The role of oxygen free radicals in isoniazid-induced hepatotoxicity

This report describes the glycosaminoglycans, collagen and elastin--composition of leiomyosarcoma. Studies were performed on leiomyosarcoma removed during surgery. The material was taken from 7 patients. Rearrangement of extracellular matrix in leiomyosarcoma has been found. There was an increase of total collagen content in comparison to control uterus. In both tissues type I collagen was found to be the predominant one. Both tissues, normal and neoplastic contain all known glycosaminoglycans types. Among them heparan sulphate was found to be the most abundant. A slight decrease in the content of this glycosaminoglycan was observed in leiomyosarcoma. A possible role of these alterations in tumour biology is discussed.     

Pathophysiology of experimental nonoliguric acute renal failure

We have identified an integral membrane protein of 145 kD (estimated by SDS-PAGE) of rat liver nuclear envelopes that binds to WGA. We obtained peptide sequence from purified p145 and cloned and sequenced several cDNA clones and one genomic clone. The relative molecular mass of p145 calculated from its complete, cDNA deduced primary structure is 120.7 kD. Antibodies raised against a synthetic peptide represented in p145 reacted monospecifically with p145. In indirect immunofluorescence these antibodies gave punctate staining of the nuclear envelope. Immunogold EM showed specific decoration of the nuclear pores. Thus p145 is an integral membrane protein located specifically in the "pore membrane" domain of the nuclear envelope. To indicate this specific location, and based on its calculated relative molecular mass, the protein is termed POM 121 (pore membrane protein of 121 kD). The 1,199-residue-long primary structure shows a hydrophobic region (residues 29-72) that is likely to form one (or two adjacent) transmembrane segment(s). The bulk of the protein (residues 73-1199) is predicted to be exposed not on the cisternal side but on the pore side of the pore membrane. It contains 36 consensus sites for various kinases. However, its most striking feature is a repetitive pentapeptide motif XFXFG that has also been shown to occur in several nucleoporins. This nucleoporin-like domain of POM 121 is proposed to function in anchoring components of the nuclear pore complex to the pore membrane.     

Role of endotoxin and nitric oxide in the pathogenesis of renal failure in obstructive jaundice

BACKGROUND: There is an increased incidence of postoperative renal failure in patients with obstructive jaundice. The purpose of this study was to investigate the role of endotoxaemia and nitric oxide in this association. METHODS: In bile duct-ligated, sham-operated and control rats, plasma total bilirubin levels, creatinine clearance and plasma endotoxin were determined. Endothelium-dependent vasodilatation to acetylcholine, and endothelium-independent vasodilatation to nitroglycerine and forskolin were evaluated in isolated perfused rat kidney. RESULTS: Twenty-one of 27 bile-duct ligated rats had endotoxaemia. Plasma bilirubin levels were higher and creatinine clearance was significantly reduced in the bile duct-ligated endotoxin-positive group compared with values in the other groups. Furthermore, in the isolated perfused rat kidney from rats with endotoxaemia, basal perfusion pressure and renal vascular relaxation to acetylcholine and nitroglycerine which is mediated by guanosine cyclic 3',5'-cyclic monophosphate (cGMP) were significantly reduced, but relaxation to forskolin mediated by adenosine cyclic 3',5'-cyclic monophosphate did not change. CONCLUSION: Endotoxaemia in obstructive jaundice may induce overproduction of nitric oxide that may lead to impairment of cGMP-associated vasodilatation and disrupt autoregulation of the renal vascular bed. This may contribute to renal failure in obstructive jaundice.     

