Aspirin Tolerance Induced in Aspirin-Sensitive Asthmatics

Twenty-nine patients with asthma and aspirin-sensitivity were studied in an attempt to induce tolerance to aspirin (ASA). Starting with the smallest ASA doses eliciting bronchial obstruction (threshold doses) we doubled the doses on subsequent days and finally achieved good tolerance of 600 mg ASA per day in 27 patients. It was more difficult to achieve tolerance in patients with low ASA-thresholds than in patients with high ones. Daily ASA administration led to prolongation of the refractory state but when the intervals between consecutive doses were increased, aspirin hypersensitivity recurred. The pause sufficient for a recurrence of sensitivity to ASA was measured in 16 patients and ranged from 24 h to 9 days. Twelve patients challenged with indomethacin after ASA-desensitisation showed good drug tolerance.     

Diet selection and metabolic fuels in three models of diabetes mellitus

Dietary self-selection and circulating metabolic fuels (glucose, free fatty acids, ketones) were examined in three forms of experimental diabetes mellitus in rats: pancreatectomy and streptozotocin treatment in adult and neonatal rats. Changes in diet selection resulting from insulin replacement also were examined. Differences were found in diet selection and circulating metabolic fuels between these types of diabetes. Mildly diabetic rats selected large amounts of fat while more severely diabetic rats primarily selected protein. Insulin treatment enhanced carbohydrate intake of diabetic rats and nearly normalized diet selection and circulating metabolic fuels. All diabetic groups exhibited severe glucose intolerance. These results support the observations of the beneficial effects of low-carbohydrate diets, question the generality of the use of high-fat diets, and suggest a more important role for high-protein diets in energy regulation in severely diabetic rats.     

Willignes to drive when drunk and personality: A twin study

In a laboratory study of psychomotor sensitivity to alcohol, twins were asked “Would you drive a car now?” at 1, 2, and 3 h after drinking a standard dose of ethanol (0.75 g/kg). Correlations among these binary items, the Eysenck personality scales, and age were investigated using PRELIS and LISREL. Willingness to drive and Extraversion correlate at all three times in both males and females. In males, willingness to drive also correlates with Psychoticism, and in females it correlates negatively with the Lie (or Social Desirability) scale. Most correlations between cotwins in willingness to drive were significant in both monozygotic (MZ) and dizygotic (DZ) male twins but correlations were lower in female twins. Factor and Markovian models were fitted. In males there seem to be both genetic and cultural influences on willingness to drive when drunk. About half the genetic variance seems to be the pleiotropic effects of genes influencing Extraversion. The correlationswith Psychoticism, on the other hand, seem to be largely environmental in origin. The small sample size and lack of proper significance tests mean that these results must be interpreted with caution.     

Ruthenium red affects the contractile apparatus but not sarcoplasmic reticulum Ca2+ release of skinned papillary muscle

Ruthenium red has been shown to have a positive inotropic effect on isolated perfused hearts. The cellular mechanism of this action is not clear. Ruthenium red is able to block the Ca²⁺ release channel in isolated sarcoplasmic reticulum (SR) vesicle and reconstituted channel preparations. However, the effect of ruthenium red on SR Ca²⁺ release has not been studied in skinned cardiac muscle preparations. In the present study we investigated the actions of ruthenium red on both the characteristics of force generation by the contractile apparatus and Ca²⁺ release from the SR in chemically skinned rat papillary muscle. Ruthenium red (2 and 10 M) significantly increased the Ca²⁺ sensitivity of the contractile apparatus (decreasing Ca²⁺ required for the half-maximal response from 1.56±0.04 M to 1.46±0.05 M) but had no effect on the maximal Ca²⁺-activated force in triton X-100 treated fibers. This result may suggest one explanation for the positive inotropic effect of ruthenium red on the heart. On the other hand, ruthenium red had no significant effect on either caffeine-induced Ca²⁺ release or Ca²⁺-induced Ca²⁺ release from the SR in saponin-skinned muscle fibers. Lack of a blocking effect on SR Ca²⁺ release by ruthenium red in skinned fibers suggests that the SR Ca²⁺ channels in intact preparations have characteristics that are different from those of either vesicular or reconstituted channel preparations.     

