Estrogen receptor genotype modulates myocardial perfusion in young men

Most of the effects of estrogens are mediated by estrogen receptors. Vascular endothelial cells and smooth muscle cells express estrogen receptor (ESR1) in both genders. A long genotype group of a common thymine-adenine (TA) dinucleotide repeat polymorphism in the regulatory region of this gene has previously been related to coronary artery disease. The present study examined whether coronary blood flow is affected by this genotype. A total of 49 healthy men were genotyped by PCR and divided into three groups according to median number of the ESR1 promoter TA repeat (=19), i.e., in the short allele genotype group both alleles were of fewer than 19 repeats whereas in the long allele group both alleles were 19 repeats or more. The intermediate group comprised men who had one short and one long allele. Myocardial blood flow was measured by positron emission tomography using [¹⁵O]water, performed at rest and during adenosine stimulation. Men with long alleles had lower adenosine-stimulated coronary flow than those with short alleles and those with one short and one long allelle. Our results suggest that adenosine-stimulated myocardial perfusion is lower in subjects with ESR1 long alleles than the other TA repeat genotypes.     

Studies in kidney tubulogenesis

Summary The formation of secretory tubules in the embryonic mouse metanephrogenic mesenchyme in vitro has been produced with embryonic spinal cord serving as inductor. The activity of NADH-tetrazolium reductase, acid phosphatase, thiamine pyrophosphatase and ATP-ase activities was assayed cytochemically on frozen sections of cold-formalin fixed explants.What was apparently the first phase of differentiation of kidney tubules became evident in the form of cell condensations. These were accompanied by an increased NADH-tetrazolium reductase activity, suggesting the maturation of both mitochondria (particulate reaction product) and endoplasmic reticulum (homogeneous staining). Furthermore, in the young explants there were visible areas of distinct enzyme activity, with no histological characteristics of the cell condensations. It was considered that these probably represented the earliest phase of differentiation detected by microscopic technique. Thiamine pyrophosphatase activity appeared in the Golgi apparatus of the cells during their organization into tubular epithelium and the formation of lumen. A subsequent increase in acid phosphatase activity of the cytoplasm was noticed. All of the active cytoplasmic organelles, marked by the enzyme activity cytochemically demonstrable, were moved to the apical side of the tubule cells in the course of their cytodifferentiation. After seven days of cultivation, the ATP-ase activity appeared first both in the cell membranes and in the cytoplasm of the tubule cells. At this phase of development, the kidney tubules induced in vitro thus displayed many of the cytochemical characteristics known to exist in the secretory tubules of the mature kidney.Supported by grant from the Sigrid Jusélius Foundation, by grant from Finnish Medical Research Council and by grant C-5347 from the National Cancer Institute, National Institutes of Health, Public Health Service to Prof. Toivonen and Dr. Saxén.     

Cardiorespiratory and thermal effects of wearing gas protective clothing

Summary Six healthy men aged 25 to 37 walked on a treadmill at work levels of 21 and 41% of their for 25 to 30 min wearing gas protective clothing (GPC) consisting of an impermeable suit with a self-contained breathing apparatus (total weight 25 kg) or shorts (control tests, CT) in a temperate environment (t _a 24.3°C ± 1.0°C, rh 30–50%). When the GPC was worn at 21 and 41% , the most prominent increases, compared with the CT, were noted in the heart rate ( ± SE, 120 ± 5 vs 76 ± 3 beats min^–1 and 171 ± 5 vs 103 ± 3 beats min^–1), mean skin temperature (36.1 ± 0.2 vs 31.3° C ± 0.1°C and 36.9 ± 0.3 vs 30.9°C ± 0.4°C) and sweat rate (473 ± 51 vs 70 ± 23 g m^–2 h^–1 and 766 ± 81 vs 135 ± 18 g m^–2 h^–1) indicating a high cardiovascular and thermoregulatory strain, which was not decreased by ventilating the suit with an air flow of 281 min^–1 at 41% . The ventilation, oxygen consumption and production of carbon dioxide increased in relation to the extra weight of the GPC, partly dependent on the dynamic work level. It was concluded that the increase in the physiological load caused by the GPC was so high that the work-rest regimens, workers' level of physical fitness, cardiovascular health and heat tolerance should be considered whenever gas protective clothing is used.     

European school of nuclear medicine 3rd seminar

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European school of nuclear medicine 3rd seminar     

Control of mesenteric arterial tone in vitro in humans and rats

The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75–1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. How-ever, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N ^G-nitro-l-arginine methyl ester (l-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the β-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K⁺ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca²⁺ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca²⁺-induced contractions in human arteries. Received: 1 October 1998 / Accepted: 4 January 1999     

Anandamide prodrugs. 1. Water-soluble phosphate esters of arachidonylethanolamide and R-methanandamide.

Phosphate esters of arachidonylethanolamide (AEA) and R-methanandamide were synthesized and evaluated as water-soluble prodrugs. Various physicochemical properties (pK(a), partition coefficient, aqueous solubility) were determined for the synthesized phosphate esters. The chemical stability of phosphate esters was determined at pH 7.4. In vitro enzymatic hydrolysis rates were determined in 10% liver homogenate, and in a pure enzyme-containing (alkaline phosphatase) solution at pH 7.4. The intraocular pressure (IOP) lowering properties of R-methanandamide phosphate ester were tested on normotensive rabbits. The phosphate promoiety increased the aqueous solubility of the parent compounds by more than 16500-fold at pH 7.4. Phosphate esters were stable in buffer solutions, but rapidly hydrolyzed to their parent compounds in alkaline phosphatase solution (t(1/2)<15 s) and liver homogenate (t(1/2)=8-9 min). The phosphate ester of R-methanandamide reduced IOP in rabbits. These results indicate that the phosphate esters of AEA and R-methanandamide are useful water-soluble prodrugs.     

