N(G)-monomethyl-L-arginine improves survival in a pig model of abdominal sepsis

OBJECTIVE: To test the effect of a continuous infusion of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on survival rate and hemodynamics in a pig model of endogenous peritoneal live bacterial sepsis. DESIGN: Prospective, randomized trial. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty-five pigs with an average weight of 26 kg (range 21 to 33). INTERVENTIONS: After surgical preparation, animals (control, n=6) given anesthesia and fluids were observed for 9 hrs. Fifteen experimental animals received 0.5 g of cecal content/kg of body weight intraperitoneally after surgery. Nine of these animals received standard anesthesia and fluids and were observed for 9 hrs or until death. Six animals received a continuous infusion of L-NMMA (10 mg/kg/hr) 3 hrs after sepsis induction. Starting 3 hrs after surgery, five nonrandomized animals were given anesthesia and fluids and received a 6-hr continuous infusion of L-NMMA (10 mg/kg/hr). An additional nine animals were anesthetized and blood samples were taken to determine plasma nitrate concentrations in nonoperated pigs. MEASUREMENTS AND MAIN RESULTS: L-NMMA treatment increased 9-hr survival in septic animals from 11% to 83% (p < .001), prevented a further decrease in mean arterial pressure and restored mean arterial pressure to control levels (p < .00002 vs. nontreated septic animals). Mean pulmonary arterial pressure increased slightly during L-NMMA infusion (p < .0003). Coronary blood flow was preserved during L-NMMA treatment. Cardiac index and urine production reached and maintained control levels during L-NMMA treatment of septic animals. Mean central venous pH did not deteriorate during L-NMMA treatment. Animals treated with L-NMMA had plasma nitrate concentrations similar to nonseptic control animals. The results from the nonseptic control group receiving L-NMMA suggest that a substantial part of the effect of L-NMMA in this model of septic shock may be due to inhibition of the constitutive nitric oxide production. CONCLUSIONS: In this porcine model of peritoneal sepsis, infusion of L-NMMA increased survival rate and maintained mean arterial pressure without worsening tissue oxygenation. Coronary blood flow, cardiac index, systemic vascular resistance, and urine production were well maintained during L-NMMA treatment.     

Lack of involvement of mast cell degranulation in the antiarrhythmic effect of preconditioning in rats

It has been proposed that the cardioprotective effects of myocardial ischaemic preconditioning may involve the release of mast cell mediators. The aim of the study was to determine whether mast cells are involved in the antiarrhythmic effect of ischaemic preconditioning in rat hearts. Preconditioning was achieved, both in anaesthetised rats and in rat isolated hearts, by a 3-min temporary occlusion of the left main coronary artery followed by 10 min of reperfusion before a 30-min permanent occlusion. Preconditioning had a marked antiarrhythmic effect, reducing the number of ventricular ectopic beats from 1,176 +/- 69 to 490 +/- 139 and the incidence of ventricular fibrillation from 40% to 0. Administration of the mast cell-stabilising drugs lodoxamide tromethamine and sodium cromoglycate (20 mg/kg/h i.v. 30 min before and throughout experimental protocol) did not modify the antiarrhythmic effect of preconditioning. Sodium cromoglycate, but not lodoxamide tromethamine, itself significantly reduced the number of ectopic beats that occurred over a 30-min period of ischaemia (from 760 +/- 181 to 153 +/- 33 in nonpreconditioned animals). Both drugs abolished the decrease in arterial blood pressure that occurred on coronary artery occlusion. The decrease in arterial blood pressure produced by the mast cell-degranulating compound 48/80 (50 microg/kg; i.v.) was attenuated to a similar degree by both drugs (decreases in pressure of 53 +/- 7, 31 +/- 1, and 25 +/- 3 mm Hg in control, sodium cromoglycate-treated, and lodoxamide tromethamine-treated animals, respectively). In rat isolated hearts, degranulation of mast cells with three consecutive doses of 50 microg of compound 48/80 had no antiarrhythmic effects and did not modify the antiarrhythmic effect of preconditioning. It is concluded that cardiac mast cells do not play a major role in the protection offered by ischaemic preconditioning on arrhythmogenesis in rat hearts.     

