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N Nolan

Publications and source records attributed to N Nolan.

At least 19 recordsLinked to original sources
PubMed2004

Cholestatic pruritus - the role of cutaneous mast cells and nerves.

BACKGROUND: The pathogenesis of pruritus in cholestatic liver disease is poorly understood. Cutaneous mast cells and nerves are thought to contribute to pruritus in several dermatological diseases. AIM: To determine if cutaneous mast cell density, neural density and mast cell-neural interaction are increased in patients with pruritus and cholestatic liver disease. METHODS: Skin biopsy specimens from (i). patients with pruritus due to cholestatic liver disease (CLDP+; n = 6), (ii). patients with chronic liver disease without pruritus (CLDP-; n = 5), and (iii). healthy controls (n = 6) were studied. Biopsies were dual stained immunohistochemically for mast cells and nerves. RESULTS: Mast cell density in the control group was not significantly different from that in CLDP+ group or from that in the CLDP- group. Similarly neural density was not significantly different between groups when assessed either in terms of total nerve area, or in terms of the number of neural elements seen. The frequency of mast cell-nerve contact was not significantly different between groups. CONCLUSIONS: These findings suggest that mast cells, nerves or interaction between the two may not contribute to cholestatic pruritus. Therefore, therapies targeted at cutaneous mast cells or nerves are unlikely to be of benefit.

Adult↗
PubMed2004

Palpable epigastric liver as a physical sign of cirrhosis: a prospective study.

OBJECTIVE: Large numbers of patients present with abnormal liver function tests, but only a minority have significant liver disease. Physical examination may help in identifying patients with significant liver disease and in selecting patients who may require liver biopsy. Over a number of years we noted that a palpable liver in the epigastrium was common in patients with cirrhosis. The aim of this study was to evaluate this clinical sign in a cohort of patients undergoing liver biopsy. METHODS: We prospectively studied 138 consecutive patients undergoing liver biopsy in a university teaching hospital. The main outcome measure was liver fibrosis measured using the standard METAVIR scoring system. RESULTS: Thirty-eight patients had no fibrosis on biopsy, 11 patients had grade 1, eight patients had grade 2, 14 patients had grade 3 and 42 patients had grade 4 (cirrhosis). Palpable epigastric liver had a sensitivity of 86% and a specificity of 67% for the diagnosis of cirrhosis in this cohort. CONCLUSION: We suggest that a palpable liver in the epigastrium is a useful physical sign of cirrhosis in clinical practice.

Abdomen↗
PubMed2001

Transjuglar liver biopsy: a review.

Transjugular liver biopsy is advocated as the technique of choice for use in those with contraindications to standard transabdominal biopsy. This technique was introduced to our unit in 1995. We audited our experience in performing transjugular liver biopsies over a three year period. Eighty-eight biopsies were performed in seventy-eight patients. We identified no major procedure related complications, despite the presence of coagulopathy and thrombocytopenia in 85% and 47% of cases respectively. Biopsy provided histological diagnosis in 97.7% of cases. Availability of the technique allowed us to perform liver biopsy safely and quickly in patients with both acute and chronic liver problems in whom standard techniques were contraindicated. We conclude that transjugular liver biopsy is a safe and effective technique, invaluable in the investigation and management of patients in a liver diseases referral unit.

Biopsy, Needle↗
PubMed2000

The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C.

BACKGROUND & AIMS: In hepatitis C infection, several studies have examined the role of the major histocompatibility complex (MHC) in determining outcome, with variable results. To clarify the importance of MHC, we examined class II DR and DQ antigens in a homogenous cohort of women exposed to hepatitis C genotype 1b from a single inoculum. METHODS: Of 243 participants, 95 had spontaneous viral clearance and 148 are chronically infected. The frequencies of HLA class II DR and DQ antigens were compared between the 2 groups and between liver biopsy findings of 145 chronically infected subjects. RESULTS: DRB1*0101 and DQB1*0501 alleles were more frequent in subjects who sustained viral clearance than in chronically infected subjects (32.3% and 36.8% vs. 8.8% and 14.2%, respectively; P = 0.002). DRB1*03011 and DQB1*0201 occurred more frequently in chronically infected subjects than in those who cleared the virus (41.5% and 42.6% vs. 16.7% and 15.8%, respectively; P = 0.001). Both DRB1*03011 and DQB1*0201 were significantly less frequent in those with higher inflammatory scores on liver biopsy. CONCLUSIONS: We show that in a homogenous cohort of women infected with the same hepatitis C virus, several HLA antigens are associated with either viral clearance or persistence. This suggests a strong role for host immunogenetic factors in determining outcome in hepatitis C infection.

