Safety and efficacy of additional levofloxacin in tuberculous meningitis: A randomized controlled pilot study.

BACKGROUND: Levofloxacin is an effective bactericidal category III antitubercular drug. There is paucity of studies comparing the role of additional levofloxacin to standard antitubercular regimen in the patients with tuberculous meningitis (TBM). AIMS: To compare the safety and efficacy of adding levofloxacin to standard four drug ATT regimen (RHZE). SUBJECTS AND METHODS: The patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid (CSF) and MRI criteria were included. Children below 15 years, patients with pregnancy, seizures, liver failure, kidney failure and malignancy were excluded. The baseline clinical, CSF and MRI characteristics were noted and consciousness was evaluated by Glasgow Coma Scale (GCS). The patients were randomized to RHZE (rifampicin, isoniazid, pyrazinamide and ethambutol) and RHZEL (RHZE and levofloxacin) groups. Outcome was defined at 6 months. Primary outcome was death and secondary outcomes were disability as assess by Barthel Index score and adverse events. RESULTS: Out of 110 TBM patients screened, 57 fulfilled the inclusion criteria. Their median age was 35 (15-75) years. 29 patients received RHZEL and 28 RHZE. The baseline clinical, biochemical and MRI characteristics were similar in the two groups. At 6 months, 11 (19.3%) patients died, 38 (66.7%) had good and 7 (12.3%) poor outcome. There was insignificant survival benefit in RHZEL group compared to RHZE (HR-2.61, 95% CI 0.73-9.36, P = 0.14), 25% patients died in RHZE where as 13.8% in RHZEL group. The disability was not significantly different between the two groups. The composite side effects were also similar between the two groups except for a higher frequency of seizure in RHZEL group (5 Vs 0) which resulted in withdrawal of levofloxacin. CONCLUSION: There was insignificant survival benefit in RHZEL which was associated with high frequency of seizures.

Is VEGF a marker of severity of scrub typhus infection?

Vascular endothelial growth factor (VEGF) and its receptors have been reported as severity markers of septicemia. Scrub typhus (ST) results in multi-organ dysfunction but the role of VEGF has not been evaluated. We report VEGF and its receptors in ST and its correlation with severity, outcome and laboratory findings. Thirty patients with ST diagnosed by solid phase immune chromatographic assay and Weil-Felix tests were included. Their clinical details, Glasgow Coma Scale (GCS), SOFA and modified Rankin Scale (mRS) scores and laboratory findings were noted. VEGF, VEGFR1 and VEGFR2 were done by ELISA at admission and repeated at 1 month. Outcome was defined at 1 month. Serum VEGF and VEGF-R1 levels were significantly higher and VEGFR2 was significantly lower in the ST patients compared to the controls. These levels significantly improved at 1 month. VEGF level correlated with SOFA score (p = 0.05) and SGPT (p = 0.04). VEGFR1 correlated with hemoglobin (p = 0.04), platelet count (p = 0.03), serum CK (p = 0.001), weakness (p = 0.04) and mRS score (p = 0.04). VEGFR2 did not correlate with any clinical or laboratory parameters. All the patients recovered with doxycycline. Serum VEGF and VEGFR1 levels increased in ST and suggest disease severity but do not predict outcome.

A Study on Apoptosis and Anti-apoptotic Status in Wilson Disease.

