Biomedical subjects
Publications and source records attributed to H Xu.
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The metabolic thermograms and heat output of mitochondria isolated from carp liver have been determined by using an LKB bioactivity monitor. The thermogram can be divided into four parts: the lag phase, active recovery phase, stationary phase, and decline phase. The thermokinetic equation was established for the active recovery and decline phase of metabolism as follows: dP/dt = k(m)P (1-SP). The rate constants k1 and k2 of two phases of active recovery and decline phase have been also calculated. The metabolism activity of mitochondrial inhibited by a high concentration of trace element selenium has been studied. The metabolic heat released, time of each phase, and rate constants can be significantly influenced by excess of selenite added. These results suggested that a high concentration of selenium can damage the structure and function of mitochondria, and thus influence their metabolism.
Studies conducted after the development of the rapid filtration assay for opiate receptors, and before the recognition of multiple opioid receptors, failed to detect changes in opioid receptors induced by chronic morphine. Recent experiments conducted in our laboratories were designed to examine the hypothesis that only one of several opioid receptor types might be altered by chronic morphine. Using binding surface analysis and irreversible ligands to increase the "resolving power" of the ligand binding assay, the results indicated that chronic morphine increased both the Bmax and Kd of the opioid receptor complex, labeled with either [3H][D-Ala2,D-Leu5]enkephalin, [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin or [3H]6-desoxy-6 beta-fluoronaltreone. In the present study rats were pretreated with drugs known to attenuate the development of tolerance and dependence [the irreversible mu-receptor antagonist, beta-funaltrexamine (beta-FNA), and the inhibitor of tryptophan hydroxylase, para-chlorophenylalanine], prior to subcutaneous implantation of morphine pellets. The results demonstrated that 1) unlike chronic naltrexone, beta-FNA failed to upregulate opioid receptors and 2) both beta-funaltrexamine and PCPA pretreatment attenuated the chronic morphine-induced increase in the Bmax, but not the Kd, of the opioid receptor complex. These results provide evidence that naltrex-one-induced upregulation of the opioid receptor complex might occur indirectly as a consequence of interactions at beta-funaltrexamine-insensitive opioid receptors and that morphine-induced upregulation (increased Bmax) of the opioid receptor complex is a relevant in vitro marker related to the development of tolerance and dependence. These data collectively support the hypothesis that endogenous antiopiate peptides play an important role in the development of tolerance and dependence to morphine.
Recent pharmacological data strongly support the hypothesis of delta receptor subtypes as mediators of both supraspinal and spinal antinociception (delta 1 and delta 2 receptors). In vitro ligand binding data, which are fully supportive of the in vivo data, are still lacking. A previous study indicated that [3H][D-Ala2,D-Leu5]enkephalin labels two binding sites in membranes depleted of mu binding sites by pretreatment with the site-directed acylating agent, 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimid azole-HCI (BIT). The main goal of the present study was to develop a ligand-selectivity profile of the two delta ncx binding sites. The data indicated that naltrindole and oxymorphindole were relatively selective for site 1 (20-fold). [D-Ser2,Thr6]Enkephalin and deltorphin-II were only 2.7-fold and 2.2-fold selective for site 1. [D-Pen2,D-Pen5]Enkephalin and deltorphin-I were 80-fold and 38-fold selective for site 2. 3-Iodo-Tyr-D-Ala-Gly-Phe-D-Leu was 52-fold selective for site 1. Morphine had moderate affinity for site 1 (Ki = 16 nM), and was about 11-fold selective for site 1. Thus, of the 10 drugs studied, only DPDPE and DELT-I were selective for site 2. Viewed collectively with other data, it is likely that the delta 1 receptor and the delta ncx binding site are synonymous.
Previous experiments resolved four kappa binding sites in guinea pig brain termed kappa 1a, kappa 1b, and kappa 2b. The present study was undertaken to examine the occurrence of kappa receptor subtypes in rat and human brain. [3H]U69,593 and [3H]bremazocine were used to label kappa 1 and kappa 2 binding sites, respectively, present in brain membranes depleted of mu and delta binding sites by pretreatment with the irreversible ligands, BIT and FIT. Low levels of [3H]U69,593 binding precluded a detailed quantitative study of kappa 1 binding sites in these species. Quantitative examination of [3H]bremazocine binding resolved two kappa 2 binding sites in both rat and human brain whose ligand selectivity patterns differed from that of the guinea pig. These observations suggest that there may be considerable variation in the ligand recognition site of kappa receptor subtypes among mammalian species.
