Central effects of galcanezumab in migraine: a pilot study on Steady State Visual Evoked Potentials and occipital hemodynamic response in migraine patients

BackgroundThe discovery of the prominent action of Calcitonin Gene Related Peptide –CGRP- on trigeminal afferents and meningeal vessels, opened a new era in migraine treatment. However, how the block of nociceptive afferents could act on central mechanisms of migraine is still not clear. In this pilot study we aimed to test the effect of 3 months Galcanezumab (CGA) therapy on occipital visual reactivity in migraine patients, using the Steady State Visual Evoked Potentials-SSVEPs and Functional Near Infrared Spectroscopy –fNIRS.MethodThirteen migraine patients underwent clinical and neurophysiological examination in basal condition (T0), 1 h after GCA injection (T1) and after 3 months of GCA treatment (T2). Ten healthy volunteers were also evaluated.ResultsAt T2, there was a reduction of headache frequency and disability. At T2, the EEG power significantly diminished as compared to T0 and T1 at occipital sites, and the topographical analysis confirmed a restoration of SSVEPs within normal values. The Oxyhemoglobin levels in occipital cortex, which were basically increased during visual stimulation in migraine patients, reverted to normal values at T2.ConclusionsThe present pilot study indicates that Galcanezumab could act on cortical targets located beyond the pain network, restoring the abnormal occipital reactivity. This effect could indicate the possible disease modifying properties of CGRP related monoclonal antibodies.     

Are Diabetes,Hypertension, and Obesity Independent Risk Factors for Endometrial Polyps?

Study ObjectiveTo investigate whether diabetes, hypertension (HTN), and obesity can be considered risk factors for endometrial polyps (EPs) independently of age and menopausal status.DesignRetrospective analysis (Canadian Task Force classification III).SettingDepartment of Obstetrics and Gynecology of the University of Foggia, Italy.PatientsA total of 353 Caucasian women undergoing office hysteroscopy to assess abnormal uterine bleeding, infertility, cervical polyps, and abnormal sonographic patterns.InterventionsDemographic characteristics and data on diabetes, HTN, and menopausal status were collected and anthropometric parameters were analyzed. Vaginoscopic hysteroscopy was performed with a 5-mm continuous-flow operative office hysteroscope. When present, EPs were treated during the same procedure by means of 5-Fr scissors or electrode.Measurements and Main ResultsIn 134 (38%) of 353 cases, EPs were found. Univariable and multivariable analysis were performed to verify the presence of a statistically significant association among age, menopause, HTN, obesity, diabetes (independent variables), and the presence of EPs. Univariable logistic analysis showed a statistically significant association among age, menopause, HTN, obesity, and the presence of EPs. However, when multivariable logistic regression was performed, all the independent variables, except age, lost statistical significance (OR 1.05, 95% CI 1.02–1.07, p <.001).ConclusionAlthough it appears that EP is a disorder of aging, the significance of diabetes, HTN, and obesity, as well as menopause, on the development of EPs should be reconsidered.     

Cluster Randomized Trial of Text Message Reminders to Retail Staff in Tanzanian Drug Shops Dispensing Artemether-Lumefantrine: Effect on Dispenser Knowledge and Patient Adherence

Artemisinin combination therapies are available in private outlets, but patient adherence might be compromised by poor advice from dispensers. In this cluster randomized trial in drug shops in Tanzania, 42 of 82 selected shops were randomized to receive text message reminders about what advice to provide when dispensing artemether-lumefantrine (AL). Eligible patients purchasing AL at shops in both arms were followed up at home and questioned about each dose taken. Dispensers were interviewed regarding knowledge of AL dispensing practices and receipt of the malaria-related text messages. We interviewed 904 patients and 110 dispensers from 77 shops. Although there was some improvement in dispenser knowledge, there was no difference between arms in adherence measured as completion of all doses (intervention 68.3%, control 69.8%, p [adjusted] = 0.6), or as completion of each dose at the correct time (intervention 33.1%, control 32.6%, p [adjusted] = 0.9). Further studies on the potential of text messages to improve adherence are needed.     

