Biomedical subjects
Publications and source records attributed to L Brown.
Sarcoidosis causing the superior vena caval syndrome has been only rarely documented in the literature. We report surgical management of this problem with a spiral vein graft.
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The frequency of autoimmune features was compared in adult-onset diabetic subjects either requiring insulin treatment within 12 months of diagnosis or progressing to insulin therapy after a latency of at least 5 years. Adult-onset insulin-treated diabetic subjects were sampled from the population-based Canterbury Diabetes Registry (n = 1580). There were 237 (15%) registrants who met the study criteria of age < 75 years at 1 January 1993, age at diagnosis of diabetes > or = 45 years and duration of diabetes between 5 and 15 years; 101 subjects commenced insulin 5-15 years after diagnosis (group 1) and 80 subjects commenced insulin within 1 year of diagnosis (group 2). C-peptide levels, islet cell antibodies (ICA) and antibodies against glutamic acid decarboxylase (anti-GAD) were determined in all individuals from group 1 (n = 27) and group 2 (n = 23) who agreed to be recruited to the study. The group 1 and group 2 samples did not differ significantly in their demographic characteristics, nor were they different from the two groups from which they were drawn (mean age, 64.2 years; age at diagnosis, 53.5 years; duration of diabetes, 10.7 years; body mass index, 28.6 kg/m2). Overall, 12 of the 50 (24%) study subjects tested positive for anti-GAD; 43% (10) of group 2 subjects were anti-GAD positive compared with only 7.4% (2) of group 1 subjects (P < 0.01). Postprandial C-peptide levels were significantly lower in group 2 subjects compared with group 1 subjects (627 vs 1124 pM, P < 0.05). All subjects were ICA negative. These observations suggest that autoimmune destruction of beta-cells explains early requirement for insulin in adult-onset diabetes.
Determination of the molecular mechanisms involved in organophosphate-induced axonopathy may help to elucidate those involved in normal axonal maintenance and in other neurodegenerative conditions. In this study we aimed to define the cellular distribution of neuropathy target esterase, the primary target protein for neuropathic organophosphates. A synthetic peptide corresponding to the sequence of a proteolytic fragment of neuropathy target esterase purified from chicken brain was used to raise a rabbit antiserum designated R28. The antiserum was shown by immunoprecipitation and western blotting of brain extracts to react with a polypeptide of the expected molecular size (155,000 mol. wt); this reaction was blocked by preincubating the antiserum with the immunizing peptide. Prominent intracellular immunostaining by R28 was seen in neuronal cell bodies and, in some cases, proximal axon segments in frozen sections of chicken brain cortex, optic tectum, cerebellum, spinal cord, and dorsal root ganglia. Cells with glial morphology were not immunostained, neither were normal sciatic nerve or motor end plates. However, 8-12 h following sciatic nerve ligation, immunoreactive material was seen to accumulate both proximal and, to a lesser extent, distal to the ligature, indicating that neuropathy target esterase undergoes fast axonal transport. No gross qualitative or quantitative changes in the above pattern of neuropathy target esterase immunoreactivity were detected in tissue obtained from chickens one or three days following treatment with a neuropathic organophosphate. The presence of neuropathy target esterase in essentially all neurons indicates that the selective vulnerability of long axons to neuropathic organophosphates is dependent on factors additional to the presence of the target protein.
The dose response relationship of 25-, 50-, and 100-U doses of an inactivated hepatitis A vaccine was examined in 358-seronegative volunteers in a 2-dose schedule. The 50-U and 100-U groups had statistically significantly higher seroconversion rates than the 25-U group at weeks 2, 4, 8, and 24. Seroconversion was statistically significantly greater for the 100-U compared with the 25- and 50-U doses 2 weeks after the first injection but was not significantly different by 4 weeks after the first injection in the 50- and 100-U dose groups. After 2 injections, all subjects in all groups seroconverted. The vaccine was well tolerated at all dosage levels.
In rats, monocrotaline causes pulmonary vascular damage leading to pulmonary hypertension, right ventricular hypertrophy, and eventually heart failure. This study determined the inotropic and chronotropic responses in isolated cardiac tissues from pulmonary hypertensive rats (single treatment with monocrotaline, 105 mg/kg) to noradrenaline, forskolin, EMD 57033 (calcium sensitizer), and calcium chloride. Further, vasoconstrictor responses to noradrenaline, 5-hydroxytryptamine (5-HT), and KCl were measured in isolated pulmonary artery and thoracic aortic rings. Marked right ventricular hypertrophy was evident 4 weeks after treatment; at 6 weeks, treated rats additionally showed symptoms of severe heart failure. Pulmonary hypertension led to marked increases in pulmonary artery responses to 5-HT and to decreases in positive inotropic responses in right ventricular papillary muscles to all compounds except calcium chloride. The development of heart failure maintained or increased these changes. Positive chronotropic responses were unchanged. In the right ventricle, beta1-adrenoceptor density decreased only in heart failure; beta2-adrenoceptor density was unchanged. The densities of both beta-adrenoceptor subtypes were decreased in the lungs but increased in the liver of pulmonary hypertensive rats. The functional changes in the failing human heart are similar to those in rats with monocrotaline-induced right ventricular hypertrophy. This may be a useful model to define adequate therapy in human right ventricular failure.
