Migrant mortality from diabetes mellitus across Europe: the importance of socio-economic change

The first objective of this study was to determine and quantify variations in diabetes mortality by migrant status in different European countries. The second objective was to investigate the hypothesis that diabetes mortality is higher in migrant groups for whom the country of residence (COR) is more affluent than the country of birth (COB). We obtained mortality data from 7 European countries. To assess migrant diabetes mortality, we used direct standardization and Poisson regression. First, migrant mortality was estimated for each country separately. Then, we merged the data from all mortality registers. Subsequently, to examine the second hypothesis, we introduced gross domestic product (GDP) per capita of COB in the models, as an indicator of socio-economic circumstances. The overall pattern shows higher diabetes mortality in migrant populations compared to local-born populations. Mortality rate ratios (MRRs) were highest in migrants originating from either the Caribbean or South Asia. MRRs for the migrant population as a whole were 1.9 (95% CI 1.8-2.0) and 2.2 (95% CI 2.1-2.3) for men and women respectively. We furthermore found a consistently inverse association between GDP of COB and diabetes mortality. Most migrant groups have higher diabetes mortality rates than the local-born populations. Mortality rates are particularly high in migrants from North Africa, the Caribbean, South Asia or low-GDP countries. The inverse association between GDP of COB and diabetes mortality suggests that socio-economic change may be one of the key aetiological factors.     

H295R cells as a model for steroidogenic disruption: a broader perspective using simultaneous chemical analysis of 7 key steroid hormones

The effects of three model endocrine disruptors, prochloraz, ketoconazole and genistein on steroidogenesis were tested in the adrenocortical H295R cell line to demonstrate that a broader mechanistic understanding can be achieved in one assay by applying chemical analysis to the H295R assay. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone and 17β-estradiol) were analyzed using a novel and thoroughly validated GC-MS/MS method. In addition to the simultaneous quantification of 7 steroid hormones, the present method also negates the potential problems of cross-reactivity that can be encountered in some immunoassays. Although all 3 test compounds decrease the concentrations of the main sex steroids, the chemicals exerted different effects upstream in the pathway. Exposure to prochloraz resulted in increased hormone levels upstream of steroid 17 alpha-hydroxylase/17,20 lyase (P450c17) and decreases downstream. Ketoconazole inhibited the entire pathway, while exposure to genistein resulted in increased hormone levels upstream of 3-β-hydroxysteroid dehydrogenase (3β-HSD) and decreases downstream. The results demonstrate that chemical analysis combined with the H295R cell assay is an useful tool for studying the mechanisms by which endocrine disruptors interfere with the steroidogenic pathway.     

Absorption of dietary alkylresorcinols in ileal-cannulated pigs and rats

Alkylresorcinols (AR) are amphiphilic 1,3-dihydroxy-5-alkyl phenolic lipids. AR in food are only found in the outer layers of wheat and rye grains, and in whole grains are present at concentrations of 500-1000 microg/g. In wheat and rye, there are five main homologues, differing in the length of the odd-numbered alkyl chain (from seventeen to twenty-five C atoms long). Because AR may be bioactive, and might serve as biomarkers for these cereals, their absorption was investigated in model experiments with pigs and rats. Pigs with a cannula in the terminal ileum were fed four diets containing rye fractions with different levels of AR and the ileal effluents were analysed. The ileal recovery of AR was found to vary between 21 and 40 %, with no major difference between different chain-length homologues. The absorption of AR by rats was investigated by feeding (14)C-labelled heneicosylresorcinol (C21 : 0). Of the total activity, about 34 % was recovered in the urine, showing that the labelled AR was absorbed and metabolised by rats. AR were mostly cleared from rats by 60 h. It is concluded that AR are absorbed in the small intestine of single-stomached animals and excreted in metabolised form in the urine, and might contribute to the nutritional qualities of wholegrain wheat and rye diets.     

