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Biomedical subjects

H Brown

Publications and source records attributed to H Brown.

At least 19 recordsLinked to original sources
PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗
PubMed1992

Correlation of bronchial eosinophil and mast cell activation with bronchial hyperresponsiveness in children with asthma.

Bronchial hyperresponsiveness in asthma has been associated with increased numbers of eosinophils and mast cells in the bronchial airway. It is unclear if these cells are important in the pathogenesis of hyperresponsiveness, and the role of mast cells has been discounted because they are effectively stabilized by beta-adrenergic drugs. Because the pathogenesis of asthma in children may be different from that in adults, and to find out if cellular activation is associated with bronchial reactivity, we studied 17 children with mild to moderately severe chronic asthma who had been treated with intermittent brochodilator therapy and compared their bronchial responsiveness to histamine with the levels of eosinophil cationic protein and mast cell tryptase in broncholavage fluid. The number of eosinophils in lavage fluid was correlated with histamine responsiveness (r = -0.444, p < 0.05) but not with levels of cationic protein (r = 0.33, p = NS). Bronchial responsiveness to histamine was highly correlated with mast cell tryptase (r = -0.714, p < 0.005), but there was no correlation with eosinophil cationic protein (r = -0.355, p = NS). We conclude that in children with chronic asthma mast cells as well as eosinophils contribute to bronchial hyperresponsiveness. Activated mast cells may play a primary role, possibly by tryptase-induced upregulation of bronchial smooth muscle tone.

Adolescent↗
PubMed1992

Paracentral rheumatoid corneal ulceration. Clinical features and cyclosporine therapy.

Six patients with rheumatoid arthritis (eight eyes) presented with small paracentral perforating corneal ulcers in otherwise quiet eyes. Initial management in five patients (seven eyes) consisted of systemic immunosuppression and therapeutic tissue adhesive with a bandage contact lens or tectonic keratoplasty. Ulceration recurred in all of these eyes, and recurrent ulcers treated with repeat tectonic keratoplasty or therapeutic tissue adhesive and a bandage contact lens all developed recurrent ulceration. The introduction of topical cyclosporine therapy in five eyes with recurrent corneal ulceration was associated with arrest of keratolysis and rapid re-epithelialization of the ulcer in all cases. One corneal ulcer was successfully treated initially with topical cyclosporine, tissue adhesive, and a bandage contact lens. In patients with rheumatoid arthritis and small paracentral corneal ulcerations or perforations, application of tissue adhesive and a bandage contact lens and introduction of topical cyclosporine may be the preferred initial treatment.

Aged↗
PubMed1991

The effect of in vivo glutathione depletion with buthionine sulfoximine on rat embryo development.

Glutathione is an abundant endogenous nucleophile whose depletion may have adverse effects on a number of cellular processes, including protein and DNA synthesis, amino acid transport, and detoxification of reactive electrophiles. Previous studies have indicated that a certain basal level of glutathione is essential for normal development in vitro in the whole rat embryo culture system. The objective of this study was to determine the effect of glutathione depletion with buthionine sulfoximine on the development of rat embryos in vivo. Timed pregnant Sprague-Dawley rats were treated by gavage on days 10 and 11 of gestation with saline (control) or with L-buthionine-(S,R)-sulfoximine (4 or 8 mmol/kg). Pregnancy outcome was assessed on day 12 or day 20 of gestation. The glutathione content of embryos and of maternal organs was measured on day 12. Glutathione concentrations were significantly decreased in the embryos and in maternal muscle and ovary but not in maternal liver and kidney. Glutathione depletion, when assessed on day 12 of gestation, was found to result in an increase in the numbers of dead and malformed embryos. Treatment with the higher dose of buthionine sulfoximine resulted in the death of 13.2% of the total implanted embryos; of the surviving embryos, 21.7% were malformed. There was also a significant decrease on day 12 after treatment with the higher dose of buthionine sulfoximine in the embryonic total morphological score, a measure of the developmental stage of the embryos (control, 57.7 +/- 1.0; 8 mmol/kg buthionine sulfoximine, 52.8 +/- 1.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Fasting and post-prandial splanchnic blood flow is reduced by a somatostatin analogue (octreotide) in man.

1. The effects of the subcutaneous administration of a long-acting somatostatin analogue (octreotide) or of placebo on the splanchnic blood flow response to a mixed solid meal has been examined in eight normal subjects by using a transcutaneous Doppler ultrasound technique. Each subject was studied on two occasions more than 1 week apart. 2. On the control day, feeding had a pronounced effect on both superior mesenteric artery and portal venous blood flows, causing a peak rise of 82% in superior mesenteric artery blood flow at 15 min and of 75% in portal venous blood flow at 30 min post-prandially (P less than 0.001). Blood flows remained elevated 2 h after the meal. Pulse and blood pressure showed no significant changes from baseline. 3. Octreotide reduced fasting superior mesenteric artery blood flow by 59% (P less than 0.05) and portal venous blood flow by 49% (P less than 0.01) and blunted the normal post-prandial rise. Pulse and blood pressure did not change in response to either the injection or the ingestion of the meal. 4. Octreotide suppressed the release of insulin, glucagon and pancreatic polypeptide in response to feeding and resulted in post-prandial hyperglycaemia. 5. The mechanism of action of octreotide on splanchnic blood flow is uncertain. It may be mediated via a direct vascular effect or it may act via suppression of vasoactive intestinal hormones.

