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

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

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

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

Standardisation framework for the Maudsley staging method for treatment resistance in depression

Background: Treatment-resistant depression (TRD) is a serious and relatively common clinical condition. Lack of consensus on defining and staging TRD remains one of the main barriers to understanding TRD and approaches to intervention. The Maudsley Staging Method (MSM) is the first multidimensional model developed to define and stage treatment-resistance in “unipolar depression”. The model is being used increasingly in treatment and epidemiological studies of TRD and has the potential to support consensus. Yet, standardised methods for rating the MSM have not been described adequately. The aim of this report is to present standardised approaches for rating or completing the MSM. Method: Based on the initial development of the MSM and a narrative review of the literature, the developers of the MSM provide explicit guidance on how the three dimensions of the MSM–treatment failure, severity of depressive episode and duration of depressive episode– may be rated. Result: The core dimension of the MSM, treatment failure, may be assessed using the Maudsley Treatment Inventory (MTI), a new method developed for the purposes of completing the MSM. The MTI consists of a relatively comprehensive list of medications with options for rating doses and provisions treatment for multiple episodes. The second dimension, severity of symptoms, may be assessed using simple instruments such as the Clinical Global Impression, the Psychiatric Status Rating or checklist from a standard diagnostic checklist. The standardisation also provides a simple rating scale for scoring the third dimension, duration of depressive episode. Conclusion: The approaches provided should have clinical and research utility in staging TRD. However, in proposing this model, we are fully cognisant that until the pathophysiology of depression is better understood, staging methods can only be tentative approximations. Future developments should attempt to incorporate other biological/ pathophysiological dimensions for staging

The Lack of ADAM17 Activity during Embryonic Development Causes Hemorrhage and Impairs Vessel Formation

Background: ADAM17/TACE activity is important during embryonic development. We wished to investigate possible roles of this metalloprotease, focusing on vascular development. Methodology/Principal Findings: Mice mutant in the enzymatic activity of ADAM17 were examined at various stages of embryonic development for vascular pattern and integrity using markers for vessel wall cells. We observed hemorrhage and edema starting at embryonic day E14.5 and becoming more severe as development proceeded; prior to embryonic day E14.5, embryos appeared normal. Staining for PECAM-1/CD31 revealed abnormalities in the patterns of branching of the embryonic vasculature at E14.5. Conclusions/Significance: These abnormalities preceded association of pericytes or monocyte/macrophage cells with the affected vessels and, therefore, presumably arise from defects in endothelial function consequent upon failure of ADAM17 to cleave one or more substrates involved in vascular development, such as Notch, Delta, VEGFR2 or JAM-A. Our study demonstrates a role for ADAM17 in modulating embryonic vessel development and function

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

A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression

Background Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. Methods We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients’ treatment assignments. Results Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and the psychotherapy group, as compared with 73 percent in the combined-treatment group (P Conclusions Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone