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Biomedical subjects

M Houston

Publications and source records attributed to M Houston.

At least 19 recordsLinked to original sources
PubMed2001

p21(WAF1/cip1) is an important determinant of intestinal cell response to sulindac in vitro and in vivo.

Sulindac, a nonsteroidal anti-inflammatory drug, inhibits intestinal tumorigenesis in humans and rodents. Sulindac induced complex alterations in gene expression, but only 0.1% of 8063 sequences assayed were altered similarly by the drug in rectal biopsies of patients treated for 1 month and during response of colonic cells in culture. Among these changes was induction of the cyclin-dependent kinase inhibitor, p21(WAF1/cip1). In Apc1638(+/-) mice, targeted inactivation of p21 increased intestinal tumor formation in a gene-dose-dependent manner, but inactivation of p21 completely eliminated the ability of sulindac to both inhibit mitotic activity in the duodenal mucosa and to inhibit Apc-initiated tumor formation. Thus, p21 is essential for tumor inhibition by this drug. The array data can be accessed on the Internet at http://sequence.aecom.yu.edu/genome/.

Animals↗
PubMed2001

Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition.

Inducible activation of nuclear factor-kappaB (NF-kappaB) inhibits the apoptotic response to chemotherapy and irradiation. Activation of NF-kappaB via phosphorylation of an inhibitor protein IkappaB leads to degradation of IkappaB through the ubiquitin-proteasome pathway. We hypothesized that inactivation of proteasome function will inhibit inducible NF-kappaB activation, thereby increasing levels of apoptosis in response to chemotherapy and enhancing antitumor effects. To assess the effects of proteasome inhibition on chemotherapy response, human colorectal cancer cells were pretreated with the dipeptide boronic acid analogue PS-341 (1 microM) prior to exposure to SN-38, the active metabolite of the topoisomerase I inhibitor, CPT-11. Inducible activation of NF-kappaB and growth response were evaluated in vitro and in vivo. Effects on p53, p21, p27 and apoptosis were determined. Pretreatment with PS-341 inhibited activation of NF-kappaB induced by SN-38 and resulted in a significantly higher level of growth inhibition (64-75%) compared with treatment with PS-341 alone (20-30%) or SN-38 alone (24-47%; P < 0.002). Combination therapy resulted in a 94% decrease in tumor size compared with the control group and significantly improved tumoricidal response to treatment compared with all treatment groups (P = 0.02). The level of apoptosis was 80-90% in the treatment group that received combination treatment compared with treatment with single agent alone (10%). Proteasome inhibition blocks chemotherapy-induced NF-kappaB activation, leading to a dramatic augmentation of chemosensitivity and enhanced apoptosis. Combining proteasome inhibition with chemotherapy has significant potential to overcome the high incidence of chemotherapy resistance. Clinical studies are currently in development to evaluate the role of proteasome inhibition as an important adjuvant to systemic chemotherapy.

Animals↗
PubMed1999

Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling.

Concentrations of up to 1.5 milliunits/ml xanthine oxidase (XO) (1.1 micrograms/ml) are found circulating in plasma during diverse inflammatory events. The saturable, high affinity binding of extracellular XO to vascular endothelium and the effects of cell binding on both XO catalytic activity and differentiated vascular cell function are reported herein. Xanthine oxidase purified from bovine cream bound specifically and with high affinity (Kd = 6 nM) at 4 degreesC to bovine aortic endothelial cells, increasing cell XO specific activity up to 10-fold. Xanthine oxidase-cell binding was not inhibited by serum or albumin and was partially inhibited by the addition of heparin. Pretreatment of endothelial cells with chondroitinase, but not heparinase or heparitinase, diminished endothelial binding by approximately 50%, suggesting association with chondroitin sulfate proteoglycans. Analysis of rates of superoxide production by soluble and cell-bound XO revealed that endothelial binding did not alter the percentage of univalent reduction of oxygen to superoxide. Comparison of the extent of CuZn-SOD inhibition of native and succinoylated cytochrome c reduction by cell-bound XO indicated that XO-dependent superoxide production was occurring in a cell compartment inaccessible to CuZn-SOD. This was further supported by the observation of a shift of exogenously added XO from extracellular binding sites to intracellular compartments, as indicated by both protease-reversible cell binding and immunocytochemical localization studies. Endothelium-bound XO also inhibited nitric oxide-dependent cGMP production by smooth muscle cell co-cultures in an SOD-resistant manner. This data supports the concept that circulating XO can bind to vascular cells, impairing cell function via oxidative mechanisms, and explains how vascular XO activity diminishes vasodilatory responses to acetylcholine in hypercholesterolemic rabbits and atherosclerotic humans. The ubiquity of cell-XO binding and endocytosis as a fundamental mechanism of oxidative tissue injury is also affirmed by the significant extent of XO binding to human vascular endothelial cells, rat lung type 2 alveolar epthelial cells, and fibroblasts.

