Biomedical subjects
Publications and source records attributed to D Kelleher.
Hepatitis C is a complex disease and a significant public health problem. The long-term outcome of HCV infection is difficult to predict, as the virus may be eliminated or may persist to establish a chronic infection. Further investigation is required to clarify factors that determine or influence the outcome of infection, although unique host factors appear to significantly affect the prognosis for infected patients.
Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.
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BACKGROUND: There is concern that the incidence of non-Hodgkin's lymphoma (NHL) will rise with increasing use of immunosuppressive therapy. AIMS: Our aim was to determine the risk of NHL in a large cohort of patients with inflammatory bowel disease (IBD), and to study the association between IBD, NHL, and immunosuppressive therapy. METHODS: We studied 782 IBD patients (238 of whom received immunosuppressive therapy) who attended our medical centre between 1990 and 1999 (median follow up 8.0 years). Standardised incidence ratios (SIRs) and 95% confidence intervals (CI) were calculated. Expected cases were derived from 1995 age and sex specific incidence rates recorded by the National Cancer Registry of Ireland. RESULTS: There were four cases of NHL in our IBD cohort (SIR 31.2; 95% CI 2.0-85; p=0.0001), all of whom had received immunosuppressive therapy: azathioprine (n=2), methotrexate (n=1), and methotrexate and cyclosporin (n=1). Our immunosuppressive group had a significantly (59 times) higher risk of NHL compared with that expected in the general population (p=0.0001). Three cases were intestinal NHL and one was mesenteric. Mean age at NHL diagnosis was 49 years, mean duration of IBD at the time of NHL diagnosis was 3.1 years, and mean duration between initiation of immunosuppressive therapy and diagnosis of NHL was 20 months. CONCLUSIONS: Although underlying IBD may be a causal factor in the development of intestinal NHL, our experience suggests that immunosuppressive drugs can significantly increase the risk of NHL in IBD. This must be weighed against the improved quality of life and clinical benefit immunosuppressive therapy provides for IBD patients.
The aetiology of hepatic dysfunction in patients with HIV infection is multifactorial. Re-activation of hepatitis C infection, drug toxicity, and opportunistic infections are all potential causes. Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used as part of combination antiretroviral therapy for the treatment of HIV infection. It is associated with a significant incidence of hepatotoxicity, usually occurring in the initial month of therapy. We report the case of a 49-year-old man who developed NVP-induced prolonged hepatotoxicity 5 months after commencing antiretroviral therapy.
BACKGROUND/AIMS: Our objectives were: (1) to assess the clinical benefits and costs of performing ultrasound-guided liver biopsy with an automated needle compared to blind biopsy with a conventional Trucut needle in patients with chronic hepatitis C; (2) to compare the histological yield of automated needles with Trucut needles. METHODS: We prospectively studied 166 patients with hepatitis C virus who underwent either ultrasound-guided biopsy using automated ASAP needles or blind biopsy using conventional Trucut needles. Both groups were matched for age, sex, cirrhosis, needle gauge and operator experience. Patient tolerance, complications and histological adequacy were assessed. In a separate in vitro study, we assessed the histological adequacy of liver biopsy specimens obtained using automated and Trucut needles from 10 fresh autopsy cases. RESULTS: Ultrasound-guided biopsy caused significantly less biopsy pain (36.4% vs. 47.3%; p < 0.0001) and significantly less pain-related morbidity (1.8% vs. 7.7%, p < 0.05). Although, there was no significant difference in diagnostic yield between guided and blind biopsy (98% vs. 94%, p = 0.15), 3 blind biopsies (3.3%), including 2 which yielded extra-hepatic tissue, had to be repeated. The additional expense of performing guided liver biopsy with automated needles was 42 Irish Pounds per patient. In vitro, automated ASAP 15G needles provided liver specimens comparable to Trucut 15G needles and had the highest histopathologic score among the automated needles assessed. CONCLUSIONS: Even in the absence of major complications, ultrasound-guided liver biopsy with an automated needle in HCV patients is safer, more comfortable and only marginally more expensive than blind Trucut biopsy.
Primary cutaneous B-cell lymphoma is a low-grade malignancy, distinct from other lymphomas in terms of biological activity and response to treatment. We describe a 77-year-old woman with a five-year history of chronic hepatitis C infection who developed a lower-limb lesion over a period of 3 months which was diagnosed as a high-grade cutaneous B-cell lymphoma. Despite a lack of definitive evidence implicating hepatitis C virus (HCV) in the aetiology of lymphomas, there is considerable research which establishes a strong association between these two diseases. On the basis of published research and the demonstration of HCV RNA in the lymphomatous tissue, we consider this to be a rare case of primary cutaneous lymphoma in association with hepatitis C.
