Biomedical subjects

H Wong

Publications and source records attributed to H Wong.

At least 109 records · Page 6Linked to original sources

PubMed1996

Distribution of neurokinin-2 receptors in the guinea-pig gastrointestinal tract.

The distribution of neurokinin-2 (NK2) tachykinin receptors was investigated by immunohistochemistry in the guinea-pig oesophagus, stomach, small and large intestine. Receptor immunoreactivity occurred at the surfaces of smooth muscle cells throughout the digestive tract. Nerve fibre varicosities in enteric ganglia were also immunoreactive. In myenteric ganglia, these varicosities were most numerous in the ileum, frequent, but less dense, in the proximal colon and caecum, rare in the distal colon, extremely infrequent in the rectum and duodenum, and absent from the stomach and oesophagus. Reactive varicosities were rare in the submucous ganglia. Reactive nerve fibres in the mucosa were only found in the caecum and proximal colon. Strong NK2 receptor immunoreactivity was also found on the surfaces of enterocytes at the bases of mucosal glands in the proximal colon. Receptors were not detectable on the surfaces of nerve cells or on non-terminal axons. Reactivity did not occur on nerve fibres innervating the muscle. Denervation studies showed that the immunoreactive varicosities in the myenteric plexus of the ileum were the terminals of descending interneurons. Immunoreactivity for nitric oxide synthase was colocalised with NK2 receptor (NK-R) immunoreactivity in about 70% of the myenteric varicosities in the small intestine. Bombesin immunoreactivity occurred in about 30% of NK2-R immunoreactive varicosities in the small intestine.

Animals↗

PubMed1996

The effects of menopause and hormone replacement therapies on prednisolone and erythromycin pharmacokinetics.

The pharmacokinetics of oral and intravenous prednisolone and intravenous erythromycin were examined in premenopausal women, postmenopausal women not undergoing hormone replacement therapy, postmenopausal women undergoing estrogen replacement therapy, and postmenopausal women undergoing estrogen and progestin replacement therapy. The unbound clearance of prednisolone was significantly lower in postmenopausal women (11.6 +/- 2.3 ml/min/kg) than in premenopausal women (16.6 +/- 3.5 ml/min/kg). A comparable difference was also observed in total clearance and in half-life. The bioavailability and volume of distribution of prednisolone were unaffected by menopausal status. Hormone replacement therapies did not significantly affect prednisolone pharmacokinetics. In contrast to prednisolone elimination, erythromycin elimination, as measured by the erythromycin breath test, was not significantly affected by either menopausal status or hormone replacement therapy. In addition, there was no correlation between prednisolone clearance and the erythromycin breath test result. Although cytochrome P450 3A4 (CYP3A4) has been implicated in steroid hormone metabolism, these results suggest that another enzyme system, which is decreased in menopause (rather than simply an age effect), is also involved in prednisolone metabolism.

Adult↗

PubMed1996

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects.

1. Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week. 2. The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase. 3. The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50 mg to 600 mg day-1, with a weak indication of saturation at the higher 900 mg day-1 dose rate. 4. The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid Emax model and the C50 values for oxypurinol were 26.38 +/- 4.87, (mean +/- s.d.) 36.58 +/- 8.36 and 24.61 +/- 9.08 microM, respectively. 5. 1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C50 for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar. 6. The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C50, was lower than those often observed in clinical practice.

Adult↗

PubMed1996

Fat-induced ileal brake in the dog depends on peptide YY.

