Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries

We previously showed that hydrogen peroxide (H2O2) contributes to flow-induced dilation in human coronary resistance arteries (HCRAs); however, the source of this H2O2 is not known. We hypothesized that the H2O2 is derived from superoxide (O2*-) generated by mitochondrial respiration. HCRAs were dissected from right atrial appendages obtained from patients during cardiac surgery and cannulated with micropipettes. H2O2-derived radicals and O2*- were detected by electron spin resonance (ESR) using BMPO as the spin trap and by histofluorescence using hydroethidine (HE, 5 micromol/L) and dichlorodihydrofluorescein (DCFH, 5 micromol/L). Diameter changes to increases in pressure gradients (20 and 100 cm H2O) were examined in the absence and the presence of rotenone (1 micromol/L), myxothiazol (100 nmol/L), cyanide (1 micromol/L), mitochondrial complex I, III, and IV inhibitors, respectively, and apocynin (3 mmol/L), a NADPH oxidase inhibitor. At a pressure gradient of 100 cm H2O, ubisemiquinone and hydroxyl radicals were detected from effluents of vessels. Including superoxide dismutase and catalase in the perfusate reduced the ESR signals. Relative ethidium and DCFH fluorescence intensities in HCRAs exposed to flow were enhanced (1.45+/-0.15 and 1.57+/-0.12, respectively compared with no-flow) and were inhibited by rotenone (0.87+/-0.17 and 0.95+/-0.07). Videomicroscopic studies showed that rotenone and myxothiazol blocked flow-induced dilation (% max. dilation at 100 cm H2O: rotenone, 74+/-3% versus 3+/-13%; myxothiazol, 67+/-3% versus 28+/-4%; P<0.05). Neither cyanide nor apocynin altered flow-induced dilation. These results suggest that shear stress induced H2O2 formation, and flow-induced dilation is derived from O2*- originating from mitochondrial respiration.     

Heart Failure Following Anterior Myocardial Infarction: An Indication for Ventricular Restoration,a Surgical Method to Reverse Post-Infarction Remodeling

Anterior myocardial infarction produces abrupt left ventricular (LV) dysynergy and global systolic dysfunction. Rapid intense neurohumoral activation, infarct expansion, and early ventricular chamber dilatation all contribute to restoring a normal stroke volume despite a persistently depressed ejection fraction. Continued neurohumoral activation provokes late remodeling of the remote non-infarcted myocardium, characterized by an abnormal progressively increasing LV volume/mass ratio that leads to further LV remodeling.Heart failure is a progressive disorder of LV remodeling. Heart failure from post-infarction remodeling is unique because of the persistent non-functioning scar that self- perpetuates abnormal loading conditions and neurohumoral activation. Medical therapy attenuates remodeling and improves survival but does not change the size of the scar. Surgical ventricular restoration to exclude the non-functioning infarct from the ventricular cavity decreases ventricular volumes, increases global ejection fraction, attenuates neurohumoral activation and yields an excellent 5-year survival. Combined medical and surgical therapy is recommended in this patient population.     

Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia

INTRODUCTION: Although some have suggested that certain vitamins or calcium supplements may reduce adenoma recurrence, our own prior retrospective study found no such effects. The purpose of this case-control study was to further investigate whether regular vitamin or calcium supplement intake influenced the incidence of recurrent adenomatous polyps in patients with previous neoplasia who were undergoing follow-up colonoscopy. METHODS: This study enrolled 1,162 patients who underwent colonoscopy by one of three surgeons at Columbia-Presbyterian Medical Center in New York City between March 1993 and February 1997. Of these patients 448 (250 males) had a previous diagnosis of colorectal neoplasia (cancer, adenomas, or dysplasia). Of these, 183 (40.8 percent) had an adenoma at the index colonoscopy. Information was collected on personal and family history of colonic diseases, cigarette smoking, medication, and vitamin and micronutrient supplement usage on a questionnaire that was completed by the patients before the colonoscopy. Odds ratios were obtained by unconditional logistic regression analysis, adjusting for age and gender, and used adenoma recurrence at index colonoscopy as the outcome. RESULTS: The mean interval between colonoscopic examinations was 37 months for the recurrent adenoma group and 38 months for the nonrecurrent group of patients (P = not significant). In this case-control study we found a protective effect for the use of vitamin supplements in general (any vitamin) on the recurrence of adenomas (odds ratio, 0.41; 95 percent confidence interval, 0.27–0.61). Specifically, this protective effect was observed for the use of multivitamins (odds ratio, 0.47; 95 percent confidence interval, 0.31–0.72), vitamin E (odds ratio, 0.62; 95 percent confidence interval, 0.39–0.98), and for calcium supplementation (odds ratio, 0.51; 95 percent confidence interval, 0.27–0.96). Nonsignificant protective effects were noted for carotene/vitamin A, vitamin D, and vitamin C. CONCLUSIONS: The use of multivitamins, vitamin E, and calcium supplements were found to be associated with a lower incidence of recurrent adenomas in a population of patients with history of previous colonic neoplasia. Prospective, randomized trials are needed to better assess the impact of these agents and to determine whether the use of these supplements is associated with a protective effect against recurrent adenomas.Supported by United States Surgical Corporation, Norwalk, Connecticut.Read at the meeting of The American Society of Colon and Rectal Surgeons, San Antonio, Texas, May 2 to 7, 1998.     

