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Biomedical subjects

M Carr

Publications and source records attributed to M Carr.

At least 19 recordsLinked to original sources
PubMed2006

Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, with subsequent extracellular matrix (ECM) production and smooth muscle cell (SMC) proliferation. Changes in the ECM can modulate vasoreactivity and SMC contraction. Galectin-1 (Gal-1) is a hypoxia-inducible beta-galactoside-binding lectin produced by vascular, interstitial, epithelial, and immune cells. Gal-1 regulates SMC differentiation, proliferation, and apoptosis via interactions with the ECM, as well as immune system function, and, therefore, likely plays a role in the pathogenesis of PH. We investigated the effects of Gal-1 during hypoxic PH by quantifying 1) Gal-1 expression in response to hypoxia in vitro and in vivo and 2) the effect of Gal-1 gene deletion on the magnitude of the PH response to chronic hypoxia in vivo. By constructing and screening a subtractive library, we found that acute hypoxia increases expression of Gal-1 mRNA in isolated pulmonary mesenchymal cells. In wild-type (WT) mice, Gal-1 immunoreactivity increased after 6 wk of hypoxia. Increased expression of Gal-1 protein was confirmed by quantitative Western analysis. Gal-1 knockout (Gal-1(-/-)) mice showed a decreased PH response, as measured by right ventricular pressure and the ratio of right ventricular to left ventricular + septum wet weight compared with their WT counterparts. However, the number and degree of muscularized vessels increased similarly in WT and Gal-1(-/-) mice. In response to chronic hypoxia, the decrease in factor 8-positive microvessel density was similar in both groups. Vasoreactivity of WT and Gal-1(-/-) mice was tested in vivo and with use of isolated perfused lungs exposed to acute hypoxia. Acute hypoxia caused a significant increase in RV pressure in wild-type and Gal-1(-/-) mice; however, the response of the Gal-1(-/-) mice was greater. These results suggest that Gal-1 influences the contractile response to hypoxia and subsequent remodeling during hypoxia-induced PH, which influences disease progression.

Animals↗
PubMed2006

An outbreak of Cryptosporidium hominis infection at an Illinois recreational waterpark.

Cryptosporidium has become increasingly recognized as a pathogen responsible for outbreaks of diarrhoeal illness in both immunocompetent and immunocompromised persons. In August 2001, an Illinois hospital reported a cryptosporidiosis cluster potentially linked to a local waterpark. There were 358 case-patients identified. We conducted community-based and waterpark-based case-control studies to examine potential sources of the outbreak. We collected stool specimens from ill persons and pool water samples for microscopy and molecular analysis. Laboratory-confirmed case-patients (n=77) were more likely to have attended the waterpark [odds ratio (OR) 16.0, 95% confidence interval (CI) 3.8-66.8], had pool water in the mouth (OR 6.0, 95% CI 1.3-26.8), and swallowed pool water (OR 4.5, 95% CI 1.5-13.3) than age-matched controls. Cryptosporidium was found in stool specimens and pool water samples. The chlorine resistance of oocysts, frequent swimming exposures, high bather densities, heavy usage by diaper-aged children, and increased recognition and reporting of outbreaks are likely to have contributed to the increasing trend in number of swimming pool-associated outbreaks of cryptosporidiosis. Recommendations for disease prevention include alteration of pool design to separate toddler pool filtration systems from other pools. Implementation of education programmes could reduce the risk of faecal contamination and disease transmission.

Adolescent↗
PubMed2005

Tropical to mid-latitude snow and ice accumulation, flow and glaciation on Mars.

Images from the Mars Express HRSC (High-Resolution Stereo Camera) of debris aprons at the base of massifs in eastern Hellas reveal numerous concentrically ridged lobate and pitted features and related evidence of extremely ice-rich glacier-like viscous flow and sublimation. Together with new evidence for recent ice-rich rock glaciers at the base of the Olympus Mons scarp superposed on larger Late Amazonian debris-covered piedmont glaciers, we interpret these deposits as evidence for geologically recent and recurring glacial activity in tropical and mid-latitude regions of Mars during periods of increased spin-axis obliquity when polar ice was mobilized and redeposited in microenvironments at lower latitudes. The data indicate that abundant residual ice probably remains in these deposits and that these records of geologically recent climate changes are accessible to future automated and human surface exploration.

Climate↗
PubMed2001

An investigation of the cause of low variability on the fourth chromosome of Drosophila melanogaster.