BACKGROUND & AIMS: Fat in the distal gut inhibits transit through the proximal small intestine as the ileal brake. Although the mediator of this response is not established, peptide YY (PYY) has been considered the most likely peptide candidate because inhibition of intestinal motility by fat in the distal gut correlated with the release of PYY but not other distal gut peptides such as enteroglucagon or neurotensin. Although intravenous administration of PYY inhibits intestinal transit, the role of this peptide remains to be confirmed because systemic PYY may not exert its effect by the same regulatory pathway as fat-induced ileal brake. The aim of this study was to definitively test the hypothesis that PYY mediates fat-induced ileal brake using the technique of peptide immunoneutralization. METHODS: In a fistulated dog model, intestinal transit during perfusion of the distal gut with 60 mmol/L oleate (ileal brake) was examined after intravenous administration of 0.5 mg/kg of PYY antibody (anti-PYY), nonspecific immunoglobulin G (control), or 0.15 mol/L NaCl. Intestinal transit result (cumulative percent recovery of 99mTc) was normalized within each animal against the transit result of the 0.15 mol/L NaCl experiment. RESULTS: Intestinal transit accelerated with PYY immunoneutralization, increasing cumulative percent recovery from 25.9 +/- 6.2 (control) to 81.2 +/- 6.3 (anti-PYY). CONCLUSIONS: Fat-induced ileal brake depends on PYY.

Animals↗

PubMed1996

Doppler grid surface scanning applications for pulmonary subsurface parenchymal perfusion assessment.

Subsurface perfusion to lung parenchyma underlying the pleura is difficult to assess in live ventilated animals. The purpose of this study was to assess applicability of a newly developed laser Doppler grid scanning imaging technology that measures perfusion of pleural subsurface lung regions in intact normal and abnormal animal lungs. Eighty-six Doppler grid perfusion measurements were performed in five New Zealand White Rabbits (3-5 kg); four with unilateral bullous lung disease, one normal control. Left upper lobe lung surface was exposed to 10 1-sec spot Nd:YAG exposures (70 W/cm2). One week following laser exposure, all rabbits underwent sequential bilateral open thoracotomy. Unaffected left lower lobes in these animals and all four lobes of a previously untreated rabbit were used as controls. Pleural subsurface perfusion measurements were recorded over a contiguous 900-pixel square surface grid using quantitative noncontact laser Doppler imaging during open thoracotomy procedures. Scans were obtained in a normal volume ventilation mode, at 30 cm of inspiratory hold airway pressure, and postinflation. A perfusion-pressure response curve was obtained in normal lung at 10-, 20-, and 30-cm static airway pressure. Post mortem measurements were used as 0 flow controls. Normal lung tissue was found to have relatively high pleural subsurface perfusion (1362 +/- 328 corrected units on a scale of 0-4095). Areas of atelectasis had decreased perfusion (659 +/- 512 U., 48.4 +/- 12.5% compared to normal lung, p < 0.02), but returned to normal levels after inflation of the lung (1253 +/- 363 U., p = 0.21 compared to normal). Pleural subsurface perfusion decreased uniformly and progressively as lung inflation pressure increased (p < 0.0001). Perfusion increased immediately to supranormal values following release of high inspiratory inflation pressure holds (1603 +/- 626 U., 117 +/- 18% compared to normal lung, p = 0.03). Bullae had markedly decreased perfusion (541 +/- 68 U.) that was not further reduced by increased inflation pressures. Noncontact laser Doppler grid perfusion imaging appears to provide a new tool for measuring pleural subsurface perfusion over a large area of lung surface in clinical experimental settings. Results are rapid, reproducible, and consistent. Sampling errors inherent in current point sampling Doppler flow techniques are reduced by the multiple contiguous measurements. We have used this technique to demonstrate inspiratory pressure-related reduction in pleural subsurface perfusion in normal lung, reversible decreased perfusion in atelectatic regions, and reduced perfusion in bullous and laser-treated lung regions.

Analysis of Variance↗

PubMed1996

CO2 and Nd:YAG laser-induced pulmonary parenchymal lung injury in a rabbit model.