Wilson disease (WD) is characterized by hepatolenticular degeneration, but there is no report on apoptosis and anti-apoptotic markers in WD patients with neurological manifestation (WDN). The aim of this study was to evaluate active caspase-3 and X-linked inhibitors of apoptosis protein (XIAP) level in WDN and correlate these with disease severity and markers of death (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, malondialdehyde (MDA), and Cu) and survival signals (glutathione). Fifty-four patients with WDN and 36 healthy matched controls were included. Their severity, Burke-Fahn-Marsden (BFM) scores, blood counts, hemoglobin, serum chemistry, ceruloplasmin, and free copper and 24-h urinary copper were measured. Cranial MRI findings were noted. Serum active caspase-3, XIAP, TNF-α, IL-8, and plasma glutathione and MDA were measured using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and spectrophotometer respectively. In the patients with WDN, active caspase-3 (0.55 ± 0.11 vs 0.38 ± 0.06 ng/ml), TNF-α (76.05 ± 29.01 vs 36.05 ± 21.01 pg/ml), IL-8 (590.19 ± 89.19 vs 193.43 ± 71.01 pg/ml), and MDA (4.92 ± 0.39 vs 3.43 ± 0.21 nmol/ml) levels were increased whereas XIAP (84.66 ± 10.39 vs 95.76 ± 10.11 ng/ml) and glutathione (GSH) (2.03 ± 0.29 vs 2.98 ± 0.27 mg/dl) levels were decreased compared to controls. Active caspase-3 was correlated with neurological severity (r = 0.48), BFM score (r = 0.37), ceruloplasmin (r = -0.39), hemoglobin (r = -0.34), and serum Cu (r = 0.39). XIAP levels were correlated with neurological severity (r = -0.40), BFM (r = -0.51), serum Cu (r = -0.42), and ceruloplasmin (r = 0.34). The XIAP level positively correlated with survival (GSH) and inversely with death signals (TNF-α, IL-8, MDA and free serum Cu) whereas active caspase-3 positively correlated with death (TNF-α, IL-8, serum Cu, MDA) and inversely with survival signal (GSH). Serum active caspase-3 level increased in WDN and positively correlated with the severity of disease, death signals (TNF, IL-8, MDA, and free Cu) and inversely with GSH and XIAP.

VEGF and its receptors in dengue virus infection.

Vascular permeability determines the severity of dengue virus infection. Vascular endothelial growth factor (VEGF) and its (receptor 1) R1 and (receptor 2) R2 receptors may provide insight about the neurological complications of dengue. We report VEGF and its R1 and R2 receptors level in dengue patients and correlate these with neurological complications. Consecutive patients with dengue were subjected to clinical and neurological evaluations. Their blood counts, serum chemistry, including liver and kidney function tests, serum creatine kinase (CK), and albumin were measured. VEGF, VEGFR1 and VEGFR2 were measured by ELISA in the patients and 16 matched controls. Twenty four patients with dengue were included whose ages ranged between 15 and 67 years, and nine of whom were females. Serum VEGF level was insignificantly lower in dengue patients whereas VEGFR1 was significantly higher (P = 0.01) and VEGFR2 was significantly lower (P = 0.005) compared to controls. VEGFR2 correlated with systolic blood pressure, coagulopathy, and serum CK levels. None of the other clinical and biochemical parameters correlated with VEGF and VEGFR1 levels. VEGFR1 and R2 normalized at 1 month. VEGFR2 correlates with the clinical severity of dengue and muscle dysfunction.

Safety and efficacy of levofloxacin versus rifampicin in tuberculous meningitis: an open-label randomized controlled trial.

OBJECTIVES: We report the efficacy and safety of levofloxacin versus rifampicin in tuberculous meningitis (TBM). PATIENTS AND METHODS: In this open-label, randomized controlled trial from India, patients with TBM diagnosed on the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organ transplantation, malignancy, pregnancy, lactation, allergy, seizure, age <15 years and antitubercular treatment ≥1 month were excluded. Sixty patients each were randomized to levofloxacin (10 mg/kg, maximum 500 mg) or rifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisolone and aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeat MRI changes and serious adverse events (SAEs). RESULTS: The median age of the patients was 34.5 (16-75) years. The baseline clinical and MRI findings were similar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23 out of 60 (38.3%) patients in the rifampicin arm had died (P = 0.07). On Cox regression analysis, survival in the levofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04-4.34, P = 0.04). The functional outcome (P = 0.47) was, however, not significantly different between the two groups. On intention-to-treat analysis, 10 out of 47 (21.3%) in the levofloxacin arm and 5 out of 37 (13.5%) in the rifampicin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontinued more frequently than rifampicin due to SAEs (16 versus 4, P = 0.01). CONCLUSIONS: Levofloxacin is superior to rifampicin in reducing 6 month death in TBM but not disability. Levofloxacin may be used in TBM especially in those patients with hepatotoxicity and without seizure.

