SOD-like activity of 5-membered ring nitroxide spin labels.
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Animals↗
Biomedical subjects
J B Mitchell
Publications and source records attributed to J B Mitchell.
Facilitation of sexual behaviors in the male rat in the presence of stimuli previously paired with systemic injections of morphine.
Male rats were tested for sexual behaviors in an environment previously associated with injections of morphine. Both gonadally intact and castrated males displayed more frequent female-directed behavior, such as pursuit of the female, anogenital exploration, and partial mounts, and gonadally intact animals had shorter latencies to initiate copulation when tested for sexual behaviors in the environment previously associated with morphine. These results suggest that a conditioned state induced by stimuli previously paired with the positive incentive effects of an opiate drug can facilitate or modulate behaviors under the control of other primary positive incentives.
Animals↗
Facilitation of sexual behaviors in the male rat associated with intra-VTA injections of opiates.
Male rats were tested for sexual behaviors after bilateral injections of morphine sulfate or dynorphin1-13 into the ventral tegmental area. Both morphine and dynorphin1-13 increased, in a dose-orderly manner, the number of males that mounted, and the display of female-directed behavior. Repeated administration of morphine, but not dynorphin1-13, into the region of the ventral tegmental area increased dopamine (DA) metabolism in the nucleus accumbens, a terminal field of the mesolimbic DA system. These results suggest that activation of elements within the region of the VTA activated by mu and kappa selective agonists are able to facilitate some aspects of sexual behavior, but that only morphine appears to activate dopaminergic elements within the VTA.
Animals↗
Misonidazole hypoxic cytotoxicity and chemosensitization in two cell lines with different intracellular glutathione levels.
Nitroimidazoles such as misonidazole (Miso) or SR-2508 are known to be cytotoxic to hypoxic cells and, with preincubation under hypoxic conditions, to sensitize cells to certain chemotherapy drugs, notably melphalan. In addition, these nitroimidazoles afford hypoxic radiosensitization; however, high intracellular glutathione (GSH) levels have been shown to significantly reduce radiosensitization by some nitroimidazoles. Using two cell lines that have an 8-fold difference in cellular GSH content, we have investigated whether inherent GSH levels influence Miso-induced hypoxic cytotoxicity, hypoxic GSH depletion, or chemosensitization to melphalan. Hypoxic incubation with varying concentrations of Miso resulted in greater cytotoxicity in Chinese hamster V79 cells than in A549 human lung adenocarcinoma cells, which have much higher GSH levels. However, the rate of GSH depletion for three concentrations of Miso was the same in the two cell lines, despite the large difference in inherent GSH levels. While the inherent sensitivity to melphalan was markedly different between the cell lines, hypoxic preincubation with 2 mM Miso with subsequent aerobic exposure to melphalan resulted in similar levels of sensitization. These results indicate that the potentiation of melphalan cytotoxicity by hypoxic Miso preincubation can occur independent of intracellular GSH levels.
Animals↗
Influence of carbohydrate ingestion on counterregulatory hormones during prolonged exercise.
This study was undertaken to determine the effects of ingesting 5.0 (CHO-5), 6.0 (CHO-6), and 7.5 g/100 ml (CHO-7.5) carbohydrate (CHO) solutions on blood glucose and counterregulatory hormonal responses during prolonged intermittent exercise. Eight well-trained cyclists performed four trials consisting of seven 12-min cycling bouts at 70% of VO2max with 3 min rest between each ride. A final 12 min ride was an all-out self-paced performance ride. During the rest interval the subjects ingested either a water placebo (WP) or one of the CHO solutions at a rate of 8.5 mg/kg/h (approx. 150 ml). Blood samples were taken at 0, 25, 55, 85, and 115 min of exercise and were assayed for glucose, glucagon (GG), cortisol (CT), insulin (IN), epinephrine (EP), and norepinephrine (NE). Blood glucose levels were significantly lower in the WP trial compared to the CHO trials at 25 (4.6 +/- 0.2 vs 5.7 +/- 0.5 mmol/l) and 55 min (4.4 +/- 0.3 vs 5.0 +/- 0.8 mmol/l). At 85 min blood glucose was significantly lower in the WP compared to the CHO-6 and CHO-7.5 trials. GG and IN levels were not significantly different between trials; however, the GG:IN molar ratio was significantly higher in the WP than in the CHO-7.5 trial. CT was significantly elevated in the WP trial compared to the CHO-7.5 trial. EP and NE levels were not affected by CHO ingestion. These data suggest that CHO feedings prevent the typical hormonal responses which are responsible for hepatic glucose release, thus eliciting a possible hepatic glycogen sparing.