Impact of selected risk factors on expected lifetime without long-standing, limiting illness in Denmark

OBJECTIVE: To estimate the impacts of tobacco smoking, high alcohol consumption, physical inactivity and overweight on expected lifetime with and without long-standing, limiting illness. METHODS: Life tables for each level of exposure to the risk factors were constructed, mainly on the basis of the Danish National Cohort Study. Expected lifetime without long-standing, limiting illness was estimated for exposed and unexposed persons by combining life tables and prevalence data from the Danish Health Interview Survey 2000 (14,503 participants aged 25+). RESULTS: The life expectancy of 25-year-olds was 9-10 years shorter for heavy smokers than for those who never smoke, and all the lifetime lost would have been without long-standing, limiting illness. Similarly, all 5 years of expected lifetime lost by men with high alcohol consumption would have been without illness. The expected lifetime without long-standing, limiting illness was 8-10 years shorter among sedentary than physically active people. Obesity shortened lifetime without illness by 5 years for men and ten years for women. CONCLUSION: The results of this study could be used in health policy-making, as the potential gains in public health due to interventions against these risk factors could be evaluated, when the prevalence of exposure to the risk factor is available.     

Epidermal growth factor-mediated activation of the map kinase cascade results in altered expression and function of ABCG2 (BCRP).

Epidermal growth factor (EGF) is a multifunctional growth factor known to play a major role in proliferation and differentiation processes. EGF-induced differentiation is a prerequisite for function of various cell types, among them cytotrophoblasts, a functionally important cellular fraction in human placenta. Stimulation of cytotrophoblasts with EGF results in formation of a multinuclear syncytium representing the feto-maternal interface, which protects the fetus against exogenous substances. It is well established that part of this protection system is based on ATP-binding cassette (ABC) transporters such as ABCG2 (breast cancer resistance protein, BCRP). However, little is known about regulation of transport proteins in the framework of EGF-mediated cellular differentiation. In the present work we show a significant increase of ABCG2 expression by EGF in cytotrophoblasts, BeWo, and MCF-7 cells on both mRNA and protein levels. This increase resulted in decreased sensitivity to the ABCG2 substrates mitoxantrone and topotecan. In each cell type, EGF increases expression of ABCG2 by activation of mitogen-activated protein kinase cascade via phosphorylation of extracellular regulated kinase (ERK)1/2 and c-jun NH-terminal kinase/stress-activated protein kinase (JNK/SAPK). Consequently, the increase of ABCG2 by EGF was abolished by pretreatment of cells with the tyrosine kinase inhibitor 4-(3-chloroanillino)-6,7-dimethoxyquinazoline (AG1478) or the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'methoxyflavone (PD 98059), thereby reestablishing sensitivity toward mitoxantrone. Moreover, analysis of ABCG2 expression during placental development revealed a significant increase in preterm versus term placenta. Taken together, our data show regulation of ABCG2 expression by EGF. In view of EGF signal transduction as a target for drugs (e.g., gefitinib), which are in turn substrates and/or inhibitors of ABCG2, this regulation has therapeutic consequences.     

The regulation of subcutaneous blood flow in patient with Dercum's disease

Dercum's disease or adiposis dolorosa is a poorly understood disorder with painful fatty deposits in the skin localized to the lower extremities. The etiology is unknown. In such a patient the mechanisms of local regulation of blood flow in subcutaneous tissue was investigated by the local 133Xenon washout technique. The patient was reinvestigated one week after treatment with intravenous lidocaine. The local vasoconstrictor response to increase in venous transmural pressure was not present in this patient, but reappeared after lidocaine treatment. Autoregulation of blood flow in subcutaneous tissue was present before as well as after lidocaine treatment. It seems likely that a pain elicited increase in sympathetic activity in the vasoconstrictor fibres abolished the normal vasoconstrictor response to increase in venous transmural pressure. The mechanism of pain relief after intravenous lidocaine infusion is uncertain, but central as well as peripheral mechanisms may be considered.     

Sympathetic reflex control of subcutaneous blood flow in patients with congestive heart failure

Central and local regulation of forearm subcutaneous vascular resistance (FSVR) during postural changes were studied in congestive heart failure (CHF). Blood flow was measured by the local 133Xe-washout technique. Nine patients with severe CHF (baseline angiographic ejection fraction, 23 +/- 2%, mean +/- SEM; cardiac index, 2.2 +/- 0.2 litres min-1 m-2; increased left ventricular pressures and dimensions) were compared with seven control subjects who had normal cardiac performance. Baseline FSVR and plasma concentrations of noradrenaline and adrenaline were substantially higher in patients with CHF than control subjects. However, the patients, like control subjects, increased FSVR by 46 +/- 3% in response to increase in local venous transmural pressure and disclosed a normal response to decrease in forearm perfusion pressure. Both responses to changes in vascular transmural pressure were preserved after either proximal nervous blockade or local beta-receptor blockade. Central sympathetic stimulation was induced with use of 45 degrees upright tilt. Control subjects developed vasoconstriction (FSVR increased by 59 +/- 5%), which was completely abolished after proximal nerve blockade. Patients with CHF developed vasodilatation (FSVR decreased by 24 +/- 8%), which was not only abolished but reversed after proximal nerve blockade (FSVR increased by 22 +/- 7%), probably owing to the increased humoral vasoconstrictor activity. The paradoxical vasodilator response to central sympathetic stimulation in these patients was reversed after local beta-receptor blockade (FSVR increased by 19 +/- 9%). The local vasoconstrictor reflex responsiveness and intrinsic vascular reactivity were not affected by the augmented baseline sympathetic vasoconstrictor activity in patients with CHF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different effects of calcium antagonist and beta-blocker therapy on left-ventricular diastolic function in ischemic heart disease. A direct comparison of the impact of mibefradil and atenolol.