Predictors of outcome of myasthenic crisis.

There is paucity of study on predictors of myasthenic crisis (MC), prolonged ventilation and their outcome, a reason why this study was undertaken. Sixty-four patients with myasthenia gravis (MG) were included whose median age was 45 (6-84) years. Their clinical treatment, presence of thymoma, anti-acetylcholine receptor antibody (AchRAb), thymectomy, comorbidities, offending drugs and occurrence of MC were noted. Patients needing prolonged ventilation (>15 days) were noted. Hospital mortality, MG quality of life (QOL) at discharge and thereafter annual hospital visit, admission, expenditure and work day loss were enquired. Fourteen (21.9 %) patients had MC within 1-120 (median 8.5) months of disease onset within a median follow-up of 48 (3-264) months. The precipitating factors were infection in six, surgery in five, tapering of drugs in two and reaction to iodinated contrast in one patient. Male gender, bulbar weakness, AchRAb, thymoma, surgery and comorbid illnesses were related to MC. Eight of them (57.1 %) needed prolonged ventilation. Half the patients with MC had recurrent crisis (2-4 attacks). Death was not related to MC although MC patients had worse QOL, higher annual treatment expenditure with frequent hospital visit and hospitalization. In conclusion, association of comorbid illness with MC and prolonged ventilation highlights the need of close follow-up and appropriate management.

Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: a randomized controlled trial.

BACKGROUND: There is no randomized controlled trial (RCT) evaluating the efficacy and safety of low molecular weight heparin (LMWH) compared to unfractionated heparin (UFH) in cerebral venous sinus thrombosis (CVST). In this RCT, we have evaluated the efficacy and safety of LMWH versus UFH in CVST. METHODS: Consecutive patients with CVST diagnosed on the basis of MR venography (MRV) who was free of bleeding diathesis, malignancy, hepatic or renal failure were prospectively enrolled. History, clinical findings and risk factors were evaluated. MRI and MRV findings were recorded. The patients were randomized to LMWH and UFH groups for 14 days followed by oral anticoagulant. The hospital mortality and 3 months outcome as assessed by Barthel index (BI) score were noted. RESULTS: 32 patients received UFH and 34 received LMWH. The baseline demographic, clinical and radiological parameters were similar in both the groups. Six patients died and all were in UFH group (P = 0.01). At 3 months, insignificantly higher number of patients recovered completely in LMWH compared to UFH group (30 vs. 20). There was no serious side effect needing withdrawal of drugs except one was withdrawn from UFH because of heparin-induced thrombosis. CONCLUSION: Low molecular weight heparin resulted in significantly lower hospital mortality in CVST compared to UFH.

Dengue-associated transient muscle dysfunction: clinical, electromyography and histopathological changes.

BACKGROUND: Dengue is commonly associated with myalgia, but there is paucity of studies on the frequency, severity, and basis of muscle involvement. The aim of this study was to document the clinical, electromyographic, and histological changes in dengue-associated muscle dysfunction. MATERIALS AND METHODS: Seropositive dengue patients admitted to the neurology ward during 2010 were enrolled in this study. Detailed medical history, including bleeding diathesis and organomegaly, were noted. Muscle power on a 0-5 scale, muscle tone, reflex, sensations and coordination were tested. Blood counts, hemoglobin, and serum chemistry, including creatine kinase (CK) evaluations, were carried out. Concentric needle electromyography (EMG) and muscle biopsy were performed when clinical conditions were suitable. RESULTS: The study cohort comprised 39 patients with dengue, with a median age of 28 years. Of these, 31 patients showed evidence of muscle involvement-16 with clinical and 15 with subclinical muscle involvement. Eight of these patients had severe weakness and five had hyporeflexia. Thrombocytopenia was present in 26 patients, elevated serum creatinine in three patients and liver dysfunction in 31 patients. The median CK level was 837 (range 194-3,832) U/L. The EMG revealed polyphasic normal to short duration motor unit potentials, but spontaneous activity was absent. Muscle biopsy in three patients revealed interstitial hemorrhage with occasional necrosis and myophagocytosis. There was no vasculitis, but subtle inflammatory changes were present in one patient. The severity of muscle weakness correlated with the platelet count and CK level. All patients improved by 15 days of treatment initiation. CONCLUSION: Dengue commonly results in benign and self-limiting transient muscle dysfunction.

