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Biomedical subjects

E Ryan

Publications and source records attributed to E Ryan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Intrahepatic hepatitis C viral RNA status of serum polymerase chain reaction-negative individuals with histological changes on liver biopsy.

For individuals testing anti-HCV positive but negative for HCV RNA in serum, diagnosis remains unclear. Debate exists over whether these individuals have resolved infection or have similar clinical, histological, and virological profiles as serum PCR-positive individuals. The aim of this study was to assess the significance of histological changes in the liver of 33 serum PCR-negative women by investigation of clinical, histological, and intrahepatic HCV RNA status. For comparison, clinical and histological data from 100 serum PCR-positive women is presented. Viral RNA status was determined in snap-frozen liver biopsies using a sensitive nested PCR with an internal control. Although serum PCR-positive and -negative individuals shared similar age at diagnosis, source, and duration of infection, they differed from a clinical, histological, and virological perspective. Mean serum ALT levels were significantly lower in serum PCR-negative women (27.4 IU/L +/- 18 vs. 58.7 IU/L +/- 40 P <.001). Similarly, although inflammation (82%) and mild fibrosis (15%) were observed in PCR-negative biopsies, the mean HAI/fibrosis scores were significantly lower than in serum PCR-positive biopsies (1.9 +/- 1.5/0.15 +/- 0.4 vs. 4.2 +/- 1.4/1.1 +/- 1.3, respectively). Finally, HCV RNA was not detectable in serum PCR-negative liver biopsies but was detectable in all serum PCR-positive control biopsies. In conclusion, serum PCR-negative individuals may have mild histological abnormalities more suggestive of nonspecific reactive changes, steatosis or nonalcoholic steatohepatitis rather than chronic HCV, even when significant antibody responses are present in serum. Negative serum PCR status appears to reflect cleared past-exposure in liver.

Aged↗
PubMed2001

Genetic hemochromatosis, a Celtic disease: is it now time for population screening?

In populations of northern European ancestry, hereditary hemochromatosis (HH) is tightly linked to mutations within the hemochromatosis gene (HFE gene). Over 93% of Irish HH patients are homozygous for the HFE gene C282Y mutation, providing a reliable diagnostic marker of the disease in this population. However, the prevalence of the C282Y mutation and that of the second HFE gene mutation, H63D, have yet to be determined within the Irish population. The objective of this study was to identify the true prevalence of the genetic form of HH in the Irish population. DNA was extracted from 1002 randomly selected newborn screening cards and analyzed for the C282Y and H63D mutations within the HFE gene. Complete results were obtained from 800 cards. Mutations were identified in 364 (46%) neonates. Eight (1%) neonates were homozygous for C282Y and 8 (1%) were homozygous for H63D. One hundred and fifty-five (19%) neonates were C282Y heterozygous and 226 (28%) were H63D heterozygous. Of these, 33 (4%) carried one copy of both C282Y and H63D mutations, i.e., compound heterozygous. Allele frequencies for C282Y and H63D were 11% and 15%, respectively. The high C282Y allele frequency in the Irish population together with its close linkage to HH indicate that C282Y genotyping is the preferred screening strategy for this disease in Ireland.

Ethnicity↗
PubMed2001

The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection.

BACKGROUND/AIMS: The cohort of Irish women infected with hepatitis C virus (HCV) genotype 1b via contaminated anti-D immunoglobulin in 1977 represent a unique homogenous group to investigate the natural course of HCV infection. METHODS: The clinical status of 87 polymerase chain reaction (PCR) positive and 68 PCR negative women was investigated at diagnosis (1994/95) and after 4-5 years of follow up (21/22 years after inoculation). Other features investigated included: histological status/progression, psychosocial impact of HCV infection, extrahepatic manifestations, and HLA class II associations. RESULTS: The most common symptoms reported were fatigue and arthralgia. Furthermore, 77% of women fell within the clinical range for psychological distress. A history of icteric hepatitis was reported in 20.6% of PCR negative and 3.4% of PCR positive women after inoculation (p=0.002). The mean histological activity index/fibrosis scores of PCR positive and negative women were 4.1 (1.4)/1.1 (1.3) and 2.1 (1.5)/0.15 (0.36) at diagnosis and 4.1 (1.2)/1.0 (1.0) in 44 PCR positive women after five years of follow up. Cirrhosis or hepatocellular carcinoma was not observed. The DRB1*01 allele was present in 28.8% of PCR negative and 8.7% of PCR positive women (p=0.004). The prevalence rates of mixed cryoglobulinaemia, sicca complex, positive thyroid autoantibodies, antinuclear antibody, rheumatoid factor, and antimitochondrial antibody in PCR positive women were 12.7%, 7.6%, 13.9%, 5.1%, 3.8%, and 3.8%. CONCLUSIONS: A benign course of HCV infection with lack of disease progression was observed in women with chronic HCV, 22 years after inoculation. Acute icteric hepatitis and the HLA DRB1*01 allele were associated with viral clearance. Despite this favourable outcome, high levels of psychological distress and poor quality of life were present.