Electrophysiologic studies in nonsustained ventricular tachycardia: Relation to underlying heart disease

Electrophysiologic studies were performed in 83 patients with spontaneous episodes of nonsustained ventricular tachycardia (VT). The clinical arrhythmia was reproduced in 63% (in 42 patients by programmed stimulation and in 10 by isoproterenol infusion). In 15 patients sustained VT could be reproducibly induced by programmed stimulation. Inducibility was related to the associated heart diseases: programmed stimulation induced VT in 25 of 33 patients (75%) with coronary disease, 6 of 18 patients (33%) with cardiomyopathy (dilated in 16, hypertrophic nonobstructive in 2), in 4 of 8 patients (50%) with mitral valve prolapse and in 7 of 24 patients (29%) without structural heart disease. Isoproterenol infusion induced VT in no other patient with coronary artery disease, 1 other patient with mitral valve prolapse, 3 patients with cardiomyopathy, and in 6 of 24 patients without structural heart disease. Sustained VT was induced only in patients with structural heart disease, and correlated with the presence of left ventricular aneurysms: Sustained VT was induced in 9 of 13 patients with left ventricular aneurysms. The study demonstrates that electrophysiologic techniques can reproduce episodes of nonsustained VT in most patients with spontaneous arrhythmias. Some patients who demonstrate only nonsustained VT spontaneously have inducible, sustained VT, most often in the setting of coronary artery disease and left ventricular aneurysms.     

Rapid suppression of hematopoiesis by standard or pegylated interferon-alpha

BACKGROUND & AIMS: Treatment of chronic hepatitis C with interferon (IFN)-alpha often has hematotoxic effects. We evaluated the effects of acute vs. chronic and standard vs. pegylated IFN-alpha on hematopoiesis. METHODS: We studied hematopoiesis in 46 patients with chronic hepatitis C receiving single high-dose IN-Falpha2b followed by daily dose standard or weekly pegylated IFN before combination antiviral therapy. RESULTS: Single high-dose therapy resulted in a significant drop in hemoglobin (HB), leukocytes, and platelet count. Although platelets, stimulated by a significant increase in thrombopoietin (TPO), and leukocytes recovered quickly, HB remained below baseline for 7 days. Daily standard or weekly pegylated IFN-alpha leads to a more pronounced drop in all 3 lineages with concomitant increases in TPO and erythropoietin (EPO). No difference was observed between standard and pegylated IFN, except for HB, which fell more during pegylated IFN therapy. Consecutive combination antiviral therapy aggravated the anemia but not the drop in leukocytes or thrombocytes. CONCLUSIONS: The drop in all 3 hematopoietic lineages through IFN-alpha treatment, high-dose standard, standard daily dose, or pegylated, is caused by a combination of bone marrow inhibition and probably some other rapid acting mechanisms. Hematopoietic growth factors are increased as a consequence but cannot overcome the bone marrow suppression.     

Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure

The effect of therapeutic doses of digitalis in modifying neural activity has been the subject of considerable controversy. In earlier studies we reported an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. Heart failure was associated with an increase in serotonin in five nuclei: the mammillary; bodies, ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the ventromedial and the centralis superior.+2     

Bisphosphonate mechanism of action

The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, this is achieved through osteoclast inhibition, which leads to reduced bone turnover, increased bone mass, and improved mineralization. The molecular targets of bisphosphonates (BPs) have recently been identified. This review will discuss the mechanism of action of BPs, focusing on alendronate and risedronate, which are the two agents most widely studied. They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation. This mechanism is responsible for N-BP suppression of osteoclastic bone resorption and reduction of bone turnover, which leads to fracture prevention.     

A phase I study of the safety of honeybee venom extract as a possible treatment for patients with progressive forms of multiple sclerosis.

Although several reports suggest that bee venom may be an effective treatment for patients with multiple sclerosis (MS), patients may be subjected to real risks of serious allergic reactions as well as emotional and economic costs. This study was conducted to evaluate the safety of bee venom extract as a possible treatment for patients with progressive forms of MS. A total of nine bee venom nonallergic patients with progressive forms of MS, who were 21-55 years of age with no other illnesses, were entered into four groups (A, B, C, and D) on a structured 1-year immunization schedule. Hyperreactivity to bee venom was evaluated by questionnaire, physical examination, and a battery of hematologic, metabolic, and immunologic tests. Responses to therapy were evaluated by questionnaire, functional neurological tests, and changes in measurement of somatosensory-evoked potentials. Although no serious adverse allergic reactions were observed in any of the nine subjects, four experienced worsening of neurological symptoms, requiring termination in the study; this could not be ascribed to side effects of the therapy. Of the remaining five subjects, three felt that the therapy had subjective amelioration of symptoms and two showed objective improvement. Although this preliminary study suggests safety, because of the small numbers studied, there were no definite conclusions regarding efficacy and therefore there was little evidence to support the use of honeybee venom in the treatment of MS. Larger and more carefully conducted multicenter studies will be required to establish efficacy.     

Impact of the diagnostic procedure on outcome measures of swallowing rehabilitation in head and neck cancer patients

This study was designed to determine whether swallow rehabilitation outcomes were affected by the type of evaluation procedure utilized by the clinician. The two evaluation techniques compared were the bedside examination and videofluoroscopy (the modified barium swallow). Ten institutions participated in this study, enrolling a total of 103 partial laryngectomized patients, 21 in the bedside arm and 82 in the videofluoroscopy arm. Data on recovery of oral intake were collected weekly. All patients received an X-ray study of swallow at 3 months after the operation. Mean time to oral intake of food was significantly lower in patients assessed with bedside examination. Overall swallow measures of transit times and swallow efficiencies after 3 months revealed significantly better function in the videofluoroscopy group. Results are discussed in terms of the visibility of swallow physiology with the two assessment techniques, the accuracy of therapy planning with the bedside examination versus videofluoroscopy and the ability of head and neck cancer patients to tolerate some aspiration without developing aspiration pneumonia. This research was funded by NIH grant PO1 CA40007