Epstein Barr virus encephalitis: clinical diversity and radiological similarity.

Clinico-radiological features of two patients with cerebrospinal fluid polymerase chain reaction-positive Epstein Barr virus (EBV) encephalitis have been reported. Both the patients presented with fever and altered sensorium, one had visual hallucination, decerebration followed by visual loss and the other had downward ocular deviation and orofacial and upper limb choreiform movement. Magnetic resonance imaging (MRI) revealed parieto-occipital involvement in both the patients. Follow-up MRI at one month was normal in one and revealed regression of lesion in the other. Both the patients, however, had severe neurologic sequelae at 18 months' follow-up. EBV encephalitis may have diverse clinical presentation with characteristic parieto-occipital involvement.

Loss of cell surface TFII-I promotes apoptosis in prostate cancer cells stimulated with activated α2 -macroglobulin.

Receptor-recognized forms of α2 -macroglobulin (α2 M) bind to cell surface-associated GRP78 and initiate pro-proliferative and anti-apoptotic signaling. Ligation of GRP78 with α2 M also upregulates TFII-I, which binds to the GRP78 promoter and enhances GRP78 synthesis. In addition to its transcriptional functions, cytosolic TFII-I regulates agonist-induced Ca(2+) entry. In this study we show that down regulation of TFII-I gene expression by RNAi profoundly impairs its cell surface expression and anti-apoptotic signaling as measured by significant reduction of GRP78, Bcl-2, and cyclin D1 in 1-Ln and DU-145 human prostate cancer cells stimulated with α2 M. In contrast, this treatment significantly increases levels of the pro-apoptotic proteins p53, p27, Bax, and Bak and causes DNA fragmentation. Furthermore, down regulation of TFII-I expression activates agonist-induced Ca(2+) entry. In plasma membrane lysates p-PLCγ1, TRPC3, GRP78, MTJ1, and caveolin co-immunoprecipitate with TFII-I suggesting multimeric complexes of these proteins. Consistent with this hypothesis, down regulating TFII-I, MTJ1, or GRP78 expression by RNAi greatly attenuates cell surface expression of TFII-I. In conclusion, we demonstrate that not only does cell surface GRP78 regulate apoptosis, but it also regulates Ca(2+) homeostasis by controlling cell surface localization of TFII-I.

Factors predicting surgical outcome of thymectomy in myasthenia gravis: A 16-year experience.

AIM: To assess the surgical outcome of myasthenia gravis (MG) following thymectomy and to determine the outcome predictors to such therapeutic approach. MATERIALS AND METHODS: This study is a retrospective review of 80 consecutive thymectomies performed for MG over a 16-year period. RESULTS: There were 41 females and 39 males (mean age, 34.32 years) with mean disease duration of 17.45 months prior to surgery. Stagewise distribution of the patients revealed 2.5% in stage I, 48.7% in stage IIA, 33.8% in stage IIB, 8.7% in stage III, and 6.3% in stage IV. The surgical approach was either trans-sternal (n=67) or video-assisted thoracoscopic route (n=13). Follow-up was obtained in 91.2% (n=73) of patients with mean duration of 67.7 months. At their last follow-up, 26.0% were in complete remission, 35.6% were asymptomatic on decreased medications, and 17.8% had clinical improvement on decreased medications. Overall, 79.4% of patients benefited from surgery, 8.2% had unchanged disease status, and 12.3% worsened clinically. Factors influencing favorable outcome include sex, disease stage, gland weight, and preoperative medication with anti-cholinesterase (P<0.05). There was one death in the perioperative period due to septicemia. Two patients died at fourth and seventh month following thymectomy. CONCLUSION: Thymectomy for MG is safe and effective. Certain influencing factors may shape treatment decisions and target higher risk patients.

Evaluation of cognitive function and P300 in patients undergoing cardiac surgery.