The RpoS sigma factor of enteric bacteria is required for the increased expression of a number of genes that are induced during nutrient limitation and growth into stationary phase and in response to high osmolarity. RpoS is also a virulence factor for several pathogenic species, including Salmonella typhimurium. The activity of RpoS is regulated at both the level of synthesis and protein turnover. Here we investigate the posttranscriptional control of RpoS synthesis by using rpoS-lac protein and operon fusions. Substitution of the native rpoS promoters with the tac or lac UV5 promoters allowed essentially normal regulation after growth into stationary phase in rich medium or after osmotic challenge. Regulation of these fusions required the function of hfq, encoding the RNA-binding protein host factor I (HF-I). Short deletions from the 5' end of the rpoS transcript did not affect regulation very much; however, a larger deletion mutation that still retains 220 bp upstream of the rpoS ATG codon, including a proposed antisense element inhibitory for rpoS translation, was no longer regulated by HF-I. Several models for regulation of rpoS expression by HF-I are discussed.
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A project with several strands was carried out with a local Volunteer Stroke Scheme (VSS) which evaluated current practice; identified gaps in practice on which a training programme was based: and then evaluated the outcome of this training in subsequent activities.
The aim of this study was to assess the ability of transvaginal sonography (TVS) and office hysteroscopy with sharp curettage to characterize the morphological changes in the uteri of asymptomatic postmenopausal women taking long-term tamoxifen for breast cancer. The overall acceptability of a single-visit screening clinic for these women was also evaluated. Fifty-eight women were recruited from patients undergoing regular follow-up at the Leicester Royal Infirmary for breast cancer. A single-visit clinic was acceptable to 94.8% of these women. Transvaginal sonography detected endometrial thickness of greater than 5 mm in 84.5% of cases, but there was no relationship between total tamoxifen exposure and endometrial thickness. Transvaginal sonography also detected uterine lesions such as fibroids and endometrial cysts in 34.5% of cases. Hysteroscopy detected the latter uterine lesions in 53.4% of cases, with three cases (5.2%) of endometrial polyps also being identified in these women. Sharp curettage sampling of the endometrium produced specimens sufficient for diagnosis in 84.5% of cases; 70.7% of specimens were reported as showing types of 'quiescent' endometrium with 13.8% of specimens showing 'active' endometrium. In the latter group, there was a case of complex hyperplasia detected and also a case with granulomatous endometritis. For each histopathological diagnosis identified, there was a wide range of endometrial thickness recorded by TVS. A single-visit screening clinic involving TVS and hysteroscopy with sharp curettage was acceptable to asymptomatic women taking tamoxifen. However, hysteroscopy was more effective than TVS in detecting endometrial lesions such as polyps, fibroids and cystic areas. Although TVS detected endometrial thickness greater than 5 mm in the majority of cases, there were no malignancies detected and, for each histopathological classification, there was a wide range of endometrial thickness associated. Thus, the isolated use of TVS is insufficient for screening the endometria of these women.
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OBJECTIVES: To evaluate the development of resistance to fosfomycin or fucidic acid in severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and to assess the relationship with serum levels of vancomycin METHODS: A retrospective study was performed in patients hospitalized in our intensive care unit during a 3-year period (1993-1995) who were treated for severe MRSA infection with continuous infusion vacomycin and fosfomycin or fucidic acid. We analyzed the development of resistance and serum levels of vancomycin. RESULTS: During this period, only 20 patients received continuous infusion vancomycin plus fucidic acid or fosfomycin. MSRA resistant to fucidic or fosfomycin developed in 9. Vancomycin serum levels were significantly lower in patients who developed resistance to focidic acid or fosfomycin, both during the first 5 days of treatment (16.68 +/- 1.07 micrograms/ml vs. 22.64 +/- 1.05 mg/ml, p < 0.01) and throughout treatment duration (17.29 +/- 1.07 micrograms/ml vs. 21.85 +/- 0.78 microgram/ml, p < 0.01). CONCLUSIONS: Our findings confirm that in spite of continuous vancomycin infusion at an initial rate of 2 g/24 h, Staphylococcus aureus resistance to fosfomycin or fucidic acid an develop during ongoing treatment. Vancomycin levels of at least 20 micrograms/ml should be obtained as rapidly as possible.
