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Biomedical subjects

L Cobb

Publications and source records attributed to L Cobb.

18 recordsLinked to original sources
PubMed1995

Perinuclear anti-neutrophil cytoplasmic antibodies are spontaneously produced by mucosal B cells of ulcerative colitis patients.

Approximately 60% of sera from ulcerative colitis (UC) patients contains Igs reactive with neutrophil components, raising the question of the origin of these anti-neutrophil cytoplasmic Abs (ANCA). Our assertion that ANCA is a marker for a mucosal disease-related immune response predicts the existence of ANCA producing B cell clones in the lamina propria lymphocyte (LPL) fraction of UC patients. This hypothesis was tested by examining 12-day culture supernatants of LPL ANCA expression. LPL were isolated from surgically removed mucosa from patients with UC, Crohn's disease (CD), and diverticulitis. Normal mucosa was obtained from accident victims or normal margins of colon cancer resections. Supernatants were assayed by a fixed neutrophil ELISA. The ANCA staining pattern of supernatants expressing ANCA, as determined by ELISA, was assessed by indirect immunofluorescent staining of alcohol-fixed neutrophils. ANCA was found in 70% of culture supernatants from UC LPL fractions. In contrast, only approximately 11% of supernatants from CD and diverticulitis/normal (noninflammatory bowel disease (IBD)) LPL displayed ANCA binding. A perinuclear (pANCA) staining pattern was obtained with 70% of ANCA-expressing UC LPL supernatants, whereas ANCA-expressing CD and non-IBD LPL supernatants displayed a cytoplasmic reaction. PBL and mesenteric lymph node lymphocytes lacked spontaneous pANCA production, and pANCA production from PBL was not inducible. These findings indicate the existence of pANCA-producing B cell clones in mucosal lesions of UC patients and support our hypothesis that pANCA production is a consequence of a mucosal immune response specific to UC.

Autoantibodies↗
PubMed1995

Investigation of lung tumour induction in BALB/cJ mice following paternal X-irradiation.

Evidence of an enhanced incidence of lung tumours (benign adenomas and adenocarcinomas) was sought in the BALB/cJ mouse following paternal germ cell X-irradiation. In a series of replicate studies spanning approximately 1 year, males were exposed to single, acute X-ray doses of 0, 250 and 500 cGy. In each of the 2 consecutive weeks immediately thereafter they were placed with two females to generate progeny that were derived from irradiated post-meiotic cells (spermatozoa to late spermatids). These animals were then examined at 8 or 12 months for lung tumours. While the proportion of fertile females and mean litter size was affected by the radiation, showing a dose-dependent, dominant lethal response, and while cases of mutant offspring were detected, the paternal radiation did not affect lung tumour incidence in the offspring. The incidence did not vary significantly between germ cell stages irradiated (week of mating), sex of offspring, or radiation dose. However, significant differences between lung tumour incidence (mostly representing benign adenomas) were found between different replicates, these being high at the start of the study, declining and then rising to yet higher levels at its close. The finding that lung tumour incidence in BALB/cJ mice is not affected by paternal germ cell irradiation does not accord with Nomura's reports using other strains of mice. This, in turn, weakens biological support for a causal association between the raised incidence of childhood leukaemia and non-Hodgkin lymphoma near Sellafield and the father's recorded radiation exposure during employment by the nuclear industry.

Adenoma↗
PubMed1995

Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus.

The agouti locus on mouse chromosome 2 encodes a secreted cysteine-rich protein of 131 amino acids that acts as a molecular switch to instruct the melanocyte to make either yellow pigment (phaeomelanin) or black pigment (eumelanin). Mutations that up-regulate agouti expression are dominant to those causing decreased expression and result in yellow coat color. Other associated effects are obesity, diabetes, and increased susceptibility to tumors. To try to define important functional domains of the agouti protein, we have analyzed the molecular defects present in a series of recessive viable agouti mutations. In total, six alleles (amJ, au, ada, a16H, a18H, ae) were examined at both the RNA and DNA level. Two of the alleles, a16H and ae, result from mutations in the agouti coding region. Four alleles (amJ, au, a18H, and ada) appear to represent regulatory mutations that down-regulate agouti expression. Interestingly, one of these mutations, a18H, also appears to cause an immunological defect in the homozygous condition. This immunological defect is somewhat analogous to that observed in motheaten (me) mutant mice. Short and long-range restriction enzyme analyses of homozygous a18H DNA are consistent with the hypothesis that a18H results from a paracentric inversion where one end of the inversion maps in the 5' regulatory region of agouti and the other end in or near a gene that is required for normal immunological function. Cloning the breakpoints of this putative inversion should allow us to identify the gene that confers this interesting immunological disorder.

