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Biomedical subjects

C Black

Publications and source records attributed to C Black.

At least 127 records · Page 7Linked to original sources
PubMed1994

Increased urinary LTE4 excretion following inhalation of LTC4 and LTE4 in asthmatic subjects.

Urinary leukotriene E4 (LTE4) increases during exacerbations of asthma and following antigen challenge. We determined whether urinary LTE4 excretion reflects sulphidopeptide leukotrienes in the airways of asthmatic patients. Urinary LTE4 concentration was measured prior to and 1.5 and 3.5 h following inhalation of bronchoconstrictive doses of leukotriene C4 (LTC4) or LTE4 in eight asthmatic subjects. Increasing doses of agonist were inhaled until a 35% fall in specific airways conductance (sGaw) was achieved. There was no significant difference between the 53 +/- 3% (mean +/- SEM) fall in sGaw following inhalation of LTC4 (63.1 ng geometric mean, GM, range 5.8-527.5 ng) and the 43 +/- 4% fall in sGaw following inhalation of LTE4 7.94 ng/GM (range 132-3701 ng). The LTE4 excretion rate increased significantly from 2.95 (range 0.6-17.5) ng.h-1 to 4.67 (range 0.8-20) ng.h-1 at 1.5 h following LTC4 inhalation; and from 1.8 (range 0.07-6.7) ng.h-1 to 6.9 (range 2.9-27.3) ng.h-1 at 1.5 h following LTE4 inhalation; and had returned from baseline by 3.5 h. There was a correlation between the dose of LTC4 inhaled and LTE4 excreted in the urine (r = 0.82 and r = 0.72, respectively). The % recovery of LTE4 in the urine, of the total dose of inhaled LTC4 or LTE4 administered, was 6.9 +/- 4.1% and 0.8 +/- 0.3%, respectively. Thus, inhalation of bronchoconstricting doses of LTC4 or LTE4 alter urinary LTE4 excretion in a dose-dependent fashion. This indicates that urinary LTE4 can be used as a marker of sulphidopeptide leukotriene synthesis in the lungs of patients with asthma.

Administration, Inhalation↗
PubMed1993

Epidemiologic analysis of Kaposi's sarcoma as an early and later AIDS outcome in homosexual men.

The authors separately studied the epidemiology (risk and risk factors) of Kaposi's sarcoma occurring as an initial acquired immunodeficiency syndrome (AIDS) outcome (early Kaposi's sarcoma) and later after a different initial AIDS outcome (later Kaposi's sarcoma) in a cohort of 2,591 human immunodeficiency virus type 1-infected gay men of the Multicenter AIDS Cohort Study between 1984 and 1992. Among 844 AIDS cases, 202 presented with early Kaposi's sarcoma, 101 subsequently developed later Kaposi's sarcoma, and 541 were not diagnosed with Kaposi's sarcoma. Overall, 37.4% of AIDS cases were diagnosed with Kaposi's sarcoma prior to death. Kaposi's sarcoma diagnosed on the skin was significantly more common with early Kaposi's sarcoma (77.3%) than with later Kaposi's sarcoma (65.1%). Men presenting with an AIDS outcome other than Kaposi's sarcoma were at high risk for later Kaposi's sarcoma. Later Kaposi's sarcoma onset in men with a previous AIDS outcome was associated with the following characteristics: 1) lower immune status prior to AIDS and 2) longer post-AIDS survival. A Kaposi's sarcoma diagnosis in a man with a previous AIDS illness approximately doubled the risk (hazard) for death. Histories of urethral gonorrhea and scabies prior to study entry were more common in early Kaposi's sarcoma cases than in later Kaposi's sarcoma cases. However, self-reported sexual activity at study entry and prior to AIDS onset was highest in the later Kaposi's sarcoma group. In this cohort, cigarette smoking had a protective association against all Kaposi's sarcoma in univariate and multivariate models. Only 21.0% of the later Kaposi's sarcoma and 25.0% of the early Kaposi's sarcoma men smoked at least one-half pack of cigarettes daily at study entry compared with 33.8% of non-Kaposi's sarcoma and 35.5% of seroprevalent men still AIDS free. The reasons for this surprising association are unclear. However, other evidence which documents that habitual smoking alters the immune system (and possibly cytokine levels) in ways that could perhaps influence Kaposi's sarcoma pathogenesis should be considered.