Alanine Transaminase↗
PubMed2001

Diffusion tensor imaging of patients with HIV and normal-appearing white matter on MR images of the brain.

BACKGROUND AND PURPOSE: HIV enters the CNS early in the course of infection and produces neuropsychiatric impairment throughout the course of illness, which preferentially affects the subcortical white matter. The development of a neuroimaging marker of HIV may allow for the earliest detection of cognitive impairment. The purpose of this study was to determine whether MR diffusion tensor imaging can detect white matter abnormalities in patients who have tested positive for HIV. METHODS: Ten patients with HIV (eight men and two women; mean age, 42 years) underwent MR imaging of the brain with MR diffusion tensor imaging, which included routine fluid-attenuated inversion recovery and fast spin-echo T2-weighted imaging. Diffusion constants and anisotropy indices were calculated from diffusion tensor maps. Peripheral viral load, Centers for Disease Control staging, and cluster of differentiation 4 levels were determined. RESULTS: All patients had normal results of MR imaging of the brain, except for mild atrophy. Four of 10 patients had undetectable viral loads. These patients were receiving highly active antiretroviral therapy. The diffusion constant and anisotropy were normal. Four of 10 patients had viral loads between 10,000 and 200,000. Diffusion anisotropy in the splenium and genu was significantly decreased (P < .02). The diffusion constant of the subcortical white matter was elevated in the frontal and parietooccipital lobes (11%). Two of 10 patients had viral loads >400,000. Anisotropy of the splenium was half normal (P < .0004) and of the genu was decreased 25% (P < .002). The average diffusion constant was diffusely elevated in the subcortical white matter. CONCLUSION: Calculating the diffusion constant and anisotropy in the subcortical white matter and corpus callosum in patients with HIV detected abnormalities despite normal-appearing white matter on MR images and nonfocal neurologic examinations. Patients with the highest diffusion constant elevations and largest anisotropy decreases had the most advanced HIV disease. Patients with the lowest viral load levels, who had normal anisotropy and diffusion constants, were receiving highly active antiretroviral therapy.

Adult↗
PubMed2000

Sequencing of oligosaccharides by collision-induced dissociation matrix-assisted laser desorption/ionization mass spectrometry.

A study of the collision-induced dissociation post-source decay (PSD) spectra of free oligosaccharides is presented. These spectra, when obtained with helium as collision gas, show (1,5)X fragments containing the reducing end sugar. The presence of these fragments permits Y ions and, consequently, B and C peaks to be identified. This is a common behaviour from which it has been possible to delineate a general method for the easy assignment of the peaks in PSD spectra of underivatized neutral sugars, allowing the sequence of a real unknown to be obtained.

Carbohydrate Sequence↗
PubMed2000

Immunohistochemistry of the Hfe protein in patients with hereditary hemochromatosis, iron deficiency anemia, and normal controls.

In 1996 two mutations in Hfe, the gene affected in hereditary hemochromatosis, were identified as C282Y (c.845G. A) and H63D (c.187C. G). Immunohistochemical studies have localized the protein product of Hfe to the deep crypts of the duodenum, the maximum site of iron absorption. To date, there are no published data on the cellular location and regulation of Hfe in patients with hemochromatosis who are homozygous for C282Y. The aim of this study was to identify the cellular localization of Hfe in genotyped individuals and to study possible regulation of this protein by the mutations described in the Hfe gene locus and iron deficiency. Duodenal biopsy specimens and serum for iron, ferritin, and transferrin saturation were taken from controls (n = 10) and patients with hereditary hemochromatosis (n = 10) and iron deficiency anemia (n = 10). All participants were genotyped for C282Y and H63D mutations. Expression of Hfe in the duodenum was demonstrated by immunohistochemistry. Hfe was expressed in the deep crypts of the duodenum in all three groups in a perinuclear fashion. Hfe staining was weaker in the hemochromatosis and iron deficiency patients (mean transferrin saturation 69.6%, SD 23% and 15%, SD 11%, respectively) when compared to controls (mean transferrin saturation 33.1%, SD 15%). There was no difference in the intensity of Hfe staining within the hemochromatosis group who were iron overloaded when compared to their iron-depleted counterparts. In summary, Hfe is expressed strongly in the deep crypts of the small intestine of normal subjects. Homozygosity for C282Y and conditions of iron deficiency result in a downregulation of Hfe. Furthermore, Hfe is not regulated by therapeutic iron depletion in patients with hemochromatosis who are homozygous for the C282Y mutation.