OBJECTIVE: To examine the gastrointestinal (GI) immune system in rheumatoid arthritis (RA) for evidence of activation. METHODS: Duodenal biopsies from 25 patients with RA were obtained by endoscopy. Single cell suspensions from the epithelial layer and lamina propria were prepared. Flow cytometry was used to examine the expression of CD4, CD8, T cell receptor-gammadelta (TCR-gammadelta), TCR-alphabeta, HLA-DR, CD44, and interleukin 2 receptor on gut T lymphocytes. Fifteen disease control (DC) individuals and 6 patients with osteoarthritis (OA) taking longterm nonsteroidal antiinflammatory drug (NSAID) therapy were also investigated. Peripheral blood T lymphocytes from all individuals were examined for the expression of these surface molecules. RESULTS: HLA-DR expression was significantly increased on intraepithelial lymphocytes (IEL) and enterocytes from patients with RA (n = 13) compared with the 2 control groups (p<0.01). Immunohistochemistry also revealed increased expression of HLA-DR on enterocytes from patients with RA. RA IEL (n = 6) expressed significantly higher levels of CD44 (p<0.02). In the lamina propria, a small but significant gammadelta T lymphocyte population (mean 5.5%, range 2-12%) was detected in rheumatoid factor positive RA patients (n = 8) compared with RF negative RA patients (n = 8, mean 2%, range 0.4-6%; p<0.01) and the disease control group (n = 15, mean 2%, range 0.5-5%; p<0.01). None of these changes were detectable in peripheral blood lymphocytes from patients with RA. CONCLUSION: This study demonstrates evidence of activation of specific components of the GI immune system in RA. Peripheral blood T lymphocytes from patients with RA did not show increased expression of activation markers, suggesting that changes in the RA GI tract are not systemic but localized. Moreover, these changes appear to be independent of NSAID therapy.
T cells activated via integrin receptors can polarize and start crawling locomotion with repeated cycles of cytoskeletal reassembly processes, many of which depend on phosphorylation. We demonstrate that protein kinase C (PKC) activation represents an essential event in induction of active T cell motility. We find that in crawling T cells triggered via cross-linking of integrin LFA-1 two PKC isoenzymes, beta(I) and delta, are targeted to the cytoskeleton with specific localization corresponding to the microtubule-organizing center (MTOC) and microtubules, as detected by immunocytochemistry and immunoblotting. Clustering of LFA-1 associated with its signaling function also occurs at the membrane sites adjacent to the MTOC. We further show that cells of a PKC-beta-deficient clone derived from parental PKC-beta-expressing T cell line can neither crawl nor develop a polarized microtubule array upon integrin cross-linking. However, their adhesion and formation of actin-based pseudopodia remain unaffected. Our data demonstrate the critical importance of the microtubule cytoskeleton in T cell locomotion and suggest a novel microtubule-directed intracellular signaling pathway mediated by integrins and involving two distinctive PKC isoforms.
OBJECTIVES: To evaluate, over 12 weeks, the antiretroviral activity and safety of abacavir, used alone and in combination with zidovudine (ZDV), as treatment for HIV-1-infected subjects who had limited or no antiretroviral treatment. DESIGN: Seventy-nine HIV-1-infected subjects, with CD4 cell counts 200-500 x 10(6)/l and <12 weeks of previous treatment with ZDV were enrolled in a multicenter study. Subjects were randomly assigned to one of four cohorts receiving abacavir monotherapy for the first 4 weeks (200, 400, or 600 mg every 8 h daily, or 300 mg every 12 h daily) and, thereafter, combination therapy of abacavir with 600 mg ZDV or ZDV placebo, administered in a double-blind manner for an additional 8 weeks. METHODS: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4+ cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities during the 12-week period and for 4 weeks post-treatment. RESULTS: Treatment with abacavir, alone or in combination with ZDV, produced marked decreases in plasma HIV-1 RNA loads and increases in CD4+ cell counts in all groups. At week 4, median plasma HIV-1 RNA loads decreased by 1.11-1.77 log10 copies/ml and median CD4+ cell counts increased by 63-111 x 10(6)/l in all groups. At week 12, median HIV-1 RNA loads decreased by 1.02-2.24 log10 copies/ml (abacavir monotherapy) and by 1.81-2.01 log10 copies/ml (abacavir-ZDV); median CD4+ cell counts increased by 79-195 x 10(6)/l (abacavir monotherapy) and by 93-142 x 10(6)/l (abacavir-ZDV). At week 12, the percentage of subjects who had plasma HIV-1 RNA levels below 400 and 40 copies/ml were 28 and 11%, respectively (abacavir monotherapy) and 69 and 22%, respectively (abacavir-ZDV). Eight subjects (10%) discontinued the study prematurely because of adverse events; nausea (n = 4) and hypersensitivity (n = 3) were the most common reasons for withdrawal. There were no deaths among the study subjects. CONCLUSIONS: In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.