Respiratory failure in acute pancreatitis: the role of free fatty acids

Hypertriglyceridemia has been noted in patients with acute pancreatitis and respiratory failure. Utilizing an isolated, perfused, canine pulmonary lobe, the effect of triglyceride infusion on pulmonary function was evaluated. When heparin was used to anticoagulate the perfusion circuit, the addition of triglyceride to the autologous blood perfusate resulted in massive weight gain (226 gm), intrapulmonary shunting (36%), and a marked drop in pulmonary compliance (congruent to 50%). Heparin activates lipoprotein lipase, and therefore some triglyceride in the perfusate was lipolyzed with a resultant increase in serum free fatty acids (FFAs) to 253 mumole/dl. When anticoagulation of the perfusion circuit was accomplished by defibrinogenation with Arvin, the addition of triglyceride to the autologous blood perfusate caused minimal weight gain (28 gm), no intrapulmonary shunting, and only a slight decrease in pulmonary compliance (22%). Arvin has no effect on lipoprotein lipase, and the FFA level in the perfusate remained normal (less than 70 mumole/dl). Thus it appears that FFA release secondary to the action of pulmonary lipoprotein lipase on blood triglyceride is the important pathogenic step in the induction of respiratory failure in this model.     

Leptospirosis: an ignored cause of acute renal failure in Taiwan

Leptospirosis, caused by a spirochete, is the most common zoonosis in domestic or wild animals. Animals excrete infected urine in soil or water and may cause human infections through abrased wound, mucosa, conjunctiva, or by swallowing contaminated water. Clinical presentations of leptospirosis are mostly subclinical. Five to ten percent of leptospirosis are fatal, causing fever, hemorrhage, jaundice, and acute renal failure (Weil's syndrome). Leptospirosis has been ignored as a cause of acute renal failure in Taiwan. We report two patients with leptospirosis who presented with high fever, abdominal pain, jaundice, and acute renal failure. Patient 1 died on day 12 of admission of multiple organ failure associated with pancytopenia, hypogammaglobulinemia, and reactive hemophagocytosis. Leptospirosis was recognized after death. Patient 2 was admitted with similar presentations 2 weeks later. Penicillin and doxycycline were given early in the course, and azotemia, jaundice, respiratory failure, and aseptic meningitis gradually improved. Renal biopsy showed interstitial nephritis. Several tubular clearance tests showed proximal tubular defect with severe bicarbonate wasting (FeHCO3- 20.9%) and incomplete type II renal tubular acidosis without affecting the distal nephron. After 80 days of treatment, this patient was discharged with recovery of conscious level and renal function. This is the first leptospirosis patient with detailed tubular functional and morphological studies of the kidney. Diagnosis of leptospirosis was made by microscopic agglutination test (MAT) for antibody to leptospira and by polymerase chain reaction (PCR) for leptospira DNA in blood and urine (interrogans serogroup australis in case 1 and Leptospira borgpetersenii serogroup ballum in case 2). Because active surveillance has resulted in 13 cases diagnosed as leptospirosis islandwide thereafter, underestimation and ignorance of leptospirosis as a cause of acute renal failure may occur in Taiwan. Therefore, an area with a low leptospirosis incidence may actually have a very high incidence. Leptospirosis should be suspected in febrile patients with jaundice and renal failure when pathogens cannot be identified by traditional culture for microorganisms.     

Effect of oxygen free radicals on myosin in muscle fibres

The Palmaz-Schatz stent delivery system (PS 153) and "bare" PS 204 stents are relatively high-profile, rigid devices that can be difficult to deliver to lesions beyond tortuous, irregular, or rigid proximal segments. Described herein is a method of mounting and shaping a Palmaz-Schatz stent on a low-profile balloon that provides a steerable, low-profile, and secure stent delivery system. Also described is the successful use of this method in four consecutive cases where Palmaz-Schatz stents could not be delivered to the lesion site due to severely angulated, irregular, or rigid proximal vessel segments.     

The role of active oxygen radicals in blood system reactions in inflammation

On the model of carrageenan-induced acute aseptic peritonitis in rats with using of alpha-tocopherol it is shown that the active oxygen metabolites increase granulomonocytopoiesis, leukocytosis and stimulation of blood neutrophils, accumulation and activation of neutrophils of an inflammatory focus, decrease accumulation and stimulation of monocytes of an inflammatory focus and thus they are pro-inflammatory modulators of the blood system's reactions.     