Agouti Signaling Protein↗
PubMed1995

Nuclear localization of the antigen detected by ulcerative colitis-associated perinuclear antineutrophil cytoplasmic antibodies.

Antineutrophil cytoplasmic antibodies (ANCAs) identified in the serum of 50 to 80% of ulcerative colitis (UC) patients yield a perinuclear staining pattern (pANCA) with alcohol-fixed neutrophils. The ANCAs of UC are distinguishable from those described for Wegener's granulomatosis and other vasculitidies. These various non-UC ANCAs recognize neutrophil granule constituents, but the antigenic moiety specific for the UC pANCA remains unknown. Although the perinuclear nature of some ANCA reactions is an artifact of the alcohol fixation of neutrophils, which causes cytoplasmic granules to redistribute around the nucleus, the UC pANCA reaction has been found not to be similarly affected. We postulated a nuclear localization for the UC-associated pANCA antigen and used both confocal laser microscopy and immunoelectron microscopy to examine the neutrophil reaction of UC-associated pANCA-containing sera. Confocal microscopy revealed a nuclear reaction for 88% (22/25) of the sera with 72% (18/25) showing the reaction localizing to the inner side of the nuclear (membrane) periphery. Immunoelectron microscopy showed that the UC-associated pANCA reaction localized primarily over chromatin concentrated toward the nuclear periphery, although the sera did not recognize double-stranded DNA. These results confirm the nuclear localization of the UC-associated pANCA antigen.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Comparison of CT, low-field-strength MR imaging, and high-field-strength MR imaging. Work in progress.

To assess objectively the sensitivity and specificity of low-field-strength (0.064 T) magnetic resonance (MR) imaging, a prospective blind study of 280 examinations was performed to compare low-field-strength MR imaging with computed tomography (CT) and with high-field-strength (1.5-T) MR imaging of the cranium. The sensitivity (defined as the true-positive rate) with high-field MR imaging was superior to that with low-field MR imaging and CT in helping detect overall abnormalities. Sensitivities were generally similar over a broad range of specific cranial central nervous system diseases. Low-field and high-field MR imaging were equivalent in the blind diagnoses of neoplasms and white matter disease, whereas low-field MR and CT were equivalent in the blind diagnoses of contusion, subdural and epidural hematoma, sinus disease, normality, and abnormality. The specificities with low-field MR imaging and CT were substantially better than those with high-field MR imaging.

Brain↗
PubMed1990

Age-related prognosis after acute myocardial infarction (the Multicenter Diltiazem Postinfarction Trial).

The basis for the excess mortality with age after acute myocardial infarction (AMI) is not clear, nor is it known whether the mode of death is altered with age. Age-related factors predictive of mortality and age-related mechanisms of the 333 deaths were examined in 2,466 patients who were enrolled in a placebo-controlled trial to determine the effect of diltiazem on mortality and reinfarction after AMI. There were 3 age groups with increasing mortality rates: ages 25 to 49 (n = 499), 50 to 64 (n = 1,228) and 65 to 75 years (n = 739). There was a significant age-related increase in the proportion of patients with baseline risk factors. These baseline characteristics did not differ by treatment (placebo vs diltiazem). However, multivariate survivorship analysis still identified age as an independent risk factor for cardiac death. The proportion of arrhythmic and myocardial failure deaths did not differ by treatment or age group.

Adult↗
PubMed1989

Power analysis of statistical methods for comparing treatment differences from limiting dilution assays.

Six different statistical methods for comparing limiting dilution assays were evaluated, using both real data and a power analysis of simulated data. Simulated data consisted of a series of 12 dilutions for two treatment groups with 24 cultures per dilution and 1,000 independent replications of each experiment. Data within each replication were generated by Monte Carlo simulation, based on a probability model of the experiment. Analyses of the simulated data revealed that the type I error rates for the six methods differed substantially, with only likelihood ratio and Taswell's weighted mean methods approximating the nominal 5% significance level. Of the six methods, likelihood ratio and Taswell's minimum Chi-square exhibited the best power (least probability of type II errors). Taswell's weighted mean test yielded acceptable type I and type II error rates, whereas the regression method was judged unacceptable for scientific work.

