Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response

Background: Selective serotonin reuptake inhibitors take several weeks to achieve their full antidepressant effects. Post-synaptic 5-HT<sub>2A</sub> receptor activation is thought to be involved in this delayed therapeutic effect. Pipamperone acts as a highly selective 5-HT<sub>2A</sub>/D<sub>4</sub> antagonist when administered in low doses. The purpose of this study was to compare citalopram 40 mg once daily plus pipamperone 5 mg twice daily (PipCit) versus citalopram plus placebo twice daily for magnitude and onset of therapeutic effect. Method: An 8-week, randomized, double-blind study in patients with major depressive disorder was carried out. Results: The study population comprised 165 patients (citalopram and placebo, n=82; PipCit, n=83) with a mean baseline Montgomery–Asberg Depression Rating Scale (MADRS) score of 32.6 (S.D.=5.5). In the first 4 weeks, more citalopram and placebo than PipCit patients discontinued treatment (18% v. 4%, respectively, p=0.003). PipCit patients had significantly greater improvement in MADRS score at week 1 [observed cases (OC), p=0.021; last observation carried forward (LOCF), p=0.007] and week 4 (LOCF, p=0.025) but not at week 8 compared with citalopram and placebo patients. Significant differences in MADRS scores favoured PipCit in reduced sleep, reduced appetite, concentration difficulties and pessimistic thoughts. Mean Clinical Global Impression–Improvement scores were significantly improved after 1 week of PipCit compared with citalopram and placebo (OC and LOCF, p=0.002). Conclusions: Although the MADRS score from baseline to 8 weeks did not differ between groups, PipCit provided superior antidepressant effects and fewer discontinuations compared with citalopram and placebo during the first 4 weeks of treatment, especially in the first week

H+/K+ ATPase activity is required for biomineralization in sea urchin embryos

AbstractThe bioelectrical signatures associated with regeneration, wound healing, development, and cancer are changes in the polarization state of the cell that persist over long durations, and are mediated by ion channel activity. To identify physiologically relevant bioelectrical changes that occur during normal development of the sea urchin Lytechinus variegatus, we tested a range of ion channel inhibitors, and thereby identified SCH28080, a chemical inhibitor of the H+/K+ ATPase (HKA), as an inhibitor of skeletogenesis. In sea urchin embryos, the primary mesodermal lineage, the PMCs, produce biomineral in response to signals from the ectoderm. However, in SCH28080-treated embryos, aside from randomization of the left-right axis, the ectoderm is normally specified and differentiated, indicating that the block to skeletogenesis observed in SCH28080-treated embryos is PMC-specific. HKA inhibition did not interfere with PMC specification, and was sufficient to block continuing biomineralization when embryos were treated with SCH28080 after the initiation of skeletogenesis, indicating that HKA activity is continuously required during biomineralization. Ion concentrations and voltage potential were abnormal in the PMCs in SCH28080-treated embryos, suggesting that these bioelectrical abnormalities prevent biomineralization. Our results indicate that this effect is due to the inhibition of amorphous calcium carbonate precipitation within PMC vesicles

Whole genome sequencing reveals a 7 base-pair deletion in DMD exon 42 in a dog with muscular dystrophy

Dystrophin is a key cytoskeletal protein coded by the Duchenne muscular dystrophy (DMD) gene located on the X-chromosome. Truncating mutations in the DMD gene cause loss of dystrophin and the classical DMD clinical syndrome. Spontaneous DMD gene mutations and associated phenotypes occur in several other species. The mdx mouse model and the golden retriever muscular dystrophy (GRMD) canine model have been used extensively to study DMD disease pathogenesis and show efficacy and side effects of putative treatments. Certain DMD gene mutations in high-risk, the so-called hot spot areas can be particularly helpful in modeling molecular therapies. Identification of specific mutations has been greatly enhanced by new genomic methods. Whole genome, next generation sequencing (WGS) has been recently used to define DMD patient mutations, but has not been used in dystrophic dogs. A dystrophin-deficient Cavalier King Charles Spaniel (CKCS) dog was evaluated at the functional, histopathological, biochemical, and molecular level. The affected dog’s phenotype was compared to the previously reported canine dystrophinopathies. WGS was then used to detect a 7 base pair deletion in DMD exon 42 (c.6051-6057delTCTCAAT mRNA), predicting a frameshift in gene transcription and truncation of dystrophin protein translation. The deletion was confirmed with conventional PCR and Sanger sequencing. This mutation is in a secondary DMD gene hotspot area distinct from the one identified earlier at the 5′ donor splice site of intron 50 in the CKCS breed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00335-016-9675-2) contains supplementary material, which is available to authorized users