Talc-induced expression of C-C and C-X-C chemokines and intercellular adhesion molecule-1 in mesothelial cells

Treatment of symptomatic carcinomatous pleural effusions is primarily directed at local palliation with a wide variety of sclerosing agents, of which talc is considered to be the most successful. The mechanism whereby talc achieves this effect is unknown. The objective of this study was to investigate whether talc stimulates pleural mesothelial cells (PMC) to release C-X-C and/or C-C chemokines and express adhesion molecules that initiate and amplify the inflammatory process in the pleural space. When PMC were challenged with talc in vitro, interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) levels were increased (p < 0.001) both at the protein and the mRNA level as compared with unstimulated cultures. Talc-stimulated PMC culture supernatant showed chemotactic activity for neutrophils and monocytes. The chemotactic activity of PMC culture supernatant was blocked by 44.2% with IL-8-specific antibody and by 55.7% with MCP-1-specific antibody, demonstrating that PMC-derived chemokines are bioactive. Talc also enhanced intercellular adhesion molecule-1 (ICAM-1) expression in PMC. The data demonstrate that talc stimulates PMC to release chemokines and express adhesion molecules that may play a critical role in pleurodesis.     

Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder

An 18-month-old dog was examined because of ascites of 1 month's duration. Typical causes of ascites, including hepatic failure, heart failure, and protein-losing enteropathy, were ruled out. The dog's history included being hit by a car 6 months earlier, and the caudal vena cava had an S shape on thoracic radiographs. In addition, the abdominal fluid had a high protein concentration and low cellular content. These findings were all consistent with a diagnosis of postsinusoidal hypertension secondary to obstruction of hepatic venous outflow (Budd-Chiari-like syndrome). During exploratory thoracotomy, the pericardium appeared to have been torn from the heart and was partially wrapped around the caudal vena cava, causing a constriction. The pericardium was removed and the dog recovered without any further complications. Blunt trauma has been previously reported to cause kinking of the caudal vena cava and Budd-Chiari-like syndrome in dogs; but in these dogs, clinical signs of ascites developed a few days to several weeks after the traumatic incident. It appears that, depending on the cause of the hepatic venous outflow obstruction, onset of Budd-Chiari-like syndrome may be delayed for months.     

Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy

BACKGROUND: Salvage radical prostatectomy is a treatment option for patients with recurrent cancer following radiation therapy. This study was conducted to identify predictors of survival for patients treated with salvage radical prostatectomy. METHODS: The authors studied 86 prostate carcinoma patients who underwent salvage radical prostatectomy for locally persistent or recurrent prostate carcinoma at Mayo Clinic between 1967 and 1996. The mean interval from radiation therapy to biopsy-proven recurrence was 3.7 years (range, 6 months to 17 years). Patient age at surgery ranged from 51 to 78 years (median, 66 years). The mean follow-up after surgery was 5.8 years (range, 1.0-15.2 years). Cox proportional hazards models were used to identify clinical and pathologic factors associated with distant metastasis free survival and cancer specific survival. RESULTS: Actuarial distant metastasis free survival, cancer specific survival, and overall survival were 83%, 91%, and 85% at 5 years and 69%, 64%, and 54% at 10 years, respectively. In multivariate analysis, radical prostatectomy Gleason score and DNA ploidy were independent predictors of distant metastasis free survival and cancer specific survival. CONCLUSIONS: Postirradiation Gleason score and DNA ploidy were highly predictive of the clinical outcomes of patients treated by salvage radical prostatectomy after radiation therapy.     

Transmyocardial laser revascularization in allograft coronary artery disease

We used transmyocardial laser revascularization to treat accelerated cardiac allograft atherosclerosis in 2 patients. One patient received transmyocardial laser revascularization as sole therapy, the other as an adjunct to coronary artery bypass grafting. The systolic function improved in both patients, although the patient who had adjunctive transmyocardial laser revascularization died of systemic infection and renal failure on postoperative day 55. The second patient is alive and well 1 1/2 years after the laser procedure. We discuss 4 other patients who received transmyocardial laser revascularization treatment elsewhere in the United States. Transmyocardial laser revascularization has the potential to become important in the treatment of transplant atherosclerosis. Randomized clinical trials are warranted to assess the efficacy of transmyocardial laser revascularization in this setting.     