Laser exposure of the pulmonary parenchyma during treatment of emphysema and other clinical indications causes acute lung injury. Animal investigations are needed to understand and control laser-induced lung injury. We hypothesized that lung injury is deeper from Nd:YAG laser exposures than CO2 exposures because of deeper penetration of Nd:YAG wavelength light. We compared the temporal evolution of histologic injury in rabbits resulting from continuous mode shallow CO2 and Nd:YAG laser pulmonary parenchymal exposures applied in rabbits. Forty-six New Zealand white (NZW) rabbits underwent treatment with CO2 laser (n=18), Nd:YAG laser (n=18), or sham thoracotomy control (n=10) to the visceral pleural surface using 1 min of exposure (5 watts, defocused to 70 W/cm2 power density for both lasers). Animals were killed at 0, 4, 7, 21, and 49 d after exposure. Lung injury, similar to that seen clinically in humans, developed in all laser-treated animals. Injury progressed from ischemia and vascular congestion, to edema and necrosis, followed by pleural and parenchymal fibrosis. The acute injury was qualitatively distinct and slightly deeper in CO2 than Nd:YAG-treated animals (p<0.02) despite the shallower depth of penetration of the CO2 laser. These findings may imply that higher absorption coefficient for CO2 laser energy results in greater focal temperatures and injury in the areas of direct exposure, and suggest that Nd:YAG laser exposure at these settings may cause shallower injury than CO2 lasers in humans undergoing clinical treatment.

Absorption↗

PubMed1996

Dose-dependent cigarette smoking-related inflammatory responses in healthy adults.

The aim of this study was to determine the dose-response relationship between cigarette smoke exposure and pulmonary cell and cytokine concentrations in bronchoalveolar lavage (BAL). BAL cells and BAL supernatant concentrations of tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-1 beta, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 from 14 healthy smokers and 16 healthy nonsmokers were quantified. Statistically greater concentrations of neutrophils, macrophages, IL-1 beta, IL-6, IL-8 and MCP-1 were observed among smokers compared with nonsmokers (p < or = 0.0007 in all cases). Cigarette smoking, categorized ordinally as: less than one pack, one pack, or greater than one pack per day, was predictive of BAL macrophages (p < 0.0001), neutrophils (p = 0.015), IL-1 beta (p < 0.001) and IL-8 (p = 0.02). We conclude that concentrations of macrophages, neutrophils, IL-1 beta and IL-8 are elevated in the pulmonary microenvironment of smokers in a cigarette dose-dependent manner. Based on the present findings, we would caution against simple analyses that treat current smokers as a homogeneous group and which do not account for smoking intensity.

Adolescent↗

PubMed1996

Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity.

Although chlorine gas is a common irritant exposure, little is known about airway responses to chlorine inhalation among persons with baseline airway hyperreactivity. We wished to determine whether such persons manifest an exaggerated response to chlorine compared with normal subjects. We studied 10 subjects, five with and five without airway hyperresponsiveness (HR) after exposure to 1.0 ppm chlorine and five persons, all with HR, to 0.4 ppm chlorine. After 1.0 ppm inhalation, there was a significant (p < 0.05) fall (mean +/- SE) in FEV1 immediately following exposure among normal (-180 +/- 37 mL) and HR subjects (-520 +/- 171 mL). The fall was greater among the HR compared with the normal subjects (p = 0.04). Specific airway resistance (Sraw) increased to a greater degree among the HR group compared with normal subjects (p = 0.04). Among all subjects (n = 10), the proportional change in FEV1 after 1.0 ppm chlorine correlated with baseline reactivity (Spearman rank correlation r = 0.64, p < 0.05). At 24-h follow-up, there were no significant chlorine-related pulmonary function deficits. After 0.4 ppm chlorine inhalation, there was no significant pulmonary function effect. These data indicated that persons with hyperreactive airways manifest an exaggerated airway response to chlorine at 1.0 ppm. This suggests that when large numbers of persons are exposed to chlorine, a susceptible subpopulation may acutely respond with a greater decrement in pulmonary function.

Adult↗

PubMed1995

Increased activity of p53 in senescing fibroblasts.