Acquired Immunodeficiency Syndrome↗
PubMed1993

A rapid biochemical method for measuring antigen-induced pulmonary eosinophil margination in allergic guinea pigs.

The ability of purified guinea pig peritoneal eosinophils (EOS) to oxidise 3,3',5,5'-tetramethylbenzidine (TMB) was assessed in the presence/absence of Br- (3 mM), and compared with that of unpurified elicited peritoneal polymorphonuclear leukocytes (PMN). Br- selectively stimulated EOS peroxidase activity in a cell number-dependent manner, which was not significantly affected by the presence of diluted lung homogenate. By comparison with the peroxidase activity of added purified EOS, lung parenchyma homogenate from naive guinea pigs was estimated to contain 1.04 +/- 0.18 x 10(5) cells/mg wet tissue (n = 6), a value comparable to those calculated from published histological analyses. This was not significantly increased by ovalbumin (OA) allergen inhalation in unsensitised guinea pigs (1.4 x 10(5) EOS/mg), but was increased two-fold over the latter control to 3.0 +/- 0.18 x 10(5) cells/mg after 17 h in animals sensitised by a single injection of OA and subsequently exposed to an aerosol of bronchoactive allergen (n = 13, p < 0.05). Similar results were obtained in a parallel study using bronchoalveolar lavage (saline challenge, 20.2 +/- 2.2% EOS in lavage fluid; OA challenge, 47.1 +/- 3.6% EOS; n = 6, p < 0.05). In animals that had been doubly sensitised (two injections) to OA, the pulmonary eosinophilic response measured biochemically was more pronounced (4.9 +/- 0.2 x 10(5) cells/mg) and was significantly greater than both a non-specific protein inhalation in this sensitisation group, and OA inhalation in singly sensitised animals (n = 12, p < 0.05). Sera from the latter group was shown to contain five times less specific anti-OA IgG than the doubly sensitised animals, suggesting that EOS margination in guinea pigs is proportionate to the animals' immune status for a defined immunological challenge. These data demonstrate that in vivo EOS migration into the whole guinea pig lung can be rapidly determined by biochemical methods, and thus facilitate the in vivo assessment of novel therapeutic agents against the eosinophilic inflammation characteristic of human allergic asthma.

Animals↗
PubMed1993

A molecular and serologic analysis of the major histocompatibility complex and complement component C4 in systemic sclerosis.

OBJECTIVE: To investigate the contributions of the major histocompatibility complex (MHC) and C4 alleles to systemic sclerosis (SSc), and to pulmonary fibrosis and autoantibody expression in SSc, by analysis at the DNA level. METHODS: One hundred fifteen patients with SSc were tested serologically for alleles of the class I MHC loci, and were tested for class II alleles (DRB, DQA, and DPB) by a combination of restriction fragment length polymorphism (RFLP) analysis and oligonucleotide probes with polymerase chain reaction amplification. C4 was studied by protein phenotyping and RFLP analysis in 80 patients. Correlations were made between disease status, pulmonary fibrosis, and expression of anticentromere antibodies (ACA) and anti-Scl-70. RESULTS: The C4A-null phenotype was found to provide the strongest disease association factor of the MHC region (P = 0.000064, relative risk [RR] = 2.8, etiologic fraction [EF] = 32.1). The primary MHC susceptibility allele was found to be DQA2 (Pcorr = 0.0009, RR = 2.5, EF = 35.6), which is in linkage disequilibrium with both DR3 and DR11. DR2 was protective, but only for female patients (P = 0.0021, RR = 0.42, protective fraction = 19.4). DR52a was the primary MHC allele associated with pulmonary fibrosis in SSc patients. Expression of ACA was associated with the presence of either DR1 or DR4 (P = 0.0015, RR = 6.7, EF = 78.0). Anti-Scl-70 expression correlated with an acidic residue of DP beta (DPB1:69:E) (P = 0.0063, RR = 4.6, EF = 53.1). CONCLUSION: Of all the potential markers of disease susceptibility analyzed, the C4A locus was the strongest. C4AQ0 and DQA2 are independent susceptibility factors for SSc. The development of pulmonary fibrosis in SSc patients can be predicted using combined MHC and autoantibody analysis. The MHC alleles associated with the expression of disease-specific autoantibodies are not markers for disease susceptibility.

Alleles↗
PubMed1993

Assessment of the in vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors.

