Leukocyte subsets and abdominal aortic aneurysms detected by screening in men.

OBJECTIVE: In the present case-control study, we describe the associations between leukocyte subsets in blood and early, screening-detected AAA in men. An abdominal aortic aneurysm (AAA) may result in a life-threatening rupture of the aortic wall. The trigger for AAA formation remains unknown, but the vascular adventitia of advanced AAAs is infiltrated by various leukocytes, indicating that the pathogenesis may involve inflammation. METHODS: In Sweden, all 65-year-old men are invited to an ultrasound examination for detection of AAA. At the Gothenburg screening site, 16 256 men were examined in 2013-2017, 1.2% of whom had an AAA (diameter of the infrarenal aorta ≥30 mm). All men with AAA at screening as well as a randomized selection of AAA-free screened men were invited to participate in a case-control study. RESULTS: The median diameter of AAAs was 33 mm. Men with an AAA (n = 151) had a higher frequency of smoking, hypertension and statin use than controls (n = 224). Blood levels of neutrophils, lymphocytes, monocytes and basophils were higher in individuals with an AAA, but eosinophil count did not differ from controls. Odds ratios (95% confidence interval) for AAA were 8.6 (4.2-17.4), 3.5 (1.9-6.6) and 3.3 (1.8-6.3) for the highest versus lowest quartile of neutrophils, lymphocytes and monocytes, respectively. For neutrophils and lymphocytes, the association with AAA remained significant after adjustment for smoking and other known risk factors/markers. CONCLUSION: Several, but not all, subsets of circulating leukocytes are associated with screening-detected AAA in men, which is insufficiently explained by associations with smoking and other confounders.

Low serum vitamin D is associated with increased mortality in elderly men: MrOS Sweden.

UNLABELLED: In elderly man, low serum 25-hydroxyvitamin D (25(OH)D) was associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l, but the association attenuated with time. INTRODUCTION: The aim of the present study was to determine whether poor vitamin D status was associated with an increase in the risk of death in elderly men. METHODS: We studied the relationship between serum 25(OH)D and the risk of death in 2,878 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health and lifestyle measures and serum 25(OH)D measured by competitive RIA. Men were followed for up to 8.2 years (average 6.0 years). RESULTS: Mortality adjusted for comorbidities decreased by 5% for each SD increase in 25(OH)D overall (gradient of risk 1.05; 95% confidence interval 0.96-1.14). The predictive value of 25(OH)D for death was greatest below a threshold value of 50-70 nmol/l, was greatest at approximately 3 years after baseline and thereafter decreased with time. CONCLUSIONS: Low serum 25(OH)D is associated with a substantial excess risk of death compared to 25(OH)D values greater than 50-70 nmol/l, but the association attenuates with time. These findings, if causally related, have important implications for intervention in elderly men.

Low bone mineral density is associated with increased mortality in elderly men: MrOS Sweden.

SUMMARY: We studied the nature of the relationship between bone mineral density (BMD) and the risk of death among elderly men. BMD was associated with mortality risk and was independent of adjustments for other co-morbidities. A piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD (p = 0.020). Low BMD was associated with a substantial excess risk of death, whilst a higher than average BMD had little impact on mortality. INTRODUCTION: Previous studies have demonstrated an association between low BMD and an increased risk of death among men and women. The aim of the present study was to examine the pattern of the risk in men and its relation to co-morbidities. METHODS: We studied the nature of the relationship between BMD and death among 3,014 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health questionnaires, life style questionnaires and BMD measured using DXA. Men were followed for up to 6.5 years (average 4.5 years). Poisson regression was used to investigate the relationship between BMD, co-morbidities and the hazard function of death. RESULTS: During follow-up, 382 men died (all-cause mortality). Low BMD at all measured skeletal sites was associated with increased mortality. In multivariate analyses, the relationship between BMD and mortality was non-linear, and a piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD (p = 0.020). CONCLUSIONS: Low BMD is associated with a substantial excess risk of death compared to an average BMD, whereas a higher than average BMD has a more modest effect on mortality. These findings, if confirmed elsewhere, have implications for the constructing of probability-based fracture risk assessment tools.

Cardiac concentric remodelling induced by non-aromatizable (dihydro-)testosterone is antagonized by oestradiol in ovariectomized rats.