Anemia, Iron-Deficiency↗
PubMed2000

Mortality association of enhanced CD44v6 expression is not mediated through occult lymphatic spread in stage II colorectal cancer.

BACKGROUND AND AIMS: In the absence of other metastatic disease, the presence of lymph node metastasis remains the most important determinant of survival in colorectal cancer (CRC). Cluster designation 44 variant 6 (CD44v6) over-expression is associated with worse outcome in all stages of CRC. The CD44v6 is believed to confer metastatic potential through its facilitation of migration, extravasation and proliferation, although the specific means by which it conveys an adverse prognosis in CRC is unknown. The aim of the present study was to determine if CD44v6 over-expression in Stage II CRC subjects was associated with the presence of lymph node micrometastases. METHODS: We assessed tumour CD44v6 expression in 43 randomly sampled subjects who had resections for Stage II CRC between 1984 and 1991 by using immunohistochemistry. Micrometastases were sought in corresponding lymph node (LN) sections using keratin immunohistochemistry. RESULTS: There was a statistical trend between tumour CD44v6 over-expression and mortality (P = 0.09) and a significant relationship between LN cytokeratins and mortality (P = 0.01). There was no association between the detection of LN cytokeratins and tumour CD44v6 over-expression. CONCLUSION: We conclude that the adverse survival effect of CD44v6 over-expression is not mediated though lymphatic spread and postulate that it may therefore facilitate haematogenous metastasis.

Colorectal Neoplasms↗
PubMed2000

The detection of cytokeratins in lymph nodes of Duke's B colorectal cancer subjects predicts a poor outcome.

OBJECTIVES: The objectives of this study were to examine the frequency of lymph node micrometastases detected by keratin immunohistochemistry and their relationship with survival behaviour. METHODS: A total of 133 consecutive patients staged as Duke's B, who had curative resection for colorectal cancer (CRC), comprised the study population. Patients who had died of a non-CRC-related cause or who became lost to follow-up were excluded, resulting in an amended population of 100. Study end-points were defined as disease-free survival of 5 years or CRC-related death. Paraffin-embedded lymph node sections were stained with a commercial cytokeratin antibody using a standard avidin-biotin technique. RESULTS: One quarter of subjects had micrometastases. Fifty-six per cent of subjects with positive lymph nodes had an adverse outcome, compared with 11% of subjects with negative nodes. A highly significant association was found between lymph node cytokeratin expression and mortality in both the univariate (log rank P = 0.0001) and multivariate (Cox proportional hazards P = 0.0123) analysis. CONCLUSIONS: Lymph node micrometastases detected by this inexpensive and simple technique are significantly associated with mortality in Duke's B CRC. This technique may be used to select patients for adjuvant chemotherapy.

Biomarkers, Tumor↗
PubMed1999

Functional electrical stimulation exercise increases GLUT-1 and GLUT-4 in paralyzed skeletal muscle.

The study purpose was to determine the effect of functional electrical stimulation (FES)-leg cycle ergometer training (30 minutes on 3 d/wk for 8 weeks) on the GLUT-1 and GLUT-4 content of paralyzed skeletal muscle. Biopsy samples of vastus lateralis muscle were obtained pre- and post-training from five individuals with motor-complete spinal cord injury ([SCI] four men and one woman aged 31 to 50 years, 3 to 25 years postinjury involving C5-T8). Western blot analysis indicated that GLUT-1 increased by 52% and GLUT-4 increased by 72% with training (P < .05). This coincided with an increase in the muscle oxidative capacity as indicated by a 56% increase in citrate synthase (CS) activity (P < .05) and an improvement in the insulin sensitivity index as determined from oral glucose tolerance tests (P < .05). It is concluded that FES endurance training is effective to increase glucose transporter protein levels in paralyzed skeletal muscle of individuals with SCI.