Adult↗
Testosterone, cortisol, and creatine kinase levels in male distance runners during reduced training.
The purpose of this study was to examine if reduced training would reestablish normal testosterone, cortisol, and creatine kinase (CK) levels in male distance runners. Ten male runners (mean +/- SE) age 32.0 +/- 2.6 yrs, body fat 9.6 +/- 1.0%, VO2max 61.8 +/- 1.1 ml/kg/min) were monitored during 4 weeks of normal training (baseline training, BT) and 3 weeks of reduced training (RT). During BT running distance averaged 81 +/- 5 km/week, 6 days/week. During RT the runners reduced weekly training volume by 70% of BT to 24 +/- 2 km/week and training frequency to 5 days/week. Weekly resting blood samples were obtained between 0600-0900 hrs after an overnight fast. During BT resting total testosterone levels averaged 5.10 +/- 0.21 ng/ml, which is within the low ranges previously reported in male distance runners. Testosterone levels were not affected by RT (avg of 5.38 +/- 0.31 ng/ml). Cortisol levels were in the high range of normal during BT (23.61 +/- 1.18 ug/dl) and were not altered with RT (avg of 23.14 +/- 1.56 ug/dl). Creatine kinase was elevated (168 +/- 15 U/L) during BT and was significantly reduced (P less than 0.001) at weeks 1-3 of RT (avg of 99 +/- 9 U/L). These results suggest that normally training male runners have low resting total testosterone levels and cortisol levels in the high-normal range. Resting testosterone and cortisol were not responsive to the training reduction. Creatine kinase appears to be sensitive to relative changes in training.
Adaptation, Physiological↗
Reduced training maintains performance in distance runners.
This investigation examined endurance runners during a 3-week reduction in training volume and frequency. Ten well-conditioned runners were monitored for 4 weeks while training at their normal weekly training distance (mean +/- SE) (81 +/- 5 km/week, 6 days/week). This period was designated as baseline training (BT). Sixty km/week were run at approximately 75% VO2max, and the remainder (21 km/week) at approximately 95% VO2max in the form of intervals and races. The runners then reduced weekly training volume (RT) by 70% of BT to 24 +/- 2 km/week and frequency by 17% to 5 days/week for 3 weeks. During RT 17 km/week was performed at approximately 75% VO2max and the remainder (7 km/week) at approximately 95% VO2max (intervals and races). The runners were tested weekly and performed 5-km races on a 200-m indoor track during Bt and after 2 and 3 weeks of RT. Maximal heart rate (HR) increased (P less than 0.05) by approximately 4 beats/min at RT week 3, which may have been associated with a decrease in estimated plasma volume (P less than 0.01) of 5.62 +/- 0.43%. Time to exhaustion during the VO2max tests increased (P less than 0.05) by 9.5% at RT week 3. No significant (P greater than 0.05) changes occurred with RT in body weight, % body fat, overall 5 km race times, VO2max, muscular power (vertical leap and Margaria power test), and citrate synthase activity (at 2 weeks of RT). No alterations in venous lactate, energy expenditure, and HR were observed during submaximal running at two speeds (approximately 65% and 85% VO2max) with RT.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Changes in selected blood measures during repeated days of intense training and carbohydrate control.
