Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: A genome-wide association and polygenic scoring study.

Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 Wiley Periodicals, Inc.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Natural genetic variation of root system architecture from Arabidopsis to Brachypodium: towards adaptive value.

Root system architecture is a trait that displays considerable plasticity because of its sensitivity to environmental stimuli. Nevertheless, to a significant degree it is genetically constrained as suggested by surveys of its natural genetic variation. A few regulators of root system architecture have been isolated as quantitative trait loci through the natural variation approach in the dicotyledon model, Arabidopsis. This provides proof of principle that allelic variation for root system architecture traits exists, is genetically tractable, and might be exploited for crop breeding. Beyond Arabidopsis, Brachypodium could serve as both a credible and experimentally accessible model for root system architecture variation in monocotyledons, as suggested by first glimpses of the different root morphologies of Brachypodium accessions. Whether a direct knowledge transfer gained from molecular model system studies will work in practice remains unclear however, because of a lack of comprehensive understanding of root system physiology in the native context. For instance, apart from a few notable exceptions, the adaptive value of genetic variation in root system modulators is unknown. Future studies should thus aim at comprehensive characterization of the role of genetic players in root system architecture variation by taking into account the native environmental conditions, in particular soil characteristics.

Neonatal treatment with recombinant ectodysplasin prevents respiratory disease in dogs with X-linked ectodermal dysplasia.

Patients with defective ectodysplasin A (EDA) have X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM#305100), a condition comprising hypotrichosis, inability to sweat, abnormal teeth, and frequent pulmonary infections. The XLHED dogs show the same clinical signs as humans with the disorder, including frequent respiratory infections that can be fatal. The respiratory disease in humans and dogs is thought to be due to the absence of tracheal and bronchial glands which are a vital part of the mucociliary clearance mechanism. In our XLHED model, the genetically missing EDA was replaced by postnatal intravenous administration of recombinant EDA resulting in long-term, durable corrective effect on adult, permanent dentition. After treatment with EDA, significant correction of the missing tracheal and bronchial glands was achieved in those dogs that received higher doses of EDA. Moreover, successful treatment resulted in the presence of esophageal glands, improved mucociliary clearance, and the absence of respiratory infection. These results demonstrate that a short-term treatment at a neonatal age with a recombinant protein can reverse a developmental disease and result in vastly improved quality of life.

Poly-epsilon-caprolactone intravitreous devices: an in vivo study.

PURPOSE: The objective of this study was to evaluate the long-term safety and pharmacokinetic profile of a dexamethasone-loaded poly-epsilon-caprolactone (PCL) intravitreous implant. METHODS: The PCL devices were prepared by compression and were inserted into the vitreous of pigmented rabbits. At different time points, vitreous samples were retrieved, and dexamethasone concentration was analyzed by high-performance liquid chromatography. The biodegradation of the implants was evaluated by scanning electron microscopy, and the dexamethasone remaining was evaluated at the end of follow-up. Clinical and histologic examinations were performed to evaluate the implant's tolerance. RESULTS: The PCL implant allows for a controlled and prolonged delivery of dexamethasone in rabbits eyes since it released the drug within the therapeutic range for at least 55 weeks. At 55 weeks approximately 79% of the drug was still present in the implant. Biodegradation study showed that PCL implants degradation is very slow. Clinical and histologic observations showed that the devices were very well tolerated in the rabbit eye. CONCLUSIONS: This study demonstrates the feasibility and tolerance of intravitreous PCL drug delivery systems, which can offer a wide range of applications for intraocular drug delivery because of their controlled and prolonged release over months or even years.

Double Concentric Autofluorescence Ring in NR2E3-p.G56R-linked Autosomal Dominant Retinitis Pigmentosa.

Purpose: We report an unusual appearance of fundus autofluorescence (FAF) associated with NR2E3-p.G56R-linked autosomal dominant retinitis pigmentosa (ADRP).Methods: Patients were enrolled among three generations in a Swiss family. Molecular diagnosis identified a c.166G>A (p.G56R) mutation. Ophthalmic examination included fundus photography, FAF, near-infrared autofluorescence (NIA), optical coherence tomography (OCT) and visual fields (VF).Results: Fundus examination revealed a wide range of features from unremarkable to attenuated arterial caliber, clumped and spicular pigment deposits in the mid-periphery and optic nerve pallor. FAF showed a double concentric hyperautofluorescent ring: an inner perimacular ring which tended to be smaller in older patients, and an outer ring located along the vascular arcades, which appeared to extend over time towards the periphery and eventually became hypoautofluorescent. The inner and outer hyperautofluorescent rings were seen both on NIA and FAF at a similar localization. There was also a spatial correspondence between the loss of photoreceptor inner segment and outer segment junction on OCT and the area delimited by both double FAF and NIA rings. VF showed either midperipheral annular scotoma or constricted visual field loss in advanced cases, correlating with dystrophic non-functional retinal regions demarcated by the hyperautofluorescent annuli. A double ring of hyperautofluorescence was observed in all but one patient of two additional families, but not in patients harboring mutations in other ADRP genes, including PRPF3, RHO, RP1, PRPH2, PROM1 and CTRP5.Conclusions: The presence of a double concentric hyperautofluorescent ring of FAF may represent a highly penetrant early phenotypic marker of NR2E3-p.G56R-linked ADRP.