Animals↗
PubMed1998

Xanthine oxidase reaction with nitric oxide and peroxynitrite.

Nitric oxide (.NO) and peroxynitrite (ONOO-) inhibit enzymes that depend on metal cofactors or oxidizable amino acids for activity. Since xanthine oxidase (XO) is a 2(2Fe2S) enzyme having essential sulfhydryl groups linked with Mo-pterin cofactor function, the influence of .NO and ONOO- on purified bovine XO was determined. Physiological (</=1 microM) and supraphysiological (</=100 microM) concentrations of dissolved .NO gas did not inhibit the catalytic activity or alter the spectral characteristics of XO at 25 degreesC and pH 7.0, differing from reports showing XO inhibition by .NO. The apparent decrease in XO activity observed previously was the result of depressed rates of uric acid accumulation in XO assay systems, due to ONOO--mediated oxidation of uric acid upon reaction of residual .NO with XO-derived superoxide (O*-2). Nitric oxide derived from S-nitrosoglutathione also did not inhibit cultured vascular endothelial cell XO activity. In contrast, purified and vascular endothelial cell catalase, a heme enzyme reversibly inhibited by .NO, was inhibited by similar concentrations and rates of production of . NO. In contrast to .NO, ONOO- inhibited XO (0.2 microM, 50 mU/ml) with an IC50 of 57 microM (for 3 microM/min infusion of ONOO-) or 120 microM (for bolus addition of ONOO-). Addition of 1% bovine serum albumin, 50 microM xanthine, or 10 microM uric acid protected XO from inactivation by ONOO-. Thus, in the presence of purine substrates and other more readily oxidized components of the biological milieu, XO should not be inhibited by either .NO or ONOO-. These observations reveal that .NO will not serve as an indirect antioxidant by inhibiting XO-derived production of reactive species and that the XO-derived products O*-2 and uric acid readily modify the reactivities of .NO and ONOO-.

Animals↗
PubMed1998

Normative sexual behavior in children: a contemporary sample.

OBJECTIVE: Sexual behavior in children can cause uncertainty in the clinician because of the relationship between sexual abuse and sexual behavior. Consequently, it is important to understand normative childhood sexual behavior. DESIGN: Sexual behavior in 1114 2- to 12-year-old children was rated by primary female caregivers. These children were screened for the absence of sexual abuse. A 38-item scale assessing a broad range of sexual behavior (Child Sexual Behavior Inventory, Third Version) was administered along with the Child Behavior Checklist and a questionnaire assessing family stress, family sexuality, social maturity of the child, maternal attitudes regarding child sexuality, and hours in day care. RESULTS: Sexual behavior was related to the child's age, maternal education, family sexuality, family stress, family violence, and hours/week in day care. Frequencies of sexual behaviors for 2- to 5-, 6- to 9-, and 10- to 12-year-old boys and girls are presented. CONCLUSIONS: A broad range of sexual behaviors are exhibited by children who there is no reason to believe have been sexually abused. Their relative frequency is similar to two earlier studies, and this reinforces the validity of these results.

Age Factors↗
PubMed1997

Interaction of the receptor binding domains of Pseudomonas aeruginosa pili strains PAK, PAO, KB7 and P1 to a cross-reactive antibody and receptor analog: implications for synthetic vaccine design.

