Although antimitochondrial auto-antibodies are characteristically present in the serum of patients with primary biliary cirrhosis (PBC), there is a discrepancy between the positivity for antimitochondrial antibody (AMA) and that for anti-M2 auto-antibody. In an attempt to explain the discrepancy, this study investigates the relationship between the AMA titre, determined by indirect immunofluorescence, and immunoreactivity to four inner mitochondrial membrane proteins (M2 proteins) with molecular weights of 70, 50, 47, and 40 kDa in 129 patients with PBC. Antimitochondrial antibody positivity was identified in 114 (88%) of 129 patients with clinically and histologically confirmed PBC. There were no significant differences between the AMA-negative and AMA-positive groups in clinical characteristics or histologically determined disease stage. Immunoblot analysis showed that all patients had anti-M2 auto-antibodies to one or more of the four M2 proteins. Nine (60%) of the 15 AMA-negative patients had antibodies to only one M2 protein (either 70 or 47 kDa). In contrast, 34 (53%) of the 64 patients with high AMA titres (> or = 1:320) had antibodies to all four M2 proteins. There was a significant rank correlation between the AMA titre and the number of antibodies to M2 proteins (P < 0.01). These findings indicate that the AMA titre is not influenced by the immunogenicity of M2 proteins but by the number of M2 proteins that elicit an antibody response and that decreased immunoreactivity to M2 proteins may induce AMA negativity in PBC serum samples.

Adult↗

PubMedDate not supplied

Changes in the extracellular glutamate concentrations in the rat cortex following localized by hyperthermia.

The mechanisms involved in cellular injury caused by hyperthermia in the central nervous system (CNS) remain unknown. In order to test the hypothesis that glutamate excitotoxicity may play a role in hyperthermia-induced CNS injury, we measured the extracellular glutamate concentrations, using intracerebral microdialysis, in the rat brain following localized hyperthermia The glutamate concentration in the dialysate was not increased by mild hyperthermia (41 degrees C), but it reached 250% of the control level 40 min after a 20-min period of moderate hyperthermia (43 degrees C) and then decreased rapidly When serve hyperthermia (45 degrees C) was induced, the glutamate concentration reached approximately 300% of the control level and was maintained at that level for 100 min after hyperthermia cessation. The elevated extracellular glutamate concentrations by local hyperthermia reached neurotoxic levels. The results presented here suggest that glutamate-mediated, 'excitotoxic' process plays an important role in hyperthermia-induced cellular injury in the CNS.

Animals↗

PubMedDate not supplied

Physiologically based pharmacokinetics of a new penem, SUN5555, for evaluation of in vivo efficacy.

SUN5555, (5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-[(R)-2- tetrahydrofuryl]-4-thia-1-azabicyclo-[3.2.0]-hept-2-ene-carboxylic acid, is a newly developed and orally effective penem with a broad antibacterial spectrum. SUN5555 was degraded in rat tissue homogenates and serum, and its degradations in the kidney and lung homogenates were significantly inhibited by cilastatin, an inhibitor of dehydropeptidase I. The pulmonary extraction was evaluated to be 0.033 by comparing the AUCs resulting from iv and intra-arterial administration of 10 mg/kg. From the arterial-to-venous concentration differences under steady state conditions in rats, extraction ratios of SUN5555 across the kidney, hind leg, gut, and liver were determined to be 0.333, 0.104, 0.071 and 0.053, respectively, whereas no appreciable extraction across the brain was observed. Therefore, organ clearances of SUN5555 are limited by the product of plasma unbound fraction and organ intrinsic clearances in various tissues. Using a physiologically based pharmacokinetic model, unbound concentrations of SUN5555 in the tissue interstitial fluids, which are the measure of in vivo antibacterial efficacy, were estimated to be almost identical with, or higher than, those in plasma in rats. Similarly, serum concentration-time profiles of SUN5555 after iv administration in other animal species were predicted and found to be in good agreement with the observed data in dogs. A preliminary prediction of the pharmacokinetics of SUN5555 in a human subject was also attempted by animal scale-up technique.

Animals↗

PubMedDate not supplied

Successful four-hour heart-lung preservation with core-cooling on cardiopulmonary bypass: a simplified model that assesses preservation.