The Tenckhoff catheter in acute renal failure

The results of a retrospective study of routine measurement of haemoglobin at the examination of one-year-old children at Gr?land mother and child clinic during 1989-91 showed that 37% of the children had anaemia. There was no difference between immigrants and the European population. There was no correlation between anaemia and sex in either of the population groups. This may imply that routine haemoglobin measurement should be generally introduced as part of the regular control of one-year-old children.     

Use of mannitol and propranolol in the treatment of experimental acute renal failure (histomorphological study)

Experimental research was carried out in order to ascertain whether administration of drugs capable of acting on the renal circulation, such as mannitol and propanol, in addition to improving the renal function, also have a protective effect on the histomorphological alterations induced by the acute renal ischemia. On the basis of the results of the research the Authors conclude by asserting that the combined use of mannitol and propanol has a real protective effect in preventing or attenuating lesions of the kidney caused by serious acute renal failure.     

Involvement of oxygen-derived free radicals in L-arginine-induced acute pancreatitis

This study was aimed at an assessment of the role of oxygen-derived free radicals in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat, by measuring the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase, and superoxide dismutase (Mn- and Cu,Zn-SOD) in the pancreatic tissue, and evaluating the protective effect of the xanthine oxidase inhibitor allopurinol. Acute pancreatitis was induced in male Wistar rats by injecting 2 x 250 mg/100 g body weight of Arg intraperitoneally in a 1-hr interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. Allopurinol, 100 or 200 mg/kg, was administered subcutaneously 30 min before the first Arg injection. Rats were killed at 6, 12, 24, and 48 hr following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 hr after the Arg injection (30,800+/-3813 vs 6382+/-184 units/liter in the control) and normalized at 48 hr. The tissue concentration of MDA was significantly elevated at 24 hr and reached the peak value at 48 hr (5.00+/-1.75 vs 0.28+/-0.05 nM/mg protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 hr, and the Cu,Zn-SOD activity was significantly lower at 12 hr after the Arg injection as compared with the controls. Allopurinol treatment markedly reduced the serum amylase elevation (12.631+/-2.257 units/liter at 24 hr) and prevented the increase in tissue MDA concentration (0.55+/-0.09 nM/mg protein at 48 hr). Both doses of allopurinol significantly ameliorated the pancreatic edema, necrosis, and inflammation at 48 hr after Arg administration. Oxygen-derived free radicals are generated at an early stage of Arg-induced acute pancreatitis. Prophylactic allopurinol treatment prevents the generation of reactive oxygen metabolites, reduces the serum amylase concentration, and exerts a beneficial effect on the development of histopathological changes.     

Esophageal reconstruction with free jejunal grafts: an experimental study

Replacement of a long segment of esophagus for esophageal atresia or severe stenosis remains a special problem in children. The following studies were designed to test the hypothesis that a section of small bowel without serosa could survive as a free autologous transplant to replace part of the mediastinal esophagus. Laparotomy was performed in 20 adult cats, a loop of small bowel was resected and an end-to-end jejunojejunostomy was completed. The serosa of the resected bowel was removed and the mucosa-muscularis graft was used to replace a segment of the middle esophagus that was resected via a right thoracotomy. The interposed graft was entirely wrapped with adjacent skeletal muscle flaps. Postoperative studies include barium swallow and cine esophagograms, histology and blood vessel casts. Results are presented which show anatomical and functional survival of 16 grafts without blood vessel anastomoses or intrinsic vascular pedicles.     

