Hepatitis: Ray S

Maheshwari A, Ray S, Thuluvath PJ. · Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Lancet. · Pubmed #18657711 No free full text.

Abstract: Symptomatic acute hepatitis C occurs in only about 15% of patients who are infected with hepatitis C virus (HCV). Acute hepatitis C is most often diagnosed in the setting of post-exposure surveillance, or seroconversion in high-risk individuals (eg, health-care professionals or injecting drug users) previously known to be seronegative. Although transmission via transfusion and injecting drug use has declined in developed countries, unsafe blood products and medical practices continue to increase transmission of HCV in many developing countries. Clinically, acute hepatitis C can increase concentrations of alanine aminotransferase to ten times the upper limit of normal but almost never causes fulminant hepatic failure. Diagnosis of HCV infection in the acute phase is difficult since production of antibodies against HCV can be delayed by up to 12 weeks, and about a third of infected individuals might not have detectable antibody at the onset of symptoms. Therefore, testing for HCV RNA by PCR is the only reliable test for the diagnosis of acute infection. Symptomatic patients with jaundice have a higher likelihood of spontaneous viral clearance than do asymptomatic patients, and thus should be monitored for at least 12 weeks before initiating antiviral therapy. By contrast, asymptomatic patients have a much lower chance of spontaneous clearance, and might benefit from early antiviral therapy. Antiviral therapy for 12 weeks is generally effective in treating patients who are HCV RNA negative after 4 weeks of treatment; lengthier courses could be needed for those who relapse or fail to show early virological clearance.

Yao ZQ, Ray S, Eisen-Vandervelde A, Waggoner S, Hahn YS. · Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville 22908, USA. · Viral Immunol. · Pubmed #11792059 No free full text.

Abstract: Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence and chronic hepatitis. HCV-induced chronic hepatitis is a major risk factor for the development of hepatocellular carcinoma. The high incidence of HCV persistence suggests that this virus has evolved one or more mechanisms to evade and possibly suppress host immune responses. To understand the mechanism(s) involved in the establishment of HCV persistence, we have identified an HCV core protein as an immunomodulatory molecule to suppress host immune response. We have further determined a molecular mechanism of HCV core-mediated immune suppression by searching for a potential host protein(s) capable of associating with the HCV core protein. Interestingly, the Clq complement receptor, gC1qR, can bind to the HCV core. Clq is a ligand of gClqR and is involved in the early defense against viral infection as well as regulation of adaptive immune response. Similar to Clq, the HCV core can inhibit human T-lymphocyte proliferative response through its interaction with the gC1qR. It implicates that HCV core/gClqR-induced immune suppression may play a critical role in the establishment of persistent infection.

Ray S, Gragoudas E. · Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA. · Int Ophthalmol Clin. · Pubmed #11198149 No free full text.

Abstract: Despite the growing list of agents that can present as neuroretinitis, nearly one-half remain idiopathic. However, many of the candidate etiologies are treatable conditions, and accurate diagnosis can result in visual rehabilitation. A complete workup in patients presenting with acute neuroretinitis should include a thorough history and general medical evaluation. Exposure history should be thoroughly explored, including recent travel, unpasteurized and uncooked foods, sexual experience, and animal contacts. A detailed physical examination should be performed to note hidden rashes and inoculation sites and should include routine measurements of blood pressure and heart rate. Laboratory tests should be tailored to the history and may include complete blood count; erythrocyte sedimentation rate; bacterial, fungal, and viral blood cultures; antinuclear antibody test; angiotensin-converting enzyme; anti-double-stranded DNA; and C3. Serological evaluation should look for syphilis, Lyme disease, histoplasmosis, brucellosis, chlamydia, HIV, toxoplasmosis, Epstein-Barr virus, viral hepatitis B and C, and tuberculin skin test. Neuroretinitis is a clinical entity in which there is inflammation of the retinal architecture and optic nerve. There are numerous entities that can cause a picture of neuroretinitis ranging from vascular to infectious to autoimmune. With regards to the infectious etiologies, it is interesting to note that many of these organisms are obligate intracellular pathogens. The microorganisms B. henselae, T. gondii, R. typhi, T. pallidum, Mycobacterium tuberculosis, Histoplasma capsulatum, and various viruses, such as HIV, mumps, and HSV, are known intracellular agents. Other major infectious agents, such as B. burgdorferi and Leptospirosis spp. are known to remain sequestered within the circulatory system. It is possible that in this way these agents are able to breach the delicate blood-brain barrier. The implication of such findings on the treatment and management of neuroretinitis remains to be explored. Interestingly, the vast majority of infected patients do not develop neuroretinitis or demonstrate CNS involvement. Detailed examination of this variability may provide further insight into the pathogenic properties of these infectious agents, host tissue susceptibility, and mechanisms of blood-retina barrier integrity. A detailed retinal examination can provide an unobstructed view of the CNS. Careful inspection of this delicate interface may reveal subtle findings critical for accurate and rapid diagnosis of underlying systemic pathology. The varied visual and neurological symptoms of neuroretinitis attest to the fact that this is a disease of both the retina and contiguous neuronal elements. Such involvement significantly elevates the risk to the patient and emphasizes the need for early detection and prompt treatment.