This study was done to determine whether core-cooling could provide extended cardiopulmonary preservation and if reimplantation could be simulated and evaluated in the ex vivo autoperfused working heart-lung model. Twenty calves were divided into four groups and placed on cardiopulmonary bypass and rapidly cooled to 15 degrees C. Control heart and lungs were harvested after administration of cardioplegia through the aortic root and were subsequently resuscitated in the autoperfused working heart-lung circuit (group 1) or were orthotopically allotransplanted (group 2). Preserved heart and lungs were similarly excised but stored in a normal saline solution bath at 4 degrees C for 4 hours and then were resuscitated in the autoperfusion circuit (group 3) or were orthotopically allotransplanted (group 4). All groups received isoproterenol during explantation and reperfusion and were studied for 4 hours. Myocardial function was assessed by sonomicrometric techniques, and pulmonary preservation was evaluated by measurements of extravascular lung water, arterial oxygen tension on 100% inspired oxygen, and pulmonary vascular resistance. Cardiorespiratory function after 4-hour static preservation was similar in all four groups except that the arterial oxygen tension in group 1 was lower compared with group 3. Core-cooling on cardiopulmonary bypass without pulmonary artery flushing results in cold ischemic heart-lung preservation, comparable to other currently used modalities. In addition, reperfusion in the ex vivo autoperfusion circuit provides a simplified model to assess the adequacy of cardiopulmonary preservation techniques.

Animals↗

PubMedDate not supplied

Autoperfused working heart-lung preparation versus hypothermic cardiopulmonary preservation for transplantation.

The effects of preserving the heart and lungs with an autoperfused working heart-lung preparation or simple hypothermia via cardiopulmonary bypass were studied in 18 dairy calves that had combined heart-lung transplantation. Group 1 (n = 6) served as the control group in which animals were cooled with cardiopulmonary bypass and immediately had allotransplantations. In group 2 (n = 6), cardiopulmonary function was maintained in the autoperfusion circuit for 4 hours, followed by transplantation. In group 3 (n = 6), the organs were harvested after cooling by cardiopulmonary bypass, stored in cold (4 degrees C) saline solution for 4 hours, and then transplanted. Cardiopulmonary function was compared between the three groups for 6 hours after implantation. Cardiac function was determined by the ratio of the end-systolic pressure to end-systolic dimension. Pulmonary function was evaluated by the measurement of extravascular lung water, arterial oxygenation on 100% inspired oxygen static lung compliance, and histologic lung injury score. All measurements in groups 2 and 3 were similar to those of the control group at 6 hours after implantation. One may use either the hypothermic cardiopulmonary preservation method after cardiopulmonary bypass or the autoperfused working heart-lung preparation for distant organ procurement and expect adequate cardiopulmonary function after transplantation.

Animals↗

PubMedDate not supplied

Improved myocardial and pulmonary preservation by metabolic substrate enhancement in the autoperfused working heart-lung preparation.

The autoperfused working heart-lung (AWHL) preparation may provide successful cardiopulmonary preservation for up to 6 hours before transplantation. To determine whether the addition of metabolic substrate could prolong myocardial and pulmonary preservation in the AWHL model, 20 heart-lung blocks were harvested from calves. The brachiocephalic artery and superior vena cava were cannulated with extracorporeal tubing and connected to an elevated reservoir allowing total perfusion through a normothermic autoperfusion circuit. Eight heart-lung blocks were given dextrose and ribose followed by a continuous dextrose-insulin infusion, whereas the remaining 12 specimens received no additional substrates. Myocardial function was assessed by sonomicrometric techniques and pulmonary preservation evaluated by arterial oxygenation on 100% inspired oxygen, static lung compliance, and serial lung biopsies. The addition of substrate prolonged organ survival from 5 +/- 1 to 12 +/- 3 hours (p less than 0.001) and was associated with preservation of myocardial and pulmonary function. Application of substrate addition to the AWHL model will extend the interval of preservation for both heart and heart-lung transplantation.

Animals↗

PubMedDate not supplied

Differences in the pathogenesis of first-set allograft rejection and acute xenograft rejection as determined by sequential morphologic analysis.

To examine the pathogenesis of unmodified heart xenograft and allograft rejection, a sequential morphologic analysis was undertaken. Heterotopic cardiac allografts and xenografts were performed by implanting donor hearts into the abdomen of Lewis rats. Xenograft donors were Golden Syrian hamsters and allograft donors were ACI rats. Both xenografts and allografts were excised and examined by light microscopy at specific postoperative intervals. Allograft rejection was found to be a cell-mediated process, beginning with interstitial infiltrates and perivascular cuffing, which progressed to focal myocyte necroses. Ultimately, complete replacement of the myocardium by mononuclear cells was noted in fully rejected hearts. Xenograft rejection was markedly different. Although xenograft rejection was characterized first by interstitial mononuclear cell infiltrates, unlike allografts there was only minimal progression of cellular rejection. Instead, subsequent rejection was characterized by marked interstitial edema and arteriolar vasculitis and thrombosis, leading to extensive infarcts and hemorrhage in fully rejected hearts. Fibrinoid arteriolar changes and the rapid development of edema in the absence of significant cellular infiltrate suggest that cytotoxic antibodies alter xenograft vascular permeability. These data suggest that humoral immunity is largely responsible for acute concordant xenograft rejection, whereas first-set allograft rejection is mainly a cell-mediated process.