Adult↗
PubMed2000

Expansion of peripheral blood CD5+ B cells is associated with mild disease in chronic hepatitis C virus infection.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is associated with the development of chronic liver disease and extra-hepatic manifestations, which include autoantibody production, immune-mediated diseases such as cryoglobulinaemia and B-cell lymphoproliferation. Recent identification of intra-hepatic clonal B cells capable of rheumatoid factor production, selective infection of B cells over T cells and of an HCV receptor on B lymphocytes strongly supports a central role for these cells in the immune response to HCV infection. In particular, CD5+ B cells which are capable of producing natural antibodies with autoreactive specificities are likely to be important in the development of HCV-associated autoimmunity and lymphoproliferation. METHODS: We have investigated the presence of CD5+ B cells in a unique cohort of HCV-infected women who were infected with a single inoculum of HCV genotype 1b following immunisation with contaminated anti-D immunoglobulin in 1977. RESULTS: CD5+ B cells are significantly increased in chronic HCV infection (37.66+/-1.92%) as compared with those with resolved infection (25.33+/-1.90%). High levels of CD5+ B cells were associated with the production of rheumatoid factor. The number of peripheral blood CD5+ B cells correlated negatively with histological activity index. CONCLUSIONS: The expansion of this B cell population in patients with active HCV infection may give rise to immune-mediated sequelae associated with HCV infection. This expanded population of CD5+ B cells may protect against the development of progressive liver disease.

Adult↗
PubMed2000

Differential expression of lymphoid and myeloid markers on differentiating hematopoietic stem cells in normal and tumor-bearing adult human liver.

The presence and phenotype of lineage-committed hematopoietic progenitors in the normal adult human liver (AHL) were investigated and compared with the profiles of differentiating hematopoietic precursor populations detected in liver bearing metastases of colonic origin. Levels of hematopoietic stem cells (HSCs) (CD34(+)CD45(+)) detected in hepatic mononuclear cell (HMNC) populations were increased 6-fold when compared with matched peripheral blood samples. In normal liver, less than 5% of HSCs expressed the myeloid-associated antigen, CD33, whereas considerable proportions expressed lymphoid-associated markers (T cell, 33.39%; B cell, 17.39%; and natural killer [NK] cell, 37.17%). Significant increases were observed in the relative proportions of hepatic HSCs coexpressing CD33 (20.53%; P =.001), and the T-cell marker (CD7, 58. 13%; P =.02) in tumor-bearing liver compared with normal liver. HSCs with B-cell progenitor phenotype (CD19(+)) were significantly decreased in tumor-bearing liver (0.06%; P =.02). Despite these differences, the activation status of hematopoiesis, as measured by the coexpression of the differentiation and activation markers, CD38 and CD45RA, did not differ significantly between normal and tumor-bearing liver. These results indicate that the normal AHL harbors lineage-committed hematopoietic progenitors, and the vast majority of these progenitors express lymphoid-associated antigens with changes occurring in both the myeloid and lymphoid compartments of the hepatic hematopoietic pathway on tumor challenge. While tumor-bearing livers are enriched for intrahepatic myeloid precursors and T-cell progenitor cells, further studies are required to establish the origin and in situ development potential of hepatic HSCs in the adult human and their role in tumor immunity.

Adolescent↗
PubMed1999

Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist.

J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist.

Animals↗
PubMed1998

Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes.

