Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding

To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat-fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/l plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.     

Thrombocytopenia following liver transplantation is associated with platelet consumption and thrombin generation

PSA-based screening substantially increases the prostate cancer detection rate and the percentage of organ-confined tumors. It appears that there is some benefit from screening for prostate cancer because of the increased amount of potentially curable disease discovered and the fact that 96% of the pathologically staged tumors detected have histologic features associated with aggressive cancer. Additional evidence that nearly all tumors detected on the basis of initial PSA screening are apt to be clinically significant may be derived from the information that PSA-based screening decreases the incidence of incidental A1 grade III and A2 tumors but does not increase the detection of clinically insignificant A1 grade I and II tumors. At this time, PSA represents the most effective and valuable tool to detect early prostate cancer; therefore, PSA should be used to improve early diagnosis of prostate cancer. Some advances have been made with the introduction of age-specific reference ranges and the ability to measure free to total PSA ratios. The data presented support the clinical usefulness of age-specific reference ranges for serum PSA. Calculation of the free to total PSA ratio is valuable in deciding which screening volunteers require further evaluation, increases the specificity of PSA screening, and as demonstrated may be useful in deciding which patients with isolated PIN should undergo repeat biopsies. Based on these facts, PSA truly can be described as the most important and useful marker for adenocarcinoma of the prostate. Based on these encouraging results and the obligingness of the social insurances, we will be able to continue PSA screening for early detection of prostate cancer for all concerned Tyrolean men in the future.     

Chemoprevention of pulmonary carcinogenesis by aerosolized budesonide in female A/J mice

This investigation is part of a continuing effort to develop effective chemoprevention for carcinogenesis of the lung. The present study explores the use of aerosol administrations for this purpose. The agent selected for initial study was the synthetic glucocorticoid budesonide. This selection was based on previous work in which budesonide added to the diet was found to inhibit pulmonary adenoma formation in female A/J mice. However, high dose levels were required, i.e., of the order of 300 microg/kg, of body weight [L. W. Wattenberg and R. D. Estensen, Carcinogenesis (Lond.), 18: 2015-2017, 1997]. For aerosol administration of budesonide, a nose-only technique has been developed that entails nebulization of the compound dissolved in ethanol and subsequent stripping off of the solvent (less than 3 microl ethanol/liter of air remaining at the site of inhalation). The budesonide particles produced by the apparatus had a mass median aerodynamic diameter of less than 1 microm. An experiment has been carried out in which the inhibitory effects of aerosolized budesonide, given for 1 min six times a week, were studied. Concentrations of budesonide of 26, 81, and 148 microg/liter of air (calculated doses of 23, 72, and 126 microg/kg of body weight) were used. The aerosols were started 1 week after three oral administrations of benzo(a)pyrene (2 mg/20 g of body weight) to female A/J mice. All three doses of budesonide resulted in more than 80% inhibition of pulmonary tumor formation compared to the aerosol control and 90% or greater compared to mice not exposed to aerosol. The difference in inhibition is due to the aerosol procedure itself, which produces a reduction in tumor formation. A decrease in splenic weight (evidence of a systemic effect) occurred at all doses of budesonide. To the best of our knowledge, this is the first published effort at the use of aerosol administration to prevent neoplasia of the respiratory tract. The results of the present study show that administration of a potential chemopreventive agent by aerosol at a low dose can inhibit the occurrence of pulmonary carcinogenesis in female A/J mice.     