Adult↗
PubMed1991

Personality. Type A behavior, and the effects of beta-blockade.

In a previous report, it was shown that a dimension of personality entitled dependence/independence could be used to distinguish the cardiovascular and catecholaminergic response to stress in type A individuals. This study is a continuation of the previous work. It examines the relative effects of beta-blockade on stress-induced changes in heart rate, blood pressure, and catecholamines in two groups of type A individuals who differ in reactivity. Sixty-six healthy, middle-aged men with type A behavior were classified as dependent (high reactivity) or independent (low reactivity). The effects of beta-blockade on the two groups were tested in a randomized, double-blind, crossover trial utilizing a mental stressor, a physical stressor, and work day monitoring. Results showed that, in comparison with the independent type As, those who had been classified as dependent had higher heart rates in all three stress conditions and had higher epinephrine levels during both the mental and physical stressors. For both groups, beta-blockade lowered the heart rate and systolic blood pressure but increased norepinephrine with the mental stressor and epinephrine and norepinephrine with the physical stressor. It also reduced the mean work day heart rate. For the dependent type As, the drug had a greater effect on increasing epinephrine during the physical stressor and by reducing the percent of the work day spent in high heart rate zones. The results are discussed from the point of view of identifying type As who may be particularly coronary prone and the potential effects of beta-blockade on the reactivity associated with type A behavior.

Adult↗
PubMed1991

Antibiotic treatment and associated prolonged prothrombin time.

The incidence and type of pathology causing a prolonged prothrombin time and clinical bleeding episodes were assessed in a multicentre study of 1109 patients receiving cefotetan, a N-methyl-thiotetrazole (NMTT), or equivalent antibiotics. There was no significant difference in the incidence of a prolonged prothrombin time (9.9% with cefotetan, 8.0% with comparable antibiotics) of clinical bleeding episodes. However, prothrombin time increases of greater than 12 seconds were significantly (p = 0.002) greater with cefotetan (3.8%) than with comparators (0.8%). In both antibiotic groups increases in prothrombin time were more likely following surgery and in patients who were older, with a high platelet count, low albumin, or higher urea and creatinine concentrations. All antibiotic treatment can be associated with prolonged prothrombin times and new agents should always be assessed in a large multicentre study before the practical, clinical importance of haemostatic defects can be defined.

Adolescent↗
PubMed1991

Basic medical physiology: the whole is more than the sum of its parts.

In this article we examine the role of basic medical physiology in medical school education. We discuss the historical background, courses in this subject, and methods of teaching it. We conclude that the teaching of medical physiology should emphasize the study of organ systems and of the intact body. The techniques should emphasize meticulous observation, the posing of hypotheses, and the subsequent testing of the hypotheses, i.e., the use of the method used successfully in research. Students should learn the power of the experimental approach and to appreciate the immense variability possible in responses in complex organisms. They should also learn that principles of statistical probability applied logically can detect important differences in data that may be obscured by this variability. They should learn that there are no rigid answers when studying an individual and that they must continue to learn throughout their lives.

Animals↗
PubMed1989

Temazepam withdrawal in elderly hospitalized patients: a double blind randomised trial comparing abrupt versus gradual withdrawal.

31 of 36 elderly mainly confused hospitalized patients (69-98 years) taking temazepam 10 mgs nocte for more than one month completed a double blind randomised placebo controlled trial comparing abrupt versus gradual withdrawal of temazepam. Hours of sleep were recorded for all patients during a 7 day baseline period while taking temazepam 10 mg nocte. Then the abrupt withdrawal (AW) group (n = 15) received placebo for 10 nights and the gradual withdrawal (GW) group (n = 16) received temazepam 5 mg for the first 4 nights, 2 mg for the next 4 nights and placebo for the last 2 nights. There was no significant difference in mean hours of nightly sleep during the baseline period between the AW group (5.9 +/- 1.1 SD) and GW group (5.8 +/- 1.1 SD) and between the baseline and withdrawal periods in each group (withdrawal periods, AW 5.6 +/- 1.2, GW 5.6 +/- 1.0). There was no rebound insomnia when temazepam was withdrawn either abruptly or gradually in long-term hospitalised elderly patients and may not be effective as a long-term hypnotic.

Aged↗
PubMed1989

Responses of left and right ventricular ejection fractions to aerobic and anaerobic phases of upright and supine exercise in normal subjects.

The effects of aerobic and anaerobic exercise on ventricular performance were studied in 13 normal subjects who underwent simultaneous pulmonary gas exchange evaluation and exercise radionuclide ventriculography in the supine and upright postures. Right and left ventricular ejection fraction was measured serially at 2-minute intervals during exercise. The anaerobic threshold occurred at 74% and 80% of maximum heart rate, respectively, during upright and supine exercise. Left and right ventricular ejection fractions rose from rest to the anaerobic threshold (p less than 0.01, p less than 0.01, respectively) and there was a further increase between the anaerobic threshold and maximum exercise (p less than 0.01, p less than 0.01, respectively). The rate of rise of ejection fraction beyond the anaerobic threshold was slightly blunted compared with the rise prior to attaining the anaerobic threshold. There was no significant difference in ventricular performance between supine and upright exercise. The data demonstrate that ventricular performance increases steadily during exercise and is not limited by the conversion of aerobic to anaerobic metabolism.

Adult↗