Cell Survival↗
PubMed1989

Comparison of statistical methods for the analysis of limiting dilution assays.

This study reports the results of a critical comparison of five statistical methods for estimating the density of viable cells in a limiting dilution assay (LDA). Artificial data were generated using Monte Carlo simulation. The performance of each statistical method was examined with respect to the accuracy of its estimator and, most importantly, the accuracy of its associated estimated standard error (SE). The regression method was found to perform at a level that is unacceptable for scientific research, due primarily to gross underestimation of the SE. The maximum likelihood method exhibited the best overall performance. A corrected version of Taswell's weighted-mean method, which provides the best performance among all noniterative methods examined, is also presented.

Cell Survival↗
PubMed1989

Low incidence of glomerulosclerosis in normal kidneys.

Forty normal kidneys were selected from a series of 146 renal samples obtained at forensic autopsies of American Indians and whites. Glomeruli were counted and the percentage of globally sclerosed, obsolescent glomeruli was calculated for each case. The mean for sclerotic glomeruli was less than 3% in any age group younger than 56 years. This finding is in agreement with the results of similar studies, but substantially lower than the figures quoted in textbooks. Analysis of the combination of our data with studies performed by other authors shows that the 90th percentile of glomerular sclerosis can be calculated for any age by subtracting 10 from half the patient's age. No ethnic- or sex-related differences were seen in any age group.

Adolescent↗
PubMed1988

An attachable silver-impregnated cuff for prevention of infection with central venous catheters: a prospective randomized multicenter trial.

PURPOSE: Percutaneously inserted central venous catheters are widely used. Catheter-related bacteremia or fungemia is the most frequent serious complication of these catheters. In an attempt to reduce the frequency of such infections, a subcutaneous cuff constructed of a biodegradable collagen matrix impregnated with bactericidal silver was developed. Our goal was to assess, in a multicenter clinical trial, the effectiveness of this cuff in preventing catheter-related infection. MATERIALS AND METHODS: Central venous catheters needed for fluid or drug therapy, hemodynamic monitoring, or hyperalimentation in patients in three centers were randomly assigned to be inserted with or without the cuff. Patients and catheters in the two groups were comparable in terms of risk factors predisposing to infection, including colonization of skin about the insertion site. RESULTS: The results with 234 catheters inserted into a new site showed that catheters inserted with the cuff were threefold less likely to be colonized on removal (more than 15 colony-forming units) than were control catheters (28.9 percent versus 9.1 percent, p = 0.002) and were nearly fourfold less likely to produce bacteremia (3.7 percent versus 1.0 percent). Adverse effects from the cuff were not seen. The cuff did not confer protection, however against infection with catheters inserted over a guidewire into old sites. Most of the catheter-related infections identified in this study, including four of the six bacteremias, appear to have been caused by microorganisms colonizing skin about the insertion site, affirming the pathogenetic basis for benefit seen with the cuff in this clinical trial; two may have derived from contamination of the catheter hub. CONCLUSION: This novel, silver-impregnated, attachable cuff can substantially reduce the incidence of catheter-related infection with most percutaneously inserted central venous catheters, can extend the time catheters can be left in place safely, and can prove cost-beneficial.

Adult↗
PubMed1988

Enhanced exercise noradrenaline concentrations during propranolol treatment: a limiting factor in cardiac beta-adrenoceptor blockade.

Treatment with beta-adrenoceptor blocking drugs may result in augmented plasma concentrations of noradrenaline during exercise. The effect of propranolol on exercise heart rate and its relationship to plasma concentrations of propranolol and noradrenaline were examined in 10 hospitalized volunteers following treatment with propranolol, in doses of 80 mg and 320 mg daily. Responses to submaximal treadmill exercise during propranolol treatment and following discontinuation of the higher dose were compared to pre-drug and post drug placebo values. Exercise noradrenaline was increased by 67% over baseline values by treatment with the 320 mg daily dose of propranolol; this increment was present at 4 h and returned to baseline by 16 h after drug administration. Augmentation of exercise noradrenaline was correlated with plasma propranolol concentrations; the threshold concentration for this effect was 10-fold higher than the threshold for reduction in exercise heart rate. The effect of propranolol on heart rate was blunted in relation to the augmentation of exercise noradrenaline (P less than 0.001). These relationships suggest that, in patients taking high doses of propranolol, drug induced augmentation of plasma levels of noradrenaline during exercise may have physiologic importance. Enhanced effects on adrenergic receptors could have clinical relevance in certain groups of patients.