OBJECTIVE: This study reports cognitive, P300 and MRI changes in the patients undergoing open heart surgery. DESIGN: 18 patients undergoing open heart surgery were included who were aged > or = 18 years of age and educated at least up to 5th standard. Patients with preoperative neuropsychiatric, and metabolic illnesses were excluded. The operative and post operative events wer recorded Cognitive tests included Mini Mental State examination (MMSE), forward and backward digit span, trail making test (TMT), motor speed and precision test (MSPT), Luria's 3 step, Benton visual retention test (BVRT) and hospital anxiety and depression (HAD). P300 study was carried out using auditory oddball paradigm and recording from Cz, Fz and Pz referred to mastoids. Clinical psychometry, MRI and P300 studies were repeated after 6 weeks. RESULTS: The median age of the patients was 51 years and 7 were females. Coronary artery bypass graft (15) was done off pump and valve replacement (7) and atrial septal defect (2) were done on pump. Clinical psychometric tests did not change significantly after surgery except BVRT and MSPT were improved significantly after the surgery. The pre and post surgical P300 latency and amplitude were also not different. Follow up MRI in 10 patients also did not reveal any additional findings. CONCLUSION: Cognitive decline was not observed after open heart surgery as assessed by clinical psychometry and P300 studies.

Bladder dysfunction in spinal tuberculosis: clinical, urodynamic and MRI study.

STUDY DESIGN: An observational study. OBJECTIVE: We report clinical, MRI and urodynamic findings in spinal tuberculosis. SETTING: Tertiary care teaching hospital. METHOD: Patients with spinal tuberculosis having micturition disturbances or high postvoidal residual (PVR) urine were subjected to clinical evaluation, urodynamic and spinal MRI. Urinary symptoms were scored as per the American Urological Association Symptom (AUAS) Index. The outcome was defined at 12 months into complete, partial and poor. RESULTS: Of 30 spinal tuberculosis patients, 15 had micturition disturbance and included urinary retention in 4, stress incontinence in 2, hesitancy in 6, urgency in 11 and urge incontinence in 9 patients. Thirteen patients had paraparesis and one had quadriparesis. Spinal MRI revealed granuloma in 2, dorsal vertebral involvement in 12 and cervical and lumbar vertebral involvement in 1 patient each. On urodynamic study, detrusor hyperreflexia (DH) with high-pressure voiding was present in six, detrusor areflexia (DA) in four, normal study in one and increased PVR urine in the remaining patients. AUAS score improved on follow-up. DA changed to DH with high-pressure voiding in one patient. The 15 patients without micturition disturbance had no horizontal sensory level, milder or no weakness and only 2 had spinal cord signal changes. Patients with micturition disturbances had poorer functional recovery at 1 year compared to those without micturition disturbances. CONCLUSION: Bladder symptoms were present in 50% of the admitted patients with spinal tuberculosis and related to severity of paraplegia, horizontal sensory level, cord signal abnormality and poorer outcome compared to those without spinal tuberculosis. Urodynamic study helped in categorization and management.

Inhibition of NF-kappaB1 and NF-kappaB2 activation in prostate cancer cells treated with antibody against the carboxyl terminal domain of GRP78: effect of p53 upregulation.

Ligation of cancer cell surface GRP78 by activated alpha2-macroglobulin (alpha2M*) triggers pro-proliferative and anti-apoptotic signaling pathways. Cancer patients who develop autoantibodies to the alpha2M* binding site in GRP78 have a poor prognosis since these antibodies are receptor agonists. The NF-kappaB family of transcription factors induces expression of genes affecting cell growth and differentiation. NF-kappaB1 plays a major regulatory role in controlling innate immunity and inflammation, whereas NF-kappaB2 plays a greater role in cancer cell proliferation. Here we report that treatment of prostate cancer cells with antibody directed against the carboxyl terminal domain of GRP78 inhibits alpha2M*-induced activation of NF-kappaB2 by approximately 50% while exerting a lesser effect of approximately 20% on NF-kappaB1 activation. Treatment of these cells nearly abolished alpha2M*-induced activation of IKKalpha involved in the activation of NF-kappaB2. This antibody also suppressed alpha2M*-induced phosphorylation of IKKalpha, IKKalpha/beta, IkappaBalpha, and IkappaBbeta as well as levels of NIK. Antibody treatment of cancer cells elevated pro-apoptotic p21WAF and p27kip while reducing cyclin D1 levels. These studies demonstrate that antibody directed against the carboxyl terminal domain of GRP78 inhibits the pro-proliferative NF-kappaB signaling cascade in cancer cells.

