Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis

Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.     

Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response

Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype. CONCLUSION: Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression.     

Dronedarone reduces arterial thrombus formation

Dronedarone has been associated with a reduced number of first hospitalisation due to acute coronary syndromes. Whether this is only due to the reduction in ventricular heart rate and blood pressure or whether other effects of dronedarone may be involved is currently elusive. This study was designed to investigate the role of dronedarone in arterial thrombus formation. C57Bl/6 mice were treated with dronedarone and arterial thrombosis was investigated using a mouse photochemical injury model. Dronedarone inhibited carotid artery thrombus formation in vivo (P?<?0.05). Thrombin- and collagen-induced platelet aggregation was impaired in dronedarone-treated mice (P?<?0.05), and expression of plasminogen activator inhibitor-1 (PAI1), an inhibitor of the fibrinolytic system, was reduced in the arterial wall (P?<?0.05). In contrast, the level of tissue factor (TF), the main trigger of the coagulation cascade, and that of its physiological inhibitor, TF pathway inhibitor, did not differ. Similarly, coagulation times as measured by prothrombin time and activated partial thromboplastin time were comparable between the two groups. Dronedarone inhibits thrombus formation in vivo through inhibition of platelet aggregation and PAI1 expression. This effect occurs within the range of dronedarone concentrations measured in patients, and may represent a beneficial pleiotropic effect of this drug.     

A new β chain hemoglobin variant with increased oxygen affinity: Hb Santa Giusta Sardegna [β93(F9)Cys→Trp; HBB c.282T>G

During a screening program for the identification of β-thalassemia (β-thal) carriers in Sardinia, Italy, we identified two subjects with increased hemoglobin (Hb) levels and an abnormal Hb variant. The same variant was detected in a family member. DNA sequencing revealed a TGT > TGG mutation at codon 93 of the β-globin gene. Structural analysis demonstrated that the cystine residue at position 93 of the β chain was substituted by tryptophan. Since this amino acid substitution had not yet been reported, we designated this variant Hb Santa Giusta Sardegna for the place of birth of the subjects. This amino acid substitution occurs at the tyrosine pocket of the β chain as well as at the α1β2/α2β1 contact of the quaternary structure of the molecule. The presence of this Hb in the hemolysate causes an increased oxygen affinity, a slightly reduced Bohr effect and a reduced heme-heme interaction (n(50), Hill's constant) in comparison with those of Hb A.     

First detection of Hb Taybe [α38(C3) or α39(C4) Thr→0 (α1)] in an Italian child

Hb Taybe [α38(C3) or α39(C4) Thr→0 (α1)] is an unstable hemoglobin (Hb) variant caused by a deletion of a threonine residue at codon 39 of the α1-globin chain. Usually asymptomatic or with minimal hematological abnormalities in the heterozygous state, Hb Taybe becomes clinically evident in compound heterozygosity with α-thalassemia (α-thal) or in homozygous patients. To date, Hb Taybe has been described in Israeli-Arab and Greek individuals. We report, for the first time, a patient with chronic hemolytic anemia due to the presence of Hb Taybe in trans to the α2 initiation codon mutation ATG>ACG in an Italian child. Hb Taybe was not evident at Hb analysis with cellulose acetate electrophoresis and high performance liquid chromatography (HPLC). Globin biosynthetic studies revealed an α/β-globin ratio in the range of β-thal trait. Consequently, an investigation of the α- and β-globin genes was requested in order to avoid missing any rare globin chain variant and to offer accurate genetic counseling.     

Left-handedness is statistically linked to lifetime experimentation with illicit drugs

Handedness has been linked to an enhanced risk of alcohol abuse, while less is known about other drugs. A convenience sample of 1004 male and female Italian participants (females=58%) from the general community (18 to 65 years old: average age = 30; standard deviation = 10, median = 25) was asked about: handedness (preference in writing); lifetime use of alcohol, tobacco, and illicit drugs; levels of psychological distress, as measured by the General Health Questionnaire (GHQ); and levels of delusion proneness, as measured by the Peters et al. Delusions Inventory (PDI). Overall, 92 individuals (9.2%) were classified as left-handed, with no significant difference reported among genders. Lifetime use of illicit drugs, primarily cannabis, was reported by 20% of the sample. In a multiple logistic regression analysis, after taking into account sex, age, and caseness on GHQ and PDI, left-handed people in the sample were statistically more likely to report lifetime experimentation with heroin, ecstasy/amphetamine, and, marginally, hallucinogens, but not alcohol or tobacco. Different mechanisms might contribute to an explanation of greater lifetime experimentation with some illicit drugs among left-handed people as compared to right-handed people. However, replications with clinical samples are necessary before any definitive statements can be made.     

Psychiatric screening for migraine patients

Psychiatric disorders in migraine patients have a higher prevalence than general population. The presence of psychiatric comorbidities may influence the complexity of the migraine pictures and be related to medication overuse. Severely impaired chronic migraineurs presenting with medication overuse are a challenge for headache clinics. Psychiatric comorbities, such as dependency-like behaviors, anxiety and mood symptoms, might account for headache-related disability and recurrent relapses into medication overuse after a successful detoxification. Within a sample of 63 chronic migraineurs with medication overuse and severe disability, we investigated to which extent clinical severity, affective states and attitudes about medication impact the overall functioning at time of detoxification. To unravel whether some of these factors could predict their long-term outcome, we followed and retest them 1 year after withdrawal. We hypothesized that the detoxification would have led to a partial improvement and not modified the attitudes toward medication and dependence. Detoxification improves most of the clinical and affective measures, but does not free from significant levels of pain intensity and headache-related disability. The partial benefit from detoxification, the severity bias and the maladaptive cognitive profile led us to believe that subgroups of chronic-relapsing migraineurs deserve a multidisciplinary approach that addresses not only the reduction of clinical severity but also specific cognitive and behavioral impairments.