Previous studies on the cardiovascular effects of androgens in females, most of them using testosterone treatment, have yielded conflicting results. Testosterone is metabolized into oestradiol (E2) and dihydrotestosterone (DHT) within cardiovascular tissues. The aim of the present study was to explore the cardiovascular effects exerted by E2 and the non-aromatizable androgen DHT and to study possible interactions between these in female rats. Ovariectomized rats were treated with DHT, E2, or DHT+E2 for 6 weeks. DHT increased left-ventricular posterior wall thickness, assessed by echocardiography, whereas left-ventricular dimension, as well as total heart weight and calculated left-ventricular mass, were unchanged. DHT also increased the levels of insulin-like growth factor-I mRNA in the left ventricle. E2 abolished the effect of DHT on left-ventricular remodelling and insulin-like growth factor-I mRNA when the two treatments were given in combination. E2 also reduced androgen receptor mRNA levels in the heart. Neither E2 nor DHT changed blood pressure measured by telemetry. In conclusion, treatment with the endogenous non-aromatizable androgen DHT causes cardiac concentric remodelling in ovariectomized rats, possibly mediated by increased local levels of insulin-like growth factor-I. The effect of DHT on cardiac wall thickness was antagonized by E2, possibly through downregulation of cardiac androgen receptors. These mechanisms may be of importance for the concentric left-ventricular geometric pattern developing in women after menopause.

Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice.

IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer's disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I(-/-)), resulting in an approximately 80-85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I(-/-) and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I(-/-) mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF(-/-) mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I(-/-) mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I(-/-) mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.

Growth hormone and the cardiovascular function.

In this review, the great importance of growth hormone (GH) for the maintenance of cardiac function in adult life is discussed. Physiological effects of GH are discussed as well as the cardiac dysfunction caused both by GH excess (acromegaly) and by GH deficiency in adult hypopituitary patients. In both acromegaly and adult GH deficiency, there is also increased cardiovascular morbidity and mortality. Finally, the effect of GH treatment in heart failure is discussed.

Similar cardiovascular effects of growth hormone and insulin-like growth factor-I in rats after experimental myocardial infarction.

Accumulating data show that growth hormone (GH) and insulin-like growth factor-I (IGF-I) have major effects on the cardiovascular system. In the present study we have directly compared GH and IGF-I in an in vivo rat model of experimental myocardial infarction. Four weeks after ligation of the left coronary artery, male rats were treated with recombinant human (rh) GH 1.1 mg/kg per day, rhIGF-I 3.0 mg/kg per day or saline s.c. for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. Both GH and IGF-I reduced total peripheral resistance (P< 0.01), end-systolic wall stress (P< 0.01) and end-systolic short-axis area (P< 0.001 and P< 0.05). GH also increased area fractional shortening (P< 0.05). Stroke volume (SV) and SV index were improved by IGF-I (P< 0.0001), and SV tended to be increased by GH (P= 0.12). In conclusion, GH and IGF-I had similar beneficial effects on systolic function and peripheral resistance after experimental myocardial infarction.

The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction.

Several studies have shown that GH can enhance cardiac performance in rats after experimental myocardial infarction and in humans with congestive heart failure. In the present study, the hemodynamic effects of hexarelin (Hex), an analog of GH-releasing peptide-6 and a potent GH secretagogue, were compared with the effects of GH. Four weeks after ligation of the left coronary artery male rats were treated sc twice daily with hexarelin [10 microg/kg x day (Hex10) or 100 microg/kg x day (Hex100)], recombinant human GH (2.5 mg/kg x day), or 0.9% NaCl for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. GH, but not Hex, increased body weight gain. GH and Hex100 decreased total peripheral resistance (P < 0.05) and increased stroke volume (P < 0.05 and P < 0.01, respectively) and stroke volume index (P = 0.06 and P < 0.01, respectively) vs. NaCl. Cardiac output was increased by GH and Hex100 (P < 0.05), and cardiac index was increased by Hex100 with a borderline significance for GH (P = 0.06). In conclusion, Hex improves cardiac function and decreases peripheral resistance to a similar extent as exogenous GH in rats postmyocardial infarction. The mechanisms of these effects are unclear; they could be mediated by GH or a direct effect of Hex on the cardiovascular system.

The role of the GH/IGF-I axis for cardiac function and structure.