Modulation of the unfolded protein response in prostate cancer cells by antibody-directed against the carboxyl-terminal domain of GRP78.

Receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) bind to cancer cell surface GRP78, which functions as a signaling receptor promoting proliferation and survival. Patients with prostate, ovary, and skin cancer may develop auto-antibodies to the alpha(2)M* binding site which are receptor agonists whose presence indicates a poor prognosis. By contrast, antibodies directed against the COOH-terminal domain of GPR78 (anti-CTD antibody), are antagonists which down regulate pro-proliferative signaling and upregulate p53. Unfolded protein response (UPR) signaling plays an important role in cell survival and proliferation as well as apoptosis. We, therefore, studied the effect of anti-CTD antibody on UPR signaling in 1-LN and DU-145 prostate cancer cells. Treatment of these cells, which express GRP78 on their cell surface, with this antibody significantly downregulated IRE1-alpha, PERK, and ATF6alpha-dependent UPR signaling. By contrast, the pro-apoptotic protein GADD153 was elevated. Anti-CTD antibody treatment also elevated apoptotic components, cleaved PARP-1, and Erdj5. In general, a two to threefold effect was observed for the parameters which were studied. These studies suggest that anti-CTD antibody induces growth inhibitory and pro-apoptotic effects by modulating UPR signaling in human prostate cancer cells.

PFT-alpha inhibits antibody-induced activation of p53 and pro-apoptotic signaling in 1-LN prostate cancer cells.

Antibodies against the COOH-terminal domain of cell surface GRP78 induce apoptosis in cancer cell lines via activation of p53 signaling. We now have studied the effects of PFT-alpha, an inhibitor of p53-mediated apoptotic pathways, on anti-GRP78 antibody-induced activation of p53 and pro-apoptotic signaling in 1-LN prostate cancer cells. Pretreatment of 1-LN cancer cells with this agent significantly inhibited antibody or doxorubicin-induced upregulation of p53. Concomitantly, PFT-alpha treatment prevented down regulation of ERK1/2 activation by either antibody or doxorubicin. Likewise, PFT-alpha prevented increases in the pro-apoptotic proteins BAD, BAK, BAX, PUMA, and NOXA as well as activation of caspases-3, -7, and -9. We conclude that antibody-induced apoptosis in prostate cancer cells is mediated predominantly by p53 using the mitochondrial pathway of apoptosis.

Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells.

Receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) bind to cell surface-associated GRP78 and induce proliferative and survival signaling in prostate cancer cells. As part of the cellular response to alpha(2)M*, GRP78 expression is itself upregulated. In response to other stimuli, the transcription factor TFII-I upregulates GRP78 by binding to its gene promoter. We have, therefore, studied the role of TFII-I in transcriptional upregulation of GRP78 in 1-LN human prostate cancer cells stimulated with alpha(2)M*. This treatment caused a two- to threefold increase in TFII-I and GRP78 synthesis from [(35)S]-labeled precursor amino acids. Synthesis of both TFII-I and GRP78 were significantly reduced by silencing TFII-I gene expression or pretreatment of cells with genistein or actinomycin D. Confocal microscopy was employed to demonstrate relocation of TFII-I to the nucleus. In alpha(2)M*-stimulated cells, moreover, TFII-I bound to the GRP78 promoter as determined by CHIP assay. We also demonstrate binding of TFII-I to the c-fos promoter, consistent with its role in upregulating c-fos gene expression. In non-lymphoid cells, phosphorylated c-Src is an activator of TFII-I. Ligation of GRP78 on 1-LN cells with alpha(2)M* was followed by tyrosine phosphorylation of c-Src as well as TFII-I. We conclude that alpha(2)M*-induced increase in GRP78 synthesis is caused by transcriptional upregulation of TFII-I which binds to the GRP78 promoter and thus potentiates its cell survival and antipoptotic functions in 1-LN prostate cancer cells.

