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Biomedical subjects

J M Pearson

Publications and source records attributed to J M Pearson.

At least 19 recordsLinked to original sources
PubMed2002

Crude open biopsy rates for benign screen detected lesions no longer reflect breast screening quality--time to change the standard.

OBJECTIVES: To investigate the changing nature of the benign screen detected breast abnormalities removed at open biopsy over a seven year period and to compare this with the improving cancer detection rate and non-operative diagnosis rate. SETTING: The Bolton, Bury, and Rochdale Breast Screening Programme. METHODS: The histopathology reports of the benign lesions removed from patients undergoing open biopsy for screen detected abnormalities between 1 April 1994 and 31 March 2001 were reviewed and the lesions classified on the B1 to B5 scale. Cancer detection rates and non-operative cancer diagnosis rates were ascertained from the breast screening computer system. RESULTS: 148 benign surgical biopsies were performed in the seven year period. There was a moderate increase in the overall benign biopsy rate over the period (from 1.26 open biopsies per 1000 women screened for the three years 1994-97 to 1.63 open biopsies per 1000 women screened for the three years 1998-2001). The biopsy rate for B2 (benign) lesions decreased slightly over the study period but the biopsy rate for B3 lesions (that is, of uncertain malignant potential) more than doubled. The majority (84%) of the B3 lesions were radial scars. There was a steady improvement in the cancer detection rate and the non-operative cancer diagnosis rate over the period, similar to that seen nationally. CONCLUSIONS: Improvements in screening technique and detection ability result in an increase in the number of subtle radiologically indeterminate or suspicious lesions detected. Many of these are radial scars, which require excision. Crude benign open biopsy rates for screening programmes are no longer meaningful, and should now be refined with separate rates for B2 lesions and B3 lesions. High quality programmes can expect to have low B2 open biopsy rates and high B3 open biopsy rates. It is inappropriate to have an upper limit for the B3 open biopsy rate.

Biomarkers↗
PubMed2001

Evidence of nerve sheath differentiation and high grade morphology in sclerosing epithelioid fibrosarcoma.

Sclerosing epithelioid fibrosarcoma is a recently described sarcoma in which ultrastructural evidence of fibroblastic differentiation forms part of the diagnostic criteria. This report describes a further case of this tumour, which showed evidence of both fibroblastic and perineurial differentiation by immunohistochemistry and electron microscopy, and which had areas of high grade morphology. The tumour metastasised and the patient died of disease 12 months after presentation. The relevance of these findings to diagnosis and differentiation in these tumours is discussed.

Cell Differentiation↗
PubMed2001

Life style characteristics associated with nutritional risk in elderly subjects aged 80-85 years.

A logistic regression model was applied to 627 elderly men and women, who participated in all three data collections of the SENECA study in 1989, 1993, and 1999, to test the hypothesis that nutritional status in 80-85 year old persons was related to functional and cognitive status, but not significantly affected by living arrangement. Additionally, the authors hypothesized that relationships between cognitive status and self-care ability, between self-care ability and living situation, and between cognitive status and living situation would be stronger with increasing age. Nutritional status was categorized as being well nourished (> or = 24) or at nutritional risk (<24) using the 18-item mini-nutritional assessment questionnaire (MNA). Diminished self-care ability was defined as inability to perform all 7 self-care items on the ADL instrument. Respondents were deemed to have possible cognitive impairment if they scored <24 on the MMSE test. Residence situation was categorized as either living alone, with spouse/partner, or with others. Nutritional risk was found to be associated with diminished cognitive status and diminished self-care ability, but not associated with living alone. Elderly people with diminished cognitive function and diminished self-care ability had a more than two times higher risk of being at nutritional risk. In addition, the strength of relationships between cognitive status and self-care ability, self-care ability and living situation, and cognitive ability and living situation all increased over time. In the oldest old lifestyle characteristics and functional ability appeared to be stronger predictors of risk for malnutrition than in younger adults.

Activities of Daily Living↗
PubMed1999

Induction of humoral and cellular responses in cynomolgus monkeys immunised with mannan-human MUC1 conjugates.

Mice immunised with oxidised mannan conjugated to the human mucin 1 (MUC1), produce MHC Class 1 restricted CD8+ cytotoxic T-cells which eradicate MUC1 + tumours, indicating potential for the immunotherapy of MUC1 + cancers in humans. We now describe preclinical studies performed in cynomolgus monkeys immunised with human or murine MUC1 conjugated to oxidised mannan, where immune responses and toxicity were examined. High titred antibodies specific for MUC1 were produced, MUC1 specific CD4+ and CD8+ T-cell proliferative responses and specific cytotoxic precursor cells (CTLp) were found, but not MUC1 specific cytotoxic T-cells (CTL). There was no toxicity and monkeys can be immunised against human MUC1 with mannan-MUC1 conjugates, but a humoral response (Th2 type) predominates. The results contrast with those obtained in mice when a CTL response (Th1 type) predominates.