The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats

Eight independent chl (chromosome loss) mutants were isolated using yeast haploid strain disomic for chromosome III. In these mutants, chromosome III is lost during mitosis 50-fold more frequently than in the wild-type strains. chl mutants are also incapable of stable maintenance of circular and linear artificial chromosomes. Seven of the eight mutations are recessive, and one is semidominant. Complementation tests placed these mutants into six complementation groups (chl11 through chl16). Based on tetrad analysis, chl12, chl14 and chl15 correspond to mutations in single nuclear genes. Tetrad analysis of the other mutants was not possible due to poor spore viability. Complementation analysis was also carried out between collection of chl mutants and ctf mutants (chromosome transmission fidelity) (Spencer et al., 1990). The chl3, chl4, chl8, chl12 and chl15 mutants were unable to complement ctf3, ctf17, ctf12, ctf18 and ctf4, respectively. Three CHL genes were mapped by tetrad analysis. The CHL3 gene is placed on the right arm of chromosome XII, between the ILV5 (33.3 cM) and URA4 (21.8 cM) loci. The CHL10 gene is located on the left arm of chromosome VI, 12.5 cM from the centromere. The CHL15 gene is tightly linked to the KAR3 marker of the right arm of chromosome XVI (8.8 cM). The mapping data indicate that these three genes differ from other genes known to affect chromosome stability in mitosis. Therefore, the total number of the CHL genes identified (including those described by us earlier) is 13 (CHL1-CHL10, CHL12, CHL14 and CHL15).     

Mechanisms of insulin-like growth factor-I-induced accelerated recovery in experimental ischemic acute renal failure

Every year more than one million fractures of the proximal femur occur in the world, especially in older persons. Given the continuous aging experienced by populations, such fractures will become more frequent from year to year and will constitute a growing public health problem. The largest increase is expected to occur in countries of Latin America around the year 2050. Since nearly 70% of all atraumatic fractures in persons over 45 are due to osteoporosis, a case-control study was conducted in the city of Mar del Plata, Argentina, for the purpose of investigating the incidence of and the risk factors associated with proximal femur fractures due to osteoporosis. Between 1 August 1992 and 31 July 1993, a record was kept of all fractures of the proximal femur due to osteoporosis in persons over 50 years of age that visited any of the city's 30 public and private health centers. A total of 246 cases was recorded. The incidence rate per 100,000 inhabitants in the above-50 population was 259 among women and 92 among men, for a ratio of 2.8:1. The incidence was consistently higher in the older age groups, especially in persons over 75. Factors associated with a statistically significant increased risk of fracture of the proximal femur were: a history of neurologic disorders, psychotherapeutic drug use, alcohol consumption, previous fractures, cardiovascular disease, and a decreased intake of milk products. There were no observed differences between cases and controls with respect to age at menopause, weight, height, previous activity, smoking habits, or sun exposure, nor were such differences detected in terms of the percentage of women who had undergone oophorectomy.     

The role of oxygen radicals in the physiology and pathology of human sperm

Reactive oxygen species in low doses are necessary compound of sperm capacitation and hyperactivation. Superoxide anion, hydroxyl radical and hydrogen peroxide initiate sperm capacitation. The edding of antioxidant enzymes inhibits the spontaneous and induced sperm hyperactivation. The process of capacitation is accompanied with the superoxide anion production output by spermatozoa. High doses of reactive oxygen species block the sperm motility through the inhibition of ATP synthesis by the mitochondrial enzymes and cell membrane compounds injury.     

Biocompatible dialysis membranes and acute renal failure: a study in post-operative acute tubular necrosis in cadaveric renal transplant recipients