OBJECTIVE: To compare the effect of a calcium antagonist and a beta-blocker on left-ventricular diastolic function in patients with ischemic heart disease. METHODS: 138 patients with chronic stable angina pectoris were randomized in a multicenter, double-blind trial to treatment with either mibefradil or atenolol for 6 weeks (50 mg once daily for 2 weeks followed by 100 mg once daily for 4 weeks). The ratio between early (E) and late (A) diastolic mitral flow velocities (E/A), the E wave deceleration time (DT) and the left ventricular isovolumetric relaxation time (IRT) were measured by Doppler echocardiography as parameters of left-ventricular diastolic function initially, after 4 and after 6 weeks of treatment. RESULTS: Mibefradil did not change the E/A ratio significantly (+4%, NS), while atenolol treatment resulted in a significant increase in the E/A ratio (+20%, p < 0.001). Mibefradil treatment, on the other hand, resulted in a significant decrease (-8%, p < 0.001) in IRT, while atenolol treatment did not change IRT. Neither mibefradil nor atenolol treatment changed DT significantly. CONCLUSIONS: Both mibefradil and atenolol treatment significantly improves echocardiographic indices of left-ventricular diastolic function in patients with chronic stable angina. However, they affect different parameters and thus apparently act through different mechanisms.     

Vasoconstrictor use in liver transplantation: is there evidence for rational use?

Liver transplantation is a challenging surgical operation performed in recipients with major hemodynamic perturbations related to portal hypertension. The pathophysiologic alterations in portal hypertension include a hyperdynamic circulation and decline in systemic vascular resistance and mean arterial pressure. Cardiac function can also be depressed due to cirrhosis related cardiomyopathy. These cirrhosis related changes often lead to a tenuous state in which organ perfusion is threatened and declines rapidly in the setting of many other insults including blood loss, infection, and use of medications which can cause a decline in blood pressure. This can result in renal failure as well as reduced perfusion of other organs. Additionally, direct consequences of portal hypertension include risk of bleeding from porto-systemic collaterals both in the gastrointestinal tract as well as during abdominal dissection in liver transplantation. In this milieu the management of hemodynamic alterations during liver transplant surgery is a daunting task. Recent approaches have utilized various vasoconstrictor therapies along with judicious use of intravenous fluids to maintain systemic pressures and organ perfusion. Added advantages of this approach include the potential for reducing portal pressure and thus the severity of intra-abdominal hemorrhage during surgery as well as potentially increasing renal blood flow and reducing mesenteric hyperemia. Avoidance of liberal fluid use to maintain systemic pressures also has the advantage of reducing the severity of pulmonary edema and risk of reintubation or prolonged intubation after surgery. Although these approaches utilizing vasoconstrictors are promising, many questions remain. Randomized controlled trials like those performed in the pretransplant population are sparse in the setting of liver transplantation. The optimal vasoconstrictors including combinations and doses have not been defined. Most of the benefits demonstrated thus far have been surrogate outcomes such as reduced transfusion requirement, decreased need for reintubation and improved systemic hemodynamics and reduced portal pressures during surgery. There may be different outcomes of these approaches in patients with varying severities of liver disease. The safety of minimization of fluids, along with vasoconstrictor therapy during liver transplantation has been questioned in patients with higher risk of renal failure including recipients with high MELD scores. Other factors besides disease severity, including organ quality and cold ischemia times, need to be accounted for in future trials. Optimal outcomes including postoperative patient and graft survival, hospital stay and renal function should also be incorporated in future trials of vasoconstrictor therapy during liver transplantation.