BACKGROUND/AIMS: Murine and human studies have documented the existence of subpopulations of lymphocytes in particular tissues that differ phenotypically and functionally from those in peripheral blood and may mature locally. Since little is known about lymphocyte subpopulations in the normal human liver, we have analysed the surface phenotypes of lymphocytes isolated from liver specimens taken from 15 donors at the time of liver transplantation, and compared these with those of peripheral blood lymphocytes. METHODS: Hepatic lymphocytes were prepared by mechanical dissociation and enzymatic digestion of liver tissue. The cells were stained with a panel of monoclonal antibodies (CD3, CD4, CD8, CD19, CD56, gammadeltaTCR, alphabetaTCR, CD8alpha-chain, CD8alphabeta dimer), and analysed by flow cytometry. In situ characterisation of hepatic lymphocytes was by haematoxylin and eosin staining of fixed liver sections and by immunohistochemical staining for common leukocyte antigen and CD3. RESULTS: Significant numbers of hepatic T lymphocytes were localised to the portal tracts and parenchyma of normal liver specimens. Flow cytometry revealed that the CD4/CD8 ratio (1:3.5) was consistently reversed compared with that in peripheral blood (2:1). Other lymphocyte populations identified include double positive CD3+CD4+CD8+ cells which accounted for a mean of 5.5% (range 3-11.6%) of hepatic CD3+ cells compared with 1.3% in blood (range 0.7-3.6%; p < 0.007), and double negative CD3+ CD4-8- cells (14.5%; range 2.7-29% compared with 5.0%; range 2.1-10.8%, p < 0.02). Over 15% (range 6.8-34%) of all hepatic CD3+ cells expressed a gammadeltaTCR compared to 2.7% (range 0.9-4.7%) of CD3+ peripheral blood lymphocytes (p < 0.004) and almost 50% of these coexpressed CD8. The CD8 alpha-chain was expressed without the beta-chain (CD8alpha+beta-) by 15.4% (range 4-29.1%) of hepatic T cells, but this phenotype was undetectable among peripheral blood lymphocytes (p < 0.009). Cells expressing both the T cell marker CD3 and the natural killer cell marker CD56 constituted 31.6% (range 14-54%) of all hepatic CD3+ lymphocytes but were rarely present amongst peripheral blood lymphocytes (0-6%; p < 0.0001). CONCLUSIONS: These data are the first to describe and quantify unconventional T lymphocyte subpopulations in the normal adult human liver which may have specialised functions in regional immune responses and which may differentiate locally. These findings have important implications for our understanding of hepatic immunoregulation and the pathogenic mechanisms involved in viral and immune-mediated liver disease and allograft rejection.

Adolescent↗
PubMed1998

The incidence of sudden unexpected death in epilepsy (SUDEP) in South Dublin and Wicklow.

Patients with epilepsy have a mortality rate higher than that of the general population. Some of this excess mortality is attributable to sudden unexpected death (SUDEP). We examined the incidence of this phenomenon both retrospectively and prospectively in the population of South Dublin and Wicklow over the period May 1992-1995. Cases were ascertained by examination of post-mortem registers of hospitals serving the area studied. Information on cases was sought from hospital records, general practitioners and families. Fifteen cases (10 male, five female) were identified resulting in an overall incidence rate of SUDEP of 1:680/year for the 3 years of the study. This is the only study of incidence of SUDEP conducted in Ireland and our results are in keeping with incidence rates elsewhere in Europe and the USA.

Adolescent↗
PubMed1998

Barrett's esophagus and the presence of Helicobacter pylori.

OBJECTIVE: Although the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease and antral gastritis has been well documented, the role of H. pylori in esophageal disease has not been clearly defined. To clarify this issue, we analyzed 141 patients with histologically confirmed esophageal disease. METHODS: The study group consisted of 82 patients with Barrett's esophagus, 19 with adenocarcinoma of the esophagus arising in columnar epithelium and 40 patients with reflux esophagitis without columnar metaplasia of the esophagus. In each of these cases the presence or absence of H. pylori was assessed histologically. RESULTS: H. pylori was present in 19 of 82 patients (23%) with Barrett's esophagus, but was absent in all patients with adenocarcinoma of the esophagus and in patients with reflux esophagitis without Barrett's metaplasia. H. pylori was found only in areas of gastric type metaplasia in the patients with Barrett's esophagus. All of the 19 Barrett's esophagus group with H. pylori had chronic inflammation, and in 16 the inflammation was severe. H. pylori was significantly associated with severity of inflammation in patients with Barrett's esophagus (p < 0.001). Members of the Barrett's group with evidence of moderate to severe dysplasia were negative for H. pylori. CONCLUSION: These data confirm that the presence of gastric type mucosa within the esophagus is a prerequisite for H. pylori colonization, and that H. pylori may contribute to the severity of inflammation in Barrett's epithelium.

