Surfactant administration reduces testicular ischemia-reperfusion injury

PURPOSE: The mechanism of testicular ischemia-reperfusion injury has not been well delineated. We determined the efficacy of a biocompatible surfactant (tetronic 1107) to reduce tissue injury and evaluated cell membrane integrity as reflected by calcium ion permeability in an in vivo animal model of testicular ischemia-reperfusion. MATERIALS AND METHODS: Three groups of male Sprague-Dawley rats (6 per group) were studied. Group 1 was the nonoperative control, and groups 2 and 3 underwent 4 hours of unilateral testicular ischemia followed by 4 hours of reperfusion. Ten minutes after reperfusion 0.4 ml. saline was administered intravenously to group 2 and 180 mg./kg. surfactant tetronic 1107 to group 3. 99mTechnetium pyrophosphate was used to monitor calcium ion uptake by the ipsilateral and contralateral testicles. Both testicles were also examined histologically. RESULTS: The surfactant treated animals had markedly diminished hemorrhagic discoloration and vascular congestion compared to saline treated animals. These results were confirmed microscopically with improved nuclear chromicity and disarray of germ cell layers of the seminiferous tubules. The surfactant treated group also had a statistically significant (p <0.05) reduction in radiotracer uptake compared to the saline treated animals, confirming a reduction in calcium ion permeability. CONCLUSIONS: The results of this study suggest that tetronic 1107 is effective in reducing tissue damage in a testicular ischemia-reperfusion animal model.     

Clinical effects of low-dose and long-term erythromycin in diffuse panbronchiolitis with chronic respiratory failure

We studied the effects of erythromycin (EM) in diffuse panbronchiolitis (DPB) with chronic respiratory failure. Seventeen patients with DPB or sinobronchial syndrome receiving home oxygen therapy (HOT) were treated with EM of 400-600 mg/day for twelve months. Five patients discontinued HOT, and hypoxemia was improved in five other patients. Clinical effects were evident at one month after the start of EM administration, and a stable state was achieved after six months of EM therapy. FEV1 was significantly increased in pulmonary function tests. Factors which influenced the effects of EM included the period between onset of clinical symptoms and commencement of HOT and/or between commencement of HOT and administration of EM. EM was effective for patients with obstructive, but not constrictive impairment in pulmonary function tests. These findings indicate that EM is effective for DPB even in patients with chronic respiratory failure.     

Methylene blue prevents pulmonary injury after intestinal ischemia-reperfusion

OBJECTIVE: To investigate the effect of methylene blue, an inhibitor of oxygen radicals, on lung injury caused by reperfusion of ischemic tissue. METHODS: Intestinal ischemia-reperfusion injury was induced in rats by clamping the superior mesenteric artery for 1 hour. Thereafter, the experimental group was administered 1% methylene blue intraperitoneally and the control group received saline. After 4 hours, pulmonary histopathologic features were assessed, and lung wet-weight to dry-weight ratios and tissue xanthine oxidase were determined. RESULTS: The control group suffered from severe pulmonary parenchymal damage, compared with slight damage in the experimental group. The number of sequestered neutrophils was significantly higher in the control group (319 +/- 60 polymorphonuclear cells per 10 high-power fields) than in the methylene blue-treated group (91 +/- 8 polymorphonuclear cells per 10 high-power fields; p < 0.001). The wet-weight to dry-weight ratio was significantly increased in the saline-treated rats compared with the methylene blue-treated group (6.19 +/- 0.28 vs. 5.07 +/- 0.21; p < 0.001). Xanthine oxidase activity was similar in both groups. CONCLUSION: Methylene blue attenuated lung injury after intestinal ischemia-reperfusion. Inhibition of oxygen free radicals may be the protective mechanism.     