Amino Acid Sequence↗
PubMed1999

The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival.

Plasminogen activator inhibitor-2 (PAI-2), a member of the serpin gene family, is thought to serve as a primary regulator of plasminogen activation in the extravascular compartment. High levels of PAI-2 are found in keratinocytes, monocytes, and the human trophoblast, the latter suggesting a role in placental maintenance or embryo development. The primarily intracellular distribution of PAI-2 also may indicate a unique regulatory role in a protease-dependent cellular process such as apoptosis. To examine the potential functions of PAI-2 in vivo, we generated PAI-2-deficient mice by gene targeting in embryonic stem cells. Homozygous PAI-2-deficient mice exhibited normal development, survival, and fertility and were also indistinguishable from normal controls in response to a bacterial infectious challenge or endotoxin infusion. No differences in monocyte recruitment into the peritoneum were observed after thioglycollate injection. Epidermal wound healing was equivalent among PAI-2 -/- null and control mice. Finally, crossing PAI-2 -/- with PAI-1 -/- mice to generate animals deficient in both plasminogen activator inhibitors failed to uncover an overlap in function between these two related proteins.

Animals↗
PubMed1998

Differentiating cells of murine stratified squamous epithelia constitutively express plasminogen activator inhibitor type 2 (PAI-2).

In stratified squamous epithelia a critical balance among cell proliferation, differentiation, and death must be maintained in order for these tissues to fulfill their barrier function. Previous studies have demonstrated that plasminogen activator inhibitor 2 (PAI-2) is a product of differentiating epidermal keratinocytes, suggesting a role for this inhibitor during squamous differentiation. Furthermore, in certain tumor cell lines, overexpression of PAI-2 confers resistance to the induction of programmed cell death, suggesting cytoprotective function(s). In the present study we demonstrate that PAI-2 mRNA and protein are constitutively and uniquely expressed in differentiating cells of murine stratified squamous epithelia, including epidermis, esophagus, vagina, oral mucosa, and tongue. PAI-2 immunohistochemical localization patterns suggest a predominantly cytosolic distribution, consistent with biochemical identification of the major PAI-2 species as a 43-kDa, presumably non-glycosylated protein. Functional analysis shows that the majority of epithelial PAI-2 is active. In contrast to the high levels of PAI-2 expression in stratified squamous epithelia, little or no PAI-2 is detectable in simple epithelia. These findings suggest that epithelial PAI-2 may mediate inhibition of intracellular proteinases associated with events during terminal differentiation and death that are unique to stratified squamous epithelia.

Animals↗
PubMed1998

Living alone does not adversely affect nutrient intake and nutritional status of 70- to 75-year-old men and women in small towns across Europe.

This study determined the relationships between living alone and a variety of sociodemographic variables and dietary intake and nutritional status of 70- to 75-year-old men and women across Europe. Data from nine centers, collected as part of the SENECA study, were selected for analysis. Respondents were categorized as either living alone, living with a spouse/partner only, or living with a spouse/partner and/or other person(s). Analyses included chi-square statistics, t-tests, and analysis of variance, measures of relationships and differences between residential-status groups. The sample included 512 subjects who lived alone, 1017 who lived with a spouse/partner only, and 380 who lived with a spouse/partner and/or other person(s). Variables which differed significantly by living arrangement included higher vitamin A, calcium, riboflavin and water intake by both males and females living alone as compared to either those living with a spouse, those living with others, or both groups. Females who lived alone had lower energy intake than those who lived with other than a spouse/partner, and women who lived alone or as couples versus those who lived with others had lower protein and carbohydrate intakes. Males who lived alone had significantly lower intakes of vitamin C than those who lived with person(s) other than a spouse, but still they were considerably above recommended levels. Respondents who lived with a spouse/partner only were less likely to have an unfavorable BMI status than people in the other two groups. Thus, nutrient intakes of 70- to 75-year-olds across Europe are generally not adversely impacted by living alone, and relative to some nutrients, namely vitamin A, calcium, and riboflavin, their diets are better than those living in one or both of the other residential categories.