The four synthetic peptide antigens, PAK 128-144, PAO 128-144, KB7 128-144 and P1 126-148, correspond in amino acid sequence to the C-terminal receptor binding regions of four strains (PAK, PAO, KB7, P1) of Pseudomonas aeruginosa pilin. The NMR solution structures of the trans forms of the peptides show conserved beta-turns which have been implicated in antibody and receptor recognition. The interactions between these peptides and a cross-reactive monoclonal antibody, PAK-13, have been studied using two-dimensional (1)H NMR spectroscopy in order to map the antigenic determinants recognized by the antibody. Residues for which spectral changes were observed upon antibody binding differed from peptide to peptide but were mostly confined to one or both of the turn regions and to the hydrophobic pockets. Conformational changes in the beta-turns and hydrophobic pockets of these peptides upon antibody binding were also monitored by examination of the pattern of nuclear Overhauser effects (NOEs) versus transferred nuclear Overhauser effects (TRNOEs) for the free versus the bound peptides. Although TRNOEs developed strongly between side chain resonances in the hydrophobic pockets of the peptides, no additional backbone TRNOEs were observed in the presence of antibody, suggesting no major conformational changes in the secondary structures of the peptides upon binding. This implies a flexible antibody combining site, a feature which is discussed with respect to cross-reactivity, strain specificity, and the design of a synthetic peptide vaccine effective against a broad spectrum of P. aeruginosa strains. The binding of the PAK peptide to a disaccharide receptor analog, (beta GalNAc(1-4)beta Gal), was also studied using (1)H NMR in order to map the "adhesintope" recognized by the receptor. Spectral changes observed in the peptide spectrum with the binding of receptor were similar to those seen for the binding of antibody, suggesting that the epitope recognized by the antibody is structurally coincident with the adhesintope recognized by the receptor. The relevancy of this result is discussed with respect to immunogenicity versus pathogenicity, and the proper design of a vaccine which could prevent the mutational escape of the pathogen away from the host's defence systems.

Amino Acid Sequence↗
PubMed1993

Increased levels of glutathione in bronchoalveolar lavage fluid from patients with asthma.

Patients with asthma generate increased amounts of reactive oxygen species (ROS) from peripheral blood cells and cells recovered by bronchoalveolar lavage (BAL). ROS produce many of the pathophysiologic changes associated with asthma and may contribute to its pathogenesis. Although antioxidant defenses inhibit the changes produced by ROS, no data are available on local antioxidant defenses in asthma. The present study was designed to begin to explore these defenses by measuring superoxide dismutase (SOD) and catalase activities and total glutathione (GSH) levels in BAL fluid from normal subjects and patients with mild asthma. Baseline pulmonary function and methacholine bronchoprovocation tests were performed on all subjects. BAL was achieved by instilling five 20-ml aliquots of phosphate-buffered saline in each of three lung segments. The fluids recovered from the first 20-ml aliquot and that from the next four aliquots were labeled bronchial and alveolar fluid, respectively. Patients with asthma had a lower FEV1 (p < 0.005), less BAL fluid recovered (p < 0.05), and an increased percentage of bronchial eosinophils (p < 0.05). There were no differences in BAL total cell count or protein concentration. Catalase activity was not consistently detected in the unconcentrated BAL fluid from either group. SOD activity was found in both bronchial and alveolar samples, but it was similar in the two groups of subjects. The GSH concentration in bronchial fluid was higher in the patients with asthma (23.9 +/- 6.2 vs 13.0 +/- 1.8 microM/mg protein; p < 0.05); a similar trend was seen in the alveolar fluid (36.5 +/- 9.4 vs 23.3 +/- 3.0 microM/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effect of leukotriene D4 and platelet-activating factor on human alveolar macrophage eicosanoid and PAF synthesis.

Leukotrienes (LT) and platelet-activating factor (PAF) can increase nonspecific airway reactivity in normal subjects, and they have been proposed as putative mediators of asthma. Alveolar macrophages (AM), which have receptors for and synthesize leukotrienes and PAF, also may play a role in the pathogenesis of asthma. The present study was designed to determine the effects LTD4 and PAF have on bronchoalveolar lavage (BAL) fluid and cells, including AM eicosanoid and PAF synthesis, and to relate them to changes in nonspecific airway reactivity. Airway reactivity to methacholine was measured in healthy, male volunteers at least 2 days before and 6 h, 1, 3, and 7 days after inhaling either LTD4 or PAF. At least 3 wk later subjects inhaled in random order either methacholine or the mediator to which they were previously exposed, and BAL was performed the next day. This sequence was repeated with the other chemical 3 wk or more later. LTD4 inhalation increased airway reactivity and stimulated AM thromboxane synthesis while it reduced stimulated AM LTB4 synthesis. LTD4 did not affect the number of percentage of BAL cells or the BAL fluid protein and histamine concentrations. PAF inhalation increased airway reactivity and the proportion of neutrophils and eosinophils recovered by BAL, but it did not alter AM eicosanoid and PAF synthesis or the BAL fluid protein and histamine concentrations. A relationship was identified between the PAF-induced increase in airway reactivity and the percentage of BAL neutrophils, but no correlation was found between LTD4- or PAF-induced changes in airway reactivity and stimulated AM eicosanoid or PAF synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Lymphocyte proliferation responses after exercise in men: fitness, intensity, and duration effects.