Effects of alpha 1-adrenoreceptor subtype blockade on ischemia-reperfusion injury

To clarify the roles of subclasses of alpha 1-adrenoreceptors in ischemic-reperfused myocardium, we compared the effect of the nonselective alpha 1-blocker bunazosin with that of the alpha 1A-blocker WB4101 and the alpha 1B-blocker chlorethylclonidine (CEC) in isolated rat hearts. After 30 min of preperfusion, Langendorff-perfused hearts were subjected to 25 min of global ischemia followed by 30 min of reperfusion. Hearts were randomly divided into 4 groups, with one of the following substances being added to the perfusate: buffer alone (control), 10(-6) mol/L bunazosin, 10(-7) mol/L WB4101, or 10(-7) mol/L CEC. Bunazosin had a negative inotropic effect and preserved the postischemic ATP content, reduced the postischemic increase in intracellular Na+ content and then enhanced postreperfusion recovery of creatine phosphate. Bunazosin also reduced myocardial 45Ca2+ uptake during reperfusion (control 5.2 vs bunazosin 2.5 mumol/g dry weight of tissue (dwt), p < 0.01). However, the recovery of left ventricular developed pressure (DP) was not improved when bunazosin was added to the perfusate during reperfusion. WB4101 had neither a negative inotropic nor an energy-sparing effect, but it improved the recovery of DP (control 43% vs WB4101 56% of preischemic value, p < 0.05) with no reduction in myocardial 45Ca2+ uptake. CEC had a negative inotropic and energy-sparing effect and then reduced myocardial 45Ca2+ uptake (CEC 3.1 mumol/g dwt, p < 0.05), but it did not improve the recovery of DP. These results suggest that the preischemic administration of an alpha 1B-adrenoreceptor subtype blocker protected ischemic-reperfused myocardium via reduction of Ca2+ overload, whereas the selective blockade of the alpha 1A-adrenoreceptor subtype reduced myocardial damage via mechanism(s) other than Ca2+ metabolism.     

Reversal of pulmonary capillary ischemia-reperfusion injury by rolipram, a cAMP phosphodiesterase inhibitor

Isoproterenol (ISO) and forskolin, agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) via adenylyl cyclase activation, reverse lung injury associated with increased microvascular permeability. We studied the role of rolipram, a relatively isozyme-selective cAMP phosphodiesterase (PDE) inhibitor, in reversing increased capillary permeability due to ischemia-reperfusion (I/R), a form of oxidant injury in the lung, by using the isolated perfused rat lung model. Rolipram (2 microM) administered after 45 min of ischemia and 45 min of reperfusion reduced I/R-increased permeability as measured by the capillary filtration coefficient to control lung values. Computer image analysis of air space edema and perivascular cuffing, as well as wet-to-dry weight ratios, confirms the permeability reversal by rolipram administration. Rolipram inhibition of cAMP PDE in the lung was assessed by using [3H]adenine prelabeling adapted for the whole lung and perfusate [3H]cAMP accumulation. Rolipram failed to increase perfusate cAMP alone but dramatically increased perfusate cAMP above ISO alone. Dose-response relationships of ISO or rolipram show a close correlation of the half-maximal effective dose (ED50) for injury reversal and perfusate cAMP production. The combination of rolipram and ISO produced synergistic reversal of I/R injury. We conclude that reversal of I/R-induced increased microvascular permeability can be achieved with rolipram and that the mechanism of action of rolipram is probably through PDE isozyme-selective inhibition. The similarity of the ED50 values for cAMP efflux and reversal of permeability increases also supports a close coupling between cAMP accumulation and endothelial cell permeability.     

Effects of cimetidine on acute gastric mucosal injury induced by ischemia-reperfusion in rats

We investigated the effects of cimetidine on acute gastric mucosal injury induced by ischemia-reperfusion in rats. Under pentobarbital anesthesia, the celiac artery was clamped for 30 min and reperfused for 60 min. Cimetidine, famotidine and omeprazole caused a dose-dependent suppression in the total area of erosions that were induced by ischemia-reperfusion. Whereas, none of them inhibited the increase in thiobarbituric acid-reactive substances in the stomach, as an index of lipid peroxidation. The inhibitory effect of intraperitoneally administered cimetidine on mucosal damage was abolished by continuous luminal perfusion with HCl solution (pH 1.5, 1 ml/min) during ischemia-reperfusion, while luminal perfusion with the solution containing HCl and cimetidine (3 mmol/l) significantly reduced the total area of erosions compared to luminal perfusion with HCl solution alone. Cimetidine (3 mmol/l) inhibited hydroxyl radical-induced lipid peroxidation of human erythrocyte membranes by 60% in vitro. These results indicate that cimetidine possesses a protective effect against acute gastric mucosal injury induced by ischemia-reperfusion not only due to the suppression in gastric acid secretion, but also due to the antioxidant action when it is present at a high concentration in the intragastric environment.     