Ray S, Rouse K, Appis A, Novak R, Haller NA. · Department of Medicine, Akron General Medical Center, Akron, Ohio 44307, USA. · Ren Fail. · Pubmed #18704826 No free full text.

Abstract: Fibrillary glomerulonephritis (FGN) is a relatively rare cause of renal disease, found in only 0.6-1.5% of native renal biopsies. The pathogenesis of FGN is not well described, and very few associations with disease processes other than hepatitis C virus (HCV) have been made. We describe a case that provides evidence in support of the FGN-HCV association, as well as introduces the association of FGN-HCV and hypocomplementemia. The case is a 53-year-old African-American female demonstrating a classical presentation of FGN complicated by a concomitant HCV infection. Treating an HCV infection with alpha-interferon has been shown to result in subsequent improvement in the nephrotic syndrome and renal function. However, this patient is unique in that she is complicated with hypocomplementemia, creating a complex treatment situation.

Hou T, Ray S, Brasier AR. · Department of Biochemistry, and Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1060, USA. · J Biol Chem. · Pubmed #17956865 links to  free full text

Abstract: The signal transducer and activator of transcription 3 (STAT3) is an IL-6-inducible transcription factor that mediates the hepatic acute phase response (APR). Using gamma-fibrinogen (FBG) as a model of the APR, we investigated the requirement of an IL-6-inducible complex of STAT3 with cyclin-dependent kinase 9 (CDK9) on gamma-FBG expression in HepG2 hepatocarcinoma cells. IL-6 induces rapid nuclear translocation of Tyr-phosphorylated STAT3 that forms a nuclear complex with CDK9 in nondenaturing co-immunoprecipitation and confocal colocalization assays. To further understand this interaction, we found that CDK9-STAT3 binding is mediated via both STAT NH2-terminal modulatory and COOH-terminal transactivation domains. Both IL-6-inducible gamma-FBG reporter gene and endogenous mRNA expression are significantly decreased after CDK9 inhibition using the potent CDK inhibitor, flavopiridol (FP), or specific CDK9 siRNA. Moreover, chromatin immunoprecipitation (ChIP) experiments revealed an IL-6-inducible STAT3 and CDK9 binding to the proximal gamma-FBG promoter as well as increased loading of RNA Pol II and phospho-Ser2 CTD Pol II on the TATA box and coding regions. Finally, FP specifically and efficiently inhibits association of phospho-Ser2 CTD RNA Pol II on the gamma-FBG promoter, indicating that CDK9 kinase activity mediates IL-6-inducible CTD phosphorylation. Our data indicate that IL-6 induces a STAT3.CDK9 complex mediated by bivalent STAT3 domains and CDK9 kinase activity is necessary for licensing Pol II to enter a transcriptional elongation mode. Therefore, disruption of IL-6 signaling by CDK9 inhibitors could be a potential therapeutic strategy for inflammatory disease.

Ray S, Broor SL, Vaishnav Y, Dar L, Seth P, Broor S. · Department of Microbiology, All India Institute of Medical Sciences, New Delhi - 110 029, India. · Indian J Med Microbiol. · Pubmed #17642989 links to  free full text

Abstract: PURPOSE: The objective of this study was to clone a c-DNA fragment of hepatitis C virus in a eukaryotic expression vector and to measure the efficacy of humoral immune responses in mice inoculated with this recombinant plasmid. This study was an attempt to lay a foundation for HCV nucleic acid vaccine development in the future. METHODS: A c-DNA fragment of BK146, a clone of HCV type 1b, was sub-cloned into an eukaryotic expression vector pMT3. HepG2 and COS cells were transfected with this construct, named pMT3-BK146. The expression of HCV mRNA and proteins was studied by reverse transcribed polymerase chain reaction, radio Immunoprecipitation (RIPA) and immunofluorescence (IFA). The DNA of this construct was injected into the footpad of BALB/c mice and antibody response was tested by enzyme immunoassay and indirect immunofluorescence. RESULTS: COS and HepG2 cells transiently transfected with the recombinant plasmid pMT3-BK146 showed the expression of HCV proteins by RT-PCR, RIPA and immunofluorescence. This DNA clone when injected into Balb/c mice was able to generate specific antibody response to hepatitis C virus by ELISA and IFA. CONCLUSIONS: A c-DNA fragment of HCV cloned in an eukaryotic expression vector was able to express core protein. This DNA clone was also able to elicit antibody response in mice. This can be an initial step towards the development of a potential DNA vaccine for hepatitis C virus infection.

Yao ZQ, Eisen-Vandervelde A, Ray S, Hahn YS. · Department of Pathology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA. · Virology. · Pubmed #14517080 No free full text.