Adult↗
PubMed1985

Suppression, stress, and accommodation of transplanted islets of Langerhans.

Successful intrasplenic islet autotransplantation in dogs requires an islet cell mass considerably greater than what might be expected based on studies of subtotal pancreatectomy. Grafts of marginal function ultimately fail, suggesting severe limitations in the capacity of an islet graft to adapt. Accommodation was tested in established intrasplenic grafts by either chronically stressing the graft with mild carbohydrate intolerance induced by exogenous corticosteroids or chronically suppressing the graft with exogenous insulin. After these manipulations, insulin output into the portal vein in response to intravenous (i.v.) glucose was measured and compared with that of normal dogs and dogs receiving islet autografts with no further treatment with either steroids or insulin. Transplanted islets tolerated the two manipulations well in that neither exogenous steroid nor insulin led to failure of the graft as a consequence of either stress or protracted diminished demand. The major determinant of successful islet grafting is the endocrine competence of the initial graft. If that competence is provided at the outset, the graft can adapt to a considerable range of demand for insulin secretion.

Animals↗
PubMed1985

The metabolic response of intrasplenic islet autografts.

Islet tissue was prepared by collagenase ductal perfusion in mongrel dogs and transplanted to the spleen as autografts following total pancreatectomy. The graft was introduced into the spleen by reflux through tributaries of the splenic vein. Total insulin output by the in situ islet cell mass and by the heterotopically transplanted islet cell mass was studied by measuring insulin in the portal vein prior to pancreatectomy and two weeks after grafting. Basal insulin as well as the insulin output in response to 0.5 gram per kilogram of intravenous glucose were measured. Normoglycemia was achieved immediately in all grafted dogs. The results of intravenous glucose tolerance testing suggested only a mild degree of carbohydrate intolerance in the grafted dogs. Insulin output in 60 minutes after glucose stimilation was similar for in situ and grafted islet cells. The results of glucose clamp studies did not reveal any significant change in the insulin sensitivity of grafted as opposed to normal dogs. Islets of Langerhans may be harvested by the ductal perfusion method to yield a completely adequate islet cell mass for grafting purposes in the canine model following total pancreatectomy.

Animals↗
PubMed1983

Computer reconstruction of serial sections.

A computer graphics system is described which reconstructs three-dimensional images from serial sectional data. Microscopic sectional tracings are first digitized and coded with a microcomputer (APPLE II-Plus). The data are transferred to a main frame facility for reconstruction and the final result is displayed on a high-resolution color monitor (Hewlett-Packard 9845C). Depth cueing of the image is enhanced by edge ribboning and area filling. The system is very simple to operate and yet flexible enough to allow selective portions of the tissue sample to be reconstructed and displayed in various orientations.

Animals↗
PubMed1983

Islet recovery in chronic pancreatitis.

Chronic pancreatitis ablates a large majority of the acinar tissue which otherwise is a troublesome contaminant in preparing islet cells from higher mammals. Chronic pancreatitis was induced by dividing all pancreatic attachments to the duodenum, including major and minor ducts, in six dogs. After 10 weeks, biopsy of the pancreas showed marked acinar cell atrophy and fibrosis with preservation and even proliferation of islet cells. Intravenous glucose tolerance testing revealed only a minor decrease in K value from 3.4 +/- 1.0 to 2.1 +/- 0.4 during 10 weeks. All dogs then underwent total pancreatectomy and islet autotransplantation. The pancreas was dispersed to a cell suspension by perfusing the pancreatic ducts with collagenase until tissue integrity failed. The digested tissue was then chopped, dissociated by shaking, and filtered. The average cell yield from the pancreas was 7.6 X 10(7) cells of which greater than 95% were islet cells. Acid alcohol-extracted insulin values suggested an average 7% recovery of insulin content and essentially complete elimination of amylase content was demonstrated.

Amylases↗
PubMed1976

Word imagery modalities and learning in the deaf and hearing.

The study explored the modality specific hypothesis of imagery concreteness. Twenty-four male and female deaf and hearing adolescents learned lists of paired associates that were either high visual and low auditory imagery words or the obverse. It was predicted that the deaf group would perform as well as the hearing group with pairs of high visual imagery, but worse with materials of high auditory imagery. The results failed to demonstrate the expected interaction. However, indirect support for the hypothesis was provided by a third order interaction trend analysis which suggested that the deaf group experienced difficulty in learning the high auditory imagery word pairs.

Adolescent↗