Aged↗
PubMed1997

Neither platelet activating factor nor leukotrienes are critical mediators of liver injury after lipopolysaccharide administration.

The intravenous administration of lipopolysaccharide (LPS) to rats results in liver lesions characterized by the infiltration of both platelets and neutrophils into the liver and by midzonal hepatocellular necrosis. The liver injury is dependent on neutrophils, platelets and the coagulation system, as removal or inhibition of any of these components inhibits the development of hepatocellular necrosis. Platelet activating factor (PAF) and the cysteinyl leukotrienes (LTs) are potent inflammatory lipids that are critical for the development of some LPS-mediated alterations. To test the hypothesis that PAF, alone or in combination with LTs, contributes to the development of liver injury during LPS exposure, we conducted studies with the PAF receptor antagonist, WEB 2086, and the 5-lipoxygenase inhibitor, Zileuton. Female, Sprague-Dawley rats were pretreated with WEB 2086 (10 mg/kg, i.p.) alone or with Zileuton (40 mg/kg, p.o.) 1 h before the administration of LPS (4 mg/kg, i.v.) or its saline vehicle. Treatment with WEB 2086, alone or in combination with Zileuton, did not inhibit LPS-mediated hepatic neutrophil infiltration or liver injury, as assessed by histologic evaluation and increases in plasma alanine aminotransferase activity. Pretreatment with these agents also had no effect on the activation of the coagulation system or on the thrombocytopenia induced by LPS. These results suggest that PAF, alone or in combination with 5-lipoxygenase products, is not a critical mediator of LPS-induced hepatocellular injury in this model.

Administration, Oral↗
PubMed1997

Nodular erythema elevatum diutinum mimicking cutaneous neoplasms.

AIMS: We describe the cutaneous pseudoneoplastic lesions in two patients with nodular erythema elevatum diutinum, a rare chronic disorder in which polymorph nuclear fragmentation (leukocytoclasis) is present within dermal nodules showing spindle cells and fibrosis. In both cases diagnostic difficulty was encountered clinically and pathologically and various benign and malignant neoplasms were considered in the differential diagnosis. METHODS AND RESULTS: Immunohistochemically the spindle cells were negative for CAM5.2, AE1/3, S100 protein and desmin (D33). They were positive for vimentin and focally positive for CD34 and alpha-smooth muscle actin. Some of the spindle cells were positive for Mac 387 and KP1(CD68). By electron microscopy, the lesions were shown to consist of fibroblasts/myofibroblasts and fusiform macrophages. CONCLUSIONS: Increased awareness of the features described will help to avoid misdiagnosis as a neoplastic process.

Adult↗
PubMed1996

Thrombin is a distal mediator of lipopolysaccharide-induced liver injury in the rat.

Previous results demonstrated that rats given Escherichia coli lipopolysaccharide (LPS; 4 mg/kg, i.v.) experience hepatocellular necrosis that begins within 4 hr and that prior treatment with anticoagulants (e.g., heparin) which target thrombin prevents the liver injury. In this study, hepatocellular injury, as marked by increased plasma alanine aminotransferase (ALT) activity and histologic changes, was prevented when heparin or hirudin was administered to rats shortly before the onset of injury. These results suggest that thrombin is a critical mediator that acts distally in the series of inflammatory events that culminates in hepatocellular damage. To explore further this hypothesis, livers isolated from rats 2 hr after LPS administration were perfused with various media. Perfusion of livers with medium comprising diluted blood from heparin-treated donors resulted in no release of ALT activity. By contrast, perfusion with similar medium anticoagulated with ancrod, which prevents clotting by depleting fibrinogen but does not inhibit thrombin, resulted in hepatocellular injury evidenced as a time-dependent appearance of ALT activity in the medium. Moreover, when livers from rats treated 2 hr previously with LPS were perfused with buffer to which thrombin had been added, injury resulted. No injury resulted when thrombin was omitted from the buffer or when livers from saline-treated rats were used. These results indicate that thrombin is a critical and distal mediator of LPS-induced liver damage and contributes to hepatocellular injury through a mechanism that is independent of clot formation. Furthermore, inflammatory events triggered by LPS exposure are a prerequisite for thrombin-induced injury.

Alanine Transaminase↗
PubMed1996

Platelet activating factor receptor blockade alone or in combination with leukotriene synthesis inhibition does not ameliorate alpha-naphthylisothiocyanate-induced hepatotoxicity.