Ten runners were studied to determine whether selected blood measures were useful indices of the metabolic stress associated with intense training and dietary carbohydrate (CHO) deficiency. The runners performed two diet/training regimens, involving 5 repeated days of intense training approximately 80 min/d, approximately 80% VO2max) and dietary CHO control (8.0 g.kg-1.d-1, EQ-CHO; 3.9 g.kg-1.d-1, LO-CHO). Resting blood samples were obtained after a 3-day control period, after 3 and 5 days of intense training, and after 3 days of rest. Resting uric acid levels were significantly higher (P less than 0.05) after 3 and 5 days of training during the LO-CHO vs EQ-CHO regimen (353 +/- 21 vs 309 +/- 24, and 345 +/- 26 vs 302 +/- 26 mol.l-1, respectively). Resting thyroxine (T4) levels were higher (P less than 0.05) after 5 days of training during the LO-CHO vs EQ-CHO regimen (102.2 +/- 6.2 vs 83.7 +/- 4.5 nmol.l-1, respectively). While creatine kinase levels were elevated after both regimens (P less than 0.05), there was no difference between regimens. Serum cortisol (C) levels were reduced by 10% for both regimens (P less than 0.05), possibly due to an expansion in plasma volume (7.6 and 7.3% for the LO-CHO and EQ-CHO regimens, respectively). Resting FFA levels were increased (P less than 0.05) during both regimens, but there was no difference between the regimens.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Fat storage in athletes: metabolic and hormonal responses to swimming and running.
Despite similar rates of energy expenditure during training, it has been suggested that swimmers store greater amounts of body fat than runners. To investigate these discrepancies, eight male swimmers (S) and runners (R) were monitored during 45 min of swimming or running (75% VO2max), respectively, and six triathletes were monitored during swimming (ST) and running (RT). Each group was also monitored during two hours of recovery. Venous blood samples were obtained before exercise, immediately after exercise (0 min) and at 15, 30, 60 and 120 min of recovery. These samples were analyzed for glucose, lactate, glycerol, free fatty acids (FFA), insulin, glucagon, norepinephrine (NE) and epinephrine (E). Expired gases and heart rates (HR) were obtained during exercise and also during recovery. The caloric cost of recovery was similar, but the RER results suggested increased fat oxidation during recovery for the S and the ST. Serum glucose was greater (P less than 0.05) immediately after exercise for R (6.71 +/- 0.29 mmol/l) and RT (6.40 +/- 0.26) compared to the S (4.97 +/- 0.19) and ST (4.87 +/- 0.18), and was significantly elevated for the initial 30 min of recovery. FFA were similar throughout the recovery period; however, blood glycerol was greater immediately after exercise (0 min) for R compared to S (NS) and was significantly elevated after exercise (0 min) for RT compared to ST. Differences in blood glucose or fat release were not explained by differences in NE or E; however, the glucacon-to-insulin ratio was significantly greater after exercise in the S and ST compared to the R and RT.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Blood lactate threshold differences between arterialized and venous blood.
The purpose of this study was to investigate the differences between lactate thresholds determined from venous and arterialized blood. Seven endurance-trained college males performed an incremental bicycle ergometer exercise test until exhaustion. At the end of each 3 min stage, blood was sampled simultaneously from a hyperemized ear-lobe and an antecubital vein for the measurement of blood lactate (La-). Two-minute rest intervals separated each stage. Arterialized blood La-concentrations ([La-]) were significantly higher than venous blood at 350 W (14.5 and 9.7 mmol.l-1), maximal exercise (15.5 and 11.39 mmol.l-1), and throughout recovery. Arterialized [La-] was significantly higher than venous blood at the onset of blood La- accumulation (OBLA) (4.0 and 2.8 +/- 0.1 mmol.l-1), the individual anaerobic threshold (IAT) (3.4 +/- 0.3 and 2.1 +/- 0.1 mmol.l-1), and the ventilatory threshold (VT) (4.7 +/- 0.9 and 3.2 +/- 0.6 mmol.l-1). No significant differences were found between either La-threshold for arterialized or venous blood. The oxygen consumption (VO2) at OBLA was significantly lower when determined from arterialized blood La (2.3 +/- 0.2 and 2.8 +/- 0.2 l.min-1). No significant differences existed between the LT, OBLA, and IAT threshold-VO2 determinations from arterialized blood; however, significant differences were found between IAT-OBLA (2.1 +/- 0.2 and 2.8 +/- 0.2 l.min-1) and LT (2.2 +/- 0.2 l.min-1)-OBLA from venous blood. These results indicate that differences between venous and arterialized blood [La-] need to be considered when comparing different anaerobic threshold determinations.
Adult↗
Learning by doing in CABG surgery.