Long-term effect of norepinephrine on iodide uptake in FRTL-5 cells

The sympathetic nervous system plays a role in the regulation of thyroid function. In FRTL-5 rat thyroid cells, norepinephrine (NE) acutely depresses intracellular I- by increasing I- efflux. The present study was undertaken to determine the effect of NE on iodide transport after a longer time period. NE inhibited the ability of thyrotropin (TSH) to induce iodide uptake by FRTL-5 cells after 48 or 72 hours, but not after 24 hours. The effect of NE was more evident with increasing concentrations of TSH. NE did not modify the rate of I- efflux. Inhibition was associated with a decrease in the Vmax and no change in the Km for iodide influx. To determine if this was a generalized effect of NE on thyroid cell membrane, the uptake of alpha-aminoisobutyric acid (a nonmetabolizable aminoacid) and of 2-deoxyglucose was measured. NE did not inhibit TSH stimulation of the uptake of the two compounds. NE inhibited the action of dibutyryl cAMP (dbcAMP) on iodide uptake in a similar manner to TSH, but did not alter the cyclic adenosine monophosphate (cAMP) levels increased by TSH. The effects of different adrenoreceptor agonists and antagonists demonstrated that norepinephrine acts through an alpha1-adrenergic receptor.     

The nitric oxide synthase inhibitor L-NAME (N omega-nitro-L-arginine methyl ester) does not produce discriminative stimulus effects similar to ethanol

Three key aspects of Florence Nightingale remarkable life are examine. First, the influence during her formative years: the education and guidance provided by her father, the resistance by her family when she decided to become a nurse; and the rejection by Nightingale of the societal expectations of a woman in the Victorian era. Secondly, her professional life is examined, in particular how she appears to have been viewed by certain members of society, and how it turn she viewed them. It is anticipated that her position as an early feminist will be postulated and illuminated. Thirdly, an analysis of her personal and professional life indicates a way forward for the nursing profession.     

Dynamic three-dimensional echocardiographic reconstruction of congenital cardiac septation defects

DNA and FISH (fluorescence in situ hybridization) analysis were carried out in 12 patients with stigmata of Turner syndrome to determine whether the Supernumerary Marker Chromosome (SMC) found cytogenetically in each of these patients was derived from the Y chromosome. The presence of a Y chromosome in these patients may predispose them to develop gonadoblastoma. PCR-Southern blot analysis, followed by FISH, was used to detect the presence of Y chromosome material. The Sex determining Region Y (SRY), Testis Specific Protein Y-encoded (TSPY) and Y-chromosome RNA Recognition Motif (YRRM) genes, which map at Yp11.31, Yp11.1-11.2 and Yp11.2/Yq11.21-11.23, respectively, were selected as markers, because they span the whole Y chromosome, and more importantly, they are considered to be involved in the development of gonadoblastoma. It was shown that in 12 patients, all of whom had an SMC, the SMC of 11 was derived from the Y chromosome. Furthermore, the presence of the SRY, TSPY and YRRM gene sequences was determined and FISH analysis confirmed the Y origin of the SMCs. The methodology described in this report is a rapid, reliable and sensitive approach which may be easily applied to determine the Y origin of an SMC carried in Turner syndrome. The identification of an SMC is important for the clinical management and prognostic counseling of these patients with Turner syndrome.     

Smoking behavior of Styrian physicians--results of a 1995 questionnaire survey

Tobacco use among all physicians registered in the state of Styria was investigated at the beginning of the year 1995 using an anonymous questionnaire. In addition to the smoking prevalence among different specialties in medicine the main interest was focused on motives for smoking as well as for stopping it. Nearly all physicians were aware of the associated health risks. The overall prevalence of smoking was 14% which lay markedly below the Austrian average of 36%. 52% started smoking before the age of 18. In addition 70% of smoking doctors wanted to reduce or stop smoking within the next 6 months. The early start of smoking during adolescence emphasizes the importance of educational and special teaching programs because even in the medical profession there is a big difference between the intention to stop smoking and the actual success in doing so.     

Haplotype sharing analysis in affected individuals from nuclear families with at least one affected offspring

In diseases with a complex mode of inheritance, families with multiple affected individuals are difficult to ascertain. The haplotype sharing statistic (HSS) uses (hidden) co-ancestry between affected individuals from a founder population. These affected individuals will likely not only share the same mutation(s), but also the surrounding haplotype. We show that this method gives a low false positive rate, but does not detect genes in the nuclear families of Problem 2A of the GAW data. We also give evidence based on simulations and empirical studies in real population based data that the HSS method has statistical power.