Ulcerative Colitis: Shah SA

Mintz R, Feller ER, Bahr RL, Shah SA. · Division of Ophthalmology, University of Michigan, Ann Arbor, MI, USA. · Inflamm Bowel Dis. · Pubmed #15168814 No free full text.

Abstract: Extraintestinal manifestations of inflammatory bowel disease (IBD) occur in one third of patients. Ocular complications are infrequent, occurring in less than 10% of cases, but can be associated with significant morbidity, including blindness. Ocular complaints are often nonspecific; clinical relevance may not be appreciated by patient or physician and, thus, be misdiagnosed. Evaluation of the eye should be a routine component in the care of patients with IBD. Clinicians must be aware of the spectrum of ocular symptoms and know that these complaints may precede a diagnosis of ulcerative colitis (UC) or Crohn's disease (CD). We review ocular pathology in IBD to alert clinicians to the diverse, at times confusing, spectrum of eye disorders associated with these diseases. Clinical manifestations include blurred vision, teary, burning or itchy eyes, ocular pain, photophobia, conjunctival or scleral hyperemia, loss of visual acuity, and possible blindness. Many patients are unaware that IBD has a risk of eye complications and, therefore, patient education is vital.

Lombardi DA, Feller ER, Shah SA. · Gastroenterology Division, Brown University School of Medicine, One Randall Square, Providence, RI 02904, USA. · Compr Ther. · Pubmed #11894442 No free full text.

Abstract: The medical management of inflammatory bowel disease in the new millennium requires integrating cost concerns with the efficacy and safety profiles of the expanded therapeutic options available in order to achieve optimal patient outcome.

Sands BE, LeLeiko N, Shah SA, Bright R, Grabert S. · Harvard Medical School, USA. · Med Health R I. · Pubmed #19385383 No free full text.

This publication has no abstract.

Shah SA, Feller ER. · Warren Alpert Medical School of Brown University, USA. · Med Health R I. · Pubmed #19385380 No free full text.

This publication has no abstract.

Shah SA, Looby E, Volkov Y, Long A, Kelleher D. · Department of Clinical Medicine and Dublin Molecular Medicine Centre, Trinity College and St. James's Hospital, Dublin, Ireland. · Eur J Cancer. · Pubmed #16122920 No free full text.

Abstract: Deoxycholic acid (DCA) has been implicated in colonic carcinogenesis through effects mediated by protein kinase C (PKC) activation. By contrast, ursodeoxycholic acid (UDCA) is reported to reduce colon cancer incidence in ulcerative colitis. The aim of this study was to investigate whether UDCA modulated DCA-induced PKC isoenzyme translocation to its site of activity. HCT116 cells were treated with DCA, UDCA alone or pre-treated with UDCA followed by DCA. Analysis of translocation of endogenous and enhanced green fluorescent protein (EGFP) constructs of PKC isoenzymes was performed. Both DCA and phorbol myristate acetate (PMA) but not UDCA caused translocation of endogenous PKC alpha, epsilon and delta and transfected PKC beta1-, epsilon- and delta-EGFP from cytosol to plasma membrane, reflecting isoenzyme activation. Furthermore, UDCA inhibited DCA-induced translocation of PKC isoenzymes. Inhibition of DCA-induced PKC translocation may be a mechanism for UDCA-mediated chemoprevention of colon carcinogenesis.

Shah SA, Volkov Y, Arfin Q, Abdel-Latif MM, Kelleher D. · Department of Clinical Medicine and Dublin Molecular Medicine Centre, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland. · Int J Cancer. · Pubmed #16106402 No free full text.