Development and evaluation of a shaken baby syndrome prevention program.

OBJECTIVE: To evaluate parents' and nurses' opinions regarding the adequacy of an educational program on shaken baby syndrome: the Perinatal Shaken Baby Syndrome Prevention Program (PSBSPP). DESIGN: Qualitative and quantitative assessments in the form of interviews and questionnaires administered in French. SETTING: Two birthing institutions in Montréal, QC, Canada: a university hospital and a regional center. PARTICIPANTS: Two hundred and sixty-three parents (73.8% mothers, 26.2% fathers) received the intervention after the birth of their child, and 69 nurses administered it. METHODS: Parents' and nurses' assessments of the adequacy and relevance of the program and nurses' assessments of the training they received to administer the program were evaluated. RESULTS: Both parents and nurses supported this initiative. Most parents appreciated the usefulness of the information. Nurses believed the program was adequate, and their training to deliver the program was satisfactory. All participants reported that the program was highly relevant, especially for new parents. CONCLUSION: The Perinatal Shaken Baby Syndrome Prevention Program achieves the goals of (a) increasing parents' knowledge about infant crying, anger, and shaken baby syndrome and (b) helping parents identify coping strategies. The relevance of introducing the PSBSPP in all birthing institutions is supported. Future studies should focus on vulnerable and culturally diverse populations, and longitudinal follow-up could help determine if the PSBSPP reduces the incidence of shaken baby syndrome.

Focal dermal hypoplasia (goltz-gorlin syndrome): A new case with a novel variant in the PORCN gene (c.1250T>C:p.F417S) and unusual spinal anomaly.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome; OMIM 305600) is a disorder that features involvement of the skin, skeletal system, and eyes. It is caused by loss-of-function mutations in the PORCN gene. We report a young girl with FDH, microphthalmos associated with colobomatous orbital cyst, dural ectasia and cystic malformation of the spinal cord, and a de novo variant in PORCN. This association has not been previously reported, and based on these observations the phenotypic spectrum of FDH might be broader than previously appreciated. It would be prudent to alter the suggested surveillance for this rare disorder. © 2013 Wiley Periodicals, Inc.

Transapical aortic valve implantation without angiography: proof of concept.

Background: Cardiac computed tomographic scans, coronary angiograms, and aortographies are routinely performed in transcatheter heart valve therapies. Consequently, all patients are exposed to multiple contrast injections with a following risk of nephrotoxicity and postoperative renal failure. The transapical aortic valve implantation without angiography can prevent contrast-related complications. Methods: Between November 2008 and November 2009, 30 consecutive high-risk patients (16 female, 53.3%) underwent transapical aortic valve implantation without angiography. The landmarks identification, the stent-valve positioning, and the postoperative control were routinely performed under transesophageal echocardiogram and fluoroscopic visualization without contrast injections. Results: Mean age was 80.1 +/- 8.7 years. Mean valve gradient, aortic orifice area, and ejection fraction were 60.3 +/- 20.9 mm Hg, 0.7 +/- 0.16 cm(2), and 0.526 +/- 0.128, respectively. Risk factors were pulmonary hypertension (60%), peripheral vascular disease (70%), chronic pulmonary disease (50%), previous cardiac surgery (13.3%), and chronic renal insufficiency (40%) (mean blood creatinine and urea levels: 96.8 +/- 54 mu g/dL and 8.45 +/- 5.15 mmol/L). Average European System for Cardiac Operative Risk Evaluation was 32.2 +/- 13.3%. Valve deployment in the ideal landing zone was 96.7% successful and valve embolization occurred once. Thirty-day mortality was 10% (3 patients). Causes of death were the following: intraoperative ventricular rupture (conversion to sternotomy), right ventricular failure, and bilateral pneumonia. Stroke occurred in one patient at postoperative day 9. Renal failure (postoperative mean blood creatinine and urea levels: 91.1 +/- 66.8 mu g/dL and 7.27 +/- 3.45 mmol/L), myocardial infarction, and atrioventricular block were not detected. Conclusions: Transapical aortic valve implantation without angiography requires a short learning curve and can be performed routinely by experienced teams. Our report confirms that this procedure is feasible and safe, and provides good results with low incidence of postoperative renal disorders. (Ann Thorac Surg 2010; 89: 1925-33) (C) 2010 by The Society of Thoracic Surgeons