The fourth chromosome of Drosophila melanogaster lacks meiotic recombination. There is also a lack of nucleotide variation on the chromosome. This lack of variation could have been caused by a recent selective sweep, by background selection, or by a combination of these two forces. It should be possible to differentiate between the two mechanisms by studying the frequencies of polymorphic sites on the chromosome: a selective sweep should have resulted in low-frequency polymorphisms, whereas higher frequency polymorphisms would indicate the action of background selection. We have analyzed retrotransposable element insertions on the fourth chromosome in 11 strains of D. melanogaster. The polymorphisms found have a range of frequencies, with the presence of some insertions with high frequencies suggesting that the lack of variation is the result of background selection. We summarize the data using two statistics: the number of sites shared by more than one of the sample of 11 chromosomes (internal sites) and the mean number of transposable element differences in presence or absence between the sampled chromosomes. Simulations indicate that a selective sweep occurring more than 15,000 (0.03N) generations ago cannot be ruled out from the number of internal sites, although the number of differences between the chromosomes suggests either background selection or a sweep occurring more than 60,000 (0.12N) generations ago. Our results show no homoplasies and are thus consistent with no recombination occurring on the chromosome. The difficulties of distinguishing between the models using polymorphism data are discussed.

Animals↗
PubMed2000

Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study.

BACKGROUND: Postmenopausal estrogen use has been associated with reduced carotid atherosclerosis in observational studies, but this relationship has not been confirmed in a clinical trial. The impact of estrogen on atherosclerotic disease in other peripheral arteries is unknown. METHODS AND RESULTS: Postmenopausal women with coronary heart disease (CHD) and an intact uterus (n=2763) were randomly assigned to conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) daily or to placebo in a secondary CHD prevention trial. This analysis focuses on incident peripheral arterial procedures and deaths in the 2 treatment groups; peripheral vascular disease was a predefined secondary outcome. During a mean of 4.1 years of follow-up, 311 peripheral arterial events were reported in 213 women, an annual incidence of 2.9%. The number of women who had peripheral arterial events was 99 among those assigned to active estrogen/progestin and 114 among those assigned to placebo, a nonsignificant difference (relative hazard 0. 87, 95% CI 0.66 to 1.14). In the placebo group, hypertension and diabetes mellitus were independently associated with higher rates of peripheral arterial events, and plasma HDL cholesterol and body mass index were associated with lower rates of peripheral arterial events. In the estrogen/progestin group, current smoking and diabetes were independent predictors of peripheral arterial events. Incident peripheral arterial disease was not a significant predictor of coronary, cardiovascular, or total mortality. CONCLUSIONS: Treatment with oral conjugated estrogen plus medroxyprogesterone acetate was not associated with a significant reduction in incident peripheral arterial events in postmenopausal women with preexisting CHD.

Aged↗
PubMed1999

Spontaneous resolution of an in utero perirenal urinoma associated with posterior urethral valves.

Ultrasound imaging of a 26-week-gestation fetus demonstrated a large, nonemptying bladder. At 27 weeks, a distended, thick-walled bladder, left hydronephrosis, and a perirenal urinoma were present, without ascites. Observation was undertaken, as the amniotic fluid volume was normal. At 29 weeks, the left perirenal fluid collection persisted but, at 30 weeks, was absent. After delivery at 36 weeks, no ultrasound evidence for perirenal urinoma or ascites was present. Isotope renal scan showed preserved renal function bilaterally. This case illustrates that in utero urinomas associated with posterior urethral valves can resolve spontaneously, with preservation of renal function.

Adult↗
PubMed1998

Phase Ib trial of bryostatin 1 in patients with refractory malignancies.

A Phase Ib trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 microg/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nm). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 microg/m2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.

Adult↗
PubMed1997

Human tryptase fibrinogenolysis is optimal at acidic pH and generates anticoagulant fragments in the presence of the anti-tryptase monoclonal antibody B12.

Human tryptase is uniquely regulated by its association with heparin and resists inhibition by biological protease inhibitors. The effects of pH and B12, an IgG anti-tryptase mAb, on cleavage of the synthetic substrate tosyl-Gly-Pro-Lys-p-nitroanilide and of the biological substrate fibrinogen by tryptase were examined. Tosyl-Gly-Pro-Lys-pnitroanilide cleavage was optimal at neutral pH and was inhibited by the B12 mAb at acidic and neutral pH values. At pH 7.5, inhibition was reversible and noncompetitive. In contrast, the optimal pH for tryptase to cleave fibrinogen was acidic. B12 dramatically enhanced the rate and extent that tryptase cleaved all three fibrinogen subunits at pH 6.0 to 6.5, but inhibited these activities at neutral pH. Major fibrinogen cleavage fragments generated at acidic pH by the B12:tryptase complex were identical with those made by plasmin. Thus, at acid pH, tryptase alone destroyed the ability of fibrinogen to clot, while the B12:tryptase complex increased the rate of fibrinogenolysis and also generated the anticoagulant, fragment D. The acidic pH optimum for tryptase fibrinogenolysis may direct this activity to tissue sites of inflammation. A putative biological equivalent to B12 would limit tryptase fibrinogenolytic activity at sites of neutral pH, such as blood, but would augment activity at acidic sites.