Time use clusters of New Zealand adolescents are associated with weight status,diet and ethnicity

Objective : To describe New Zealand adolescent time use clusters and correlate cluster profiles. Methods : Data were from the cross‐sectional 2008/2009 National Survey of Children and Young People's Physical Activity and Dietary Behaviours, which surveyed a random sample of 10–16 year‐old New Zealanders (study subset n=679). Time use data were collected using the Multimedia Activity Recall for Children and Adults, and collapsed into 17 age‐adjusted variables for sex‐specific cluster analysis. Cluster associations with socio‐demographic, anthropometric, physical activity and dietary variables were analysed. Results : Three time use clusters were discovered for both boys and girls. For boys, the Techno‐active cluster was characterised by high levels of team sports and TV; the Quiet movers cluster by transport (active and passive) and quiet time; and the Social studious cluster by reading, study activities and social interaction. The boys’ clusters were associated with ethnicity. The girls’Social sporty cluster was characterised by sports and social interaction; the Screenie tasker cluster by TV, computer, chores and work; and the Super studious cluster by reading, study and school‐based activities. The girls’ time use cluster membership was associated with weight status and serves of extra foods. Conclusions : Distinct sex‐specific time use clusters and correlate profiles exist among NZ adolescents. Implications : These findings may assist the development of targeted time use interventions to improve adolescent health and well‐being.     

Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy

PURPOSE: Denosumab, a fully human monoclonal antibody to RANKL, suppresses bone resorption. This study evaluated the effects of denosumab in i.v. bisphosphonate (IV BP)-na?ve patients with breast cancer-related bone metastases. EXPERIMENTAL DESIGN: Eligible women (n = 255), stratified by type of antineoplastic therapy, were randomized to 1 of 5 blinded denosumab cohorts or an open-label IV BP cohort. Denosumab was administered s.c. every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg) through 21 weeks. Final efficacy results for up to 25 weeks are reported, including percentage change from baseline in urine N-telopeptide corrected for creatinine (uNTx/Cr) and incidence of skeletal-related events (SRE). Safety results are reported through the end of follow-up (up to 57 weeks). RESULTS: At week 13 and 25, the median percent changes in uNTx/creatinine (Cr) among patients with measurable uNTx were -73% and -75% for the pooled denosumab groups and -79% and -71% for the IV BP group. Among patients with > or =1 postbaseline measurement of uNTx at week 25, 52% (109 of 208) of denosumab-treated patients and 46% (19 of 41) of IV BP-treated patients achieved >65% uNTx/Cr reduction. On-study SREs occurred in 12% (26 of 211) of denosumab-treated patients and 16% (7 of 43) of IV BP-treated patients. Overall rates of adverse events were 95% in denosumab and IV BP groups. No denosumab-related serious or fatal adverse events occurred. CONCLUSIONS: In IV BP-na?ve breast cancer patients with bone metastases, denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs, with a safety profile consistent with an advanced cancer population receiving systemic therapy.     

Effects of the venom and the dermonecrotic toxin LiRecDT1 of Loxosceles intermedia in the rat liver

Brown spider bites cause dermonecrotic lesions and systemic manifestations known as loxoscelism. The Loxosceles intermedia venom contains many active proteins, as phospholipase D. There are reports of increased levels of hepatic transaminases in humans with loxoscelism, but detailed studies about the action of the Loxosceles intermedia venom on the liver functions are lacking. The aim of this study was to investigate the effects of the venom and the dermonecrotic recombinant toxin 1 (LiRecDT1) in the liver of Wistar rats injected subcutaneously with venom (80 μg) or toxin (80 μg). After 6 and 12 h the liver immunofluorescence was positive for venom and toxin. Hepatocytes from the venom group were tumefacted and apoptotic. There was leucocyte infiltration in the portal region combined with a high degree of steatosis in 12 h. In the toxin group the histological alterations were less severe. Plasma levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyl-transferase were significantly elevated only in the venom group in 6 h. Hepatic metabolism was modified: the venom, but not LiRecDT1, reduced gluconeogenesis and ureagenesis from alanine and glycogen accumulation. These results show that the venom is hepatotoxic and that the dermonecrotic toxin is only partly responsible.     

Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men

BACKGROUND: Prostate cancer is a significant public health problem in this country. Substantial data support a plausible role for androgens in the etiology of this disease. The human HSD17B3 gene encodes the testicular (or type III) 17 beta-hydroxysteroid dehydrogenase enzyme, which catalyzes testosterone biosynthesis in men. METHODS: We have investigated the G289S (glycine at codon 289 replaced by serine) polymorphism at the HSD17B3 locus as a candidate single nucleotide polymorphism (SNP) for prostate cancer risk in constitutional DNA from 103 Italian prostate cancer patients and 109 Italian disease-free centenarians to assess the role of this SNP in susceptibility to prostate cancer. RESULTS: The G289S polymorphism confers a significant increase in risk for prostate cancer (odds ratio = 2.5; 95% confidence interval, 1.03-6.07) in our study population. CONCLUSION: Our data are consistent with a plausible role of the G289S SNP in prostate cancer susceptibility. Therefore, the HSD17B3 gene may be a plausible candidate gene for prostate cancer risk.     

Modulation of dendritic release of dopamine by metabotropic glutamate receptors in rat substantia nigra

A superfusion system was used to study the effects of metabotropic glutamate receptor (mGluR) ligands upon the release of [(3)H]dopamine ([(3)H]DA) previously taken up by rat substantia nigra (SN) slices. trans-(+/-)-1-Amino-(1S,3R)-cyclopentane dicarboxylic acid (trans-ACPD; 100 and 600 microM), a group I and II mGluR agonist, evoked the release of [(3)H]DA from nigral slices. This last effect was reduced significantly by (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)-glycine (MCCG; 300 microM), an antagonist of group II mGluR, or by the addition of tetrodotoxin (D-APV; 1 microM) to the superfusion medium. D-(-)-2-Amino-5-phosphono-valeric acid (100 microM), an N-methyl-D-aspartate receptor antagonist, or the presence of Mg(2+) (1.2mM) in the superfusion medium did not modify trans-ACPD-induced [(3)H]DA release. In addition, a group II mGluR agonist such as (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG-IV; 100 microM) significantly induced the release of [(3)H]DA from nigral slices, whereas a group I mGluR agonist such as (RS)-3,5-dihydroxyphenylglycine (DHPG; 50 and 100 microM) did not modify the release of the [(3)H]-amine. Further experiments showed that the NMDA (100 microM)-evoked release of [(3)H]DA was decreased significantly by prior exposure of SN slices to trans-ACPD. Finally, partial denervation of the DA nigro-striatal pathway with 6-hydroxydopamine (6-OH-DA) increased trans-ACPD-induced release of [(3)H]DA, whereas it decreased trans-ACPD inhibitory effects on NMDA-evoked release of [(3)H]DA from nigral slices. The present results suggest that the dendritic release of DA in the SN is regulated by mGluR activation. Such nigral mGluR activation may produce opposite effects upon basal and NMDA-evoked release of DA in the SN. In addition, such mGluR-induced effects in the SN are modified in response to partial denervation of the DA nigro-striatal pathway.     

Long-term antidepressant treatment

Major depressive disorder (MDD) is a common and costly illness. Recent research suggests that MDD is a lifelong condition for many patients. This has stimulated researchers to identify risk factors associated with an increased frequency of relapse and recurrence of major depression. One of the most important of these risk factors is an incomplete response to acute treatment. These data have led investigators to pursue techniques that enhance the acute response of patients to therapy, and study whether long-term treatment with antidepressants may prevent relapse and recurrence of MDD. Data from these trials suggest that continuation and maintenance treatment of MDD confers some protection against deteriorating back into an episode after acute treatment and against developing another episode of MDD.