Animals↗

PubMedDate not supplied

Heparin coated percutaneous cardiopulmonary support for the treatment of circulatory collapse after cardiac surgery.

To overcome the hemorrhagic complications that may occur during extracorporeal circulatory support for post cardiotomy shock patients, a heparinized circuit was introduced into the percutaneous cardiopulmonary support system and decreased systemically administered heparin during bypass. Heparin coated percutaneous cardiopulmonary support with low dose systemic heparinization was instituted in 13 patients (6 men and 7 women, mean age 62.2 +/- 8.5 years) who experienced circulatory collapse after cardiac surgery. Of the 13 patients, 9 could not be weaned from cardiopulmonary bypass and 4 had circulatory collapse in the operating room or in the intensive care unit. The duration of support ranged from 1 to 66 hr (mean 27.4 +/- 26.7), and the flow rate ranged from 1 to 3 L/min (2.2 +/- 0.5). An activated coagulation time of about 150 sec was maintained with or without minimal systematically administered heparin. Of the patients cannulated, 77% (10 of 13) were successfully weaned from percutaneous cardiopulmonary support and 39% (5 to 13) were long-term survivors. The causes of death were sepsis in three, progressive heart failure in three, lower leg ischemia in one, and vital infection in one. From the results of clinical or post mortem examinations, there was no massive bleeding or evidence of thromboembolism in the major organs. From observations made within 12 hr of initiation of percutaneous cardiopulmonary support, there was no significant decrease in the number of platelets, but platelet count had significantly decreased 24 hr after initiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMedDate not supplied

Proinflammatory cytokine levels in patients undergoing cardiopulmonary bypass. Does lung reperfusion influence the release of cytokines?

Proinflammatory cytokines have been implicated in mediating tissue injury after cardiopulmonary bypass. Causative factors of inflammatory response after cardiopulmonary bypass include contact of the blood with the extracorporeal circuit and heart-lung reperfusion injury when discontinuing bypass. To evaluate proinflammatory cytokine release during cardiopulmonary bypass, plasma levels of interleukin-6, 8, and monocyte chemoattractant factor were measured in the radial artery (for systemic blood) and left atrium before and after cardiopulmonary bypass. A total of 13 patients were studied, with no deaths or complications. In both radial artery and left atrium, interleukin-6, 8, and monocyte chemoattractant factor rose significantly after cardiopulmonary bypass (p < 0.05 versus before cardiopulmonary bypass). These changes may have been caused by removal of the aortic cross clamp and recommencement of artificial ventilation, which result in reperfusion of the pulmonary capillary beds. There were no differences in cytokine levels after cardiopulmonary bypass in the radial artery and left atrium. This result suggested that lung reperfusion injury after cardiopulmonary bypass may not be the major causative factor of the release of proinflammatory cytokines.

Aged↗

PubMedDate not supplied

Effects of long-term psychological stress on sexual behavior and brain catecholamine levels.

The effects of long-term psychological stress on sexual behavior and brain catecholamines were investigated in rats. Stress was applied using the communication box developed by Ogawa and Kuwabara (1996), and a psychological stress group (n = 12), a physical stress group (n = 5), and a control group (n = 5) were established. Stress was applied for 1 hour every day for 10 consecutive weeks. Sexual behavior was observed before the start of exposure to stress and 2, 4, 6, 8, and 10 weeks thereafter. The results showed that long-term psychological stress impaired the sexual behavior of male rats. Long-term psychological stress decreased the concentrations of catecholamine and its metabolites in the brain, especially in the medial preoptic area (MPOA). Thus, we hypothesized that low catecholamine neurotransmission in the brain results in impairment of male rat sexual behavior. We then tried to restore the impaired sexual behavior by administration of a cerebral-activating drug, indeloxazine hydrochloride. The administration of indeloxazine hydrochloride for a 3-week period restored the sexual behavior that had been impaired by long-term psychological stress. These present results suggest that impairment of neurotransmission in the central nervous system could be a cause of sexual dysfunction, and activation of neurotransmission may result in restoration of impaired male sexual behavior.

Adrenal Glands↗