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

Junkie love : romance and addiction on the big screen

This article investigates the filmic construction of two disparate but intertwining cultural practices: those engaging in the life-affirming rituals of romantic love and those performing the potentially self-destructive rituals of hard drug consumption. Discussing a number of key feature films from the (mini) genre “junkie love”, it aims to show what happens when elements of mainstream romantic drama merge with the horror conventions of the heroin addiction film. Drawing amongst others on Murray Smith’s theory of “levels of [spectator] engagement” and Greg Smith’s concept of the “emotion system”, the article concludes that junkie love films, using tropes of the romantic tragedy in the tradition of Romeo and Juliet, present a more complex and nuanced approach to drug addicts than the predominantly condemnatory media coverage—one that arguably invites the spectator’s understanding and compassion

Military business and the business of the military

Contrary to dominant approaches that locate the causes for military entrepreneurialism in eastern Democratic Republic of the Congo predominantly in criminal military elites, this article highlights the importance of the Congolese military’s (FARDC) civilian context for understanding military revenue-generation. It analyses how the latter is shaped by structures of domination, signification and legitimisation that drive and are driven by the FARDC’s governance, private protection and security practices. It argues that these practices contribute to bestowing a degree of legitimacy on both the FARDC’s position of power and some of its revenue-generation activities. Furthermore, by emphasising that the FARDC’s regulatory and protection practices are partly the product of popular demands and the routine actions of civilians, the article contends that the causes of military revenue-generation are co-located in the military’s civilian environment. In this manner, it offers a more nuanced conceptualisation of military entrepreneurialism, thus opening up new perspectives on policy interventions in this area

Specific phobia predicts psychopathology in young women

Contains fulltext : 90255.pdf (publisher's version ) (Closed access)Although specific phobia is characterized by an early age at onset and by high rates of comorbidity, few studies have examined comorbid relationships prospectively. The present study investigated the association between specific phobia and the risk of a broad range of psychopathology among young women in the community. Data came from the Dresden Predictor Study in which 1,538 German women (18-25 years) completed a diagnostic interview at two time points. Women with specific phobia had a twofold increase in odds of developing any anxiety disorder, generalized anxiety disorder, depression, and any somatoform disorder during 17 months, compared to women without specific phobia. Except for depression, these associations persisted after adjustment for all comorbid mental disorders. Specific phobia thus appears to be a risk factor for a variety of problems. The result further underpins the necessity for early intervention for specific phobia to prevent later mental health problems

Magnetic resonance imaging for the differentiation of neoplastic, inflammatory, and cerebrovascular brain disease in dogs

BACKGROUND: The reliability and validity of magnetic resonance imaging (MRI) for detecting neoplastic, inflammatory, and cerebrovascular brain lesions in dogs are unknown. OBJECTIVES: To estimate sensitivity, specificity, and inter-rater agreement of MRI for classifying histologically confirmed neoplastic, inflammatory, and cerebrovascular brain disease in dogs. ANIMALS: One hundred and twenty-one client-owned dogs diagnosed with brain disease (n = 77) or idiopathic epilepsy (n = 44). METHODS: Retrospective, multi-institutional case series; 3 investigators analyzed MR images for the presence of a brain lesion with and without knowledge of case clinical data. Investigators recorded most likely etiologic category (neoplastic, inflammatory, cerebrovascular) and most likely specific disease for all brain lesions. Sensitivity, specificity, and inter-rater agreement were calculated to estimate diagnostic performance. RESULTS: MRI was 94.4% sensitive (95% confidence interval [CI] = 88.7, 97.4) and 95.5% specific (95% CI = 89.9, 98.1) for detecting a brain lesion with similarly high performance for classifying neoplastic and inflammatory disease, but was only 38.9% sensitive for classifying cerebrovascular disease (95% CI = 16.1, 67.0). In general, high specificity but not sensitivity was retained for MR diagnosis of specific brain diseases. Inter-rater agreement was very good for overall detection of structural brain lesions (j = 0.895, 95% CI = 0.792, 0.998, P < .001) and neoplastic lesions, but was only fair for cerebrovascular lesions (j = 0.299, 95% CI = 0, 0.761, P = .21). CONCLUSIONS AND CLINICAL IMPORTANCE: MRI is sensitive and specific for identifying brain lesions and classifying disease as inflammatory or neoplastic in dogs. Cerebrovascular disease in general and specific inflammatory, neoplastic, and cerebrovascular brain diseases were frequently misclassified.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1939-1676ab201