The protein kinase C family of serine-threonine kinases are important signal transducers participating in many different agonist-induced signalling cascades. PKC is activated by increases in diacylglycerol produced in response to agonist-induced hydrolysis of inositol phospholipids. PKC is thought to reside in the cytosol in an inactive conformation and translocate to the plasma membrane upon cell activation where it modifies various cellular functions through phosphorylation of target substrates. Increasing evidence has illustrated that this family of enzymes is capable of translocating to other subcellular sites than the plasma membrane. A key to understanding the functions of the members of this family is identifying their physiological substrates and their relationship with those target substrates. The idea that PKC may be an important regulator of cytoskeletal function has been suggested by numerous studies. Activation of PKC in a variety of different cell types leads to changes in the cell cytoskeleton including lymphocyte surface receptor capping, smooth muscle contraction and actin rearrangement in T cells and neutrophils. Given the ubiquitous expression of PKC and the diversity of cytoskeletons in different cell types it is not surprising that PKC has been shown to be associated with and/or phosphorylate a wide range of cytoskeletal components. This review examines the interaction of PKC with the cytoskeleton and discusses some of the cytoskeletal functions ascribed to PKC to date.
Since the burgeoning of the 'health outcomes' movement there has been an ever-increasing body of literature on health outcomes policy debates, directions, frameworks and tools for implementing health outcome-directed initiatives. There is a significant gap in the literature, however, in regard to translating a comprehensive health outcomes policy into practice at a local level. This paper addresses that gap. It describes the local implementation of a comprehensive health outcomes approach which works across the continuum of care. It identifies those organisation-wide structures and processes that support successful progress, thereby providing a useful guide to other organisations wishing to institutionalise the health outcomes approach.
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The field of pediatric nutrition continues to advance, with increasing evidence that diets early in life have long-lasting effects on health and disease well into adulthood. Pediatricians and nutritionists have long appreciated the importance of adequate nutrition in infancy for optimal growth and development, but only in recent years has the link between pediatric nutrition and diseases of so-called "adult onset" been realized. Two important topics in the field, obesity and the use of low-fat diets early in life, have been the subject of recent literature, and developments in these areas are summarized. Although the genetic basis for some causes of obesity are becoming clear, reliable assessment and treatment of obese children are still wanting in many cases. The ease with which healthy pediatric diets meet the recommended dietary guidelines for fat intake is also reviewed. Finally, the possibility that changes in federal funding of food assistance programs might have adverse effects on pediatric nutrition is also noted.
Hepatic granulomas have been detected in cases of chronic hepatitis C virus (CHCV) infection. Here we report upon three selected cases of CHCV infection who were treated with IFN alpha, in whom hepatic granulomas were absent on initial liver biopsies, but in whom granulomas developed following IFN alpha therapy. In one case, complete regression of these granulomas was noted 17 months following discontinuation of treatment, more strongly implicating IFN alpha in the aetiopathogenesis of such granulomas in this case. These findings suggest that IFN alpha may have a biological role in the pathogenesis of granulomatous liver disease in these patients. All three cases were poor/non-responders to IFN alpha, suggesting that the development of hepatic granulomas during IFN alpha therapy may be associated with a poor response to treatment.
Helicobacter pylori colonizes the gastric mucosa, and the infection is related to the development of diverse gastric pathologies, possibly by directly or indirectly affecting epithelial-cell function. We analyzed the influence of the bacteria on transepithelial electrical resistance (TER) on a model tight epithelium, T84, grown to confluence in permeable filters. H. pylori sonicates produced a dramatic decrease in TER after 1 to 2 h of exposure, while sonicates from other bacteria did not induce a significant reduction of TER. The effect induced by sonicates was mimicked by a water-soluble fraction from the bacterial surface, was not reproducible with isolated lipopolysaccharide, and was concomitant with a significant increase in the paracellular permeability of the marker molecule [14C]mannitol. Furthermore, H. pylori sonicates also provoked a significant increase in permeability to [14C]mannitol across rat gastric mucosa in vitro. The sonicate-induced decrease in TER in T84 monolayers was inhibited by the protein kinase C (PKC) activator phorbol myristate acetate. As PKC is directly involved in tight junction regulation, we suggest that H. pylori may induce intracellular signalling events counteracting PKC effects. Following long-term H. pylori stimulation, epithelial monolayers regained baseline resistance values slowly after 24 h. The resistance recovery process was inhibited by cycloheximide, indicating its dependency upon protein synthesis. No association between resistance variation and E-cadherin protein levels was observed. These results indicate that H. pylori alters in vitro the barrier properties of the epithelium, probably by generating cell signalling events counteracting the normal function of PKC. This increased permeability may provide a potential mechanism by which H. pylori antigens can reach the gastric lamina propria, thereby activating the mucosal immune system.
Extracellular matrix proteins and proteins involved in epithelial adhesion are essential for maintenance of tissue structure. Helicobacter pylori is the major aetiological agent in peptic ulcer disease and has been shown to increase gastric cancer risk up to ninefold. In this study, changes induced by H pylori on the expression of extracellular matrix proteins (collagen IV, fibronectin, and laminin) as well as two essential proteins for cell-basement and cell-cell adhesion (alpha 6-integrin and E-cadherin) were assessed. Immunohistochemistry was performed in antral biopsy sections obtained from infected and non-infected patients, and light microscopy was used to determine the distribution and intensity of specific staining. The results showed that the infection was significantly associated with downregulation of E-cadherin, an essential protein for maintenance of solid tissues and differentiation, but did not induce changes in the expression of alpha 6-integrin or the extracellular matrix proteins.
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