Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite

Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.     

Economic evaluation of Zepatier for the management of HCV in the Italian scenario

Background

Hepatitis C virus (HCV) is a major health issue worldwide. New generation of direct-active antiviral medications is an epoch-making turning point in the management of HCV infections.

Objective

Conducing a cost-effectiveness analysis comparing the combination of elbasvir/grazoprevir and sofosbuvir?+?pegylated interferon/ribavirin for the management of all HCV patients (even those in the initial stages of fibrosis).

Methods

A Markov model was built on the natural history of the disease to assess the efficacy of the alternatives. The outcomes are expressed in terms of quality adjusted life-years (QALYs) and result in terms of incremental cost-effectiveness ratio).

Results

Elbasvir/grazoprevir implies an expenditure of €21,104,253.74 with a gain of 19,287.90 QALYs and sofosbuvir?+?pegylated interferon/ribavirin implies an expenditure of €31,904,410.11 with a gain of 18,855.96 QALYs. Elbasvir/grazoprevir is thus a dominant strategy.

Conclusion

Consideration should be given to the opportunity cost of not treating patients with a lower degree of fibrosis (F0–F2).

     

Effects of calcitonin gene-related peptide on extrapyramidal motor system.

The effects of central administration of calcitonin gene-related peptide (CGRP, 1 or 100 ng/rat) on behavioral and biochemical parameters related to the extrapyramidal motor system were investigated in male rats. The peptide-induced catalepsy occurred only at the dose of 100 ng/rat and hypomotility at both doses used. Calcitonin gene-related peptide increased haloperidol-induced catalepsy and decreased apomorphine-induced hypermotility at the doses of 1 and 100 ng/rat. Although these behaviors are related to dopamine, no significant change of striatal DA or DOPAC concentration were observed after central administration of the peptide. Other neurotransmitters may be directly or indirectly involved in these behavioral effects of CGRP.     

Comparison of the effects of fluticasone propionate, aqueous nasal spray and levocabastine on inflammatory cells in nasal lavage and clinical activity during the pollen season in seasonal rhinitics

BACKGROUND: Treatment options for allergic rhinitis include antihistamines, decongestants, anticholinergics, cromolyn sodium and corticosteroids. As the nose is a small organ, comprising less than 1% of total body mass and surface area, it seems logical to confine treatment of rhinitis to the diseased organ. OBJECTIVE: To evaluate the effects of therapy with intranasal fluticasone propionate (FP), both on subjective symptoms and pathophysiological mechanisms, in rhinitis patients during pollen season when the patients were symptomatic. METHODS: We used a double-blind, placebo (PLA)-controlled, randomized, double dummy, parallel group study of the effect of 6 weeks treatment. The double-blind comparison was made between the following three treatments: FP aqueous nasal spray, 200 microg taken once daily, levocabastine (LEV) nasal spray, 200 microg taken twice daily and PLA nasal spray. Clinical evaluation and the levels of cells and mediators in nasal washing were performed before and after treatments. Twenty-four patients (11 men and 13 women, aged 17-50 years, mean age 30.1 +/- 8.5) with strictly seasonal allergic rhinitis to Parietaria entered the study. Clinical evaluation and the levels of inflammatory cells (eosinophils and activated eosinophils, i.e. EG2+) and their mediators (tryptase, eosinophil cationic protein, eosinophil protein X and neutrophil myeloperoxidase) in nasal-lavage were performed before and after treatments. RESULTS: Treatment with FP significantly increased, with respect to placebo, the percentage of days without sneezing (P < 0. 001), nasal blockage (P < 0.001), rhinorrhea (P < 0.001), nasal itching (P < 0.001). Furthermore, treatment with FP showed additional benefits with respect to LEV. The percentage of days without nasal blockage was significantly higher in the FP group that in the placebo group (P = 0.018). The same applied to rhinorrhea (P = 0.009). The percentages of days without sneezing and itching were instead not significantly different between the two groups. As expected, no significant differences were observed in baseline medians of the rhinitis symptom scores as well as in mean values of all mediators and eosinophils in nasal lavages of the various groups under study. After treatment the mean of subjective symptoms as well as all values in nasal lavage level fell significantly only in the FP group, whereas no significant changes were observed either in LEV or PLA groups. Accordingly, significant differences were observed at the end of the treatments between the values of fluticasone group vs LEV and PLA group values. Significant correlations between these values and symptom scores were found, according with literature data suggesting a pathogenetic role for these mediators and eosinophils in rhinitis. CONCLUSION: FP (200 microg once daily) affords a significant degree of improvement in rhinitis control during pollen season, as measured by subjective and objective parameters, compared with LEV (200 microg twice daily) and PLA. The therapeutic benefits of intranasal FP are reflected in, and may be caused by, the decrease in nasal inflammatory cells.     

Effects of TRH-T on spinal motoneurones in man.

The effect of thyrotropin-releasing hormone tartrate (TRH-T) on the decrease in H Max/M Max ratio, an index of the spinal motoneurone pool, induced by haloperidol, was studied in 15 healthy volunteers. In all subjects, the H response was examined by an electromyographic apparatus. The values were expressed as H Max/M Max ratio, that gives an index of excitability of the spinal motoneurone pool. It was found that the mean H Max/M Max ratio value significantly decreased after haloperidol administration, but this effect was completely reversed by the injection of TRH-T. This finding suggests that the peptide may modulate motoneurone functions.     

Pharmacokinetics and bioavailability of a Ginkgo biloba extract.

The aim of the present study was to assess the bioavailability of the main active ingredient in Ginkgo biloba extract, ginkgolid B. The study also focused on the pharmacokinetics of two different dosage regimens for orally administered Gingko biloba extract, 80 mg once daily and 40 mg twice daily for 7 days. Twelve healthy volunteers took part in the study. They were randomly assigned to one of the two treatment groups: 40 mg twice daily or 80 mg once daily, with an interval of 21 days between cycles. Statistical analysis was used to assess the main pharmacokinetic parameters. The results show that a dosage of 40 mg twice daily (every 12 hrs) is accompanied by a significantly longer half-life (t1/2) and mean residence time (MRT) than a single 80 mg dose, even though the latter causes a higher concentration peak (Cmax). The maximum concentration time (Tmax) is 2.3 hrs after administration in both treatments.     

An ambulatory persistence power curve: Motor planning affects ambulatory persistence in Parkinson's disease

Background/objectives: When performing activity associated with walking, the amount of walking a person does often will depend on their plans. This study was designed to evaluate the relationship between motor planning and ambulatory persistence in participants with Parkinson's disease (PD) and to see if ambulatory persistence was related to the ability to perform activities of daily living (ADL). Methods: 20 individuals with idiopathic PD were recruited to perform the Trail making Test (a test of motor planning) and to wear a step activity monitor for 48 h. The measurement of persistence of an ambulatory event consisted of the number of steps taken during an event and an ambulatory event was defined as continuous ambulation (taking step) without pausing for 3 or more seconds. The resumption of taking step (ambulation) after 3 or more seconds counted as a new ambulatory event. UPDRS-motor and ADL scale were also obtained. Analysis and results: The cumulative percentage of the total ambulatory events at each number of steps was plotted for each subject which when plotted could be described as a sigmoid curve. We found that this sigmoidal curve defined by the equation y = xⁿ/(kⁿ + xⁿ), fit the data well, where k represents a constant specific to each subject, x represents the number of steps during each ambulatory event, and y represents the projected percentage of movement events containing x number of steps or less. (Root Mean Square Error (RMSE) = 0.02, R² = 0.98). Trail making test part A was highly associated with the constant k (R = −0.74, p < 0.001). The constant k was also highly associated with the UPDRS ADL subscale (R = −0.81, p = 0.0001). A forward bivariate regression model including Part A of the Trail making test, and the UPDRS-ADL subscale predicted 66% of the variability of the constant k. The overall number of steps taken per day, and the UPDRS motor subscale did not contribute to the model. Conclusions: Defective motor planning in Parkinson's disease as measured by poor performance on a Trail making test is associated with a measurable alteration in ambulatory persistence, and altered ambulatory persistence, quantified by our proposed model parameter, correlates highly with the UPDRS ADL score. Thus, cognitive-motor planning defects might be a major source of disability in PD. We suggest that in future clinical practice gait tests can be used in order to quantify short-term planning ability in neurodegenerative diseases.     

Hematopoetic stem cell bank at Zagreb University Hospital Center, Zagreb, Croatia

At Zagreb University Hospital Center, the first cryopreservation of hematopoietic stem cells (HSC) was performed in 1989 at Department of Hematology. Since that time, more than 1000 products of HSC have been stored for autologous and related homologous use. In 2000, HSC Bank became organizational unit of the Department of Transfusion Medicine. The purpose of the Bank is to ensure quality in procurement, testing, processing, preservation, storage and distribution of HSC as well as transplantation traceability. Today, it serves as a central storage unit for two transplantation centers. At the moment, there are 587 HSC units on stock for 262 patients. In the future, we are planning to establish a public umbilical cord bank and laboratory for cell therapy.     

Influence of inulin on plasma isoflavone concentrations in healthy postmenopausal women

BACKGROUND: Bacterial intestinal glucosidases exert an important role in isoflavone absorption. Insoluble dietary fibers such as inulin may stimulate the growth of these bacteria in the colon and, hence, stimulate the absorption of these substances in subjects who may need isoflavone supplementation. OBJECTIVE: The objective was to assess the influence of inulin on plasma isoflavone concentrations after intake of soybean isoflavones in healthy postmenopausal women. DESIGN: Twelve healthy postmenopausal women participated in a randomized, double-blind, crossover study. They consumed 40 mg of a conjugated form of soybean isoflavones (6 mg daidzein and 18 mg genistein as free form) with or without 3.66 g inulin twice daily in two 21-d experimental phases. Blood samples were collected 0, 1, 2, 3, 4, 6, 10, 12, and 24 h after intake of isoflavones with breakfast and dinner at the end of each 21-d experimental phase. Plasma concentrations of isoflavones were assessed by HPLC with an electrochemical detector. RESULTS: Plasma 24-h areas under the curve indicated that the intake of soybean isoflavones with inulin for 21 d was followed by higher plasma concentrations of daidzein and genistein (38% and 91%, respectively) compared with the formulation without inulin. Furthermore, the time for the maximum concentration of daidzein and genistein appeared to be lower after the 21-d intake of soybean isoflavones, with or without inulin. However, the time for the maximum concentration of daidzein and genistein after supplementation with the inulin-containing formulation on day 21 was not significantly different from that after supplementation with the formulation without inulin. CONCLUSIONS: Inulin may increase the apparent plasma concentrations of the soybean isoflavones daidzein and genistein in postmenopausal women. The higher plasma concentrations of the 2 isoflavones suggests that the absorption of each was facilitated by the presence of inulin.