Topographical study of the neurons containing hpGRF immunoreactivity in monkey hypothalamus

Hypothalamic neurons producing growth hormone-releasing factor (GRF) have been characterized by immunohistochemistry in monkey hypothalamus, using an antiserum raised against hpGRF1-40, a peptide with GRF activity isolated from a human pancreatic tumor. Cell bodies with hpGRF immunoreactivity were found in arcuate and ventromedial nuclei. From these neurons, bundles of fibers innervate median eminence and appear to terminate in contact with portal vessels. In addition to median eminence, hpGRF immunoreactive fibers were found mostly in the anterior hypothalamus and the arcuate and ventromedial nuclei where they give perineuronal endings. These results correlate with earlier physiological data on hypothalamic control of growth hormone secretion and suggest that GRF is also involved in interneuronal relationships related or unrelated to neurohumoral control of pituitary secretions.     

Expansion of human nasal chondrocytes on macroporous microcarriers enhances redifferentiation

Articular cartilage has a limited capacity for self-repair. To overcome this problem, it is expected that functional cartilage replacements can be created from expanded chondrocytes seeded in biodegradable scaffolds. Expansion of chondrocytes in two-dimensional culture systems often results in dedifferentiation. This investigation focuses on the post-expansion phenotype of human nasal chondrocytes expanded on macroporous gelatin CultiSpher G microcarriers. Redifferentiation was evaluated in vitro via pellet cultures in three different culture media. Furthermore, the chondrogenic potential of expanded cells seeded in polyethylene glycol terephthalate/ polybuthylene terephthalate (PEGT/PBT) scaffolds, cultured for 14 days in vitro, and subsequently implanted subcutaneously in nude mice, was assessed.

Chondrocytes remained viable during microcarrier culture and yielded doubling times (1.07±0.14 days) comparable to T-flask expansion (1.20±0.36 days). Safranin-O staining from pellet culture in different media demonstrated that production of GAG per cell was enhanced by microcarrier expansion. Chondrocyte–polymer constructs with cells expanded on microcarriers contained significantly more proteoglycans after subcutaneous implantation (288.5±29.2 μg) than those with T-flask-expanded cells (164.0±28.7 μg). Total collagen content was similar between the two groups.

This study suggests that macroporous gelatin microcarriers are effective matrices for nasal chondrocyte expansion, while maintaining the ability of chondrocyte differentiation. Although the exact mechanism by which chondrocyte redifferentiation is induced through microcarrier expansion has not yet been elucidated, this technique shows promise for cartilage tissue engineering approaches.     

Effect of training on hormonal responses to exercise in competitive swimmers

Summary The effects of 9 weeks of training on responses of plasma hormones to swimming were studied in eight competitive swimmers who had not trained for several months. Two types of swimming tests were used: (1) 200 yd, a high intensity, exhausting type of exercise in which maximal effort was required both before and after training, and (2) 1000 yd, a pace type of exercise in which subjects swam as fast as possible prior to training and at the same rate after training. Plasma levels of glucagon increased and of insulin decreased during 1000 yd of swimming, but were not altered by 200 yd of swimming. No training effects were apparent in responses of plasma insulin and glucagon to these short-term, high intensity exercise tests. During the 1000 yd swim, plasma adrenaline was 0.8 ng/ml before vs. 0.1 ng/ml after training. Plasma noradrenaline response decreased from 3.4 to 1.2 ng/ml as a result of training. In the 200 yd swim, adrenaline, but not noradrenaline, was lower after training.R. C. Hickson and R. K. Conlee were postdoctoral research trainees supported by NIH Training Grant AM-05341.J. M. Hagberg was a postdoctoral research trainee supported by NIH Training Grant HL-07081.     