There is ample evidence to support a role for the GH/IGF-I axis in regulation of cardiac growth, structure and function. GH may act directly on the heart or through circulating IGF-I (Fig. 1). Moreover, GH has been found to regulate local production of IGF-I in the heart. Both the GH-R and IGF-I-R are expressed in cardiac tissue. Hence, the IGF-I-R receptor can theoretically be activated through locally produced IGF-I acting via autocrine/paracrine mechanisms, or via circulating IGF-I exerting its effects as an endocrine agent. During conditions of pressure and volume overload, an increased systolic wall stress triggers an induction of gene expression of IGF-I GH-R and possibly IGF-J-R implying a potential role for the GH/IGF-I axis in the development of adaptive hypertrophy of the heart and vessels. Cardiovascular effects of GH in clinical studies include beneficial effects on contractility, exercise performance and TPR, and experimental studies suggest an increased Ca2+ responsiveness as one possible underlying cause, although effects of GH and IGF-I on apoptosis may possibly also play a role. The GH secretagogue hexarelin improves cardiac function after experimental myocardial infarction either through an increased GH secretion or possibly through a cardiac GHS receptor, although this needs further investigation. Moreover, it is clear that further basic and clinical studies are required to gain insight into the GH and IGF-I mechanisms of action and to monitor long-term effects when GH is administered as substitution therapy or as an agent in the treatment of congestive heart failure.

Chiral o-phthaldialdehyde reagents for fluorogenic on-column labeling of D- and L-amino acids in micellar electrokinetic chromatography.

Following a recent communication from this laboratory (A. Tivesten et al., J. High Resol. Chromatogr. 1996, 19, 229-233) where on-column chiral derivatization of D- and L-amino acids in micellar electrokinetic chromatography (MEKC) was demonstrated for the first time, we now present further details of the labeling procedure. The basis of the method is the consecutive injection of a sample and the reagent onto the capillary as two discrete plugs. By utilizing their difference in mobility, the zones are mixed by the electrophoretic process in a controllable way. In this way the amino acids are both derivatized within a few seconds and subsequently separated in a single step. Compared with pre-column derivatization, dilution of the original sample is minimized, which is why the method is highly useful for microchemical analytical work, i.e., labeling of nano- to picoliter samples. Four different chiral thiols were compared in this study, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranose (TATG), N-acetyl-L-cysteine (AC), N-acetyl-D-penicillamine (AP), and N-isobutyryl-L-cysteine (IBC). Together with o-phthaldialdehyde (OPA) these constitute the chiral reagent. The reaction rate as well as the spectroscopic and chromatographic properties of the formed derivatives were examined. It was found that the fastest reaction is obtained with OPA/TATG, as was the case with L-alanine (L-ala), and that the rate is greatly affected by the presence and concentration of acetonitrile or methanol. Moreover, OPA/TATG yields superior resolution of D- and L-amino acids over the other OPA/thiol combinations in a sodium dodecyl sulfate (SDS) micellar buffer, whereas the OPA/AC and OPA/IBC-amino acid derivatives have a higher fluorescence quantum yield. With laser-induced fluorescence detection (He-Cd, 325 nm) the mass limit of detection is at the low amol level.

Fluorescence, photodestruction, photoionization and thermal degradation of o-phthalaldehyde/beta-mercaptoethanol-labelled aliphatic alpha-oligopeptides.

Photophysical and photochemical properties of o-phthalaldehyde/beta-mercaptoethanol-labelled aliphatic alpha-peptides were investigated. It is found that alpha-peptide derivatives have lower fluorescence quantum yields, higher photodestruction quantum yields and lower yields for formation of solvated electrons as compared to amino acid and simple alkylamine derivatives in aqueous alkaline solution. These properties of the alpha-peptide derivatives sets narrow limits for their utilization in laser-based (high light intensity) detector systems. In contrast, the thermal stability of the peptide derivatives was found to be severalfold higher than for the parent amino acid derivatives. The differential rates of thermal derivative degradation could be utilized in a new approach towards selective determination of peptides. determination of peptides. determination of peptides.

Age determination based on amino acid racemization: A new possibility.

A method has been developed to determine the age of fossil bone samples based on amino acid racemization (AAR). Approximately one hundred fossil bone samples of known age from Hungary were collected and analysed for D- and L-amino acids. As the racemization of amino acids is affected by temperature, pH, metal content of the soil, and time passed since death, these factors were eliminated by comparing the estimated age to age determined by the radiocarbon method. Determining the D- and L-amino acid contents in samples of known age, determining the half life of racemization and plotting the D/L ratio as a function of time, calibration curves were obtained. These curves can be used for the age estimation of samples after determining their D- and L-amino acid content. The D/L ratio for 2 to 3 amino acids was determined for each sample and the mean value of estimated ages based on calibration curves was considered to estimate age of the fossil samples.