had a relatively worse outcome. Conclusions: Tubercular subretinal granulomas are amenable to medical management provided an early diagnosis is made and treatment is initiated promptly. Once the diagnosis of presumed or confirmed tuberculosis is established, surgical intervention should be avoided.

Experimentally induced various inflammatory models and seizure: Understanding the role of cytokine in rat

BACKGROUND The mechanism of epileptogenesis is not well established. There is higher incidence of seizures among patients with chronic inflammatory disease. Cytokines are rapidly induced in the brain after a variety of stimuli including inflammation. Aim of this study was to produce various inflammatory models and seizure to understand the role of TNFalpha in above mentioned models. MATERIALS AND METHODS A total of 54 male rats were included in the study. Animals were divided into 3 groups of colitis, arthritis, and cotton wool granuloma. Each group had 3 subgroups of control, model and treatment. At the end of 3 days in colitis, 17 days in arthritis and 7 days in cotton wool granuloma groups a subconvulsive dose of PTZ (40 mg/kg i.p) was injected to note seizure onset and seizure score. Brain samples were subjected to DNA fragmentation testing. Presence of inflammation was confirmed by morphology and histology. Plasma and brain TNFalpha levels were measured. RESULTS The models of colitis, arthritis and CWG were effectively produced as evidenced by morphology and histology scores (p<0.001). Seizure onset was reduced and grade was increased (p<0.001). Thalidomide reduced the morphological, histological (p<0.002), DNA fragmentation and seizure grade (p<0.001) while increased seizure onset (p<0.001) in the arthritis group. TNFalpha levels in both plasma and brain were reduced following thalidomide treatment (p<0.002) in arthritis group. There were no significant findings in colitis or cotton wool granuloma groups. CONCLUSION Inflammation was associated with decreased threshold to PTZ induced seizure. Thalidomide is effective in reducing the extent of arthritis as well as reducing the seizure scoring and increasing seizure onset in the adjuvant arthritis group. Thalidomide was also effective in reducing TNFalpha levels thus contributing to its antiepileptic activity.

Serotonin transporter promoter variant: Analysis in Indian IBS patients and control population.

Background Studies of serotonin reuptake transporter (SERT-P) polymorphism and irritable bowel syndrome (IBS) have shown diverse results among different populations, which might be due to racial and ethnic difference. Aim This study was to investigate the potential association between the SERT-P polymorphism and clinical subtypes of IBS patients in the Indian population. Method This prospective case-control study included 151 IBS patients. Ninety-two patients were diarrhea-predominant IBS, 44 were constipation-predominant IBS (C-IBS), 15 were alternating diarrhea and constipation IBS, and 100 were healthy controls. SERT gene polymorphism was studied by polymerase chain reaction. Result A genotypic association was observed between SS genotype of SERT-P polymorphism and C-IBS (P<0.05). When the L/S and L/L genotypes were combined into one group, the frequency of the S/S genotype was significantly higher than that of the non-S/S genotype between C-IBS and the control group (P<0.05). There was no significant difference in the SERT-P genotype and allele frequency between c-ibs, alternating diarrhea and constipation IBS, all types of IBS cases, and controls. Conclusions A significant association was observed between the SS genotype of SERT-P polymorphism and C-IBS in the Indian population.

Synthesis and Antileishmanial activity of Piperoyl-Amino Acid Conjugates

Based on reported antileishmanial activity of naturally occurring alkaloid piperine and amino acid esters, their conjugates were synthesized by the hydrolysis of piperine to piperic acid followed by reaction with amino acid methyl esters. These conjugates were further converted to compounds with free carboxyl group and those with reduced double bonds. The synthesized compounds were evaluated for activity against promastigote and amastigote forms of L. donovani in vitro. All the compounds showed better activity than either piperine or the amino acid methyl esters. Piperoyl-valine methyl ester was the most active compound showing an IC50 of 0.075 mM against the amastigotes. Two active compounds were evaluated for in vivo activity in golden hamster model of leishmaniasis.

Immunology of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system (including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells (e.g., dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC.