A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females.

Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.

The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review.

Leptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been a subject of intensive research. In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. However, the manner in which both the leptin and ghrelin systems contribute to the development or maintenance of obesity is as yet not clear. The purpose of this review is to provide background information on the leptin and ghrelin hormones, their role in food intake and body weight in humans, and their mechanism of action. Possible abnormalities in the leptin and ghrelin systems that may contribute to the development of obesity will be mentioned. In addition, the potentials of leptin and ghrelin as drug targets will be discussed. Finally, the influence of the diet on leptin and ghrelin secretion and functioning will be described.

[A boy with Churg-Strauss syndrome and thrombosis associated with eosinophilia]. / Een jongen met churg-strauss-syndroom en trombose samenhangend met eosinofilie.

A 13-year-old boy, recently diagnosed as having Churg-Strauss syndrome, presented with a thrombus at the level of the aortic bifurcation. Echocardiography revealed a left-ventricular thrombus as well. He was treated by means of surgical thrombectomy, corticosteroids, heparinisation and a coumarine derivative. Eosinophilia (an increase in the number of eosinophilic granulocytes in the circulation or tissues) occurs in various diseases, such as allergic diseases, parasitic infestations, haematologic diseases and autoimmune diseases like the rare Churg-Strauss syndrome. It appears likely that eosinophilia played an important role in the development of both thrombi in the described patient. Eosinophils produce cationic proteins that may inhibit the effect of natural anticoagulants. Infiltration of eosinophils may also cause endocardial damage with the subsequent formation of intracardial thrombi.

Ischaemic heart disease in Turkish migrants with type 2 diabetes mellitus in The Netherlands: wait for the next generation?

OBJECTIVE: To study the prevalence of ischaemic heart disease in Turkish and Surinam-Asian migrants with type 2 diabetes mellitus in the Netherlands as compared with Europeans. METHODS: In a consecutive case-control study, 59 Turkish and 62 Surinam-Asian patients were compared with 185 Europeans referred to a diabetes clinic for treatment of type 2 diabetes in the period 1992 to 1998. Main outcome measures were ischaemic heart disease and its associated risk factors. RESULTS: The prevalence of ischaemic heart disease was lower (9%) in the Turks (p < 0.02), but higher (29%) in the Surinam-Asians compared with the Europeans (23%). The Turks (52 +/- 10 years) and Surinam-Asians (46 +/- 12 years) were younger than the Europeans (64 +/- 11 years, p < 0.001). Body mass index was 32 +/- 5 (p < 0.001) in the Turks, 27 +/- 5 in the Surinam-Asians (p < 0.05) and 29 +/- 5 in the Europeans. Turkish patients smoked less (23%, p < 0.05) and used less alcohol (4%, p < 0.05) than the Europeans. Proteinuria was found in 24% of the Turks (p < 0.05), 37% of the Surinam-Asians (NS) and 46% of the Europeans. In univariate analysis ischaemic heart disease was related to Turkish origin, OR 0.34 (0.14-0.83) p < 0.02, to Surinam-Asian origin, OR 1.84 (1.00-3.38) p = 0.05, and smoking, OR 1.78 (1.18-2.68) p < 0.01. Other variables were not related to ischaemic heart disease. Multivariate analysis in a model with ethnicity and smoking showed significant relations between ischaemic heart disease and Turkish ethnicity, OR 0.19 (0.06-0.65) p = 0.007, Surinam-Asian origin, OR 2.77 (1.45-5.28) p = 0.002, and smoking, OR 1.79 (1.20-2.66) p = 0.004. CONCLUSION: Type 2 diabetes mellitus in different ethnic groups results in a significant difference in incidence of ischaemic heart disease. The most remarkable finding is a low incidence of ischaemic heart disease in the Turkish patients with type 2 diabetes, independent of smoking. The high prevalence of ischaemic heart disease in young migrant Asians with diabetes is confirmed.

Sodium channel subtypes in the rat display functional differences in the presence of veratridine.

The alkaloid neurotoxin veratridine has the unique property of functionally distinguishing sodium channel subtypes in the rat through differences in single channel conductances, channel substates and probability of channel opening. Veratridine-activated cardiac sodium channels from rat ventricular muscle displayed a single channel conductance of 8.4 pS with no evidence of subconductance states or channel subtypes. Rat skeletal muscle sodium channels displayed both high (8.5 pS) and low conductance (4.7 pS) openings as well as a lower probability of opening (approximately 50%) at depolarized potentials than shown with brain or cardiac sodium channels (90-95%). Rat brain veratridine-activated sodium channels displayed primarily subconductance states at depolarized potentials (3-6 pS) and full conductance of approximately 9.5 pS at hyperpolarized potentials.

Calcium-complexing versus vasorelaxant effect of acetate, lactate, and other bases.

The calcium-complexing abilities of acetate, bicarbonate, lactate, succinate, and citrate were quantified, and were found to differ substantially. Acetate was a more potent vasodilator than lactate, and the vasorelaxant potencies of acetate and lactate failed to correlate with their calcium-complexing ability. The vasodilator action of acetate was not abolished after correction for complexing of ionized calcium. Strips constricted with vasopressin were especially sensitive to the vasodilator effects of acetate.

Ultrafiltration hemodynamics in an animal model: effect of a decreasing plasma sodium level.

Studies in a conscious, nonuremic dog model suggest that use of dialysate hyponatric to plasma tends to cause hypotension during dialytic ultrafiltration by accelerating the rate of contraction of plasma volume. No adverse effect of hyponatric dialysate on total peripheral resistance response could be demonstrated.

Studies of the vasorelaxant effect of acetate.

Sodium acetate caused dose-dependent relaxation of helical rat tail artery strips constricted by phenylephrine, potassium chloride and arginine vasopressin. Substantial relaxation was evident at acetate concentrations as low as 4 mM. The results suggest that the vasodilatation of acetate is not limited to receptor-dependent or voltage-dependent mechanisms. Acute increases in bath sodium chloride concentration resulted in marked relaxation of vessel strips constricted by phenylephrine and potassium chloride. Arginine vasopressin-constricted strips were quite resistant to the vasorelaxant effect of increased bath sodium chloride.