Delayed referral and gram-negative organisms increase the conversion thoracotomy rate in patients undergoing video-assisted thoracoscopic surgery for empyema

BACKGROUND: The role of video-assisted thoracoscopic surgery in the treatment of pleural empyema was assessed in a consecutive series of 328 patients between 1992 and 2002. An analysis of the predicting factors for conversion thoracotomy in presumed stage II empyema was performed. METHODS: Empyema stage III with pleural thickening and signs of restriction on computer tomography imaging was treated by open decortication, whereas a thoracoscopic debridement was attempted in presumed stage II disease. Conversion thoracotomy was liberally used during thoracoscopy if stage III disease was found at surgery. Predictive factors for conversion thoracotomy were calculated in a multivariate analysis among several variables such as age, sex, time interval between onset of symptoms and surgery, involved microorganisms, and underlying cause of empyema. RESULTS: Of the 328 patients surgically treated for stage II and III empyema, 150 underwent primary open decortication for presumed stage III disease. One hundred seventy-eight patients with presumed stage II empyema underwent a video-assisted thoracoscopic approach. Of these 178 patients, thoracoscopic debridement was successful in 99 of 178 patients (56%), and conversion thoracotomy and open decortication was judged necessary in 79 of 178 patients (44%). The conversion thoracotomy rate was higher in parapneumonic empyema (55%) as compared with posttraumatic (32%) or postoperative (29%) empyema; however, delayed referral (p < 0.0001) and gram-negative microorganisms (p < 0.01) were the only significant predictors for conversion thoracotomy in a multivariate analysis. CONCLUSIONS: Video-assisted thoracoscopic debridement offers an elegant, minimally invasive approach in a number of patients with presumed stage II empyema. However, to achieve a high success rate with the video-assisted thoracoscopic approach, early referral of the patients to surgery is required. Conversion thoracotomy should be liberally used in case of chronicity, especially after delayed referral (> 2 weeks) and in the presence of gram-negative organisms.

Renal failure after high-dose methotrexate in a child homozygous for MTHFR C677T polymorphism

We report the case of an 11-year-old female treated for mediastinal T-cell lymphoma who presented renal failure following the second cycle of high-dose methotrexate (HDMTX). Because of life threatening plasma methotrexate (MTX) levels, carboxypeptidase G2 (CPDG2) was administered resulting in a dramatic decrease within 1 hr. The patient recovered from renal failure and no other side effects were observed. Homozygosity for the methylentetrahydrofolate reductase (MTHFR) C677T polymorphism diagnosed by molecular genetic analysis was the only explanation for this toxicity.

Vacuum-assisted closure device: a useful tool in the management of severe intrathoracic infections.

Background. This study is an evaluation of the vacuum-assisted closure (VAC) therapy for the treatment of severe intrathoracic infections complicating lung resection, esophageal surgery, viscera perforation, or necrotizing pleuropulmonary infections.Methods. We reviewed the medical records of all patients treated by intrathoracic VAC therapy between January 2005 and December 2008. All patients underwent surgical debridement-decortication and control of the underlying cause of infection such as treatment of bronchus stump insufficiency, resection of necrotic lung, or closure of esophageal or intestinal leaks. Surgery was followed by intrathoracic VAC therapy until the infection was controlled. The VAC dressings were changed under general anesthesia and the chest wall was temporarily closed after each dressing change. All patients received systemic antibiotic therapy.Results. Twenty-seven patients (15 male, median age 64 years) underwent intrathoracic VAC dressings for the management of postresectional empyema (n = 8) with and without bronchopleural fistula, necrotizing infections (n = 7), and intrathoracic gastrointestinal leaks (n = 12). The median length of VAC therapy was 22 days (range 5 to 66) and the median number of VAC changes per patient was 6 (range 2 to 16). In-hospital mortality was 19% (n = 5) and was not related to VAC therapy or intrathoracic infection. Control of intrathoracic infection and closure of the chest cavity was achieved in all surviving patients.Conclusions. Vacuum-assisted closure therapy is an efficient and safe adjunct to treat severe intrathoracic infections and may be a good alternative to the open window thoracostomy in selected patients. Long time intervals in between VAC changes and short course of therapy result in good patient acceptance. (Ann Thorac Surg 2011;91:1582-90) (C) 2011 by The Society of Thoracic Surgeons