Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men.

Androgens are important regulators of bone and prostate health in elderly men. The role of serum levels of glucuronidated androgen metabolites as predictors of BMD and prostate volume in men is unclear. We show that specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men. INTRODUCTION: Androgens are important regulators of bone and prostate health in elderly men. Local synthesis and degradation of androgens are likely to be important parameters of biological action of androgens in androgen-responsive tissues. The aim of this study was to determine the role of serum levels of glucuronidated androgen metabolites as predictors of BMD and prostate volume in elderly men. MATERIALS AND METHODS: A subsample of the population-based Swedish part of the MrOS study (n = 631, average age = 75.9 years) was investigated. Bone parameters were measured using DXA. Serum levels of total testosterone (T) and dihydrotestosterone (DHT) were measured by gas chromatography/mass spectroscopy (GC-MS); androstane-3alpha,17beta-diol-3glucuronide (3G) and androstane-3alpha,17beta-diol-17glucuronide (17G) were measured by liquid chromatography/mass spectroscopy. Prostate volume (n = 159) was measured by transrectal ultrasound. RESULTS: The general pattern is that two of the glucuronidated androgen metabolites, namely 17G and 3G, are stronger positive predictors of BMD than the bioactive androgens (T and DHT). In addition, 17G is a clear positive predictor of prostate volume, explaining 4.5% of the variance in prostate volume, whereas the bioactive androgens do not display any association with prostate volume. CONCLUSIONS: Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men. Future studies should determine if the glucuronidated androgen metabolites also reflect other biological correlates of androgenic activity, including prostate cancer, and if low levels might be a marker of general androgen deficiency in men.     

Protein adsorption on ex vivo catheters and polymers exposed to peritoneal dialysis effluent.

BACKGROUND: Deposition of proteins on surfaces of medical devices has been recognized to putatively relate to the process of regulation of biomaterial-associated complications by attachment of fibrin clots, eukaryotic cells, and microbes. The molecules adsorb to a varying extent, depending not only on the physicochemical properties of the biomaterial, but also on the composition of the host fluid. OBJECTIVE: Adsorption of proteins on catheters exposed both ex vivo and in vitro to dialysate of patients on peritoneal dialysis (PD) was studied. METHODS: Peritoneal dialysis effluent was collected from 5 patients with end-stage renal disease on continuous ambulatory PD. Tenckhoff catheters were obtained from 16 patients. Deposition of proteins on excised Tenckhoff catheters and tubing of different materials exposed to PD effluent in vitro was studied using 125iodine-labeled antibodies. Adhesion of Staphylococcus aureus and Staphylococcus epidermidis strains was quantified on tubing exposed to PD effluent in vitro. RESULTS: The presence of albumin, transferrin, immunoglobulin G, fibrinogen, fibronectin, von Willebrand factor, vitronectin, and thrombospondin was determined at various concentrations in PD effluent. All proteins analyzed were detected on PD catheters removed from patients. The extent of protein deposition on Tenckhoff catheters exposed to PD effluent, in vitro, rapidly reached a plateau and remained constant, as it did on polyvinyl chloride and polyethylene tubing. Adhesion of staphylococci was enhanced on Tenckhoff catheters exposed to PD effluent compared to unused PD solution. CONCLUSIONS: The data identify surface exposed proteins that may serve as adhesion sites for microbes on peritoneal catheters indwelled in patients undergoing PD.     

Altered natural killer cell repertoire in Tap-1 mutant mice.

We have analyzed the specificity and function of natural killer (NK) cells in mice with a homozygous deletion of the major histocompatibility complex (MHC)-encoded transporter gene associated with MHC class I-restricted antigen presentation (Tap-1). These mice express very low levels of class I molecules at the cell surface, and these molecules are either devoid of peptide or occupied only by TAP-independent peptides. NK cells in Tap-1 -/- mice, through normal in number, appeared tolerant toward autologous Tap-1 -/- Con A-activated blasts, Tap-1 -/- as well as allogeneic BALB/c bone marrow cells, and RMA-S tumor cell grafts. In contrast, they killed YAC-1 cells as efficiently as did NK cells from wild-type mice. Defective Tap-1 expression was sufficient to render nontransformed target cells sensitive to NK cell-mediated lysis. It is concluded that proper expression of TAP molecules is necessary for normal development of NK cells, as well as for rendering target cells resistant to NK cell-mediated lysis. These results support the hypothesis that class I molecules of the MHC influence the sensitivity of target cells to lysis by NK cells, as well as the development of the NK cell repertoire.     

Early effects of tetraethylammonium chloride on the contractile properties of isolated rabbit basilar arteries