Adenocarcinoma↗
PubMed1997

Orthotopic liver transplantation for veno-occlusive disease complicating autologous bone marrow transplantation.

BACKGROUND: Veno-occlusive disease of the liver is a serious and often life-threatening complication after bone marrow transplantation. Although risk factors for the development of veno-occlusive disease have been postulated, there is no precise method for accurately identifying those patients who are at risk and for whom early intervention and treatment would have maximum potential benefit. Liver transplantation has been advocated as a treatment for veno-occlusive disease in selected patients. METHODS: In this report, we describe a patient who underwent liver transplantation for life-threatening veno-occlusive disease after autologous bone marrow transplantation for acute lymphoblastic leukemia. RESULTS: Liver engraftment was achieved, but the patient developed Pneumocystis pneumonia, which failed to respond to pentamidine. The patient died 6 months after liver transplantation. CONCLUSIONS: While acknowledging the limited experience of orthotropic liver transplantation in this patient population, we suggest its consideration as a feasible, potentially beneficial treatment option in patients with severe veno-occlusive disease after bone marrow transplantation.

Adult↗
PubMed1996

Morphology, mucin histochemistry and crypt cell kinetics of ileal mucosa in an experimental model.

An animal model was used to investigate the morphology, mucin hisotchemistry and crypt cell kinetics of ileal pouch mucosa. Forty-eight Sprague Dawley rats underwent control laparotomy with ileal transection and reanastomosis, leocolic transposition of a 3 cm segment of ileum or colectomy and ileal pouch rectal anastomosis. Animals were sacrificed 20 weeks later. Partial villous atrophy and chronic inflammation were found in both transposed and pouch ileum. Although mucin histochemistry showed patchy colonic type changes, overall there was preservation of a small bowel pattern in both transposed and pouch ileum. Crypt cell mitosis, measured by bromodeoxyuridine labelling index, was reduced in ileal pouch mucosa. These data indicate that predominantly villous atrophy, rather than colonic metaplasia occurs in ileal pouch mucosa and suggest that there is a low propensity for dysplastic change in such mucosa.

Animals↗
PubMed1996

The phage-like element PBSX and part of the skin element, which are resident at different locations on the Bacillus subtilis chromosome, are highly homologous.

PBSX and skin are two unusual genetic elements resident on the Bacillus subtilis chromosome. PBSX is a phage-like element located at approximately 100 degrees which is induced by the SOS response and results in cell lysis with the release of phage-like particles. The phage particles contain bacterial chromosomal DNA and kill sensitive bacteria without injecting DNA. The skin element is located at approximately 230 degrees on the chromosome and is positioned within the sigK open reading frame (ORF). It is excised at a particular stage of sporulation, leading to reconstitution of the complete sigK gene. In this paper, we show that there are phage-like operons present in the skin element which are highly homologous to the region of PBSX comprising part of the control region and the late operon. These operons are similar in terms of their gene organization, the percentage identity of the products of homologous ORFs and the positioning and strengths of ribosome-binding sites for each ORF. Although this high degree of conservation suggests that the phange-like operons in skin can be expressed, expression of the late operon was not detected during exponential growth, during sporulation or after induction of the SOS response. However two non-phage-like operons in the skin element are expressed and have distinct expression profiles that are dependent on the growth and developmental status of the cell.

