Developing the BALANCE trail--the role of the pilot study and start-up phase

Objectives:  The initial design of the BALANCE (Bipolar Affective disorder: Lithium / ANtiConvulsant Comparative Evaluation) Trial of maintenance treatment for bipolar disorder was based on the experience of previous trials in bipolar disorder and psychiatry and on the methods developed for large randomized trials in other areas of medicine. This report describes the adaptations to the initial design and trial procedures following the initial phases of the study. The rationale for the trial and full protocol have been published elsewhere.
Methods:  A pilot study and start-up phase were used to check the tolerability of the interventions, refine the trial design and develop trial procedures that are acceptable to both clinicians and patients.
Results:  Changes to the procedures included: the dropping of masking of allocated treatment from clinicians and participants; introduction of the use of postal delivery to supply medication; and dispensing with the proposed schedule of regular follow up appointments. In addition, support was made available to participating psychiatrists who often had limited experience of participating in randomized trials.
Conclusions:  Pilot studies and start-up phases are essential to refine clinical trial design and allow development of procedures that are both methodologically rigorous and flexible and robust enough to promote recruitment and follow up. BALANCE is now actively recruiting in the UK and USA.     

Quality of Life Improvement after Videothoracoscopic Splanchnicectomy in Chronic Pancreatitis Patients: Case Control Study

The authors report on the effectiveness of videothoracoscopic splanchnicectomy (VSPL) as a method of pain treatment in patients with chronic pancreatitis (CP). A minimally invasive technique, VSPL is used in CP as an alternative method of pain treatment. The aim of the investigation was to evaluate by a prospective, semirandomized case-control study the influence of VSPL on the quality of life and the level of pain suffered by patients with CP. The study groups consisted of 32 patients who underwent VSPL between March 2000 and January 2001 and a control group of 32 CP patients who received conservative treatment. The effect of the therapy on subjective pain measures and multiparametric quality of life was measured before VSPL and throughout the first year thereafter. In the follow-up period there was a significant decrease in intensity of pain and an improvement in the quality of life of the patients—most significantly concerning emotional well-being and functioning in everyday life. We conclude that the VSPL is a safe, effective, and minimally invasive procedure and recommend that it be used in such cases.     

The distal semimembranosus complex: normal MR anatomy,variants, biomechanics and pathology

OBJECTIVE: To describe the normal MR anatomy and variations of the distal semimembranosus tendinous arms and the posterior oblique ligament as seen in the three orthogonal planes, to review the biomechanics of this complex and to illustrate pathologic examples. RESULTS AND CONCLUSION: The distal semimembranosus tendon divides into five tendinous arms named the anterior, direct, capsular, inferior and the oblique popliteal ligament. These arms intertwine with the branches of the posterior oblique ligament in the posterior medial aspect of the knee, providing stability. This tendon-ligamentous complex also acts synergistically with the popliteus muscle and actively pulls the posterior horn of the medial meniscus during knee flexion. Pathologic conditions involving this complex include complete and partial tears, insertional tendinosis, avulsion fractures and bursitis.     

Grand-paternal age and the development of autism-like symptoms in mice progeny

Advanced paternal age (APA) contributes to the risk of autism spectrum disorders (ASDs) in children. In this study, we used a mouse model to investigate the effects of APA on behavioral features related to autistic syndromes (that is, social deficits, communication impairments and stereotypic/repetitive behaviors). We also examined whether such effects are transmitted across generations. To do this, males aged 15 months (APA) and 4 months (control) were bred with 4-month-old females, and the resulting offspring (F1) and their progeny (F2; conceived by 4-month-old parents) were tested for the presence and severity of ASD-like behaviors. Our results indicate that APA resulted in offspring that displayed distinctive symptoms of ASD. We found that both F1 conceived from old fathers and F2 derived from old grandfathers displayed increased ultrasound vocalization (USV) activity, decreased sociability, increased grooming activity and increased anxiety-like responses. Moreover, such abnormalities were partially transmitted to the second generation of mice, having APA grandfathers. In conclusion, our study suggests that the risk of ASD could develop over generations, consistent with heritable mutations and/or epigenetic alterations associated with APA.     

Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease

The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial disease (PAD). VLTS-589 is an investigational nonviral therapeutic comprising a plasmid-expressing Del-1 formulated with poloxamer 188 (facilitating agent). One hundred subjects with bilateral PAD and IC will be randomized after careful screening to bilateral intramuscular delivery of VLTS-589 or placebo. A total of 84 mg of plasmid or placebo will be delivered as 42 intramuscular injections (2 ml per injection, 21 injections or 42 ml in each extremity of either plasmid or placebo) in both lower extremities. The subjects in the study will be followed at regular intervals for a year after study drug administration (days 30, 90, 180, and 365) with the primary endpoint being the safety and tolerability of VLTS-589 and change in peak walking time (PWT) at day 90. The secondary endpoints include percent and absolute change in resting ankle brachial Index, claudication onset time, and quality of life measured at various time points. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD. The novel aspects of the protocol include the usage of a Del-1 plasmid-polaxamer formulation to enhance gene transfer at doses that are an order of magnitude different than other comparable trials in a unique bilateral intramuscular dosing pattern to maximize transfection/clinical efficacy and general applicability to patients with PAD.     

Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy

IgA nephropathy (IgAN) is recognized as most frequent form of primary glomerulonephritis worldwide. IgAN is associated with renal degradation occurring due to irreversible pathological changes leading to glomerulosclerosis and interstitial fibrosis. It remains poorly understood whether and to what extent these changes are followed by the activation of regenerative mechanisms. Therefore, in this study we aimed to evaluate regenerative potential of IgAN patients by quantitating the frequencies of several stem cell types, namely circulating very small embryonic-like stem cells (VSELs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) as well as different monocyte subsets with varying maturation and angiopoietic potential. Moreover, we analyzed whether changes in stem cell and monocyte frequencies were related to alterations of several chemotactic factors (stromal derived-factor (SDF-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)) and a marker of monocyte/macrophage activation, namely soluble form of CD163 receptor (sCD163). We showed that IgAN patients presented with enhanced levels of VSELs, but not other stem cell types. We also demonstrated significantly elevated numbers of intermediate monocytes known for their M2-like properties as well as high angiopoietic potential and CD163 expression. This finding was accompanied by detection of elevated sCD163 plasma levels in IgAN patients. Taking together, we demonstrated here that IgAN is associated with selective mobilization of VSELs and increased maturation of monocytes towards M2-like and angiopoietic phenotype. These findings contribute to better understanding of the role of regenerative mechanisms in the pathogenesis of chronic inflammation in the course of IgAN.     

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation

Background

Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.

Methods

We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD.

Results

We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p?=?1.85?×?10^?03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten “CNV positive” trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4.

Conclusions

Our findings suggest that rare CNVs may contribute to the etiology of OCD.