Previous experimental and human data suggests a detrimental effect on the course of acute renal failure related to exposure of blood to artificial dialysis membranes of poor biocompatibility. We performed a 2.5-year prospective randomized trial to compare the clinical course of acute renal failure (post-operative ischemic acute tubular necrosis, ATN) in patients receiving a cadaveric renal transplant requiring supportive hemodialysis in the immediate post-transplant setting. Patients were randomized to either a cuprophane or polymethylmethacrylate (PMMA) conventional hollow fiber dialyzer. All patients received a standard immunosuppressive regimen which included induction therapy with either horse anti-thymocyte gamma globulin (ATGAM) or the murine anti-CD3 monoclonal antibody (OKT3). Of 53 patients randomized, 17 were excluded (2 for intervening biopsy-proven rejection prior to recovery from ATN, 10 for primary graft nonfunction and 5 for other reasons), leaving 36 evaluable cases of uncomplicated ATN, 18 in each group. There was no difference by age, race, gender, cause of ESRD, immunosuppressive regimen, cold or warm ischemia time, use of pre-transplant dialysis, percent oliguria or the incidence of intra-dialytic hypotension between the 2 groups. There was no difference in the mean time to recovery from ATN posttransplant (8.9 days in the cuprophane group vs 9.5 days in the PMMA group, p = NS) or in the average number of hemodialysis treatments required (3.6 in both groups, p = NS). There was also no difference in long term allograft outcome in terms of the nadir serum creatinine, the number of episodes of subsequent acute rejection or in the development of chronic rejection. An intent-to-treat analysis of all 53 originally randomized patients similarly yielded no significant differences. A subsequent, non-randomized study using a membrane of intermediate biocompatibility (Hemophan) also showed no difference in recovery time from ATN. Bioincompatible membranes do not seem to have a significant clinical impact on the course of recovery of this form of acute renal failure. The striking benefits of biocompatibility in the course of ARF seen in other human trials may relate more to the non-renal systemic toxic effects of bioincompatibility.     

The application of PEDRI to the study of free radicals in vivo

Proton-electron double-resonance imaging (PEDRI) has considerable value for study of the distribution and elimination pathways of nitroxide free radicals (NFRs). This has been illustrated by its use in studies of kidney function in the living rat in which the NFR proxyl carboxylic acid (PCA) has been employed as a 'tracer'. The technique, at its present stage of development, can demonstrate location of PCA in enough detail to observe the passage through kidney cortex and medulla differentially, and to see the NFR within the major abdominal blood vessels. These studies are helping towards an understanding of the metabolic fate of PCA, as well as providing information about kidney performance after challenge with a nephrotoxin. In addition, nitric oxide complexes, formed in vivo by providing rats with a nitrite-rich diet, have been observed ex vivo using PEDRI and field-cycled DNP.     

Prospective study of tetanus-induced acute renal dysfunction: role of adrenergic overactivity

To assess the mechanisms related to tetanus-induced acute renal failure (ARF), 30 patients with tetanus had their renal function prospectively studied and factors possibly related to renal changes were evaluated during four weeks of hospitalization. Fifty percent of these patients had a glomerular filtration rate (GFR) < or = 50 ml/min in the first or second week of hospitalization (Group I) and 50% had a GFR > 50 ml/min throughout the entire hospitalization period (Group II). Age, gender, tetanus incubation time and tetanus onset time, hospitalization time, use of nephrotoxic drugs, need for mechanical ventilation with intermittent positive pressure, and presence of systemic infection were similar in both groups. None of the patients presented with oliguria. Autonomic nervous system (ANS) overactivity, characterized by intense variations in systolic and diastolic blood pressure, by increased heart rate and elevated urinary metanephrine excretion, was higher in Group I compared with Group II. Plasma renin activity, serum creatinephosphokinase levels, and myoglobinuria were not significantly different between the two groups. These results strongly suggest that tetanus-induced ARF has a high prevalence, is characterized by early onset, and is probably related to ANS overactivity.     

