A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State

OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542

Regulated Nuclear Trafficking of rpL10A Mediated by NIK1 Represents a Defense Strategy of Plant Cells against Virus

The NSP-interacting kinase (NIK) receptor-mediated defense pathway has been identified recently as a virulence target of the geminivirus nuclear shuttle protein (NSP). However, the NIK1–NSP interaction does not fit into the elicitor–receptor model of resistance, and hence the molecular mechanism that links this antiviral response to receptor activation remains obscure. Here, we identified a ribosomal protein, rpL10A, as a specific partner and substrate of NIK1 that functions as an immediate downstream effector of NIK1-mediated response. Phosphorylation of cytosolic rpL10A by NIK1 redirects the protein to the nucleus where it may act to modulate viral infection. While ectopic expression of normal NIK1 or a hyperactive NIK1 mutant promotes the accumulation of phosphorylated rpL10A within the nuclei, an inactive NIK1 mutant fails to redirect the protein to the nuclei of co-transfected cells. Likewise, a mutant rpL10A defective for NIK1 phosphorylation is not redirected to the nucleus. Furthermore, loss of rpL10A function enhances susceptibility to geminivirus infection, resembling the phenotype of nik1 null alleles. We also provide evidence that geminivirus infection directly interferes with NIK1-mediated nuclear relocalization of rpL10A as a counterdefensive measure. However, the NIK1-mediated defense signaling neither activates RNA silencing nor promotes a hypersensitive response but inhibits plant growth and development. Although the virulence function of the particular geminivirus NSP studied here overcomes this layer of defense in Arabidopsis, the NIK1-mediated signaling response may be involved in restricting the host range of other viruses

A Randomized Controlled Study of Parent-assisted Children’s Friendship Training with Children having Autism Spectrum Disorders

This study evaluated Children’s Friendship Training (CFT), a manualized parent-assisted intervention to improve social skills among second to fifth grade children with autism spectrum disorders. Comparison was made with a delayed treatment control group (DTC). Targeted skills included conversational skills, peer entry skills, developing friendship networks, good sportsmanship, good host behavior during play dates, and handling teasing. At post-testing, the CFT group was superior to the DTC group on parent measures of social skill and play date behavior, and child measures of popularity and loneliness, At 3-month follow-up, parent measures showed significant improvement from baseline. Post-hoc analysis indicated more than 87% of children receiving CFT showed reliable change on at least one measure at post-test and 66.7% after 3 months follow-up

Assessing Africa-Wide Pangolin Exploitation by Scaling Local Data

Overexploitation is one of the main pressures driving wildlife closer to extinction, yet broad-scale data to evaluate species' declines are limited. Using African pangolins (Family: Pholidota) as a case study, we demonstrate that collating local-scale data can provide crucial information on regional trends in exploitation of threatened species to inform conservation actions and policy. We estimate that 0.4-2.7 million pangolins are hunted annually in Central African forests. The number of pangolins hunted has increased by ∼150% and the proportion of pangolins of all vertebrates hunted increased from 0.04% to 1.83% over the past four decades. However, there were no trends in pangolins observed at markets, suggesting use of alternative supply chains. The price of giant (Smutsia gigantea) and arboreal (Phataginus sp.) pangolins in urban markets has increased 5.8 and 2.3 times respectively, mirroring trends in Asian pangolins. Efforts and resources are needed to increase law enforcement and population monitoring, and investigate linkages between subsistence hunting and illegal wildlife trade

Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

Treatment-Resistant Depression Revisited: A Glimmer of Hope

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically

Citalopram for Acute and Preventive Efficacy in Bipolar Depression (CAPE-BD): A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE: To assess the efficacy and safety of citalopram in the acute and maintenance phases of bipolar depression in a randomized, double-blind, placebo-controlled trial.METHODS: Between 2007 and 2014, 119 subjects with acute major depressive episodes diagnosed with DSM-IV bipolar disorder, type I or type II, were randomized blindly to citalopram or placebo, added to standard mood stabilizers. They were followed for 6 weeks for acute efficacy (primary outcome) and up to 1 year for maintenance efficacy (secondary outcome) using scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Mania Rating Scale of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). The study was powered for a clinically meaningful effect size.RESULTS: Mean \ub1 SD MADRS scores changed from a baseline value of 27.4 \ub1 9.1 to 13.1 \ub1 8.4 at the end of the acute phase for citalopram versus a change from 27.4 \ub1 7.3 to 15.2 \ub1 9.9 for placebo, a clinically and statistically nonsignificant difference. Maintenance efficacy also was not better with citalopram than with placebo. Acute manic/hypomanic episodes were similar in both groups, and subjects with type II illness did not have better outcomes than subjects with type I illness. In maintenance treatment, MRS-SADS scores were greater overall, especially in subjects with a rapid-cycling illness course, with citalopram versus placebo.CONCLUSIONS: Citalopram, added to standard mood stabilizers, did not have clinically meaningful benefit versus placebo for either acute or maintenance treatment of bipolar depression. Acute mania did not worsen with citalopram, but maintenance treatment led to worsened manic symptoms, especially in subjects with a rapid-cycling course.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00562861

Long-term worsening of bipolar disorder related with frequency of antidepressant exposure

BACKGROUND: The aim of this study of 53 persons with bipolar disorder (BD) was to evaluate the relationship between history of exposure to antidepressants (AD) and mood stabilizers (MS) and the percentage of time spent ill. METHODS: BD outpatients with more than 12 months of prospective follow- up were included. Outcome was documented using a life charting technique. Current and previous exposure to AD and MS were assessed using a scale that provides a quantitative measure of exposure to psychotropic medications. Regression models were used to correct for possible confounders. RESULTS: Previous treatment with AD was an independent predictor of polarity changes (P < .001) and mixed symptoms (P = .01). In contrast, “years of exposure to MS” was an independent predictor of time spent asymptomatic (P = .019). The ratio between exposure to AD vs MS was associated with less weeks asymptomatic (P = .03), more mixed symptomatology (P = .019), and more polarity changes (P = .001). CONCLUSIONS: Antidepressant exposure was a major predictor of mood instability in the long-term outcome of BD. The ratio used of previous exposure to AD vs MS was associated with poor outcomes, suggesting that the harmful effect of AD may be additive and related to how much they are used.Fil: Strejilevich, Sergio. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Marengo, Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Igoa, Ana. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Fassi, Guillermo. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Whitham, Elizabeth A.. Tufts Medical Center; Estados UnidosFil: Ghaemi, S. Nassir. Tufts Medical Center; Estados Unido