This study investigated the effects of intensity and duration of exercise on lymphocyte proliferation as a measure of immunologic function in men of defined fitness. Three fitness groups--low [maximal O2 uptake (VO2max) = 44.9 +/- 1.5 ml O2.kg-1.min-1 and sedentary], moderate (VO2max = 55.2 +/- 1.6 ml O2.kg-1.min-1 and recreationally active), and high (VO2max = 63.3 +/- 1.8 ml O2.kg-1.min-1 and endurance trained)--and a mixed control group (VO2max = 52.4 +/- 2.3 ml O2.kg-1.min-1) participated in the study. Subjects completed four randomly ordered cycle ergometer rides: ride 1, 30 min at 65% VO2max; ride 2, 60 min at 30% VO2max; ride 3, 60 min at 75% VO2max; and ride 4, 120 min at 65% VO2max. Blood samples were obtained at various times before and after the exercise sessions. Lymphocyte responses to the T cell mitogen concanavalin A were determined at each sample time through the incorporation of radiolabeled thymidine [( 3H]TdR). Despite differences in resting levels of [3H]TdR uptake, a consistent depression in mitogenesis was present 2 h after an exercise bout in all fitness groups. The magnitude of the reduction in T cell mitogenesis was not affected by an increase in exercise duration. A trend toward greater reduction was present in the highly fit group when exercise intensity was increased. The reduction in lymphocyte proliferation to the concanavalin A mitogen after exercise was a short-term phenomenon with recovery to resting (preexercise) values 24 h after cessation of the work bout. These data suggest that single sessions of submaximal exercise transiently reduce lymphocyte function in men and that this effect occurs irrespective of subject fitness level.

Adult↗
PubMed1990

Exercise and blood lymphocyte subset responses: intensity, duration, and subject fitness effects.

This study examined the effect of exercise intensity and duration on the percent blood lymphocytes in men of low [LF; maximal O2 uptake (VO2max) less than 50 ml.kg-1.min-1 and sedentary], moderate (MF; VO2max = 50-60 ml.kg-1.min-1 and recreationally active), and high (HF; VO2max greater than 60 ml.kg-1.min-1 and recent training history) fitness. Thirty healthy adult men (aged 20-31 yr) participated in four randomly ordered cycle ergometer rides: ride 1 (65% VO2max, 30 min), ride 2 (30% VO2max, 60 min), ride 3 (75% VO2max, 60 min), and ride 4 (65% VO2max, 120 min). Blood samples were drawn at various times before and after the exercise sessions. Lymphocyte subsets were determined by flow cytometry using monoclonal antibodies for total T (CD3+), T-helper (CD4+), and T-suppressor (CD8+) lymphocytes and for a subset of cells expressing a natural killer (NK) cell antigen (Leu7+). Plasma catecholamines were assayed to determine exercise stress. There were sharp reductions (P less than 0.01) in the percentage of pan-T and T-helper lymphocytes immediately after exercise across all fitness levels; the magnitude of this reduction was greatest after the highest intensity (ride 3) or longest duration (ride 4) work. In contrast, the absolute number of T and T-helper cells tended to increase after exercise and significantly so in the HF subjects (P less than 0.005). There was no significant effect of exercise or subject fitness category on the percentage of T-suppressor lymphocytes, although the absolute numbers of this subset increased significantly after exercise in LF subjects. Marked increases (P less than 0.01) in the percentage of NK cells occurred immediately after exercise at all intensities and durations tested; numerical increases in total NK cells were significant in all fitness groups after the highest intensity work (ride 3; P less than 0.005). Irrespective of whether the changes were expressed as percentage or total numbers, recovery to base line occurred at 30 min after exercise. The results suggest that the exercise effect on blood lymphocyte subset percentages in men is transient and occurs across all fitness levels. Concomitant changes in plasma catecholamine concentrations are only weakly associated with these lymphocyte subset percentage responses to exercise. Furthermore, this study shows that the exercise-induced changes in lymphocyte percentages do not consistently reflect changes in the absolute numbers of cells.