A modified peptide-based indirect ELISA technique for the detection of HIV-1 specific antibodies in the sera of HIV-1 seropositive individuals is described. We found that the reduction of non-specific binding of HIV-1 seropositive sera to the ELISA plate was essential for the reliable detection of serum antibodies in the peptide based indirect ELISA. Optimal results were obtained using Immulon microtitre plates, different concentrations of denatured. purified grade of casein in the blocking (1%) and washing (0.25%) solutions and by diluting HIV-1 seropositive sera 1 in 1600. These conditions reduced non-specific binding and improved assay sensitivity. We show that the inclusion of a control peptide is essential to reducing the incidence of false positive and false negative results. Taken together, the modifications described in this report improve reliability of the peptide-based indirect ELISA without compromising its sensitivity and have particular relevance for those wishing to apply the peptide-based indirect ELISA technique to serum samples which exhibit high levels of non-specific binding. To illustrate this, levels of antibody in the sera of HIV-1 seropositive and seronegative donors that are specific for peptides derived from a conserved region of HIV-1 gp120 sharing homology with the FAS apoptosis antigen were analysed using this technique.
Angiotensin II mediates its effects through activation of specific angiotensin (AT) receptors which can be regulated during cardiovascular disease. This study has investigated whether an increased cardiac and renal AT receptor density is important in the development of left ventricular and renal hypertrophy in three rat models of hypertension [spontaneous hypertensive (SHR), deoxycorticosterone acetate (DOCA)-salt and 2K1C renal hypertensive rats]. Although all hypertensive rats developed left ventricular and renal hypertrophy, AT receptor density increased only in the left ventricle and kidney of SHR during the development of hypertension. Thus, cardiac and renal hypertrophy per se do not increase AT receptor density. AT receptors were increased in the liver of DOCA-salt rats, 2K1C rats and 52-week-old SHR and in adrenal glands of DOCA-salt rats and SHR. A plausible explanation for tissue-dependent AT receptor regulation involves tissue-selective control of local renin-angiotensin systems independent of circulating hormone levels, combined with disease-induced cell damage.
Formalin-inactivated, alum-adsorbed, hepatitis A vaccine was evaluated in 100 healthy adults who were stratified at enrollment into two age groups: 18-39 years: n = 50; 40-65 years: n = 50. All individuals received vaccine at 25 U of viral antigen. After stratification, both groups were randomized to receive either vaccination at 0 and 24 weeks or vaccination at 0.2 and 24 weeks. Subjects were bled for serology at 0, 2, 4, 24, 28 weeks and 1 year. The seroconversion rate and geometric mean titer (GMT = mIU ml-1) after one dose of vaccine was lower for older subjects [second week: < 40 years: 15/25 (60%) (GMT: 12.9). > 40 years: 5/22 (23%) (GMT: 6.1): fourth week: < 40 years: 20/22 (91%) (GMT: 29.0), > 40 years: 16/23 (70%) (GMT: 14.3)]. After a second dose at 2 weeks the seroresponse improved so that there were no longer differences between age groups [24 weeks: < 40: 21/22 (95%) (GMT: 123.9), > 40: 22/23 (96%) (GMT: 106.1)]. A third dose at 24 weeks resulted in a 20-40-fold increase in GMT in both age groups. As a separate evaluation height, weight, skin fold thickness, and body mass index (BMI) were assessed by logistic regression for their ability to predict serologic response. Serologic response was significantly associated with lower weight (P = 0.032) and BMI (P = 0.024) but not with height or skin fold thickness. Hepatitis A vaccine was well tolerated, with no serious adverse experiences. Adults older than 40 years appear to respond less well than younger adults to a single dose of 25 U of hepatitis A vaccine but equally well after two doses of vaccine. The slower antibody response to hepatitis A vaccine in overweight individuals was not attributable to skin adipose tissue.
OBJECTIVES: We attempted to characterize how drug released into the perivascular space enters the arterial wall and how it is cleared from the local environment. BACKGROUND: Drug released into the perivascular space can enter the artery either from the adventitial aspect or from the lumen after absorption by the extraarterial capillaries and mixing within the systemic circulation. Some investigators suggest that this latter mechanism dominates, and they question whether local drug release is synonymous with local deposition. METHODS: We investigated both the pathways by which adventitially released drug is cleared from the perivascular space and those by which drug enters the blood vessel wall. Inulin was used to follow drug release from implanted devices and subsequent entry to the circulation, because of its first-pass urinary excretion. Heparin was used to follow arterial deposition because of its vasoactivity and tissue-binding properties. The different potential pathways of drug entry and egress were systematically removed and the effects on metabolism and deposition determined. RESULTS: Ligature occlusion of the artery did not decrease inulin excretion or heparin deposition. Extravascular wraps designed to shield the device from extramural capillaries reduced inulin excretion rates 10-fold but did not alter heparin deposition into the vessel wall. The deposition of drug after perivascular delivery was 500 times higher than after intraperitoneal administration. CONCLUSIONS: Although almost all the drug released into the perivascular space is cleared through the extravascular capillaries, virtually all the deposited drug diffuses directly from the perivascular space, and little arrives from the endovascular aspect. These data support the view that local drug release leads directly to increased local drug concentration.