Adult↗
PubMed1999

Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin.

BACKGROUND/AIMS: The host's immune response may influence the course of hepatitis C virus (HCV) infection. The aim of this study was to examine the distribution of HLA Class II DRB1* alleles in a homogeneous cohort of individuals who were infected with HCV-contaminated anti-D immunoglobulin, and to compare frequencies of alleles in individuals with spontaneous viral clearance to those with chronic HCV infection. METHODS: HLA DRB1* typing was performed on whole blood or serum from 157 females. Of these, 73 had spontaneously recovered from infection (persistently HCV RNA negative), while 84 had chronic HCV infection (persistently HCV RNA positive). A group of 5000 healthy bone marrow donors served as a control population. RESULTS: No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, alcohol consumption, source or duration of infection. The DRB1*01 allele was found significantly more frequently in individuals with viral clearance compared to those with chronic infection (27.4% vs. 7.1% p = 0.001, odds ratio OR = 4.9, pc = 0.01). No significant association was shown between severity of liver disease and DRB1* alleles. CONCLUSIONS: DRB1*01 is associated with spontaneous viral clearance in an Irish cohort infected with HCV via contaminated anti-D immunoglobulin. HLA-DRB1* genes do not appear to influence severity of liver disease. These results suggest that host HLA-DRB1* alleles are important contributors to disease outcome.

Adult↗
PubMed1999

Effect of tamoxifen on sexual functioning in patients with breast cancer.

PURPOSE: To define the incidence of sexual dysfunction in a population of women with breast cancer treated with tamoxifen. PATIENTS AND METHODS: Breast cancer patients with a performance status of 0 to 2 who had been treated with tamoxifen for 2 to 24 months completed the following measures: the Center for Epidemiologic Studies-Depression Scale, the Sexual History Form, and the Breast Cancer Prevention Trial Symptom Checklist. Forty-nine of the participants underwent gynecologic examinations with vaginal smears for determination of estrogen effect. RESULTS: Fifty-seven women were entered onto the trial. Sexual desire, arousal, and ability to achieve orgasm were comparable to norms established in participants in the Tamoxifen Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-01). Pain, burning, or discomfort with intercourse was reported in 54% of patients and did not correlate with age, surgical treatment of the primary cancer, or chemotherapy. Estrogen effect was seen on the vaginal smears of 34 of 49 participants and was more common in older patients (P = .054). The presence of estrogen effect correlated with negative reactions during sex (P = .02) and vaginal dryness or tightness (P = .046). CONCLUSION: Women treated with tamoxifen in the adjuvant setting experienced symptoms of sexual dysfunction. The individual contributions of chemotherapy and tamoxifen to sexual dysfunction warrant prospective study.

Adult↗
PubMed1999

Depressive symptomatology and specificity of social support.

Psychosocial interventions should be based on research which reflects the multidimensionality of psychosocial constructs. This study investigated six categories of social support which were associated with depressive symptomatology in a sample of 531 college students. The Social Provisions Scale was used to measure social support while the Center for Epidemiological Studies-Depression Scale was used to measure depressive symptomatology. Standard multiple regression analysis was used to analyze the variance contributed by each of the six categories of social support found on the Social Provisions Scale to depressive symptomatology. Specifically, the following categories of social support were significantly associated with depressive symptomatology: Reassurance of Worth (for male and female respondents) and Attachment (for females only). Implications for practice and research are discussed.

Adolescent↗
PubMed1999

Immunohistochemical detection of mutant p53 protein in regional lymph nodes is associated with adverse outcome in stage II colorectal cancer.

Epidemiologic data identifies a cohort of Duke's B (CRC) patients whose survival more closely matches that of Duke's C. Lymph node micrometastases may account for this discrepancy. Lymph node expression of mutant p53 protein (Mp53P) has been linked to a reduction in survival in Japanese Duke's B patients. We aimed to determine the significance of nodal p53 expression in European Duke's B patients using immunohistochemistry. The study comprised 134 consecutive patients who had resections for CRC between 1984 and 1991. End points were 5 year disease free survival or CRC related death. Thirty-four subjects did not achieve end points and were excluded. We examined tumour and nodal sections for Mp53P by immunohistochemistry and correlated this with survival using a Kaplan-Meier (KM) and a Cox Proportional hazards model (CPHT). Five year survival was 73%. Fifty-eight percent of primary tumours expressed Mp53P. Tumour p53 expression did modulate survival behavior. Twenty-six percent of subjects' lymph nodes expressed Mp53P. Fifty-three per cent of those with positive and 17% of those with negative lymph nodes died of recurrence. The relative risk for nodal Mp53P expression was 3.1. There was a significant univariate relationship between lymph node p53 expression and mortality. (Log Rank p = 0.028). Multivariate analysis also showed a significant relationship with mortality. (CPHT p = .03). We conclude that lymph node expression of Mp53P is associated with increased mortality in Duke's B CRC.