A case of advanced gastric cancer that responded to long-term administration of low-dose 5''-DFUR]

Muscle glycogen synthesis is modulated by physiologically relevant changes in cell volume. We have investigated the possible involvement of integrin-extracellular matrix interactions in this process using primary cultures of rat skeletal muscle subject to hypo- or hyper-osmotic exposure with integrin binding peptide GRGDTP to disrupt integrin actions and the inactive analogue GRGESP as control. Osmotically induced increases (77%) and decreases (34%) in glycogen synthesis (D-[14C]glucose incorporation into glycogen) were prevented by GRGDTP (but not GRGESP) without affecting glucose transport. Cytoskeletal disruption with cytochalasin D or colchicine had similar effects to GRGDTP. Osmotically induced modulation of muscle glycogen synthesis involves integrin-extracellular matrix interactions and cytoskeletal elements, possibly as components of a cell-volume 'sensing' mechanism.     

Systemic lupus erythematosus with pulmonary hypertension--normalization of pulmonary artery pressure by long-term administration of beraprost sodium

OBJECTIVE: To determine the predictive value of angina pectoris diagnosed by Rose questionnaire for cardiovascular disease among treated hypertensives. METHODS: The cardiovascular experience of 4093 patients who had no history of cardiovascular disease and had been administered the Rose questionnaire for angina in a worksite treatment program was evaluated. RESULTS: Among 2659 men and 1434 women of similar age (53 versus 54 years), the race distribution was 44 versus 31% whites, 27 versus 41% blacks and 29 versus 28% Hispanics. Overall, the prevalence of angina by Rose questionnaire in women (15%) was twice that in men (7%) in all three races, with Hispanics having the highest (20 versus 10%) prevalence. Those with angina (Rose-plus) and those without (Rose-minus) had similar initial and final blood pressures. In 4.0 years of average follow-up study, the crude incidence rates (per 1000 person-years) of the recorded 120 myocardial infarctions and 35 strokes did not differ significantly between Rose-plus and Rose-minus patients, except for myocardial infarction in Hispanic men (20.5 versus 5.9). When myocardial infarction incidence was adjusted for age within each sex-race subgroup, only Rose-plus Hispanic men had a significantly greater relative risk with Rose-minus as referent (relative risk 3.13, 95% confidence interval 1.31-7.50). Overall, in the Cox proportional hazards regression model, angina by Rose questionnaire was not predictive of myocardial infarction after accounting for other recognized risk factors. CONCLUSIONS: The present data suggest that the Rose questionnaire as a diagnostic tool for angina is not predictive of subsequent clinical events among treated hypertensive patients.     

Assessment of oxidative stress in a pancreatic warm ischemia-reperfusion model

A simple technique for minimally invasive valve operations is described. With a 10-cm midline skin incision, excellent exposure of both the mitral and aortic valves is achieved through a right-sided partial sternotomy, which enables us to perform easy repair or replacement of these valves.     

Effects of long-term aerosol pentamidine for Pneumocystis carinii prophylaxis on pulmonary function