Certain opioid antagonists of the phenylpiperidine series (PPAs), such as LY255582, seem uniquely efficacious at producing weight loss in lean and meal-fed obese Zucker rats. Comparison of the pharmacological and receptor binding profile of PPAs that promote marked weight loss with those that do not has failed to find any obvious differences between these two groups of narcotic antagonists, which might explain the differences in their biological activities. The potent stimulatory effect of dynorphin, and other kappa agonists, on feeding behavior suggests that the antagonists that promote weight loss might have high affinity for kappa receptors. The recent demonstration by several laboratories of kappa receptor heterogeneity prompted us to test the hypothesis that the antagonists that promote weight loss might have high affinity for a subtype of kappa binding sites. In the present study, therefore, we determined the Ki values of five PPAs, naloxone, and naltrexone at mu, delta, kappa 1, kappa 2a, and kappa 2b binding sites. The data indicate that antagonists have subnanomolar Ki values and high selectivity for the kappa 2b binding site (relative to the kappa 2a binding site) are efficacious at promoting weight loss.
Research into the functional role of the opioid delta receptor has intensified with the recent in vivo identification of delta receptor subtypes, termed delta 1 and delta 2, which mediate antinociception in the mouse. A variety of data also support the hypothesis of an opioid receptor complex composed of distinct, yet interacting, mu, delta, and perhaps kappa binding sites. This model postulates two classes of delta binding sites: a delta binding site not associated with the opioid receptor complex, termed the delta ncx site, and a delta site associated with the receptor complex, termed the delta cx site. A major purpose of this study was to clarify the relationship between the delta ncx binding sites and the delta 1 and delta 2 receptors. Mouse brain membranes were depleted of mu sites by pretreatment with the site-directed acylating agent, BIT, and the delta ncx binding sites were labeled with [3H][D-Ala2,D-Leu5]enkephalin. Binding surface analysis readily resolved two binding sites (delta ncx-1 and delta ncx-2) in the absence and presence of 100 mM NaCl. Control experiments with guanine nucleotides and the ligand-selectivity analysis indicated that the two sites were not two states of a single receptor. Pretreatment of membranes with DALCE, but not [Cys4]deltorphin, decreased [3H] [D-Ala2,D-Leu5]enkephalin and [3H][D-Ser2,Thr6]enkephalin binding. Ligand-selectivity analysis of the two binding sites suggested that neither delta ncx binding site had the characteristics expected of the delta 2 receptor, and that the delta ncx-1 site, but not the delta ncx-2 site, was synonymous with the delta 1 receptor. Moreover, our finding that the racemic nonpeptide delta agonist, BW373U86, had high affinity at and selectivity for the delta ncx-2 site suggests that this site may be a novel delta receptor that mediates some of the effects of BW373U86.
Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF), an endogenous mammalian antiopioid peptide, has been shown by other laboratories to attenuate the acute antinociceptive effects of morphine, the development of morphine tolerance, and naloxone-induced withdrawal in morphine-dependent rats. The present study determined the effect of chronic NPFF on mu opioid receptors and mRNA for the endogenous opioids dynorphin and enkephalin. Rats received ICV infusions of either saline or NPFF (5 micrograms/h) for 13 days via Alzet 2002 osmotic minipumps. Homogenate binding studies, which used whole brain membranes, demonstrated that NPFF decreased the Bmax of mu binding sites (labeled by [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin) from 262 +/- 12 to 192 +/- 12 fmolmg protein, and increased the Kd from 1.1 to 2.3 nM. Quantitative receptor autoradiography and in situ hybridization experiments were conducted with sections collected at the level of the striatum. The density of mu opioid binding sites labeled by [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin was decreased in all brain areas measured except the corpus callosum, and there was no change in dynorphin mRNA or enkephalin mRNA in the caudate, the nucleus accumbens, or the ventral pallidum. Rats chronically administered ICV morphine sulfate (20 micrograms/h) for 14 days developed tolerance to morphine and a low degree of dependence, as measured by naloxone-precipitated withdrawal. Chronic administration of NPFF concurrently with morphine sulfate did not significantly alter naloxone-induced withdrawal signs or the development of morphine tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Recent studies from our laboratory resolved two subtypes of the kappa 2 binding site, termed kappa 2a and kappa 2b, using guinea pig, rat, and human brain membranes depleted of mu and delta receptors by pretreatment with the site-directed acylating agents BIT (mu-selective) and FIT (delta-selective). 6 beta-Iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan (IOXY), an opioid antagonist that has high affinity for kappa 2 sites, was radioiodinated to maximum specific activity (2200 Ci/mmol) and purified by high pressure liquid chromatography and used to characterize multiple kappa 2 binding sites. The results indicated that [125I]IOXY, like [3H]bremazocine, selectively labels kappa 2 binding sites in rat brain membranes pretreated with BIT and FIT. Using 100 nM [D-Ala2-MePhe4,Gly-ol5]enkephalin to block [125I]IOXY binding to the kappa 2b site, two subtypes of the kappa 2a binding site were resolved, both in the absence and presence of 50 microM 5'-guanylyimidodiphosphate. Viewed collectively, these results provide further evidence for heterogeneity of the kappa opioid receptor, which may provide new targets for drug design, synthesis, and therapeutics.