The prognostic role of magnetic resonance imaging and single-photon emission computed tomography in viral encephalitis.

BACKGROUND: There is a paucity of studies evaluating the prognostic role of magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) changes in viral encephalitis. PURPOSE: To study MRI and SPECT changes in patients with viral encephalitis, and to correlate these changes with clinical findings and outcome. MATERIAL AND METHODS: During 1997-2006, 31 encephalitis patients (aged 2-60 years; nine females, 22 males) underwent both MRI and SPECT studies. Their demographic and clinical data and 6-month outcome were recorded. For the diagnosis of encephalitis, polymerase chain reaction (PCR) and IgM enzyme-linked immunosorbent assay (ELISA) were carried out. Cranial MRI was done on a 1.5T scanner, and 99mTc ethylene cysteine dimer (ECD) SPECT using a gamma camera. Outcome was defined at 6 months as complete, partial, or poor recovery. RESULTS: 19 patients had Japanese encephalitis (JE), one had herpes simplex encephalitis (HSE), and 11 had nonspecific encephalitis. Movement disorders were present in 21, parkinsonian features in 19, and dystonia in 16 patients. MRI was abnormal in 20 patients, and revealed thalamic involvement in 17, basal ganglia in eight, brainstem in 11, and cortical in two. SPECT revealed hypoperfusion in 22 patients, which was cortical in 11, thalamic in 10, basal ganglia in six, and midbrain in one. Cortical involvement was more frequently found by SPECT and brainstem involvement by MRI. Outcome of encephalitis did not differ in the different groups of encephalitis and MRI changes. CONCLUSION: MRI and SPECT show a spectrum of findings in encephalitis, but these do not correlate with 6-month outcome.

Proinflammatory cytokine levels in the serum and cerebrospinal fluid of tuberculous meningitis patients.

The pathophysiology underlying tuberculous meningitis (TBM), the most prominent extra pulmonary tuberculosis and a serious public health problem in developing countries is still unclear. Whereas, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are cytokines involved in cell-mediated immune response. TNF-alpha and IFN-gamma production has earlier been shown to be associated with tissue necrosis. To see whether these cytokines have any role to play in the pathophysiology of TBM, we measured the levels of serum and cerebrospinal fluid (CSF) TNF-alpha and IFN-gamma in 31 consecutive patients of TBM by ELISA. There was a remarkable rise (P<0.001) in the levels of serum and CSF TNF-alpha and IFN-gamma levels in TBM patients with respect to 20 age and sex-matched control subjects. Furthermore, TNF-alpha and IFN-gamma levels showed a positive correlation with the severity of the disease at the end of 6 months of antibiotic therapy. Elevated TNF-alpha and IFN-gamma levels, especially in CSF, despite of these patients undergoing multidrug therapy suggests the persistence of central nervous system inflammation. We also found an associated rise (P<0.001) in the nitric oxide (NO) levels of serum and CSF but there was no correlation between NO levels and the severity of TBM. The continuous release of cytokines despite these patients undergoing anti-tubercular therapy suggests that TBM severity may result mainly from the immune response rather than the organism itself.

Elevated inflammatory markers in a group of amyotrophic lateral sclerosis patients from northern India.

The role of cytokines in the pathophysiology of amyotrophic lateral sclerosis (ALS) and its relation to clinical outcome has not been clearly defined. We evaluated tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and nitric oxide (NO) levels in the serum of 22 ALS patients and 20 controls. Serum TNF-alpha levels and IFN-gamma levels were significantly (P < 0.001) elevated in ALS patients. We also observed NO levels to be significantly (P < 0.05) increased with respect to normal subjects. We further noticed positive correlation between the duration of ALS and these proinflammatory molecule levels. Exitotoxicity and oxidative stress are known to play a crucial role in the neurodegeneration observed in ALS. Since high levels of TNF-alpha are known to be cytotoxic, it could be that a complex interplay of these effectors may be one of the factors underlying the progression of ALS. This study confirms the involvement of inflammation in ALS and the need to develop surrogate markers to check the progression of this disease.