In man, the therapeutic effectiveness of specific inhibitors of leukotriene (LT) biosynthesis against allergen-induced bronchoconstriction appears to be related to the in vivo biochemical efficacy of these compounds, as measured by inhibition of whole blood LTB4 generation (upon A23187 stimulus) and, particularly, urinary LTE4 excretion. Accordingly, we have assessed the ability of two clinically documented LT biosynthesis inhibitors, zileuton and MK-886, and the structurally novel 5-lipoxygenase activating protein antagonist, MK-0591, to inhibit the production of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (> 10 microM plasma concentrations), and inhibited the A23187-induced ex vivo production of LTB4 by venous blood by > 90%, in concordance with its potency in canine blood in vitro (IC50 = 1.1 microM). Despite this degree of inhibition in whole blood, urinary LTE4 excretion was reduced by only 52%, a profile of activity similar to that seen in clinical studies. MK-886 was less well absorbed, with plasma concentrations of 3 microM being achieved only at 25 mg/kg. These levels resulted in < 45% inhibition of LTB4 production, but a significant (p < 0.05) 47% inhibition of urinary LTE4 excretion. MK-0591 was similarly bioavailable (compared with MK-886), but 10-fold more active in vivo as a 2 mg/kg dose resulted in 41-62% inhibition of urinary LTE4 excretion (p < 0.05 vs controls; n = 4, 28). Significant inhibition of ex vivo LTB4 synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 microM and an in vitro potency of 0.2-0.4 microM (IC50) in whole blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibited LTE4 excretion by 69%, with 88% inhibition of the LT biosynthetic capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man.

Animals↗
PubMed1993

Living longer but doing worse: assessing health status in elderly persons at two points in time in Manitoba, Canada, 1971 and 1983.

Comparisons of the health status of 1971 and 1983 samples of elderly persons in Manitoba, Canada suggest that while elderly individuals were living longer in 1983, their health was poorer. This was true in both age- and sex-specific comparisons and in comparisons made of individuals in the two samples who were relatively close to death. 'Compression of morbidity' has not taken place. Elderly individuals in the 1983 sample were in poorer health whether judged by functional status (ability to perform activities of daily living), number of different health problems reported, mental status or the rate of hospitalization for serious co-morbid disease. We estimate a 29% increase in the number of elderly persons resident in Manitoba over the 12 year period studied, but a 73% increase in the number of elderly who were in poor health.

Activities of Daily Living↗
PubMed1993

Targetted phototherapy with sensitizer-monoclonal antibody conjugate and light.

Photodynamic therapy (PDT) was performed in vitro and in vivo using monoclonal antibody conjugated to hematoporphyrin (HP). The antibody (45-2D9) recognized a cell surface glycoprotein on cells derived from NIH 3T3 cells which were transformed with the ras oncogene (45-342). Radionuclide imaging with either In111 or I125 chelated to 45-2D9 or the isotype identical (IgG1) antibody MOPPC-21 revealed selectivity of 45-2D9 for 45-342 flank tumours in nude mice, and minimal targetting for a 45-342 clone which did not express the cell surface glycoprotein. The 45-2D9-HP conjugate resulted in selective killing of the 45-342 line compared with the parent line in vitro. At HP concentrations of 76 micrograms ml-1, the 45-2D9-HP conjugate resulted in significantly more long-term cures of PDT treated flank tumours compared with free HP at the same concentration. 45-2D9 alone had no effect on tumour growth. The antibody-HP conjugate resulted in significantly less local toxicity compared with standard Photofrin II PDT, and also achieved a greater number of long-term cures. This 'photoimmunotherapy' demonstrates the ability to treat established tumours with greater efficacy and decreased morbidity, probably due to specific sensitizer targetting which allows normal surrounding tissue to be spared upon illumination.

3T3 Cells↗
PubMed1993

Validity and reliability of three methods used in the diagnosis of Raynaud's phenomenon. The UK Scleroderma Study Group.

