Seeing is believing: Identifying remyelination in the central nervous system.

Remyelination is the regenerative process by which lost myelin sheaths are restored to demyelinated axons. It is a key target in the treatment of chronic demyelinating disorders such as multiple sclerosis (MS), in which inflammation results in destruction of myelin. In the central nervous system (CNS), remyelination typically requires the differentiation of oligodendrocyte progenitor cells (OPCs) into the myelinating oligodendrocytes (OL). Following successes in preclinical studies, several putative pro-regenerative therapies aimed at enhancing remyelination are under clinical investigation. However, there is a translational barrier in identifying successful outcomes: preclinical measures of remyelination do not translate well to clinical studies, and the paraclinical measures currently deployed in trials are challenging to apply to small rodent models of remyelination. Here, we describe the current approaches to identifying remyelination both in preclinical and clinical settings and highlight exciting translational candidates, which may help to bridge the current impasse.

Metabolism of vitamin A in the heart increases after a myocardial infarction.

The supply of vitamin A to the myocardium by storage organs during increased oxidative stress subsequent to myocardial infarction (MI) was examined in hemodynamically assessed rats using compartment analysis of a radio-labeled vitamin A. 3H-Vitamin A was injected into two groups of rats: an MI group and a control group. There were no differences in the plasma or myocardial content of total vitamin A (unlabeled + labeled) between the two groups. However, the proportion of 3H-vitamin A was greater in the myocardium as well as plasma of MI rats. Rats with MI also had significantly lower 3H-vitamin A levels in liver and kidney than sham controls. The greatest difference in vitamin A content was in the concentrations of 3H-labeled storage forms of vitamin A in the liver of MI animals. Activity of bile salt-dependent retinyl ester hydrolase, an enzyme responsible for hydrolyzing vitamin A storage forms, was significantly increased in the liver of MI animals. These data indicate that analysis of plasma concentrations of vitamin A to ascertain links to cardiac conditions may be inappropriate. Specifically, during MI, increased amounts of vitamin A are mobilized from the liver to the heart without changing plasma concentrations. This is facilitated by an increase in the activity of an enzyme that hydrolyzes vitamin A storage forms.

Regional differences in non-enzymatic antioxidants in the heart under control and oxidative stress conditions.

Antioxidants are known to play an important role in mitigating oxidative stress injury. Regional concentrations of non-enzymatic antioxidants, redox ratio and lipid peroxides were studied in normal, ischemic and ischemic-reperfused rat hearts. Isolated perfused rat hearts were made globally ischemic for 45 min and reperfused for 15 min. Right ventricular wall (RVW), septum (S) and left ventricular wall (LVW) from control, ischemic (I) and reperfused (I-R) hearts were analysed. Tocopherol, retinol and ascorbic acid concentrations in different regions of perfused control hearts were not different. Reduced glutathione (GSH) was significantly lower in the RVW, while S and LVW had about three-fold higher levels. Oxidized glutathione (GSSG) was lower in the RVW and most concentrated in the LVW. The GSH:GSSG ratio was highest in the septum while RVW and LVW had similar values. Lipid hydroperoxide (LPx) concentrations in the three regions of control hearts were not different from each other. In I and I-R hearts, vitamin E declined in all three regions but the loss was significant only in the septum in the I group and in the septum and LVW of the I-R group. Vitamin A showed significant loss in all three regions of the I-R group. Vitamin C declined significantly only in the RVW of the I-R group. GSH increased in the RVW of the I and I-R groups compared to controls. GSSG was increased in the RVW and septum of the I group and in all regions of the I-R group. The redox ratio, GSH:GSSG, decreased in all regions of both I and I-R groups. LPx were increased in the septum of the I group and in all regions of the I-R group. Despite unique regional differences in non-enzymatic antioxidants, a comparable increase in LPx in the I-R group and similar extent of reduction in the redox ratio in different regions of the I and I-R groups, suggest that each myocardial region may use different antioxidant mechanisms to withstand oxidative stress.

Mobilization of antioxidant vitamin pools and hemodynamic function after myocardial infarction.