Abstract: Hepatitis C virus (HCV) is efficient in the establishment of persistent infection. We have previously shown that HCV core protein inhibits T cell proliferation through its interaction with the complement receptor, gC1qR. Here we show that HCV core-induced inhibition of T cell proliferation involves a G(0)/G(1) cell cycle arrest, which is reversible upon addition of anti-gC1qR antibody. Correspondingly, the expression of cyclin-dependent kinases (Cdk) 2/4 and cyclin E/D, as well as subsequent phosphorylation of retinoblastoma (pRb), is reduced in core-treated T cells in response to mitogenic stimulation. Remarkably, degradation of p27(Kip1), a negative regulator of both Cdk4/cyclin D and Cdk2/cyclin E complexes, is significantly diminished in T cells treated with HCV core upon mitogenic stimulation. These data indicate that the stability of p27(Kip1) by HCV core is associated with blocking activated T cells for the G(1) to S phase transition and inhibiting T cell proliferation.

Ray S, Broor SL, Vaishnav Y, Sarkar C, Girish R, Dar L, Seth P, Broor S. · Virology Section, Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India. · J Gastroenterol Hepatol. · Pubmed #12653887 No free full text.

Abstract: BACKGROUND: Hepatitis C virus (HCV) is a leading cause of chronic liver disease (CLD) worldwide. The chronicity is a result of viral persistence and the ability of the virus to escape from the immune mechanisms of the host. Transforming growth factor (TGF)-beta is a cytokine thought to be responsible for viral persistence and liver fibrogenesis. METHODS: The present study examined the levels of TGF-beta messenger (m)RNA by reverse transcription polymerase chain reaction (RT-PCR) in 35 liver biopsies and HCV-transfected HepG2 cells. RESULTS: Transforming growth factor-beta mRNA was detected in nine liver biopsies from patients with chronic HCV infection, but was not detected in patients with non-HCV-related CLD or controls. On quantitation by semiquantitative PCR, TGF-beta mRNA levels ranged from 10-4.75 to 10-12.8 amol (10-7.46 +/- 3.771) in liver biopsies of HCV-related CLD. No significant difference in TGF-beta receptor levels was observed by RT-PCR in HCV- or non-HCV-related CLD by immunohistochemistry. To correlate these findings with in vitro experiments, levels of TGF-beta mRNA and its receptors were determined by RT-PCR in HepG2 cells transfected with HCV and hepatitis B virus (HBV) constructs, using mock-transfected cells as control. The TGF-beta protein levels were quantitated in these cell supernatants by enzyme immunoassay. The TGF-beta mRNA and protein levels were two logs and approximately 30 times higher in HCV-transfected HepG2 cells than in HBV- and mock-transfected cells, respectively. The TGF-beta receptors in HepG2 cells were also downregulated in HCV-transfected cells as compared with mock-transfected cells. CONCLUSION: These observations suggest upregulation of TGF-beta in HCV infection and a probable role for TGF-beta in the pathogenesis of HCV-related CLD.

Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, Strathdee SA, Vlahov D, Thomas DL. · Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD, USA. · Lancet. · Pubmed #11988247 No free full text.

Abstract: BACKGROUND: Neither previous hepatitis C virus (HCV) infection nor vaccination with HCV-derived antigens protects against reinfection. However, HCV infection and vaccination in chimpanzees has been shown to reduce the magnitude and duration of viraemia with re-challenge. We aimed to establish whether similar immunity could be achieved in man. METHODS: From a study of injecting drug users, we identified 164 people who had no evidence of previous HCV infection and 98 individuals who had been previously, but were not currently, infected with HCV. We compared the incidence and persistence of HCV viraemia in these two groups over four consecutive 6-month periods. FINDINGS: Of participants without previous infection, the incidence of HCV infection was 21% (35/164). By contrast, people previously infected were half as likely to develop new viraemia (12% [12/98]), even after accounting for risk behaviour (hazard ratio, 0.45; 95% CI 0.23-0.88). Furthermore, in HIV-1-negative people, those previously infected were 12 times less likely than people infected for the first time to develop persistent infection (odds ratio 0.05, 95% CI 0.01-0.30), and median peak HCV RNA concentration was two logs lower. HCV persisted in six of six HIV-1-positive people, even in one man who had previously cleared HCV infection when he was HIV-1 negative. INTERPRETATION: There is an alarming frequency of HCV infection and persistence among injecting drug users. Our data suggest that immunity against viral persistence can be acquired, and that vaccines should be tested to reduce the burden of HCV-related liver disease.

Ray S, Samuel T, Hawker J, Smith S. · Communicable Disease Surveillance Centre, Birmingham Heartlands Hospital, Birmingham B9 5SS. · BMJ. · Pubmed #11950735 links to  free full text

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Singh SP, Panda C, Pati B, Mishra B, Ray S. · No affiliation provided · Indian J Gastroenterol. · Pubmed #15030046 No free full text.

This publication has no abstract.