Bacillus Phages↗
PubMed1993

Management of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is thought to represent a number of biologically different processes, ranging in clinical presentation from a palpable mass to a mammographically-detected abnormality. The optimal management of DCIS is controversial. We reviewed our experience in 40 patients with DCIS, 26 with gross disease and 14 with microscopic disease. Treatment was by total mastectomy (n = 21), complete local excision (n = 16), and local excision followed by radiotherapy (n = 3). At a mean follow-up of 34 months (range 3-120), 35 patients (88%) are disease-free. All patients treated by mastectomy remained disease-free, but 3 patients (16%) treated by breast conservation surgery have had local recurrences. All local recurrences were in the same area as the original lesion, two manifesting the same subtype of DCIS and one an invasive carcinoma. The margins of excision were close to the resection margin in all cases that recurred. All four recurrences were successfully managed by mastectomy. Mastectomy is still the most secure and reliable management for DCIS, but pathologically verified wide local excision may be appropriate.

Breast Neoplasms↗
PubMed1992

Type-1 plasminogen activator inhibitor in human breast carcinomas.

We have investigated the occurrence of type-1 inhibitor of plasminogen activators (PAI-1) in human breast tumors. PAI-1 levels, measured by enzyme-linked immunosorbent assay, were significantly higher in malignant breast carcinomas (n = 178) than in benign breast tumors (n = 25). The levels of PAI-1 were found to be correlated with those of urokinase-type plasminogen activator (u-PA). The presence of PAI-1 in tumor extracts was also demonstrated by immunoblotting analysis. Immunohistochemical investigations by the use of monoclonal and polyclonal antibodies showed that PAI-1 was mostly localized in the tumor islands, associated with the tumor cells; in addition, it was present in vessel walls and in normal duct epithelia, but absent from the stroma. Analysis of RNA extracted from tumors by polymerase chain reaction revealed the presence of PAI-1 mRNA. We conclude that PAI-1 is present in human breast carcinoma cells, and that it is--at least partially-- produced locally, either by the cancer cells or by other cells in the tumors. We have previously demonstrated that a high level of u-PA in human breast carcinomas is associated with poor prognosis. These results, combined with our present findings, present 2 possibilities: either the cancer cells need PAI-1 in order to utilize the u-PA-mediated pathway of plasminogen activation for invasion and metastasis; or PAI-1 represents a defense mechanism against tumor invasion.

Animals↗
PubMed1989

Necrolytic migratory erythema with elevated plasma enteroglucagon in celiac disease.

Necrolytic migratory erythema is the distinctive skin rash of the glucagonoma syndrome. Its presence is virtually pathognomonic of a glucagon-producing pancreatic islet cell neoplasm. Results of a study of a patient with hyperglucagonemia and necrolytic migratory erythema complicating untreated celiac disease are reported. Whereas pancreatic glucagon was only mildly elevated, there was marked elevation of enteroglucagon. Immunofluorescence staining demonstrated numerous (19.6 cells per square millimeter of mucosa) enteroglucagon-positive small intestinal crypt cells. Treatment with gluten-free diet not only resulted in resolution of malabsorption and improvement in small intestinal histology but was paralleled by disappearance of necrolytic migratory erythema, normalization of plasma glucagon levels, and marked reduction in the number of enteroglucagon-producing crypt cells (0.2/mm2 mucosa). The findings demonstrate that necrolytic migratory erythema is not an exclusively paraneoplastic phenomenon and that it can occur in association with excess production of enteroglucagon by the intestinal mucosa.

Celiac Disease↗
PubMed1988

Benign peptic ulcers penetrating pericardium and heart: clinicopathological features and factors favoring survival.

Penetration of the pericardium and heart by benign peptic ulcers is rare. Before 1965 it was almost invariably fatal, but about 20% of recently reported cases have survived. We report 4 representative cases and review 91 additional cases from the literature. The ulcers arose in esophagus, hiatus hernias, abdominal stomach, and near anastomoses, and the predominant predisposing factor was previous surgery to the esophagogastric region. Whereas penetrating esophageal ulcers had a slightly better prognosis than gastric lesions, the principal determinant of clinical presentation, findings, and prognosis was the site of cardiac involvement. The clinicopathological features of pericardial, atrial, and ventricular involvement are distinct. We evaluate the different implications of these features for diagnosis, management, and prognosis and make some tentative recommendations regarding diagnostic procedures and treatment. Early diagnosis and prompt surgical intervention are critical to successful treatment of this entity, which may present with predominantly cardiac or gastrointestinal symptomatology.

Adult↗