Adult↗
PubMed1998

Hemochromatosis in Ireland and HFE.

Sixty patients diagnosed with hereditary hemochromatosis with grade 3 or 4 hepatic iron overload and 18 patients diagnosed with hereditary hemochromatosis who had less than grade 3 hepatic iron overload were examined for the HFE gene mutations, 845A (C282Y) and 187G (H63D). Control samples were obtained from 109 randomly selected individuals. Fifty-six of 60 unrelated hereditary hemochromatosis patients (93%) with grade 3 or 4 hepatic iron deposition were homozygous for the C282Y mutation. Fourteen of the 18 hereditary hemochromatosis patients with <3+ iron deposition (76%) were homozygous for the C282Y mutation. Three of 8 patients who were heterozygous for the C282Y mutation were also heterozygous for the H63D mutation. Thirty-one of 109 control individuals were heterozygous for the C282Y mutation and 27 were heterozygous for the H63D mutation. Our finding that 93% of hereditary hemochromatosis patients who fulfil standard diagnostic criteria are homozygous for the C282Y mutation provides clear evidence that this mutation is strongly associated with hereditary hemochromatosis. The allele frequency of 14% for the C282Y mutation in our control population is the highest reported and supports the hypothesis of a Celtic origin for the hereditary hemochromatosis gene.

Adolescent↗
PubMed1998

Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children.

Recent clinical trials have demonstrated that new generation acellular pertussis vaccines can confer protection against whooping cough. However, the mechanism of protective immunity against Bordetella pertussis infection induced by vaccination remains to be defined. We have examined cellular immune responses in children immunized with a range of acellular and whole cell pertussis vaccines. Immunization of children with a potent whole-cell vaccine induced B. pertussis-specific T cells that secreted interferon-gamma (IFN-gamma), but not interleukin-5 (IL-5). In contrast, T cells from children immunized with acellular pertussis vaccines secreted IFN-gamma and/or IL-5 following stimulation with B. pertussis antigens in vitro. These observations suggest that protective immunity conferred by whole-cell vaccines, like natural immunity, is mediated by type 1 T cells, whereas the mechanism of immune protection generated with acellular vaccines may be more heterogeneous, involving T cells that secreted type 1 and type 2 cytokines.

Antigens, Bacterial↗
PubMed1998

A murine model in which protection correlates with pertussis vaccine efficacy in children reveals complementary roles for humoral and cell-mediated immunity in protection against Bordetella pertussis.

The results of phase 3 efficacy trials have shown that acellular and whole-cell pertussis vaccines can confer protection against whooping cough. However, despite the advances in vaccine development, clinical trials have not provided significant new information on the mechanism of protective immunity against Bordetella pertussis. Classical approaches based on measurement of antibody responses to individual antigens failed to define an immunological correlate of protection. A reliable animal model, predictive of acellular and whole-cell pertussis vaccine potency in children, would facilitate an elucidation of the mechanism of immune protection against B. pertussis and would assist in the regulatory control and future development of pertussis vaccines. In this study, we have shown that the rate of B. pertussis clearance following respiratory challenge of immunized mice correlated with vaccine efficacy in children. Using this model together with mice with targeted disruptions of the gamma interferon (IFN-gamma) receptor, interleukin-4 or immunoglobulin heavy-chain genes, we have demonstrated an absolute requirement for B cells or their products in bacterial clearance and a role for IFN-gamma in immunity generated by previous infection or immunization with the whole-cell pertussis vaccine. The results of passive immunization experiments suggested that protection early after immunization with acellular pertussis vaccines is mediated by antibody against multiple protective antigens. In contrast, more complete protection conferred by previous infection or immunization with whole-cell pertussis vaccines reflected the induction of Th1 cells. Our findings suggest that the mechanism of immunity against B. pertussis involves humoral and cellular immune responses which are not directed against a single protective antigen and thus provide an explanation for previous failures to define an immunological correlate of protection.

Animals↗