BACKGROUND: Although most previous studies have attempted to correlate plasma concentrations of vitamins with specific cardiovascular end points, metabolic considerations suggest that changes in myocardial tissue and storage organs may be better indicators of myocardial oxidative stress. METHODS AND RESULTS: Rats fed commercial chow or a diet enriched with vitamin E for 2 weeks were subjected to either a surgical myocardial infarction (MI) or a sham procedure. Rats were hemodynamically assessed 16 weeks after surgery, and their heart, liver, kidney, and plasma were analyzed for antioxidant vitamins E (tocopherol) and A (retinol and total retinyl esters). At 16 weeks, MI rats on a control diet showed depressed peak systolic and elevated diastolic pressures in both right and left ventricles compared with their sham controls. Plasma concentrations of vitamins E and A in MI rats were not different from sham controls fed the same diet. However, concentrations of vitamin E in left ventricle and liver and of vitamin A in liver (retinol) and kidney (retinyl esters) were decreased in rats with MI compared with the sham controls. Vitamin E supplementation improved hemodynamic function in rats with MI and increased plasma, myocardial, liver, and kidney concentrations of vitamin E. The vitamin E diet also prevented the loss of total retinyl esters from the kidney but not of retinol from the liver in MI rats. CONCLUSIONS: Dietary supplements of vitamin E can sustain better cardiac function subsequent to MI. Antioxidant vitamin levels in the myocardium or in storage organs and not in plasma may be better indicators of myocardial oxidative stress.

Right and left myocardial antioxidant responses during heart failure subsequent to myocardial infarction.

BACKGROUND: Heart failure subsequent to myocardial infarction (MI) is accompanied by depressed antioxidants and increased oxidative stress in the myocardium. Antioxidant enzyme activities and oxidative stress were examined in the viable left (LV) and right (RV) ventricles in relation to their hemodynamic function. METHODS AND RESULTS: The left coronary artery in rats was ligated. At 1 week after MI, LV systolic pressure (LVSP), LV end-diastolic pressure (LVEDP), and RV end-diastolic pressure (RVEDP) remained near control values, whereas RV systolic pressure (RVSP) was significantly elevated. In the 4, 8, and 16 week post-MI animals, LVSP was significantly reduced, with values of 112.0+/-1.57, 99.9+/-0.52, and 89.2+/-1.4 mm Hg, whereas LVEDP was significantly elevated, with values of 8.2+/-0.52, 17.4+/-1.7, and 31.4+/-1.5 mm Hg, respectively. RVEDP was higher at 8 and 16 weeks, and RVSP was significantly reduced at 16 weeks. At 1 week after MI, myocardial catalase activity in the LV was maintained near control levels, whereas in the RV, it was 134% compared with its control value. At 4, 8, and 16 weeks, catalase activity in the LV was 71%, 48%, and 28% of respective controls. Catalase activity in the RV was significantly reduced only at 16 weeks. A similar trend was seen with respect to glutathione peroxidase activity. Reduced/oxidized glutathione ratio was significantly depressed in the LV at 1, 4, 8, and 16 weeks, whereas in the RV, this ratio was significantly reduced only at 8 and 16 weeks. Myocardial lipid peroxidation in the LV at 4, 8, and 16 weeks was elevated by approximately 40%, 51%, and 100%, respectively, whereas in the RV, an increase of approximately 50% was seen only at 16 weeks. CONCLUSIONS: These data show that heart failure subsequent to MI is associated with an antioxidant deficit as well as increased oxidative stress, first in the LV, followed by the RV. Furthermore, these changes correlated with the hemodynamic function in each of the ventricles, suggesting their role in the pathogenesis of ventricular dysfunction.

Role of oxidative stress in transition of hypertrophy to heart failure.

OBJECTIVES: In an attempt to define the role of increased oxidative stress in the transition from compensatory hypertrophy to heart failure, this study examined the effects of long-term vitamin E therapy on the occurrence of heart failure subsequent to chronic pressure overload in guinea pigs. BACKGROUND: Hyperfunctional heart hypertrophy has been shown to be accompanied by an increase in the endogenous antioxidant reserve, whereas congestive heart failure is accompanied by a decrease in this reserve. The effects of vitamin E, a naturally occurring antioxidant, on the development of heart failure from a hypertrophic stage were examined. METHODS: The ascending aorta in guinea pigs was coarcted. For vitamin treatment, slow-release pellets were implanted at the time of the operation. The animals were assessed at 10 and 20 weeks for hemodynamic function, myocardial structure, antioxidant agents and oxidative stress. RESULTS: Banding of the ascending aorta in guinea pigs resulted in hyperfunctional hypertrophy at 10 weeks, which was followed by congestive heart failure at 20 weeks. Hypertrophied hearts showed decreased oxidative stress, as evidenced by a higher oxidation-reduction (redox) state and less lipid peroxidation, whereas the failure stage was characterized by increased oxidative stress. Supplementation of animals with timed-release vitamin E tablets resulted in an increased myocardial content of the vitamin, and the banded animals did not develop any signs of heart failure at 20 weeks. Hemodynamic function at 20 weeks in these vitamin E-treated animals was also better maintained. The myocardial reduced glutathione/oxidized glutathione ratio of vitamin E-treated animals at 20 weeks was higher and lipid peroxidation was less compared with the untreated animals. Ultrastructural abnormalities were significantly less in the vitamin E-treated hearts compared with the untreated failing hearts at 20 weeks. CONCLUSIONS: An improved myocardial redox state with vitamin E therapy, coupled with the modulation of the development of heart failure, may indicate a pathophysiologic role for increased oxidative stress in the pathogenesis of heart failure. This study suggests the potential therapeutic value of long-term antioxidant treatment in modulating or preventing the pathogenesis of heart failure.

Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats.

Antioxidant enzyme activities and oxidative stress were evaluated in the myocardium in relation to hemodynamic function subsequent to myocardial infarction in rats. One week after the coronary ligation, the left ventricular peak systolic pressure, left ventricular end-diastolic pressure, and aortic pressures remained near control values and there were no differences in lung and liver wet/dry weight ratios between experimental and control animals. In the 4-, 8-, and 16-week experimental animals, there was a progressive drop in left ventricular peak systolic pressure and an increase in left ventricular end-diastolic pressure. Aortic systolic pressure was depressed at 8 and 16 weeks. In myocardial infarct rats, there was a significant increase in wet/dry weight ratio of lungs at 8 weeks and at 16 weeks; this ratio was increased for lungs as well as liver. Based on the hemodynamic data as well as other observations, animals in the 1-, 4-, 8-, and 16-week groups were arbitrarily categorized into nonfailure and mild, moderate, and severe failure stages, respectively. In the nonfailure stage, there was a marginal increase in superoxide dismutase, glutathione peroxidase, and catalase activities as well as vitamin E levels. The redox state in these hearts, assessed by the reduced/oxidized glutathione ratio, was significantly increased. Superoxide dismutase activity was unchanged in mild and moderate failure stages but significantly depressed at 16 weeks. Glutathione peroxidase and catalase activities showed progressive decreases through mild, moderate, and severe failure stages. Vitamin E levels were significantly depressed at moderate and severe failure stages. There was a progressive increase in lipid peroxidation at mild, moderate, and severe stages of heart failure and the redox ratio was significantly depressed in the severe failure stage. These data suggest that heart failure subsequent to myocardial infarction may be associated with an antioxidant deficit as well as increased myocardial oxidative stress.

Organ and cell allometry in Hawaiian Drosophila: how to make a big fly.

The importance of body size in predicting many aspects of an animal's biology has become well established in recent years. However, little is known about how body size evolves at the cellular level. Some published data suggest that it is cell number and not cell size that accompanies changes in organ and body size across taxa. We examined organ and cell allometry in the wing, eye and basitarsus of adult Hawaiian Drosophila, ranging in body length from 0.2 mm to 0.8 mm. Linear measurements of all three structures exhibit a positive allometry with body length. Exponents of the allometric equation were 0.96, 0.55 and 1.50 for wing, eye and basitarsus, respectively. Surface markers were used to quantify cell size of each organ. The allometric exponents for cell size as a function of organ size were 0.53, 0.68 and 0.33 for wing, eye and basitarsus, respectively. In contrast to reports in the literature on other systems, our results for Hawaiian Drosophila indicate that cell size may contribute between one third and two thirds to evolutionary changes in organ and body size.

Teenage pregnancy prevention: an Atlanta program.

PIP: this article describes the Fulton County (Georgia) Health Department Teen Clinical Services Program, which has 3 goals: 1) to reduce unplanned teenage pregnancies in 3 high risk health service areas in Atlanta by providing sex education and access to contraception, 2) to improve the health and well-being of teeangers by offering periodic disease screening, and 3) to educate adolescents on their total health needs. Clinics are held in inner city community health centers and all services are confidential. An introductory health questionnaire is used to assess the areas of counseling to be emphasized in the initial interview. 65% of teenagers initially attending the clinic are sexually active, but only 60-65% have ever used birth control. The reasons for sexual behavior are explored during the initial interview and contraception and sexually transmitted diseases are reviewed. Teenagers who are not sexually active are encouraged to postpone sexual activity. Community outreach and education is another component of the program. Rap sessions are held during each clinic session and peer counselors work as liaisons between the schools, community, and Teen Services Program. Peer counseling is believed to facilitate feelings of acceptance and support. In 1 of the high risk areas served by the program, the adolescent birth rate fell 17% in 1979-82. 94% of clients who accepted contraception returned and maintained contraception for 1 year. Approximately 20% of participants in the program are male. This experience suggests that this type of program is effective and should be expanded to other areas of the US.^ieng