OBJECTIVE: To compare the reliability of clinical seizure lateralization in temporal lobe epilepsy patients with unitemporal and bitemporal independent interictal spikes and unilateral hippocampal atrophy or sclerosis (HA/HS) on MRI scan. PATIENTS AND METHODS: We studied 11 patients with unitemporal and 10 patients with bitemporal interictal spikes. We calculated a spike ratio by dividing the number of spikes ipsilateral to the side of HA/HS by those occurring contralaterally. RESULTS: Clinical seizure lateralization was correct, i.e., ipsilateral to the side of HA/HS, significantly more often in the unitemporal group. Spike ratios were significantly higher in seizures that were lateralized correctly as compared with both incorrectly and nonlateralized seizures. Within the individual patients, a significant positive correlation between spike ratios and the proportion of correctly lateralized seizures was found. We identified three categories of symptoms according to lateralization accuracy. Category 1 symptoms (version, postictal paresis, and early ictal vomiting/retching) lateralized to the side of HA/HS in 100% of patients in the uni- and bitemporal groups. Category 2 symptoms (dystonic posturing, mouth deviation, postictal dysnomia/dysphasia, and ictal speech) provided a 100% correct lateralization in the unitemporal but not in the bitemporal patients. Category 3 symptoms (nonversive early head turning and unilateral upper extremity automatisms) yielded erroneous lateralization in both patient groups. CONCLUSIONS: We conclude that reliable clinical seizure lateralization in mesial temporal lobe epilepsy can only be achieved in patients with unitemporal interictal spikes, whereas clinical lateralization in patients with bitemporal spikes must be viewed cautiously.     

Pharmacokinetic analysis of low-dose intra-peritoneal cis-platinum administration

Pharmacokinetic parameters after intra-peritoneal administration of low-dose cis-platinum (CDDP) were analysed in order to evaluate the possibility of applying low-dose 5-FU/CDDP therapy (1-FP) for outpatients. Four patients with advanced gastric cancer were the subjects of this study. CDDP at a dose of 20 mg/body was administered intra-peritoneally, and peripheral venous blood was collected at 30 min, 4, 8, 24, 48, 72, 96 and 120 hr after drug administration. The plasma platinum (Pt) concentration was determined by atomic absorption spectrometry. Pharmacokinetic parameters were calculated using a two-compartment open model. C max, AUC, t1/2 alpha and t1/2 beta of total-Pt were 1. 27 +/- 0.21 micrograms/ml, 95.28 +/- 16.93 micrograms.hr/ml, 1.91 +/- 0.76 hr and 190.2 +/- 125.6 hr, respectively. Total-Pt concentration at 120 hr, after administration was 0.54 +/- 0.14 microgram/ml. This result suggests that intraperitoneal low-dose CDDP administration is a promising method for 1-FP therapy for outpatients, because the plasma total-Pt level is maintained at a sufficiently high level for a long period.     

Effects of erythromycin on chemoattractant-activated human polymorphonuclear leukocytes

1. Erythromycin (2-100 micrograms ml-1) produced a concentration-related inhibition of superoxide generation and elastase release induced by in vitro exposure of human polymorphonuclear leukocytes (PMNs) to the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP; 30 nM). 2. By contrast, erythromycin (100 micrograms ml-1) did not alter the leukotriene B4 production elicited by FMLP (30 nM; in the presence of thimerosal 20 microM) or the intracellular calcium changes promoted by FMLP (30 nM; in the absence or presence of thimerosal 20 microM). 3. These results indicate that by reducing chemoattractant-triggered release of oxidative and proteolytic mediators from human PMNs, erythromycin may have clinically useful antiinflammatory effects.     

Effect of hyperbaric oxygen therapy on testicular ischemia-reperfusion injury

PURPOSE: Testicular torsion is a urologic emergency representing a form of ischemia-reperfusion (IR) injury that requires prompt care to achieve tissue salvage and a reduction in post-torsion morbidity. Hyperbaric oxygen (HBO) has shown benefits in previous musculoskeletal models of IR. We evaluated the efficacy of HBO treatment in a rat testicular torsion model. MATERIALS AND METHODS: Four groups of male Wistar rats were included in this study: 1) Sham (n=16), spermatic cords exposed but not occluded; 2) Control (n=16), 4 hours of bilateral spermatic cord occlusion; 3) HBO during ischemia (n=18), 4 hours of occlusion and administration of HBO during the last 90 minutes of ischemia; and 4) HBO on reperfusion (n=8), HBO administered immediately upon reperfusion of the testes. The animals were sacrificed at two weeks and architecture and germinal epithelial cell thickness were determined by histological examination on each testicle. Average thickness (in cell layers) of each group was compared with control using Student's t test. RESULTS: Control testicles showed a significant reduction in germinal cell thickness compared with sham (1.7 versus 6.3, p <0.05). The animals treated with HBO during ischemia showed a significant increase in epithelial cell thickness compared with control (2.8 versus 1.7, p <0.05). Hyperbaric oxygen treatment during reperfusion had the greatest beneficial effect compared with control (5.1 versus 1.7, p <0.05). CONCLUSIONS: Adjunctive HBO therapy administered during ischemia or reperfusion significantly reduced injury to the testicle in this animal model. These results suggest a potential benefit of HBO treatment in clinical situations of testicular torsion.     