This study was conducted to investigate the effect of starch in the preservation solution during hypothermic machine perfusion (HMP) on endothelial cell and hepatocyte functions in an isolated perfused rat liver model. Livers isolated from male Sprague-Dawley rats were perfused with the University of Wisconsin (UW) solution (HMP + starch group); modified UW solution (starch omitted) (HMP - starch group) at 0.4 mL/min per g liver; or simply stored in the UW solution (SCS group) at 4 degrees C for 24 hours. Following preservation, livers from HMP + starch, HMP - starch, SCS, and control group (without preservation) were perfused with Krebs-Henseleit Buffer solution at 37 degrees C for 30 minutes. Samples were taken every 10 minutes during 30-minute warm perfusion to assess hepatocyte and endothelial cell function and damage. After 24 hours of hypothermic preservation and 30 minutes rewarming, livers in the HMP + starch group displayed significantly lower lactate dehydrogenase levels and higher bile production. Endothelial cell function was also improved as indicated by hyaluronic acid uptake and shorter transient time for albumin observed in a multiple indicator dilution study. Liver wet and dry ratio and histological findings confirmed reduced edema formation in the tissue of the HMP + starch group livers compared with that of the HMP - starch and SCS group livers. These results suggest that HMP with the UW solution containing starch improve endothelial cell function and induce less hepatocellular damage following 24-hour preservation compared to SCS and HMP with the starch-free UW solution. These results also suggest that oncotic support may be an important component in preserving hepatic microcirculation in HMP.
Hypothermic machine perfusion (HMP) has a potential to relieve the current donor liver crisis by providing an improved and extended preservation method. This study examined the effect of HMP on hepatocellular functions, using a prototype liver transporter capable of preserving livers for 24 hours. Livers obtained from adult farm pigs (28 to 32 kg body weight) were divided into three groups: fresh control, HMP, and simple cold storage (n = 4 each). A 4-hour normothermic reperfusion of livers was conducted to assess hepato-metabolic and cellular functions. The hepatic transport function, as indicated by canalicular excretion of indocyanine green, was improved in the HMP group than in the SCS group. The overall tissue viability, as indicated by oxygen consumption levels, was notably improved in HMP and control livers as compared to the SCS group. Higher bile production in both the preserved groups as compared to the fresh control livers could be a result of biliary edema and leakage of plasma into the canaliculus. The hepato-cellular injury, measured by ALT, release was significantly greater in the SCS group as compared to the HMP and control groups. These findings suggest that HMP could be a better method to preserve hepatic function and overall tissue viability as compared to SCS. Improved hepatic functions are indirect indicators of superior microcirculation and sinusoidal endothelial cell functions. Further studies in progress will evaluate these functions to confirm the significance of these observations.
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1. The present study was planned to: (i) determine whether the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) was attenuated during reperfusion of short-term ischaemic myocardium; and (ii) study whether blockade of prostaglandin synthesis with indomethacin reversed the inhibitory baroreflex. 2. Arterial pressure was lowered with intravenous sodium nitroprusside before coronary occlusion and 3 min after release of a 5 min occlusion of the left circumflex coronary artery in anaesthetized rabbits. The protocol was repeated 20 min after indomethacin (5 mg/kg, i.v.) or indomethacin vehicle (50 mmol/L tris(hydroxymethyl)aminomethane buffer, pH 8.4) treatment. In addition, this study was performed in a group of vagotomized rabbits. 3. Before indomethacin treatment, the slope of the mean arterial pressure (MAP)-RSNA relationship decreased from -3.3+/-0.77 to -2.01+/-0.69% change in RSNA/mmHg (P < 0.05) during reperfusion of ischaemic myocardium in intact rabbits. The decrease in the slope was reversed by administration of indomethacin. However, the decrease in the slope was not reversed by indomethacin vehicle. Furthermore, the reduction in the slope of the MAP-RSNA relationship during reperfusion of ischaemic myocardium was abolished in vagotomized rabbits. However, there was no inhibition of the slope of the MAP-HR relationship during reperfusion of ischaemic myocardium in either intact or vagotomized rabbits. 4. In conclusion, our data suggest that prostaglandins released by ischaemic myocardium can attenuate the baroreflex-mediated response of RSNA to lowered arterial pressure via vagal afferents during reperfusion of short-term ischaemic myocardium.