Basic principles of cancer genetics

All cancer can be described as genetic, that is, due to altered DNA. Many of these mutations will be accumulated during the normal division of cells. However, some people may inherit abnormal genes, which predispose those individuals to high risk of certain malignancies. These individuals can sometimes be identified as having a family history of affected individuals, some of which might have early age of onset or multiple malignancies. Specific genes have been identified as being associated with certain of these malignancies. The hereditary cancers include (but are not limited to) ovary, breast, colon, endometrium, and to a lesser extent, prostate, skin and pancreas. Some of these cancer predisposing genes are highly penetrant with up to 80 to 90 percent of gene carriers developing the associated malignancy within a 70 year life expectancy. Molecular testing for the presence of cancer predisposing genes is available for many of the hereditary syndromes. While there currently is no way to correct a mutant gene, early detection and some techniques of chemoprevention are of clinical value. People who fear that they are at high risk only learn that they are not, can benefit from the relief of anxiety through the genetic counseling process.     

Sleep-disordered breathing in children with myelomeningocele

BACKGROUND: Although patients with myelomeningocele and the Chiari II malformation are known to have sleep apnea and respiratory control deficits, the prevalence, types, severities, and associations of sleep-disordered breathing (SDB) have not been adequately defined. METHODS: A cross-sectional study of our myelomeningocele clinic population was undertaken to correlate polysomnographic results with historical data and findings from magnetic resonance imaging of the Chiari malformation, pulmonary function results, and nocturnal pulse oximetry. RESULTS: A questionnaire survey of symptoms was available for 107 of 109 children (98% of the clinic population), and 83 patients agreed to undergo overnight polysomnography. Breathing during sleep was classified as normal in 31 cases (37%), mildly abnormal in 35 cases (42%), and moderately/severely abnormal in 17 cases (20%). Among the 17 patients with moderately/severely abnormal SDB, 12 patients had predominantly central apneas and 5 had predominantly obstructive apnea. Patients with a thoracic or thoracolumbar myelomeningocele, those who had previously had a posterior fossa decompression operation, those with more severe brain-stem malformations, and those with pulmonary function abnormalities were more likely to have moderately/severely abnormal SDB, relative risks (95% confidence intervals) 9.2 (2.9 to 29.3), 3.5 (1.3 to 8.9), 3.0 (0.9 to 10.5), and 11.6 (1.6 to 81.3), respectively. Failure of obstructive SDB to resolve after adenotonsillectomy in four patients suggested abnormal control of pharyngeal airway patency during sleep. Nocturnal pulse oximetry accurately predicted moderately/severely abnormal SDB with a sensitivity of 100% and a specificity of 67%. CONCLUSIONS: The pathogenesis of SDB in patients with myelomeningocele involves the functional level of the spinal lesions, congenital and acquired brainstem abnormalities, pulmonary function abnormalities, disorders of upper airway maintenance, and sleep state. Polysomnography and nocturnal pulse oximetry should be performed in high-risk patients to detect and classify SDB.     

Calcium induces a conformational change in the ligand binding domain of the low density lipoprotein receptor

TNF-alpha may play a role in mediating insulin resistance associated with obesity. This concept is based on studies of obese rodents and humans, and cell culture models. TNF elicits cellular responses via two receptors called p55 and p75. Our purpose was to test the involvement of TNF in glucose homeostasis using mice lacking one or both TNF receptors. C57BL/6 mice lacking p55 (p55(-)/-), p75, (p75(-)/-), or both receptors (p55(-)/-p75(-)/-) were fed a high-fat diet to induce obesity. Marked fasting hyperinsulinemia was seen for p55(-)/-p75(-)/- males between 12 and 16 wk of feeding the high-fat diet. Insulin levels were four times greater than wild-type mice. In contrast, p55(-)/- and p75(-)/- mice exhibited insulin levels that were similar or reduced, respectively, as compared with wild-type mice. In addition, high-fat diet-fed p75(-)/- mice had the lowest body weights and leptin levels, and improved insulin sensitivity. Obese (db/db) mice, which are not responsive to leptin, were used to study the role of p55 in severe obesity. Male p55(-)/-db/db mice exhibited threefold higher insulin levels and twofold lower glucose levels at 20 wk of age than control db/db expressing p55. All db/db mice remained severely insulin resistant based on fasting plasma glucose and insulin levels, and glucose and insulin tolerance tests. Our data do not support the concept that TNF, acting via its receptors, is a major contributor to obesity-associated insulin resistance. In fact, data suggest that the two TNF receptors work in concert to protect against diabetes.