This study provides empiric confirmation of the widely held belief that coronary artery bypass graft (CABG) surgery has become quicker over time as clinical and organizational improvements diffuse across hospitals. Based on a two-stage cluster sample of 74 hospitals performing CABG surgery in 1984, data on skin-to-skin procedure and pump times were analyzed for 2,784 Medicare-eligible cases over the 1972-84 period. Using multivariate regression analysis to adjust for patient characteristics and number of grafts, we found that CABG skin-to-skin times fell an average of 36.5% during the first 12 years of hospital experience while cardiopulmonary pump times fell 28.2%. Rates of decline averaged 4.5-5.4% annually initially, but tapered off to 1.5% by the twelfth year of experience. Extrapolating over a 20-year period, gains in skin-to-skin times are projected to reach 42%, resulting in nearly a halving of surgical times. Our findings have implications both for physician reimbursement and patient outcomes. Medicare CABG prevailing fees do not reflect these gains in efficiency and could be reduced substantially. Alternatively, efficient, high-volume hospitals could be identified for inclusion in a Medicare "CABG PPO" so that society might share in the productivity gains. Finally, recent research showing better outcomes in high-volume institutions may be partially explained by their shorter procedure times, which should reduce operative complications.
Aged↗
Androgen binding sites in human temporal cortex.
We have characterized putative androgen receptor binding sites in five separate biopsy samples of human temporal cortex from epilepsy patients using an in vitro exchange assay with soluble fractions and [3H]5 alpha-dihydrotestosterone as radioligand. The results revealed highly specific, saturable binding with an apparent affinity constant (Kd) of approximately 2 nM with a moderate capacity (Bmax) of approximately 50 fmol/mg protein. In competition studies, we found that only testosterone and 5 alpha-dihydrotestosterone competed effectively (i.e. at low nanomolar concentrations) for [3H]5 alpha-dihydrotestosterone binding sites. These data indicate the presence of androgen receptors in human cortex that are pharmacologically very similar to that previously described in rodent and infrahuman primate CNS, and suggest the existence of a possible mechanism whereby circulating androgens might influence neuronal events in human cortex.
Adolescent↗
Protection by indomethacin against acute radiation esophagitis.
The mechanism of radiation induced damage to the mucosal lining of the gastrointestinal tract, as well as mucositis, is not fully characterized. Prostaglandins may partially mediate the inflammatory response to radiation damage. The effect of the prostaglandin synthetase inhibitor indomethacin on radiation induced esophagitis, pneumonitis, and tumor response was evaluated in the C3H mouse. The effects of indomethacin on radiation induced damage to the esophagus was determined by evaluation of weigh lost, survival, and histologic findings at doses of 28-34 Gy. Although there is a clear difference that supports the use of indomethacin for the prevention of esophagitis, the radiation dose response for esophagitis is steep and likewise, the therapeutic index for the indomethacin amelioration of radiation esophagitis is narrow. Since the tumor response to radiation is unchanged and since indomethacin clearly lessens radiation induced esophagitis in the mouse, this study suggests that indomethacin should be studied in humans for lessening radiation mucositis without jeopardizing the therapy of tumors.
Acute Disease↗
The influence of exercise intensity on heat acclimation in trained subjects.
Low-intensity exercise (less than or equal to 50% VO2max) has been demonstrated to produce heat acclimation (HA) in trained subjects. The purpose of this study was to determine whether shorter-duration, moderate-intensity exercise would also result in HA. Nine trained runners performed two 9-d exercise heat-stress protocols. Each protocol consisted of a 90-min heat tolerance test on days 1 (HTT1) and 9 (HTT2). On days 2-8 the subjects exercised at 50% VO2max for 60 min.d-1 (T50) or at 75% VO2max for 30-35 min.d-1 (T75). Final HTT2 heart rate and rectal temperature (Tr) were significantly (P less than 0.001) reduced, as compared to HTT1, with no differences between T50 and T75. Both protocols resulted in significant (P less than 0.05) reductions in HTT2 pre-exercise Tr and total exercising caloric expenditure, both of which are known to contribute to HA. No changes in resting plasma volume, osmolality, protein, post-HTT aldosterone, and exercising sweat rate were observed. These results demonstrate that equal levels of HA were obtained with T50 and T75, which suggests that moderate-intensity, short-duration exercise in the heat can produce HA in trained subjects.
Acclimatization↗
Superoxide reaction with nitroxides.