Abstract: Deoxycholic acid (DCA) has been implicated in colorectal carcinogenesis in humans with effects on proliferation and apoptosis, mediated at least in part by activation of transcription factors nuclear factor kappa B (NF-kappaB), activator protein 1 (AP-1) and protein kinase C (PKC) enzymes. Ursodeoxycholic acid (UDCA) is reported to reduce the frequency of colonic carcinogenesis in ulcerative colitis patients. Hence, we postulated that it might differ from DCA in its regulation of these transcription factors. The aim of the study was to determine effects of DCA and UDCA on NF-kappaB and AP-1 activation and explore its relationship to PKC. Human colonic tumour cell lines HCT116 were treated with DCA, UDCA, alone or pretreated with UDCA followed by DCA or IL-1beta. In other experiments, cells were pretreated with PKC inhibitors and then stimulated with DCA and IL-1beta or PMA. Gel shift assays were performed on nuclear extracts of the cells for NF-kappaB and AP-1 analysis. Western blot analyses and immunofluorescence were performed for Rel A (p65) and IkappaB-alpha levels on the treated cells. DCA increased NF-kappaB and AP-1 DNA binding. UDCA did not increase DNA binding of NF-kappaB and AP-1 and UDCA pretreatment inhibited DCA-induced NF-kappaB and AP-1 DNA binding. PKC inhibitors blocked DCA-induced NF-kappaB and AP-1 activation. These results were validated by Western blot analysis for RelA and IkappaB-alpha. In conclusion, UDCA did not induce NF-kappaB and AP-1 DNA binding but also blocked DCA-induced NF-kappaB and AP-1 activation. These findings suggest a possible mechanistic role for UDCA in blocking pathways thought to be involved in colon carcinogenesis.

Sohn KJ, Shah SA, Reid S, Choi M, Carrier J, Comiskey M, Terhorst C, Kim YI. · Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8 Canada. · Cancer Res. · Pubmed #11559569 links to  free full text

Abstract: Mice deficient in beta(2)-microglobulin and interleukin 2 (beta(2)m(null) x IL-2(null)) spontaneously develop colon cancer in the setting of chronic ulcerative colitis (UC). We investigated mutations of the Apc and p53 genes and microsatellite instability in colonic adenocarcinomas arising in this model. Mutations of the Apc and p53 genes in the regions corresponding to mutation hot spots in human colorectal cancer were determined by sequencing in 11 colonic adenocarcinomas. Microsatellite instability was determined in matched normal and neoplastic DNA at five loci. All 11 adenocarcinomas harbored Apc mutations. Of these 11 tumors, 5 harbored truncating mutations. A total of 67 Apc mutations were found in these 11 tumors; 59 were missense mutations, whereas 8 were frameshift or nonsense mutations. Six of the 11 adenocarcinomas harbored p53 mutations. A total of seven p53 mutations were found in these 11 tumors; all mutations were transitions, 4 of which were C:G-->T:A transitions occurring in codon 229 at cytosine-guanine dinucleotides. Nine adenocarcinomas exhibited microsatellite instability in at least one of the five loci examined; 1 tumor had microsatellite instability in two loci. Molecular genetics, as well as clinical features, of colon cancer in the beta(2)m(null) x IL-2(null) mice are similar to those of human UC-associated colorectal cancer. As such, this model appears to be an excellent animal model to study UC-associated colorectal carcinogenesis.

Goggins MG, Shah SA, Goh J, Cherukuri A, Weir DG, Kelleher D, Mahmud N. · Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, St. James Hospital, Dublin, Ireland. · Mediators Inflamm. · Pubmed #11405552 links to  free full text

Abstract: BACKGROUND: Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD), and measurement of NO metabolites may be useful for monitoring disease activity. AIMS AND OBJECTIVES: To characterise urinary nitrite levels, a stable metabolite of NO, in IBD and to evaluate its potential as a marker of disease activity. METHODS: Twelve-hour urinary nitrites were measured by the microplate assay method in 46 patients with IBD (active; n = 32). Urinary samples from 16 healthy individuals served as controls. RESULTS: Increased levels of urinary nitrites were found in patients with active IBD compared with those with inactive IBD. Twenty-eight out of 32 patients (87.5%) with active IBD had detectable levels of nitrite in their urine as compared with 2/14 (14.3%) patients with inactive IBD. None of the 16 healthy controls had detectable urinary nitrite. Twelve-hour urinary nitrite in active compared with inactive IBD: 5 0.7 versus 0.1+/-0.04 micromol (P < 0.05). There was good correlation between urinary nitrite and some markers of disease activity in IBD such as C-reactive protein and microalbuminuria but not with erythrocyte sedimentation rate. Conclusions: Increased levels of nitrite were detected in urine of patients with active IBD, consistent with increased NO synthesis. This simple assay may be exploited as a potential marker of disease activity in IBD.