This study was conducted to determine the effect of footwear modification on patients with neuromusculoskeletal disorders. Two analyses, the center of pressure and the in-shoe plantar pressures, were studied with the help of healthy volunteers so that the effect of shoe modifications could be assessed. The ground force under the sole of the shoe was measured while the subjects were walking, and the plantar pressure at the foot-insole interface and its distribution were measured while the subjects were in both the standing and walking positions, wearing the trial shoes. The trial shoes had three different types of heels-standard heel, Thomas heel, and reverse Thomas heel-and had three different locations for the rocker bar--just under the metatarsophalangeal joint, 1 cm behind the metatarsophalangeal joint, and 1 cm before the metatarsophalangeal joint. The shift change at the center of pressure showed that the Thomas heel generally pushed the center of pressure more laterally and the reverse Thomas heel shifted it medially more than the standard heel did. While the subjects were in a stable standing position wearing the Thomas heel shoes, the medial forefoot and the lateral heel region's pressure showed significant reduction in the plantar pressure and the lateral forefoot and the medial heel showed a tendency to rise, compared with the standard heel condition. When the trial shoes' heels were changed to the reverse Thomas heel, the above changes tended to reverse. Tests at the foot-insole interface showed that the different types of heels and the location of the bar could change not only the pressure distribution but also the duration of the plantar pressure under the lateral area that shifted to the medial area when the subjects walked. This pressure measurement method was very useful for the design and evaluation of such footwear.
We examined the feasibility of using a polytetrafluoroethylene membrane (goretex) valve and transannular patch (TAP) for right ventricular outflow tract (RVOT) reconstruction in growing animal models. Eleven infant goats (Group A) and 12 infant sheep (Group B) underwent RVOT reconstruction under cardiopulmonary bypass. In Group A, a monocusp valve was constructed of goretex, and the RVOT was roofed over utilizing a TAP of bovine pericardium. In Group B, both a monocusp valve and a TAP were constructed of goretex. Animals were sacrificed at 6 or 12 postoperative months. Two goats in Group A died at 9 days and 4 months postoperatively due to RVOT obstruction caused by thrombus formation. Seven goats in Group A and 11 in Group B showed no pressure gradient across the valve. All animals in Group B revealed mild to moderate valvular insufficiency, but no ventricular deterioration. In contrast to the bovine pericardium, which showed a prominent fibroinflammatory reaction with calcified areas causing TAP shrinkage and RVOT stenosis, there was minimal calcification and inflammatory reaction directed against the goretex valve and TAP. We conclude that goretex can be used as a material from which to create both a monocusp valve and TAP for long-term RVOT reconstruction.
A rare case of pyoderma gangraenosum caused by Rhizopus arrhizus is reported. The patient, a 50-year-old male farmer, was admitted to hospital complaining of gangrening and festering of the right upper arm with severe pain for nearly 2 months. A lesion was found on the inside of right upper arm. The central skin part of the lesion became black dry gangrenous, the periphery was deeply ulcerated with yellow-green pus. The necrotic crust, biceps, triceps and vessels inherited a histopathologically proven fungal infection. The fungus isolated was identified as Rhizopus arrhizus. The infection was successfully treated with itraconazole.
The aim of this study was to investigate the feasibility and safety of laparoscopic radical parametrectomy and pelvic and para-aortic lymphadenectomy after previous supracervical or extrafascial hysterectomy. This is a prospective study of six patients with vaginal or cervical stump carcinoma after previous supracervical or extrafascial hysterectomy. The technique of radical parametrectomy with pelvic and para-aortic lymphadenectomy as used for open surgical cases for years was performed laparoscopically. The average operating time was 180 min, the estimated average blood loss was 220 mL, and the duration of hospitalization was 11.8 days. There was no intraoperative or postoperative complication. Laparoscopic radical parametrectomy with pelvic and para-aortic lymphadenectomy for cervical or vaginal stump carcinoma can be successfully and safely accomplished.