Stable, free radical nitroxides are commonly used ESR spectroscopy tools. However, it has recently been found that ESR observable signal from 5-membered ring spin-adducts or stable label nitroxides is lost or diminished by reaction with superoxide. A similar radical-radical annihilation was not found for six membered ring nitroxide radicals. To discern why six-membered ring nitroxides are not reduced under superoxide flux generated by hypoxanthine/xanthine oxidase, spectrophoptmetric (Cyt CIII) and chemiluminescence (lucigenin) and ESR assays were used to follow the reactions. Spectrophotometry and chemiluminescence clearly demonstrated that the six-membered piperidine-1-oxyl compounds (TEMPO, TEMPOL, and TEMPAMIN) rapidly react with superoxide: rate constants at pH 7.8 ranging from 7 x 10(4) to 1.2 x 10(5) M-1 s-1. The absence of detectable ESR signal loss results from facile re-oxidation of the corresponding hydroxylamine by superoxide. To fully corroborate the efficiency of the 6-membered nitroxide superoxide dismutase activity, they were shown to protect fully mammalian cells from oxidative damage resulting from exposure to the superoxide and hydrogen peroxide generating system hypoxanthine/xanthine oxidase. Since six-membered cyclic nitroxides react with superoxide about 2 orders of magnitude faster than the corresponding 5-membered ring nitroxides, they may ultimately be more useful as superoxide oxide dismutase mimetic agents.
Animals↗
How the physician fee schedule affects Medicare patients' out-of-pocket spending.
Simulations of the redistributive effects of the new Medicare fee schedule have focused primarily on physicians, but patients may also be affected. Using a national sample of Medicare patients, we studied the fee schedule's potential impact on both components of out-of-pocket spending: copayments and balance bill amounts. While the fee schedule would raise copayments for the average patient, this effect would be more than offset by the balance billing limits (also imposed by Congress). Nevertheless, almost 10% of patients, particularly those who are black or living in rural areas, would experience large increases in their liability. Finally, the fee schedule with balance billing limits also serves as a "catastrophic coverage" program; patients with extraordinarily high medical expenses would enjoy substantial reductions in their out-of-pocket payments.
Aged↗
Response of black and white guinea pig skin to photodynamic treatment using 514-nm light and dihematoporphyrin ether.
Differences in skin pigmentation may significantly affect light penetration during photodynamic therapy. This study evaluated the effect of skin pigmentation on dermatotoxic reaction to photodynamic therapy utilizing the photosensitizer dihematoporphyrin ether. Black and white guinea pigs were given 10 mg/kg of dihematoporphyrin ether, depilated, and treated 48 hours after injection with 30 mW/cm2 of 514-nm light. Eschar formation was observed on white skin at an average light dose of 26 J/cm2, whereas black skin showed similar changes at 58 J/cm2. Microscopically, superficial necrosis corresponded to the gross changes noted. Our results agree with data describing the difficulty of treating pigmented lesions such as malignant melanoma with photodynamic therapy. This further suggests that higher light doses may be required to treat superficial lesions and produce skin photosensitivity in dark-skinned individuals.
Animals↗
The effect of training on the norepinephrine response at rest and during exercise in 5 degrees and 20 degrees C environments.
Eleven males were examined at rest and during submaximal exercise in 5 degrees C and 20 degrees C environments to determine if the norepinephrine (NE) and other physiological responses in the cold would be altered by eight weeks of training. Blood samples were obtained at the end of 15 minutes of rest and submaximal exercise, and were assayed for NE. Pretraining resting NE levels in the 5 degrees C condition were significantly higher than those found in the 20 degrees C environment (684 +/- 89 vs 491 +/- 48 pg/ml). A significant training effect reduced resting NE levels in the 5 degrees C (502 +/- 77 pg/ml) but not the 20 degrees C (392 +/- 45 pg/ml) condition. Pre and posttraining exercise NE levels were elevated above resting in both the 5 degrees C (1477 +/- 136 vs 1559 +/- 208) and the 20 degrees C environments (1623 +/- 176 pg/ml vs 1444 +/- 224 pg/ml), but were not significantly different between conditions. Skin temperatures were significantly lower, and resting blood pressure was significantly higher in the 5 degrees C condition. These data suggest that both cold and exercise act as stimulators of NE release, but an additive effect on NE of cold and exercise does not occur. The resting NE levels pre and posttraining in the 5 degrees C condition suggest that a cross tolerance to cold stress was present.
Adaptation, Physiological↗