The p53 tumor-suppressor protein binds DNA and activates the expression of a 21-kDa protein that inhibits both the activity of cyclin-dependent kinases and the function of proliferating cell nuclear antigen. Since p21 expression has been reported to increase 10- to 20-fold as human diploid fibroblasts lose the ability to replicate, we examined the expression and activity of p53 during replicative aging. Similar levels of total p53 mRNA and protein were expressed in low-passage (young) and high-passage (old) cells but both DNA binding activity in vitro and transcriptional activity of p53 in vivo were increased severalfold in high-passage cells. While the basis of increased p53 activity is presently unclear, it is not correlated with differential phosphorylation or changes in p53-mouse double minute 2 gene product interactions. These results provide evidence for the activation of a protein involved in the control of cell cycle checkpoints during cellular aging, in the absence of increased expression.

Adult↗

PubMed1995

The cellular internalization and degradation of hepatic lipase is mediated by low density lipoprotein receptor-related protein and requires cell surface proteoglycans.

Hepatic lipase (HL) and lipoprotein lipase (LpL) are structurally related lipolytic enzymes that have distinct functions in lipoprotein catabolism. In addition to its lipolytic activity, LpL binds to very low density lipoproteins and promotes their interaction with the low density lipoprotein receptor-related protein (LRP) (Chappell, D. A., Fry, G. L., Waknitz, M. A., Muhonen, L. E., Pladet M. W., Iverius, P. H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). In vitro binding assays revealed that HL also binds to purified LRP with a KD of 52 nM. Its binding to LRP is inhibited by the 39-kDa receptor-associated protein (RAP), a known LRP antagonist, and by heparin. 125I-Labeled HL is rapidly internalized and degraded by HepG2 cell lines, and approximately 70% of the cellular internalization and degradation is blocked by either exogenously added RAP or anti-LRP IgG. Mouse fibroblasts that lack LRP display a greatly diminished capacity to internalize and degrade HL when compared to control fibroblasts. These data indicate that LRP-mediated cellular uptake of HL accounts for a substantial portion of the internalization of this molecule. Proteoglycans have been shown to participate in the clearance of LpL, and consequently a role for proteoglycans in HL clearance pathway was also investigated. Chinese hamster ovary cell lines that are deficient in proteoglycan biosynthesis were unable to internalize or degrade 125I-HL despite the fact that these cells express LRP. Thus, the initial binding of HL to cell surface proteoglycans is an obligatory step for the delivery of the enzyme to LRP for endocytosis. A small, but significant, amount of 125I-HL was internalized in LRP deficient cells indicating that an LRP-independent pathway for HL internalization does exist. This pathway could involve cell surface proteoglycans, the LDL receptor, or some other unidentified surface protein.

Animals↗

PubMed1995

Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene.

In order to gain better understanding of the function of hepatic lipase (HL) in vivo, we have generated mice that lack HL using gene targeting in embryonic stem cells. No mRNA for HL was detected in the liver of homozygous mutants, and no HL activity was detected in their plasma. Total cholesterol levels in plasma of mutant mice were increased by about 30% compared with wild type animals. Plasma phospholipids and high density lipoprotein (HDL) cholesterol were also increased, but plasma levels of triglycerides were not altered. Analysis of density fractions of plasma lipoproteins revealed that HDL1 (d = 1.02-1.04) was increased in homozygous mutants fed regular chow. In response to a diet containing high fat and high cholesterol, HDL cholesterol was doubled in the mutants, but was slightly decreased in the wild type mice. These results clearly demonstrate the importance of HL in HDL remodeling and metabolism in vivo. Various earlier studies suggested a role of HL in metabolism of triglyceride-rich particles, but the mutant mice appear to have no impairment in clearing them; the mutants clear exogenously introduced chylomicrons from plasma at a normal rate, and they tolerate acute fat loading as well as normal animals unless the loading is extreme. These differences may reflect species differences. However, it is also possible that the consequence of absence of HL as in our mutants is different from the consequence when nonfunctional HL protein is present as in the human HL-deficient patients and in rats treated with HL antibodies. We hypothesize that absence of HL in mutant mice allows other lipases to bind to the sites in the liver normally occupied by HL and facilitate the clearance of triglyceride-rich particles in these mice.

Alleles↗

PubMed1995

Overexpression of cyclin D1 blocks proliferation of normal diploid fibroblasts.

