The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.

BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

Changes in plasma, erythrocyte, and platelet magnesium levels in normotensive and hypertensive obese subjects during oral glucose tolerance test.

We evaluated the 75-g oral glucose tolerance test (OGTT)-induced modifications in glucose, insulin, and norepinephrine plasma concentrations, and in plasma, erythrocyte, and platelet magnesium levels in two groups of obese subjects (normotensive obese, NT-Ob, N = 19; hypertensive obese, HT-Ob, N = 15), and in a group of healthy control subjects (N = 12). During OGTT we detected a reduction in plasma magnesium concentrations and an increase in erythrocyte and platelet magnesium levels in the controls, whereas in both normotensive and hypertensive obese subjects, there was a reduction in plasma, erythrocyte, and platelet magnesium levels. Furthermore, no statistically significant difference was detected among the groups studied as regards delta-plasma magnesium. On the other hand, delta-erythrocyte magnesium and delta-platelet magnesium were negative in the NT-Ob (delta-erythrocyte magnesium: -0.24+/-0.08 mmol/L; delta-platelet magnesium: -0.49+/-0.09 micromol/10(8) cells) and HT-Ob (delta-erythrocyte magnesium: -0.20+/-0.10 mmol/L; delta-platelet magnesium: -0.50+/-0.11 micromol/10(8) cells) groups, and positive in control subjects (delta-erythrocyte magnesium: 0.40+/-0.08 micromol/L; delta-platelet magnesium: 0.47+/-0.09 mmol/ 10(8) cells). Finally, a direct correlation was found between delta-norepinephrine and delta-erythrocyte magnesium (r = 0.80, P < .01) in the control group, and a negative correlation was detected between delta-norepinephrine and delta-platelet magnesium (r = -0.58, P < .05) in the HT-Ob group. Our results seem to indicate that the insulin resistance status, the hyperglycemia, and the disregulation of the adrenergic system in obese subjects could be involved in the pathogenesis of the magnesium homeostasis impairment observed in the obese subjects.

[Obesity and hypertension: the role of magnesium]. / Obesità ed ipertensione: ruolo del magnesio.

We focus on the recent "ionic hypothesis", in which an alteration of ionic metabolism represents a peculiar event in the pathogenesis of obesity and hypertension. We report the results from our original studies in which we evaluated intraplatelet magnesium levels. In a study on normotensive and hypertensive patients with non insulin-dependent diabetes mellitus and healthy control subjects, we showed a common reduction of plasma, erythrocyte and platelet magnesium levels in both normotensive and hypertensive diabetics with respect to control. Anyway, hypertensive diabetics showed a greater reduction of intraplatelet magnesium concentrations when compared to normotensive diabetics. Using the same technique, we found reduced erythrocyte and platelet magnesium concentrations in patients with essential hypertension with respect to the control group. In a successive study, we found, in the group of normotensive obese, that erythrocyte and platelet magnesium levels were significantly lower than those of the control group, while in hypertensive obese patients a reduction of plasma magnesium levels has been also detected. In conclusion, in these studies has been confirmed the existence of a reduction of the intracellular magnesium concentrations, which is common in hypertensive and obese patients.

[Leptin: adipocyte hormone]. / Leptina: ormone adipocitario.

The authors reviewed the most recent literature on leptin, a protein produced by adipocytes which exerts its action on hypothalamus, modifying eating behavior and inhibiting the lust for food consumption. This one appeared to be the main, if not the only, physiologic action of leptin. Later leptin has been acknowledged a major role in the homeostasis. The regulation of the synthesis, and the mechanisms by which the protein modulates both food intake and energetic balance have been evaluated, and the hypotheses on the regulatory function exerted by leptin on the homeostasis, by acting on neuroendocrine system, on sexual maturity and fertility, on the sympathetic nervous system, on hemopoiesis and hydroelectrolytic balance have been discussed, some of which being already supported by experimental evidences.

Increased transforming growth factor-beta1 plasma concentration is associated with high plasma 3,3',5'-tri-iodothyronine in elderly patients with nonthyroidal illnesses.

OBJECTIVE: To study transforming growth factor-beta1 (TGF-beta1) plasma concentrations in elderly patients with nonthyroidal illnesses (NTI). DESIGN: Case-control study. METHODS: We measured plasma concentrations of tri-iodothyronine (T3), reverse T3 (rT3), thyroxine (T4), free T3 (fT3) and free T4 (fT4) estimates, TSH, and TGF-beta1 in 48 elderly NTI patients consecutively admitted in our Division of Internal Medicine and Metabolic Diseases, and in 11 healthy age- and sex-matched controls. RESULTS: The data on thyroid hormones enabled us to identify three groups: Group A, subjects (8 patients) with T3 and fT3 levels comparable to those in controls: Group B, subjects (30 patients) with T3 and fT3 levels lower than controls but rT3 levels comparable to those of controls; Group C, subjects (10 patients) with T3 and fT3 levels lower than those of controls and higher rT3 levels. The patients of Group C showed higher plasma levels of TGF-beta1 compared with controls. Moreover, we found a positive correlation between TGF-beta1 and rT3 (rs = 0.38, P < 0.01) in the whole group of NTI patients. CONCLUSIONS: Our data seem to confirm the hypothesis that TGF-beta1 could play a role in the pathogenesis of some modifications of thyroid function observed in patients with nonthyroidal illnesses.

Plasma interleukin-2 levels and thyroid function in elderly patients with nonthyroidal illness.

To determine whether interleukin-2 (IL-2) plasma concentrations are modified in patients with nonthyroidal illness (NTI) and thyroid function alterations, we measured plasma concentrations of T(3), T(4), free T(3) (FT(3)), free T(4) (FT(4)), TSH, and IL-2 in 34 elderly NTI patients and in 25 age- and sex-matched healthy controls. IL-2 was detectable in 11 of the 34 patients. Patients with detectable IL-2 plasma levels had significantly lower plasma T(3) and FT(3) concentrations when compared to those with undetectable IL-2. Moreover, IL-2 plasma levels were positively correlated to reverse T(3) (rT(3)), (r(S)=0.67, P<0.05), and negatively to FT(3) concentrations (r(S) =-0.64, P<0.05). These observations suggest that some of the alterations in thyroid hormone levels seen in NTI are associated with elevated plasma concentrations of IL-2.

Reduced plasma concentrations of transforming growth factor beta1 (TGF-beta1) in obese women.

OBJECTIVE: To evaluate Transforming Growth Factor beta1, (TGF-beta1) plasma concentrations and the possible relationship between this growth factor and various hormones in obese women. DESIGN: Case-control study. SETTING: Outpatient's Service for the Prevention and Treatment of Obesity at the University Hospital. SUBJECTS: Twenty-five women with mild to moderate obesity, and 15 non-obese healthy women were used as controls. MEASUREMENTS: Evaluation of TGF-beta1, insulin, prolactin, sex-hormone binding globulin, androstenedione, free triiodothyronine, free tetraiodothyronine, thyroid-stimulating hormone, dehydroepiandrosterone-sulfate, testosterone, insulin-like growth factor 1, cortisol and adrenocorticotropic hormone plasma concentrations in obese women. Blood samples were taken from fasting subjects for the determination of the above parameters. RESULTS: In obese women plasma TGF-beta1 concentrations were lower than in controls. The obese subjects also had lower GH, IGF-1 and SHBG plasma concentrations and increased insulinaemia. A positive correlation was found between TGF-beta1 and both IGF-1 (r = 0.52; P < 0.01) and DHEA-S (r = 0.43; P < 0.05), while a negative correlation was found between TGF-beta1 and SHBG (r = -0.49; P < 0.05). CONCLUSIONS: The reduction in TGF-beta1, an antilipogenic factor, may play a role in the pathogenesis of obesity and could be involved in the development of some obesity-related endocrine alterations.

Reduced intraplatelet magnesium concentrations in elderly patients with non-insulin dependent diabetes mellitus (NIDDM).

Intraplatelet magnesium concentrations were evaluated in 50 non-insulin dependent diabetes mellitus (NIDDM) patients divided into two groups of 25 each (<60 or >65 years) and in a control group of 30 healthy subjects, divided into two age-matched subgroups of 15 each. In all patients magnesium concentrations were assayed in plasma, erythrocytes and platelets by means of direct current plasma spectrometry. Plasma, erythrocyte and platelet magnesium levels in healthy elderly subjects were found to be comparable to those in the group of younger healthy subjects, whereas plasma, erythrocyte and platelet magnesium levels in diabetics were lower than in controls. The reduction in intraplatelet magnesium concentrations found in elderly diabetics was greater than in the younger diabetics. In diabetics, moreover, an inverse correlation was found between platelet magnesium and age, but not between plasma or erythrocyte magnesium and age. Our findings show that aging can influence the alterations in the metabolism and compartmentalization of magnesium determined by type 2 diabetes mellitus. This condition may underlie platelet function alterations which, in turn, can exacerbate vascular complications from diabetes.

Plasma, erythrocyte and platelet magnesium levels in type 1 diabetic patients with microalbuminuria and clinical proteinuria.

We evaluated plasma, erythrocyte and platelet magnesium levels in patients with insulin-dependent diabetes mellitus (IDDM) with normoalbuminuria (N = 10), microalbuminuria (N = 10), and clinical proteinuria (N = 7), and in a group of healthy subjects (N = 10). We found that IDDM patients had lower platelet magnesium levels when compared to controls. Lower platelet magnesium concentrations were found in patients with microalbuminuria (1.859 +/- 0.47 vs 2.340 +/- 0.46 mumol/10(8) cells, p < 0.05) and in those with clinical proteinuria (1.522 +/- 0.19 vs 2.340 +/- 0.46 mumol/10(8) cells, p < 0.01) with respect to the group with normoalbuminuria. In the groups with microalbuminuria and clinical proteinuria we detected a negative correlation between HbA1c and both plasma and platelet magnesium. Our findings indicate that microalbuminuria and clinical proteinuria are associated with an altered magnesium homeostasis. In particular, decreased platelet magnesium concentrations could represent an additional risk factor in the pathogenesis of microvascular complications of diabetes.

Altered platelet magnesium and plasma and urinary soluble form of intercellular adhesion molecule I (sICAM-1) concentrations in insulin dependent diabetes mellitus (IDDM) patients with microalbuminuria.

Magnesium concentrations in plasma, erythrocyte and platelet, and plasma and urine levels of the soluble form of Intercellular Adhesion Molecule-1 (sICAM-1) were evaluated in subjects with insulin dependent diabetes mellitus (IDDM) with or without microalbuminuria, and in a control group of healthy subjects. Using a recently introduced technique, we found that magnesium concentrations in platelets in diabetic subjects with microalbuminuria were lower than in diabetics with normal albuminuria (1.859 +/- 0.47 vs 2.065 +/- 0.62 mumol/10(8) cells; P < 0.05). Moreover, IDDM subjects had higher plasma sICAM-1 levels than control subjects; no difference, however, was found between sICAM-1 concentrations in the two groups of diabetics. An inverse correlation was found between intraplatelet magnesium and plasma sICAM-1 levels (r = - 0.64; P < 0.05) in the diabetics with microalbuminuria. It is concluded that the reduced intraplatelet magnesium content may contribute to the progression of the vascular complications in IDDM subjects with microalbuminuria.