Adult↗
PubMed1989

Organization of afferent and efferent pathways in the pudendal nerve of the female cat.

Application of horseradish peroxidase to the pudendal nerve in the female cat labelled lumbosacral afferent and efferent neurons and their processes. Afferent axons entered the spinal cord primarily at the S1 and S2 segments and traveled rostrocaudally in Lissauer's tract and the dorsal columns. A distinctive component of the dorsal column projection was located at the lamina I-dorsal column border as a densely labelled, compact bundle that distributed fibers to the dorsal horn at spinal levels near the segments of entry of the afferent axons. Afferent terminal labelling was located in the marginal zone, the intermediate gray matter, and the dorsal gray commissure in the lumbosacral and coccygeal spinal cord. A well-defined terminal field restricted to the S1 and rostral S2 segments was present in the medial third of the nucleus proprius and substantia gelatinosa. Labelled motoneurons in Onuf's nucleus (S1 and S2) exhibited longitudinal dendrites that extended rostrocaudally within the nucleus and three groups of transverse dendrites that emanated periodically from the nucleus and passed to the ventrolateral funiculus, the intermediate gray, and the dorsal gray commissure. Components of the pudendal nerve that innervate the anal and urethral sphincters were also labelled by injecting HRP into the respective sphincter muscles. Motoneurons innervating the anal and urethral sphincters were located in the dorsomedial and ventrolateral divisions, respectively, of Onuf's nucleus. Afferent projections from the two sphincters were similar; the most prominent terminations were present in the marginal zone, intermediate gray, and dorsal gray commissure. These results are discussed with respect to the physiological function of the pudendal nerve and its relationship with sacral autonomic pathways.

Afferent Pathways↗
PubMed1989

Pulmonary capillary pressures during hypoxia and hypoxemia: experimental and clinical studies.

Unlike the systemic circulation, the pulmonary vasculature constricts in response to hypoxia to divert blood flow to better-ventilated segments. The site of this response, the hypoxic pulmonary vasoconstriction, has been reported as precapillary in numerous experimental models of isolated animal lungs. In the present study, the response of intact chest dog and human lungs to hypoxia and hypoxemia, respectively, was also precapillary vasoconstriction. In dogs, hypoxia in the ipsilateral lung attenuated the normal vertical blood flow gradient. Contralateral hypoxia did not alter pulmonary regional blood flow, precapillary (Ra), postcapillary, or total pulmonary vascular resistance. In patients, an elevated alveolar-arterial oxygen pressure gradient of 50 to 150 torr resulted in significantly increased Ra. Further hypoxemia did not increase this response. In addition, the effective pulmonary capillary pressure did not bear a constant relationship to the pulmonary artery occlusion or wedge pressure (WP). Therefore, in patients in respiratory failure, WP does not reliably estimate hydrostatic pressure at the pulmonary capillaries.

Animals↗
PubMed1986

Hypertensive emergencies and urgencies: pathophysiology and clinical aspects.

A hypertensive urgency should be distinguished from a hypertensive emergency. Although the distinction may not always be obvious, certain guidelines may help the clinician determine which therapeutic approaches are most appropriate for each patient. Hypertensive emergencies include those conditions in which new or progressive severe end-organ damage is present and a delay in appropriate therapy might result in permanent damage, progression of complications, and a poor prognosis. Hypertensive urgencies include those conditions with minimal to no obvious end-organ damage in which blood pressure should be lowered expeditiously. The risk of immediate complications or organ damage is less likely to occur, and thus the immediate prognosis is better, although the ultimate prognosis, if untreated, is poor. There is a marked individual, racial, sexual, and age difference in the ability to tolerate high intraarterial pressure, as evidenced by patients' symptoms and signs of end-organ damage. Patients may have no symptoms of elevated blood pressure until significant intraarterial levels are reached. If symptoms are present, they may include headache, dizziness, blurred vision, shortness of breath (especially with exertion), chest pain, rapid pulse, palpitations, malaise and fatigue, nocturia, or pedal edema. Signs of hypertensive disease vary and depend not only on the level of blood pressure but also include funduscopic changes with arteriolar narrowing, atrioventricular nicking, hemorrhages, exudates or papilledema, central nervous system changes and neurologic abnormalities, cardiac changes with gallop rhythm, cardiomegaly, tachycardia, ectopic ventricular beats, left ventricular hypertrophy or signs of congestive heart failure, pulmonary edema, and signs of renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