Regulatory effects of interleukin-10 on lung ischemia-reperfusion injury

OBJECTIVE: Interleukin-10, a cytokine with antiinflammatory activities, was studied to determine its effects on development of early lung reperfusion injury. METHODS: Adult male rats underwent 90 minutes of left lung ischemia followed by 4 hours of reperfusion. Time-matched sham-operated control rats underwent hilar dissection but not lung ischemia. Lung injury was measured by vascular permeability to bovine serum albumin tagged with iodine 125. To evaluate the effect of exogenous interleukin-10, additional animals received interleukin-10 intravenously before ischemia. To assess the role of endogenous interleukin-10, animals received rabbit antimouse interleukin-10 immunoglobin G (or preimmune rabbit immunoglobin G) before ischemia. RESULTS: Compared with sham control rats, ischemia-reperfusion control rats demonstrated significantly more lung injury. Animals receiving interleukin-10 had significantly less lung injury than did ischemia-reperfusion control rats. Animals receiving antiinterleukin-10 had significantly more lung injury than did animals receiving preimmune immunoglobin G. Alveolar macrophages from animals after 90 minutes of lung ischemia produced more tumor necrosis factor-alpha in culture than did unstimulated macrophages; this production was reduced significantly by the addition of interleukin-10 to the culture medium. CONCLUSION: Endogenous interleukin-10 has a protective effect against early lung reperfusion injury, and interleukin-10 administration can reduce lung reperfusion injury, perhaps in part through its ability to reduce production by alveolar macrophages of tumor necrosis factor-alpha, a known proinflammatory cytokine.     

Effects of FR167653 on ischemia-reperfusion injury: evaluation through preservation and transplantation in canine hearts

BACKGROUND: Ischemia-reperfusion injury may result in the local release of proinflammatory cytokines. A newly synthesized organic compound, FR167653, has been characterized as a potent suppressant of interleukin-1beta and tumor necrosis factor-alpha. We investigated the effects of FR 167653 on ischemia-reperfusion injury of canine hearts during preservation and transplantation. METHODS: Seventeen pairs of adult mongrel dogs were used. The donor heart was removed, stored in University of Wisconsin solution at 4 degrees C for 12 hours, and then transplanted orthotopically. Recipients were divided into the FR-treated group (FR167653 1 mg/kg/hr, 8 dogs) and the control group (9 dogs). Hemodynamic parameters, including cardiac output, left ventricular pressure (LVP), and the maximum rate of increase of LVP, were assessed after 120 minutes of reperfusion. The heart specimen was then harvested for histopathologic examination. RESULTS: The values of LVP (mm Hg) of the FR-treated and the control groups were 120+/-10 and 79+/-9, respectively. The values of LV dp/dt (mm Hg/sec) in the FR-treated and control groups were 4944+/-414 and 2292+/-380, respectively. There were significant differences in LVP (P < .05) and the maximum rate of increase of LVP (P < .01) between the two groups. The values of cardiac output (L/min) of the FR-treated and control groups were 1.27+/-0.12 and 0.71+/-0.11 of the baseline, respectively, showing a significant difference (P < .05) between the two groups. Histopathologic findings included irregular glycogen distribution in myocardial cells of the control group, although this change was less frequent in the FR-treated group. CONCLUSION: FR 167653 seems to have a protective effect on tissue subjected to ischemia-reperfusion injury during the acute phase after heart transplantation.