Alpha-naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal edema, hepatic parenchymal and biliary epithelial cell necrosis, and cholestasis in the rat. A hallmark of ANIT hepatotoxicity is periportal inflammation that includes neutrophil infiltration. Neutrophils are requisite for the expression of ANIT-induced liver injury; however, the mechanism(s) of neutrophil accumulation in the liver and the role of these cells in ANIT hepatotoxicity is incompletely understood. Platelet activating factor (PAF) is a proinflammatory agent that is both a chemoattractant for and an activator of neutrophils. Therefore, we evaluated the role of PAF in ANIT-induced liver injury. Rats were treated with the PAF receptor antagonist, WEB 2086 (WEB), to determine if it afforded protection from ANIT hepatotoxicity. In a separate study, a combination of WEB and the leukotriene synthesis inhibitor, Zileuton (ZIL), was used to address the possible interaction of PAF and leukotrienes in ANIT-induced liver injury. Treatment of rats with WEB, alone or in combination with Zileuton, did not attenuate ANIT-induced liver injury as assessed by increases in plasma alanine aminotransferase or gamma-glutamyl transferase activities. In addition, neither treatment ameliorated ANIT-induced cholestasis assessed as increased plasma bilirubin concentration. These results suggest that PAF, alone or in combination with products of 5-lipoxygenase, does not contribute to ANIT-induced liver injury.

1-Naphthylisothiocyanate↗
PubMed1996

Gadolinium chloride treatment attenuates hepatic platelet accumulation after lipopolysaccharide administration.

Intravenous administration of LPS to rats results in the accumulation of both neutrophils and platelets in the liver and the development of midzonal hepatocellular necrosis. The development of liver injury entails contributions from both cellular and soluble mediators, including neutrophils, platelets, Kupffer cells, tumor necrosis factor-alpha (TNF-alpha), and components of the coagulation system. Much remains unknown about the interactions among these mediators in the pathogenesis of liver injury in vivo. Accordingly, we conducted studies with gadolinium chloride (GdCl3), an agent that inhibits Kupffer cell phagocytosis, to evaluate the role of Kupffer cells in lipopolysaccharide (LPS)-mediated liver injury, elevation in plasma TNF-alpha activity, thrombocytopenia, hepatic platelet accumulation, and activation of the coagulation system. Female Sprague-Dawley rats were pretreated with GdCl3-6H2O (10 mg/kg, i.v.) or saline vehicle 24 h before the administration of LPS (4 mg/kg, i.v.) or saline vehicle. In a preliminary study, this GdCl3 treatment regimen decreased the clearance of colloidal carbon from blood, indicating inhibition of Kupffer cell phagocytosis. Pretreatment with GdCl3 attenuated LPS-induced liver injury, monitored as increased plasma alanine aminotransferase and isocitrate dehydrogenase activities and histologic analysis. Electron micrographs of livers from rats treated with LPS revealed platelets within the sinusoids as well as Kupffer cells with phagolysosomes containing material resembling platelets. Pretreatment with GdCl3 attenuated LPS-induced thrombocytopenia and hepatic platelet accumulation, as measured by radiolabeled platelets. Treatment with GdCl3 did not, however, alter the elevation in plasma TNF-alpha activity or the activation of the coagulation system, as evidenced by a decreased in plasma fibrinogen concentration. These results suggest that Kupffer cells contribute to LPS-induced hepatic platelet accumulation and raise the possibility that protection against LPS-induced hepatic injury by Kupffer cell inactivation may be due at least partly to decreased deposition of platelets within the liver.

Alanine Transaminase↗
PubMed1996

The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat.

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.

Animals↗
PubMed1995

Platelet participation in liver injury from gram-negative bacterial lipopolysaccharide in the rat.

Intravenous administration of lipopolysaccharide (LPS) to rats results in multifocal, primarily midzonal hepatic necrosis. The hepatic injury is associated with inflammation and is dependent on neutrophils and the coagulation system. After LPS injection into rats, plasma fibrinogen concentration and numbers of blood platelets and leukocytes decrease. Results of our studies, using immunocytochemistry for the detection of neutrophils and 111indium-labeling to identify platelets, indicate that both neutrophils and platelets accumulate within the liver early after administration of LPS to rats. The accumulation of platelets in the liver before the onset of injury suggested that platelets contribute to the manifestation of LPS-induced hepatotoxicity. To test this hypothesis, the number of circulating blood platelets was decreased by the administration of an anti-rat platelet serum (APS) before LPS administration. The consequent thrombocytopenia by APS administration was associated with an attenuation of both LPS-induced liver injury and the activation of the coagulation system. However, the APS treatment did not prevent the hepatic neutrophil accumulation. These results suggest that platelets contribute to the pathogenesis of liver injury after LPS administration, perhaps through their integral role in coagulation and/or interaction with neutrophils, but they do not appear to contribute to hepatic neutrophil accumulation.