The acute vascular effects of tetraethylammonium chloride (TEA) were examined on annular segments of rabbit basilar arteries. Contractions induced by the potassium channel blocker were compared with those obtained for potassium chloride, 5-hydroxytryptamine (5-HT) and norepinephrine (NE). The greater magnitude of the contractions was of the following order: [K+] greater than 5-HT greater than TEA greater than NE. High concentrations of TEA alone (10(-2) M) generated spontaneous oscillatory contractions in cerebral vessels that were normally quiescent. Low concentrations of TEA (10(-8)-10(-6) M), which had no vasomotor properties per se, enhanced the contractile response of submaximal concentrations of 5-HT (10(-7) M) and NE (3 X 10(-6) M) and attenuated the contraction produced by 60 mM [K+]. An increased vascular response to the amines was still evident up to 3 h after the addition of TEA despite frequent rinsing with fresh buffer solutions. On arteries precontracted with TEA (10(-2) M), but not high [K+], the subsequent addition of 5-HT (10(-7) M) still induced a powerful constriction. Repeated concentration-response curves for [K+] were reproducible and, in the presence of TEA (10(-8) or 10(-6) M), the curve was displaced to the right in a competitive manner. A higher concentration of TEA (10(-4) M) was devoid of any blocking properties on the [K+]-induced response whereas, at 10(-3) M TEA, the response was potentiated, as evidenced by a shift of the curve to the left. Interactions between TEA and the cumulative response to 5-HT were difficult to interpret. Repeated exposures of the artery to 5-HT resulted in an increased maximal response with each determination (EAm = 127 +/- 9% and 149 +/- 14% of control values following the second and third applications, respectively). With TEA (10(-6) M), the increase in the maximal contractile effect noted previously was not observed. Contractions induced by single concentrations of TEA (10(-2) M) or [K+] (60 mM) were calcium dependent, were abolished completely in a calcium-free medium, and were depressed by the calcium antagonist nimodipine. 5-Hydroxytryptamine-induced contractions (10(-5) M) were less sensitive to withdrawal of calcium from the extracellular medium (31 +/- 6% relative to the maximal response at 4 mM calcium). Hence, an acute reduction in potassium conductance in cerebrovascular smooth muscle produced by TEA has complex, concentration-dependent effects and reproduces only part of the spectrum of effects of cisternal injection of blood on cerebrovascular reactivity.     

Effect of MHC class-I transfection on local tumor growth and metastasis in an H-2-negative clone derived from a chemically induced fibrosarcoma.

GR9 is a chemically induced fibrosarcoma composed of clones with different H-2 class-I expression. These clones differ with respect to local growth and spontaneous metastasis. The B9 clone (H-2 negative) is highly tumorigenic (local growth) but of low metastatic potential (spontaneous metastasis assay). We have analyzed the effect that transfection of H-2Dd and H-2Kd genes on this clone have upon local growth, lung colonization after i.v. injection and ability to form spontaneous metastases. The results showed that the effect on local growth of transfection of the Kd-gene was stronger than that of the Dd gene. In addition, B9 co-transfected with H-2Kd and Dd genes showed the highest immunogenic properties in syngeneic BALB/c mice. Interestingly, the pSV2-neo transfected clone gave almost the same result as that obtained with Dd transfection. Lung colonization after i.v. injection of the different clones (experimental metastasis), paralleled the results obtained for local growth: the number of lung nodules followed the cadence KdDd less than Kd less than Dd less than pSV2. Survival of mice was always inversely correlated with local growth, e.g., all mice injected with 5 x 10(5) B9 H-2KdDd transfected cells survived. In contrast, no mice injected with the B9 control did. These differences were abrogated in irradiated and nude BALB/c mice. Finally, all transfected clones remained non-metastatic in a spontaneous metastasis assay, behaving as the control, non-transfected B9 cells.     

Single Nucleotide Polymorphisms in the Human Gene for Osteoprotegerin are Not Related to Bone Mineral Density or Fracture in Elderly Women

Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50–0.64, C1217T P = 0.51–1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61–0.66, C1217T P = 0.14–0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.     

The costs of atopy and asthma in children: Assessment of direct costs and their determinants in a birth cohort

The aim of this study was to estimate costs accrued by the health care of children with asthma in comparison to children with atopic eczema and seasonal rhinitis and to investigate cost determinants. From the multicenter cohort study (MAS-90), we selected children with an asthma, atopic eczema and/or seasonal rhinitis diagnosis during the first 8 years of life, and overall 8-year health care utilization was estimated retrospectively by reviewing medical records. Asthma treatment (n = 76) incurs an average cost of US$ 627 per year, 44% due to hospital stays. Atopic eczema treatment (n = 91) cost on average US$ 219 and seasonal rhinitis (n = 69) US$ 57 per year. In asthma and atopic eczema, costs increase significantly with disease severity. Allergy diagnostics use accounts for only 1% of total costs. Costs for asthma and atopic eczema treatment are highest in those years when topical steroids are used for the first time, but decrease with every further year of steroid use. A remarkable 25% of asthmatic children with severe symptoms were not treated according to national guidelines, so that most steroid treatment was initiated during the first hospital stay. In the case of asthma, total direct costs increased until the 3rd year of the disease, and then decreased with further years of diagnosis, while steroid use continued to increase. These results indicate a 'learning effect' in the treatment of asthma and atopic eczema for each patient as well as considerable cost-saving potential by preventing severe asthma. Moreover, the importance of considering cost-driving factors and using cohort or longitudinal designs in cost-of-illness approaches is emphasized.     

CSF testosterone in 43 male suicide attempters.

Several studies have shown a relationship between high testosterone and violent aggressive behaviour. The general aim of this study was to gain knowledge of the importance of testosterone in suicide attempters. Testosterone in cerebrospinal fluid (CSF) was analysed in men with a recent suicide attempt, diagnostically subdivided into groups according to DSM-III-R axis I and II diagnosis and mode of suicidal behaviour. In general, our patients had lower CSF testosterone levels than aggressive violent patients in other studies. Patients with depression NOS or dysthymia showed higher CSF testosterone levels than the rest. Significant positive correlation between testosterone and irritability or a negative correlation with social desirability was found in diagnostic subgroup of patients, specifically axis II, cluster B personality disorders. The results suggest that suicide attempts may be mediated by different biological variables than aggression.