Human cyclin D1 forms complexes with several Cdks, with proliferating cell nuclear antigen, and with a recently discovered 21-kDa inhibitor of Cdk activity. Substrates for cyclin D1/Cdks have not been identified in vivo, but it has been proposed that the D class of cyclins might play a role in regulating the activity of the retinoblastoma gene product p105Rb. Here we report that normal human diploid fibroblasts that endogenously or ectopically express high levels of cyclin D1 are unable to enter S phase in response to normally mitogenic stimuli. Fibroblasts that have reached the end of their in vitro life span (senescent cells) express five-fold higher levels of cyclin D1 protein than low-passage cells and individual cells in mass culture that fail to initiate DNA synthesis in response to serum addition have severalfold higher levels of this cyclin than proliferation-competent cells. These observations provide evidence that cyclin D1 is involved with the regulation of cell proliferation by more than one mechanism.

Base Sequence↗

PubMed1995

The influence of somatostatin on glucagon and pancreatic polypeptide secretion in the isolated perfused human pancreas.

The current study was undertaken to determine whether intraislet somatostatin regulates glucagon or pancreatic polypeptide (PP) secretion in the human pancreas. A high-affinity, high-specificity monoclonal somatostatin antibody (CURE.S6) was used to immunoneutralize somatostatin in the isolated, perfused human pancreas. Single-pass perfusion was performed in pancreata obtained from cadaveric organ donors using a modified Krebs media with either 3.9 or 12.9 mM glucose. Sequential test periods separated by basal periods were performed with infusion of either exogenous somatostatin-14 (SS-14), CURE.S6, or a combined infusion. Infusion of SS-14 did not significantly alter glucagon or PP secretion during low-glucose or high-glucose perfusion. Immunoneutralization of intraislet somatostatin with CURE.S6 resulted in a significant increase of glucagon secretion under low-glucose conditions (delta X = 15 +/- 3 pM) (p < 0.05), but did not significantly effect glucagon secretion under high-glucose conditions (delta X = -2 +/- 3 pM) (p = NS). PP secretion remained unchanged during CURE.S6 infusion. Combined infusion of SS-14 and CURE.S6 did not significantly alter glucagon or PP secretion. The data suggest that intraislet somatostatin may have an inhibitory role in the regulation of glucagon secretion during low-glucose conditions and that intraislet somatostatin does not regulate PP secretion in the isolated, perfused human pancreas.

Adolescent↗

PubMed1995

Predictors of fear of falling in dizzy and nondizzy elderly.

Fear of falling may constitute an independent risk factor for disability, leading older people to unnecessarily restrict their activity. Sixty older adults with chronic dizziness and 66 healthy controls were studied to help clarify the interrelationships among demographic factors, psychological status, physical health, and fear of falling. Chronic dizziness was strongly associated with fear of falling; among dizzy patients, nearly half (47%) expressed fear of falling, in comparison with 3% of controls. In participants with dizziness, 3 factors predicted fear of falling: an activity of daily living score, the revised Symptom Checklist 90 Depression (Derogatis, 1983) score, and stability when standing with feet together. These results support the concept that fear of falling is multiply determined and that psychological factors play a major role in influencing the symptoms and responses in many older patients with dizziness.

Accidental Falls↗

PubMed1995

Welding helmet airborne fume concentrations compared to personal breathing zone sampling.

Metal fume concentrations inside the welding helmet and in the personal breathing zone in 23 experimental welding exposures were studied to explore whether welding helmet use substantially attenuates exposure to airborne metal fume. Observations produced a mean ratio of inside to outside metal fume concentrations of 0.9 +/- S.D. 0.2 with a highly variable effect. Iron fume concentration was inversely correlated with this ratio, representing greater helmet-associated attenuation with heavier exposure (r = -0.70, p < 0.001). In contrast to previous reports, these data suggest that welding helmet use provides marginal and highly variable reductions in fume exposure and cannot substitute for standard respiratory protection.

Adult↗

PubMed1995

Inhibition of bombesin-stimulated acid secretion by immunoneutralization of gastrin in dogs.