Adjuvants, Immunologic↗
PubMed1997

Basic fibroblast growth factor in the urine of children with voiding pathology.

PURPOSE: Basic fibroblast growth factor is a mediator of tissue response to injury. Voiding pathology often results in bladder abnormalities. We prospectively determined whether basic fibroblast growth factor is elevated in the urine of children with bladder dysfunction compared to that of normal controls. MATERIALS AND METHODS: A total of 97 consecutive children with myelomeningocele and 32 with voiding pathology due to other etiologies underwent urodynamic testing, and 11 children with no bladder symptoms and sterile urine served as controls. Urinary basic fibroblast growth factor levels were assayed by enzyme-linked immunosorbent assay and normalized to urinary creatinine. RESULTS: Mean urinary basic fibroblast growth factor was higher in bladder dysfunction from myelomeningocele (6,673 pg./gm. creatinine, p = 0.0015) and other etiologies (5,665 pg./gm. creatinine, p = 0.0025) compared with urine from normal bladders (2,995 pg./gm. creatinine). In the myelomeningocele group urinary tract infection was associated with higher urinary basic fibroblast growth factor than in sterile urine (9,214 versus 5,642 pg./gm. creatinine, p = 0.018). Patient age, gender, remote bladder surgery, clean intermittent catheterization, detrusor hyperreflexia, detrusor compliance, age adjusted pressure specific bladder volume, low grade reflux and degree of trabeculation did not correlate with levels of basic fibroblast growth factor (p > 0.05). CONCLUSIONS: Urinary elevation of basic fibroblast growth factor, a critical mediator of wound repair, in children with voiding pathology and clinically abnormal bladders supports the paradigm that bladder dysfunction may result from generalized response-to-injury mechanisms. The role of fibrogenic cytokines, such as basic fibroblast growth factor, merits further directed investigation in bladder pathology.

Child↗
PubMed1997

Impact of an audiology clinic in one general practice.

There is a large demand for the provision of hearing aids. However, there are lengthy delays involved between referral and fitment of National Health Service (NHS) hearing aids. This report shows that a general practice based audiology clinic can lead to an increase in the number of patients referred and fitted with a hearing aid. The introduction of the clinic also led to reduced waiting times for patients to be fitted with hearing aids.

Audiology↗
PubMed1996

Bryostatin 1 activates splenic lymphocytes and induces sustained depletion of splenocyte protein kinase C activity in vivo after a single intravenous administration.

Bryostatin 1 activates and subsequently down-regulates protein kinase C (PKC) in vitro and has potential use as an immunomodulator and as an anti-cancer agent. Despite extensive examination of its activities in vitro and anti-tumor effects in vivo, previous studies have failed to document that bryostatin 1 modulates total cellular PKC activity in tumor or normal tissues when administered in vivo. After a single bolus injection of bryostatin 1 (1.0 microgram) in normal C57BI/6 mice, blood was drawn at various intervals and assayed for bryostatin 1 levels. In addition, spleens from bryostatin-treated mice were harvested 10 min to 10 days after treatment, weighed and analyzed for cell numbers, PKC activity and cell surface phenotypes. Bryostatin 1 levels in plasma rose rapidly, reaching peak levels of 56.5 nM less than 1 min after injection, and then declined to undetectable levels by 1 h. A similar pattern was observed when bryostatin 1 was incubated with leukemia cells in vitro, raising the possibility that the rapid fall in plasma levels results from intracellular uptake and binding. Bryostatin 1 induced marked depletion of total splenocyte PKC activity (as much as 69% relative to control values) at 24-96 h after drug administration, but not at earlier times (i.e. 1 h). A single injection of bryostatin 1 also induced expression of the T cell activation marker CD69, leading to positivity in 53% of cells at 3-24 h versus 11% in control mice, and resulted in marked splenomegaly, associated with increased numbers of nucleated cells at 48-96 h. Together, these studies demonstrate that despite rapid disappearance of the drug from plasma, a single i.v. dose of bryostatin 1 exhibits significant and sustained effects on normal murine spleen cells, including early lymphocyte activation, prolonged depletion of PKC activity, splenocyte proliferation and splenomegaly. These findings may have implications for attempts to understand the in vivo effects of bryostatin 1 in normal host tissues.

Animals↗