Three different assessment methods for the classification of Raynaud's phenomenon (RP) were compared. These were (i) a previously validated method using colour charts supplemented with a short questionnaire, (ii) answers to a questionnaire based on criteria derived from the consensus opinion of a group of clinicians, and (iii) individual clinician's assessment using standard descriptions based upon the same consensus view. We report the results of a study involving six clinicians and 30 subjects investigating the level of repeatability between the three methods and also the reliability between the six clinicians. There did not exist any overall systematic bias between the six clinicians. Further, agreement between them, as assessed by the kappa statistic, ranged from moderate to good. However, there did exist systematic bias between the results from all three of the classification approaches with agreement between them ranging from only poor to moderate. We conclude that the previously validated colour chart assessment is too insensitive to detect RP. Further, a structured questionnaire based on perceived clinician's opinion could not reproduce clinicians' classification in practice. By contrast, supplying clinicians with standard descriptions did yield a reliable classification system for RP.

Humans↗
PubMed1993

Choices of training programs and career paths by women in internal medicine.

PURPOSE: To examine the choices of career paths of women in internal medicine, specifically to determine (1) whether women continue to prefer primary care practice more often than men do and (2) whether differences in career paths between men and women result from differences in the natures of the training programs they complete. METHOD: A database containing demographic, training, and clinical-practice information on 19,151 physicians (3,569 women and 15,582 men) who had been trained in internal medicine was constructed by merging data from the National Resident Matching Program matches in internal medicine for 1977-1982 with data from the 1985 American Medical Association Physician Masterfile, which contains physician practice profiles. RESULTS: Similar percentages of the men and the women chose primary care residencies (8% versus 9%, ns) and trained in the 100 major medical centers (49% versus 50%, ns). The women more frequently trained in programs affiliated with medical schools in the top prestige quartile (38% versus 33%, p < .05). The attrition rates of residents who left their training for careers in other medical fields were the same for the men and the women (14%). Fewer women obtained board certification (74% versus 80%, p < .01). The women chose to practice general internal medicine more frequently than did the men (52% versus 45%, p < .0001), regardless of the training program completed (primary care or traditional). CONCLUSION: The women pursued primary-care-oriented internal medicine to a significantly greater degree than did the men, regardless of the type of training program completed (primary care or traditional).

Career Choice↗
PubMed1993

Impaired beta-adrenergic receptor activation of adenylyl cyclase in airway smooth muscle in the basenji-greyhound dog model of airway hyperresponsiveness.

Previous studies in human asthmatics have suggested a defect in the beta-adrenergic pathway leading to cyclic adenosine monophosphate (cAMP) generation. Although these studies have suggested normal or increased numbers of beta-adrenergic receptors, limitations in the quantity of tissue available have not allowed further delineation of the biochemical or molecular mechanisms of human asthma. The basenji-greyhound (BG) dog model of nonspecific airway hyperreactivity displays similarities to human asthma, and altered functional response to beta-adrenergic agonists has been previously shown in airway tissue from this model. We have now correlated this functional impairment in beta-adrenergic response with a decreased generation of cAMP in response to isoproterenol. Organ bath studies and adenylyl cyclase assays of trachealis muscle revealed impaired responses to isoproterenol in the BG dog as compared with control dogs. Pretreatment of muscle strips from BG dogs with isoproterenol had no effect on subsequent dose-response curves to methacholine (pD2 = 7.17 +/- 0.13, 7.34 +/- 0.12, and 7.14 +/- 0.17 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively), while muscle strips from mongrel dogs had a significant shift in methacholine responses after isoproterenol pretreatment (pD2 = 7.91 +/- 0.23, 7.48 +/- 0.29, and 6.98 +/- 0.33 for control, 10(-6) M isoproterenol, and 10(-5) M isoproterenol, respectively). Adenylyl cyclase activity in response to isoproterenol was 54% in the BG trachealis membranes as compared with mongrels. Functional and biochemical responses to forskolin, NaF, prostaglandin, and dibutyryl cAMP, and the quantity of G,alpha were similar in the BG and control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Diagnosis of paraesophageal omental hiatal hernia by magnetic resonance imaging.

We present a case of an enlarging retrocardiac mass lesion in which we observed the magnetic resonance imaging (MRI) finding of a fatty tumor with contiguous blood vessels extending from the abdominal portion into the thoracic portion of the tumor. These surgically verified findings provide an MRI indication of the presence of a paraesophageal omental hiatal hernia.

Adipose Tissue↗
PubMed1992

Career differences between primary care and traditional trainees in internal medicine and pediatrics.