Bombesin-like peptides stimulate gastrin release and gastric acid secretion. The increase in gastric acid output is thought to be secondary to gastrin release. A monoclonal antibody (MAb) directed specifically to gastrin (MAb 28.2) was used to study the role of circulating gastrin in the regulation of bombesin-stimulated acid secretion in dogs. Seven conscious, fasted dogs with gastric fistulas received intravenous bombesin infusions in fourfold increasing doses from 200 to 3,200 pmol.kg-1.h-1. Each dose was given for 45 min. On separate days, dogs were pretreated with an intravenous infusion of 7 mg of MAb 28.2 or vehicle (0.1% canine serum albumin). Samples of gastric effluent were collected by gravity drainage through the gastric fistula, and acid output was measured by titration of gastric effluent to pH 7.0, using 0.2 N NaOH. Plasma gastrin concentrations were determined by radioimmunoassay. Bombesin infusion produced dose-dependent increases in plasma gastrin concentrations and gastric acid output. Administration of gastrin MAb 28.2 abolished bombesin-stimulated gastric acid output. Immunoneutralization of circulating gastrin in vivo using a gastrin monoclonal antibody in dogs indicates that the acid stimulatory response to bombesin is mediated by gastrin.

Animals↗

PubMed1995

Phenylalanine-stimulated secretion of cholecystokinin is calcium dependent.

The secretion of cholecystokinin was examined in STC-1 cells, an intestinal cholecystokinin (CCK)-secreting cell line. Exposure to the amino acid L-phenylalanine increased release of CCK by 135%, 180%, and 251% of control levels after 15-min treatments with 5, 20, and 50 mM phenylalanine, respectively. L-Phenylalanine-induced secretion of CCK was inhibited by the calcium channel blocker diltiazem (10 microM). L-Phenylalanine (20 mM) also significantly increased cytosolic calcium levels in fura 2-acetoxymethyl ester (fura 2-AM)-loaded cells, and this increase was diltiazem sensitive. D-Phenylalanine, over the dose range of 5-50 mM, produced nonsignificant increases in CCK release. Treatment of STC-1 cells with 300 ng/ml of pertussis toxin for either 4 or 24 h did not significantly affect either basal release of CCK or L-phenylalanine-stimulated secretion. Patch-clamp recordings from cell-attached membrane patches showed a stimulation in calcium channel activity after L-phenylalanine. These results indicate that, in STC-1 cells, L-phenylalanine stimulates release of cholecystokinin via a calcium-dependent process.

Animals↗

PubMed1995

Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects.

To compare markers of inflammation in secretions obtained by sputum induction (SI), bronchial wash (50 ml instillate [BW]), and bronchoalveolar lavage (4 x 60 ml instillates [BAL]), we analyzed markers of inflammation in samples obtained by these methods in 10 healthy and 10 asthmatic subjects. Of the asthmatic subjects 8 had mild disease (FEV1, % of predicted > 75%). Within subjects from both groups, we found that sputum, compared with either BW or BAL, had higher numbers of nonsquamous cells (p = 0.0001) and higher levels of eosinophil cationic protein (ECP) (p = 0.0001), albumin (p = 0.0001), and mucin-like glycoprotein (p = 0.0001). The eosinophil percentages and the ECP levels in sputum correlated more closely with those in BW (r = 0.67, p = 0.005; r = 0.69, p = 0.0008, respectively) than in BAL (r = 0.5, p = 0.03; r = 0.37, p = 0.11). Comparing the asthmatic and healthy subgroups, we found that eosinophil percentages were higher in sputum (p = 0.0003) and BW (p = 0.006) from asthmatic subjects and that ECP levels were higher in BW (p = 0.001) and BAL (p = 0.0005) from asthmatic subjects. We conclude that analysis of induced sputum reveals information qualitatively similar to that obtained by analysis of BW and BAL and that sputum induction is not only noninvasive and easily repeated but also yields samples more concentrated and richer in airway secretions than those obtained by bronchoscopy.

Adult↗