PATHOLOGY OF LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE DEFICIENCY CAUSED BY THE G1528C MUTATION

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a recently discovered disorder affecting the mitochondrial-oxidation of fatty acids. There have been few reports of the pathologic findings in-oxidation defects. We examined pathologic specimens from 16 patients with this disorder (11 patients were homozygous for the common mutation G1528C, 5 patients were siblings with a similar clinical presentation). Autopsies were performed on all 15 patients who died, and liver biopsy specimens were available from 8 patients. Hepatomegaly and steatosis of the liver, found in every patient, were often combined with fibrosis or cirrhosis. Cardiomegaly and accumulation of fat in the myocardium, renal tubules, and skeletal muscle were found in many patients. A detailed neuropathologic examination was performed on six patients, and brain specimens obtained at autopsy were examined in four others. In general, neuropathologic findings were mild and unspecific, but vacuolization was detected in the deep gray matter and in the cerebellum and brain stem nuclei of five patients. In one patient the vacuolization was prominent; in the other four it was milder and more focal. The vacuoles seemed to be either in the neuropil or associated with swollen hydropic cells. The uniform pattern of histopathologic changes facilitates the diagnostics in this severe disorder, allowing opportunities for therapy and prenatal diagnosis.     

Pre-operative serum level of tumour-associated trypsin inhibitor and residual turnour size as prognostic indicators in Stage III epithelial ovarian cancer

Objective To evaluate the use of the pre-operative tumour-associated trypsin inhibitor (TATI) level and residual tumour size at primary surgery as a prognostic indicators for patients with Stage III epithelial ovarian cancer.
Design Retrospective cohort study.
Setting Department of Obstetrics and Gynaecology, University Hospital, Helsinki, Finland.
Participants Ninety-eight women with Stage III ovarian cancer.
Methods TATI was measured by radioimmunoassay from serum samples obtained within one week before surgery. A cutoff value of 22 μg/L was used. Multivariate analysis included pre-operative TATI level, age, histologic grade and histologic type. Mantel-Cox test was used for calculating statistical significance of differences in survival between groups.
Main outcome measures Cumulative five-year survival, pre-operative serum TATI level and residual tumour size.
Results Surgery was optimal (residual tumour size ≤ 2 cm) in 55 patients and suboptimal (residual tumour size > 2 cm) in 43. Pre-operative TATI level ≤ 22 μg/L predicted better prognosis both in patients with optimal and suboptimal surgery compared with patients with pre-operative TATI level > 22 μ/L. Patients with optimal surgery and a pre-operative TATI > 22 μg/L had a twofold relative risk of death compared with those with a pre-operative TATI ≤ 22 μg/L. The cumulative survival was less than three years for patients with suboptimal surgery and pre-operative TATI > 22 μg/L.
Conclusions Pre-operative serum TATI in combination with residual tumour size may be useful in stratifying patients with Stage III ovarian cancer into different categories in randomised treatment trials.     

Purchaser–provider splits in health care—The case of Finland

The purchaser–provider split (PPS) is a service delivery model in which third-party payers are kept organizationally separate from service providers. The operations of the providers are managed by contracts. One of the main aims of PPS is to create competition between providers. Competition and other incentive structures built into the contractual relationship are believed to lead to improvements in service delivery, such as improved cost containment, greater efficiency, organizational flexibility, better quality and improved responsiveness of services to patient needs. PPS was launched in Finland in the early 1990s but was not widely implemented until the early 2000s. Compared to other countries with PPS the development and implementation of PPS in Finland has been unusual. Firstly, purchasing is implemented at the level of municipalities, which means that the size of the Finnish purchasers is extremely small. Elsewhere purchasing is mostly implemented at the regional or national levels. Secondly, PPS is also applied to primary health care and A&E services while in other countries the services mainly include specialized health care and residential care for the elderly. Thirdly, PPS in health and social services is not regulated by any specific legislation, regulative mechanisms or guidelines. Instead it is regulated within the same framework as public procurement in general.     

Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status

We recently reported that Swedish V_H3-21-using chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite V_H mutation status. To investigate this further, we analyzed the V_H and V_L gene rearrangements in 90 V_H3-21⁺ patients from Sweden, Germany, Italy, United States, Finland, and Australia and correlated these data with survival and other prognostic markers. Sixty-three percent exhibited mutated V_H genes and 37% unmutated V_H genes. Fifty (56%) patients displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif DANGMDV. Also, a highly biased V2-14 use was evident in 72% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although V_H3-21⁺ CLLs have a remarkably predominant expression, analyses of kappa deleting element indicated a conserved light-chain rearrangement order. The overall survival was poor in the V_H3-21⁺ cohort (median survival, 88 months), with no significant difference in relation to mutation status or CDR3 homology. High ZAP-70 and CD38 expression was found in both mutated and unmutated V_H3-21⁺ cases as well as a slight increase of 11q-aberrations. In summary, highly restricted B-cell receptors and worse outcome characterize V_H3-21⁺ CLLs independent of geographic origin and mutation status.