Direct current shocks to the heart generate free radicals: an electron paramagnetic resonance study

OBJECTIVES: We sought to demonstrate that direct current (DC) shocks to the heart generate free radicals. BACKGROUND: Although it is a lifesaving maneuver, defibrillation is known to have myocardial toxicity. The mechanism of this toxicity is unknown. If DC shocks generate free radicals, free radicals could be a mechanism of myocardial injury. METHODS: In a canine model, DC shocks of 10 to 100 J were delivered to the epicardium of both beating and fibrillating hearts, and 200-J transthoracic shocks were administered in dogs with beating hearts. Ascorbate free radical (AFR) concentration was measured in arterial blood and blood continuously withdrawn from the coronary sinus. In some dogs, the antioxidant enzymes superoxide dismutase (15,000 U/kg) and catalase (55,000 U/kg) (SOD/Cat) were administered before shocks. RESULTS: Ascorbate free radicals were generated by DC shocks. A peak AFR increase of 14 +/- 2% (mean +/- SEM) was seen 5 to 6 min after 100-J epicardial shocks. A peak AFR increase of 7 +/- 5% occurred after transthoracic shocks. There was a significant linear relation between the shock energy and peak percent AFR increase: %AFR increase = 0.18 (Shock energy) + 2.9 (r = 0.73, p < 0.0001). Shocks delivered to hearts in ventricular fibrillation (30 s) resulted in generation of AFR equal to but not greater than that observed during similar shocks delivered to beating hearts in sinus rhythm. Multiple successive shocks (100 J delivered twice or five times) did not result in a greater AFR increase than single 100-J shocks, indicating that peak, not cumulative, energy is the principal determinant of AFR increase. Animals receiving SOD/Cat before shock administration showed significant attenuation of the AFR increase. CONCLUSIONS: Direct current epicardial and transthoracic shocks generate free radicals; antioxidant enzymes reduce the free radical generation by shocks.     

The qualification of different free muscle transplants to reconstruct mimic function: an experimental study in rabbits

With the scutuloauricularis muscle, we developed a new model for experimental free transplantation of mimic muscles in the rabbit and studied the qualification of different muscles for free functional grafting into the position of the facial muscle, which is to be replaced. Forty adult female white New Zealand rabbits were distributed to four groups of 10 rabbits each. In group 1, the operative techniques of the new transplantation models were developed in the scutuloauricularis muscle, the pectoralis descendens muscle, and a comparable part of the rectus femoris muscle. In group 2, the scutuloauricularis muscle was transplanted orthotopically with microneurovascular anastomoses on the left side; in group 3, the pectoralis descendens muscle was transplanted into the position of the scutuloauricularis after its removal; and with the animals in group 4, a piece of the rectus femoris muscle was transplanted into the position of the mimic muscle after its removal. In all muscle transplants, the neurovascular supply was reestablished microsurgically by end-to-end anastomoses to the superficial temporal vessels and direct nerve coaptation to the facial nerve branches supplying originally the scutuloauricularis muscle. Nine months after transplantation, force measurements were performed in all transplanted muscles and the scutuloauricularis muscles of the control side. Cross-sections stained for ATPase after alkaline preincubation at pH 10.4 were used for computer-assisted planimetry of the muscle fibers. The orthotopically transplanted scutuloauricularis muscles reached with 2.84 (+/-1.04) N for maximal tetanic tension on the average 87.7 (+/-32.1) percent of that of the control scutuloauricularis muscles, the pectoralis descendens muscles with 4.25 (+/-2.15) N on the average 188.7 (+/-100.7) percent of that of the controls, and the pieces of rectus femoris muscles 6.62 (+/-2.16) N or 185.3 (+/-45.4) percent of that of the controls. All three muscles were identified as fast contracting muscles before and after transplantation. By transplantation, the content of type II muscle fibers changed from 58.2 to 68.0 percent in the scutuloauricularis muscle, from 62.4 to 74.4 percent in the musculus pectoralis descendens, and from 92.5 to 82.8 percent in the rectus femoris muscle. For the first time, an experimental model for free transplantation of mimic muscles was developed and functionally assessed. The most important result of this study was the fact that the double-sized muscle grafts developed twice the force of the control scutuloauricularis muscles, although reinnervated by the original muscle nerve branch. This result underlines the usefulness of overdimensioning during clinical muscle transplantation. It was also shown that parts of big muscles can be grafted with results similar to those experienced with complete smaller muscles.