OBJECTIVE: To assess the relation of Primary Care Residency Training to career choice, board certification, and practice location of internists and pediatricians. DESIGN: Cohort study with up to 8 years of follow-up. SETTING: The United States. PARTICIPANTS: The 17,933 residents trained in all internal medicine (13,750) and pediatrics (4,183) residency programs between 1977 and 1982 were studied using information from the National Resident Matching Program, the AMA Physician Masterfile, the Area Resource File, and a telephone survey. MEASUREMENTS: Career choice, board certification, and practice location were studied in relation to five explanatory variables: type of residency (primary care or traditional track), gender, year of medical school graduation, educational orientation of the teaching hospital, and medical school prestige. MAIN RESULTS: Graduates of primary care residency training programs chose careers in generalist primary care significantly more often than did graduates of traditional tracks in both internal medicine (72% compared with 54%) and pediatrics (88% and 81%, respectively; P less than 0.001 for both values). Board certification rates in internal medicine were statistically higher for graduates of primary care training programs (80%) than for graduates of traditional programs (76%, P = 0.002) but were not statistically significant for both groups of pediatric graduates. Graduates of primary care programs in pediatrics and internal medicine practiced in medically less served communities more often than did graduates of traditional programs. CONCLUSION: Graduates of primary care residency training programs in internal medicine and pediatrics differ from graduates of traditional residency programs in career choices, board certification rates, and practice locations.

Career Choice↗
PubMed1992

Quantitation of eosinophil Major Basic Protein cytotoxicity to rodent respiratory epithelium.

Eosinophil Major Basic Protein (MBP) may be a potent effector in damaging airway epithelium and inducing acute (2-3 h) hyperresponsiveness to agonists in primates. Accordingly, interactions between human eosinophil MBP and guinea-pig airway epithelium were quantitated biochemically. MBP was extracted from human eosinophils and purified by size-exclusion HPLC. This resulted in a single protein band on electrophoresis, which cross-reacted with antisera raised to peptides derived from the predicted sequence of human MBP. This human MBP caused modest, but statistically significant, damage to respiratory epithelium (16.4% increase in efflux of 51Cr from guinea-pig tracheal rings) after 3 h of incubation with 10(-4) M concentration, but not with lower concentrations. These data demonstrates that MBP cytotoxicity to intact epithelium can be rapidly measured in vitro, and suggests that rodent airway epithelium may be relatively resistant to the cytotoxic effects of MBP.

Animals↗
PubMed1992

Activity of oxidative routes of metabolism of debrisoquin, mephenytoin, and dapsone is unrelated to the pathogenesis of vinyl chloride-induced disease.

The hypothesis, that cytochrome P4502D6, cytochrome P4502CMP, cytochrome P4503A4 or N-acetyl-transferase may form active intermediary metabolites that could be etiologically related to vinyl chloride-induced disease was investigated in 21 drug-free workers with previous development of vinyl chloride-induced disease and in 23 drug-free workers from the same plant who did not develop the syndrome. Each subject received simultaneous oral administration of debrisoquin (10 mg), mephenytoin (100 mg), and dapsone (100 mg). Measurement of the debrisoquin recovery ratio, the 8-hour recovery of 4-hydroxymephenytoin, and the dapsone recovery ratio in the subsequent 8-hour urine sample provided in vivo phenotypic indexes of cytochromes P4502D6, P4502CMP, and P4503A4 activity, respectively. An 8-hour blood sample was used to measure the acetylation ratio, a measure of N-acetyltransferase activity. The frequency distributions of each drug metabolizing activity were similar between groups. Within this small sample, there was no evidence to implicate cytochromes P4502D6, P4502CMP, and P4503A4 and N-acetyltransferase in the pathogenesis of vinyl chloride-induced disease.

Arylamine N-Acetyltransferase↗
PubMed1992

Mixed connective tissue disease--goodbye to all that.

Since it was first described mixed connective tissue disease (MCTD) has been the subject of much debate. In particular the question of whether it is a truly distinctive disease entity has been challenged. It seems clear that the original description of MCTD as a mild disorder, rarely affecting the lungs or kidneys and requiring small doses of corticosteroids only, is no longer tenable. In this review a historical analysis of the clinical and serological features is presented. It is suggested that the concept of MCTD as a distinct disease entity is better replaced by the term 'undifferentiated autoimmune rheumatic/connective tissue disorder'. Many of these patients will later 'convert' into scleroderma or lupus; some will remain undifferentiated.

Autoantibodies↗