Alanine Transaminase↗
PubMed1994

Platelets and alpha-naphthylisothiocyanate-induced liver injury.

Administration of alpha-naphthylisothiocyanate (ANIT) to rats results in periportal cholangiolitic hepatopathy. Inflammation is a hallmark of the liver injury, and expression of toxicity is dependent on blood neutrophils. The role of other cellular mediators of inflammation in ANIT-induced hepatic insult is unknown. We hypothesized that platelets participate in the expression of ANIT hepatotoxicity. To test this, circulating platelets were decreased by administration of anti-rat platelet serum (PAb) prior to treatment of rats with ANIT. The PAb treatment regimen effectively reduced circulating thrombocytes over the course of the experiment. Twenty-four hours after oral ANIT administration, rats were euthanized and liver injury was estimated by increases in serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities. Cholestasis was assessed by measurement of serum total bilirubin concentration and bile flow. Reduction in platelet numbers was associated with attenuation of the increases in plasma ALT activity and bilirubin concentration seen after ANIT administration. However, PAb treatment did not attenuate the increase in plasma GGT, a marker of biliary epithelial cell injury. ANIT-induced changes in platelet function were assessed by evaluating platelet aggregation responses in platelet-rich plasma from rats treated with ANIT in vivo. ANIT treatment modestly decreased ex vivo platelet aggregation in response to ADP and collagen stimuli. To address further the role of platelet-derived cyclooxygenase products in ANIT hepatotoxicity, rats were treated with aspirin or ibuprofen. Neither pretreatment ameliorated ANIT-induced hepatic insult. These results suggest that platelets contribute to the expression of ANIT-induced liver injury, but they do not appear to act through the production of cyclooxygenase metabolites.

1-Naphthylisothiocyanate↗
PubMed1994

An evaluation of five different methods for estimating proliferation in human colorectal adenocarcinomas.

Five different methods of determining cell proliferation have been compared in samples taken from a group of 125 human colorectal tumours labelled in vivo with iododeoxy-uridine (IUdR). The labelling index (LI) was obtained immunocytochemically using monoclonal antibodies against proliferating cell nuclear antigen (PCNA), the Ki67 antigen and IUdR (IUdRimm). Incorporation of IUdR was also determined flow cytometrically (IUdRfcm) and PCNA expression was measured in both formalin- and methanol-fixed tissue (PCNAf and PCNAm respectively). There was significant variation in the results obtained both within and between the different assays. Paired analysis of the data showed that the correlation between the different methods of determining the LI was poor. However, the IUdRfcm LI was significantly correlated with both IUdRimm (r = 0.39; n = 78; P < 0.001 by Spearman's test) and Ki67 LIs (r = 0.32; n = 87; P < 0.001). The IUdRimm LI was also significantly related to the Ki67 LI (r = 0.44; n = 60; P < 0.001). The median IUdRfcm and IUdRimm LIs were significantly higher in the aneuploid vs. the diploid tumours (17.4% vs. 6.2% for IUdRfcm; 23.2% vs. 18.9 for the IUdRimm; P < 0.001 and P = 0.014 respectively by Mann-Whitney U-test) but none of the other proliferative indices showed this relationship. Finally, none of the LIs showed a significant association with the clinical characteristics of the tumours such as stage, grade, age, sex or fixity. The findings of this investigation highlight the need for carefully controlled studies when assessing the value of proliferation markers in solid human tumours.

Adenocarcinoma↗
PubMed1994

Value of electron microscopy in diagnosis of renal disease.

AIMS: To assess the role and value of electron microscopy in the diagnosis of renal disease. METHODS: Retrospective evaluation of 88 renal biopsy specimens received for primary diagnosis by assessment of the contribution of electron microscopy to the final diagnosis in the knowledge of the light microscopy and immunofluorescence findings. RESULTS: Electron microscopy had an important diagnostic role in 75% of cases and was essential or necessary for diagnosis in 25%. In 25% of cases electron microscopy was considered unhelpful in diagnosis. CONCLUSION: Electron microscopy has an integral role in the diagnosis of renal disease, and tissue should be taken for electron microscopy in all cases if possible. In some selected cases once the light microscopy and immunofluorescence findings are known it may be possible to forego electron microscopic examination. Electron microscopy is particularly useful in the differential diagnosis of minimal change disease and the nephrotic syndrome.

Adolescent↗