Dose-response relationship for a positive inotropic effect of insulin on isolated papillary muscle

Summary Beneficial effect of glucose and insulin on the myocardium are still a matter of discussion. The influence of insulin on isometric force of contraction of right ventricular papillary muscles of guinea pigs war studied. The papillary muscles were mounted vertically in a 95% O₂, 5% CO₂ modified Krebs-Hensuleit solution (31.5° C, 5.5 mM glucose) and stimulated 1/s. A positive inotropic effect of insulin was dedectable at a concentration of 5×10^–4 IU/ml insulin, was half maximal (52% above controle force of contraction) at 8×10^–3 IU/ml and maximal at 10^–1 IU/ml. The maximal positive inotropic effect was observed 4.7±0.6 min after addition of insulin. After the maximum there was a decrease to a steady state level of 109.8±8.5% of control (p<0.05) in 14.6±1.3 min. Higher glucose (16.5 mM) only shifted the half maximal positive inotropic effect to 5.5×10^–3 IU/ml insulin (n.s.). Inhibition of glycolysis with hypoxia or jodoacetate (5×10^–5 M) did not prevent the positive inotropic effect as known as 75% of control force was retained. When glucose transport was blocked with phlorizin (5×10^–3 M) or phloritin (5×10^–4 M) no positive inotropic action of insulin was observed. Therefore we conclude that the positive inotropic effect of insulin in isolated papillary muscles is mediated by inhanced glucose transport.     

Cell signalling-mediating insulin increase of mRNA expression for cationic amino acid transporters-1 and -2 and membrane hyperpolarization in human umbilical vein endothelial cells

Insulin induces vasodilatation in human subjects and increases l-arginine transport and NO synthesis in human umbilical vein endothelial cells (HUVEC). Cell signalling events associated with insulin effects on activity and mRNA expression of the human cationic amino acid transporters 1 (hCAT-1) and 2B (hCAT-2B) are unknown. l-Arginine transport and eNOS activity were determined in HUVEC exposed to insulin. mRNA levels for hCAT-1, hCAT-2B and eNOS were quantitated by real time RT-PCR and endothelial NO synthase (eNOS) protein was identified by Western blot analysis. Intracellular Ca²⁺, l-arginine and l-citrulline levels, l-[³H]citrulline formation from l-[³H]arginine, cGMP formation, nitrite level, ATP release and membrane potential were determined. Insulin increased l-arginine transport and the mRNA levels for hCAT-1 and hCAT-2B and eNOS expression and activity. Insulin also induced membrane hyperpolarization and increased intracellular Ca²⁺, l-[³H]citrulline, cGMP and nitrite formation. Insulin-mediated stimulation of the l-arginine/NO pathway is thus associated with increased hCAT-1 and hCAT-2B mRNA, and eNOS expression, via mechanisms involving membrane hyperpolarization, mitogen-activated protein kinases p42 and p44, phosphatidylinositol 3-kinase, NO and protein kinase C. We have characterized a cell signalling pathway by which hyperinsulinaemia could lead to vasodilatation in human subjects, and which could have implications in patients in whom plasma insulin levels are altered, such as in diabetes mellitus.     

Estradiol and insulin: independent effects on eating and body weight in rats.

The effects of ovariectomy and estradiol replacement were determined in streptozotocin-diabetic female rats maintained on daily injections of protamine zinc insulin. Similar changes in food intake and body weight in these animals and in nondiabetic control animals indicate that the effects of estradiol on these measures are probably not dependent on changes in pancreatic insulin secretion. Acute and chronic insulin challenges in ovariectomized rats maintained on estradiol benzoate, nafoxidine or oil were also examined. The effects of insulin were not attenuated by prior estrogen conditioning, and there was no evidence of insulin resistance. These experiments suggest that the effects of estradiol on body weight and food intake in female rats are not dependent upon altered insulin levels nor attenuation of the effects of insulin. Estradiol may exert its influence on eating and body weight via separate and possibly more direct pathways. The data also are consistent with the suggestion that ovariectomy-induced and hypothalamic obesities are separate phenomena.