Assessment and characterization of phenotypic heterogeneity of anxiety disorders across five large cohorts

To achieve sample sizes necessary for effectively conducting genome‐wide association studies (GWASs), researchers often combine data from samples possessing multiple potential sources of heterogeneity. This is particularly relevant for psychiatric disorders, where symptom self‐report, differing assessment instruments, and diagnostic comorbidity complicates the phenotypes and contribute to difficulties with detecting and replicating genetic association signals. We investigated sources of heterogeneity of anxiety disorders (ADs) across five large cohorts used in a GWAS meta‐analysis project using a dimensional structural modeling approach including confirmatory factor analyses (CFAs) and measurement invariance (MI) testing. CFA indicated a single‐factor model provided the best fit in each sample with the same pattern of factor loadings. MI testing indicated degrees of failure of metric and scalar invariance which depended on the inclusion of the effects of sex and age in the model. This is the first study to examine the phenotypic structure of psychiatric disorder phenotypes simultaneously across multiple, large cohorts used for GWAS. The analyses provide evidence for higher order invariance but possible break‐down at more detailed levels that can be subtly influenced by included covariates, suggesting caution when combining such data. These methods have significance for large‐scale collaborative studies that draw on multiple, potentially heterogeneous datasets. Copyright © 2016 John Wiley & Sons, Ltd.     

A GABAergic tecto–tegmento–tectal pathway in pigeons

Previous studies have demonstrated that the optic tecta of the left and right brain halves reciprocally inhibit each other in birds. In mammals, the superior colliculus receives inhibitory γ‐aminobutyric acid (GABA)ergic input from the basal ganglia via both the ipsilateral and the contralateral substantia nigra pars reticulata (SNr). This contralateral SNr projection is important in intertectal inhibition. Because the basal ganglia are evolutionarily conserved, the tectal projections of the SNr may show a similar pattern in birds. Therefore, the SNr could be a relay station in an indirect tecto–tectal pathway constituting the neuronal substrate for the tecto–tectal inhibition. To test this hypothesis, we performed bilateral anterograde and retrograde tectal tracing combined with GABA immunohistochemistry in pigeons. Suprisingly, the SNr has only ipsilateral projections to the optic tectum, and these are non‐GABAergic. Inhibitory GABAergic input to the contralateral optic tectum arises instead from a nearby tegmental region that receives input from the ipsilateral optic tectum. Thus, a disynaptic pathway exists that possibly constitutes the anatomical substrate for the inhibitory tecto–tectal interaction. This pathway likely plays an important role in attentional switches between the laterally placed eyes of birds. J. Comp. Neurol. 524:2886–2913, 2016. © 2016 Wiley Periodicals, Inc.     

Prolonged corticosterone exposure induces dendritic spine remodeling and attrition in the rat medial prefrontal cortex

The stress‐responsive hypothalamo–pituitary–adrenal (HPA) axis plays a central role in promoting adaptations acutely, whereas adverse effects on physiology and behavior following chronic challenges may result from overactivity of this system. Elevations in glucocorticoids, the end‐products of HPA activation, play roles in adaptive and maladaptive processes by targeting cognate receptors throughout neurons in limbic cortical networks to alter synaptic functioning. Because previous work has shown that chronic stress leads to functionally relevant regressive alterations in dendritic spine shape and number in pyramidal neurons in the medial prefrontal cortex (mPFC), this study examines the capacity of sustained increases in circulating corticosterone (B) alone to alter dendritic spine morphology and density in this region. Subcutaneous B pellets were implanted in rats to provide continuous exposure to levels approximating the circadian mean or peak of the steroid for 1, 2, or 3 weeks. Pyramidal neurons in the prelimbic area of the mPFC were selected for intracellular fluorescent dye filling, followed by high‐resolution three‐dimensional imaging and analysis of dendritic arborization and spine morphometry. Two or more weeks of B exposure decreased dendritic spine volume in the mPFC, whereas higher dose exposure of the steroid resulted in apical dendritic retraction and spine loss in the same cell population, with thin spine subtypes showing the greatest degree of attrition. Finally, these structural alterations were noted to persist following a 3‐week washout period and corresponding restoration of circadian HPA rhythmicity. These studies suggest that prolonged disruptions in adrenocortical functioning may be sufficient to induce enduring regressive structural and functional alterations in the mPFC. J. Comp. Neurol. 524:3729–3746, 2016. © 2016 Wiley Periodicals, Inc.     

Predictive factors of excess body weight loss 1?year after laparoscopic bariatric surgery

Background

Bariatric surgery (BS) is widely accepted for the treatment of patients with morbid obesity (MO). We aimed to determine presurgical predictors of and surgical technique-related differences in excess weight loss (EWL) 1?year after BS.

Methods

This retrospective study included 407 subjects (F/M 3:1, median age?=?44?years) who underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n?=?307) or sleeve gastrectomy (SG, n?=?100) at our University Hospital and were evaluated 1?year after surgery.

Results

Baseline median (min–max) body mass index (BMI) was 47?kg/m² (range?=?36–71). BMI was higher in the SG than in the RYGB group (53 vs. 46?kg/m², p?p?p?=?0.2), was lower in diabetic than in nondiabetic subjects (71?±?17% vs. 79?±?17%, p?p?p?=?0.4) after taking into account baseline BMI. Multiple regression and logistic analysis showed that younger individuals with lower BMI but higher WC, and lower HbA1c and TG, had higher EWL and a higher rate of successful (EWL?≥?60%) weight loss.

Conclusions

Our data indicate that some of the characteristics that would have subjects referred early for BS were associated with higher weight loss. Therefore, the timing of laparoscopic BS might be an important factor for MO individuals in which medical weight loss intervention has failed.     

Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations

Background  

Ulcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental and microbial factors drives chronic intestinal inflammation that finally leads to extensive tissue fibrosis.     

Single-incision laparoscopic cholecystectomy with routine intraoperative cholangiography and common bile duct exploration via the umbilical port

Background  

Laparoscopic cholecystectomy currently is the gold standard technique for gallbladder removal. The use of routine intraoperative cholangiography (IOC) is widely practiced during conventional four-port laparoscopic cholecystectomy (4PLC) to confirm biliary anatomy and allow for immediate management of unexpected choledocholithiasis. Single-incision laparoscopic surgery (SILS) offers a more aesthetic technique for gallbladder removal and has been reported by several groups. However, no series to date have included routine IOC without a separate incision. This study aimed to demonstrate the feasibility of the SILS technique for cholecystectomy with routine IOC (LCIOC) and common bile duct (CBD) exploration as needed via the umbilical port.     

Importance of strict patient selection criteria for combined carotid endarterectomy and coronary artery bypass grafting

BackgroundManagement of patients with severe concomitant carotid and coronary disease remains controversial. We report our experience of combined carotid endarterectomy (CEA) and coronary artery bypass surgery (CABG) over a fifteen year period using strict patient selection criteria.MethodsFrom 1st January 1995 to December 31st 2009 165 patients underwent combined CABG/CEA procedures at the Mater Hospital. Mean age was 68.2 years (range 43–88) and 127 (77%) were male. Fifty-three (32%) had symptomatic carotid disease. Indications for combined procedures were the presence of symptomatic >70% or asymptomatic >80% internal carotid artery stenosis in a patient requiring urgent CABG because of either unstable angina, recent MI, severe triple vessel disease or severe Left Anterior Descending or Left Main Stem stenosis.ResultsThirty-day stroke and death rate was 3%. All neurological events were in the hemisphere contralateral to the carotid surgery and symptoms had completely resolved prior to discharge from hospital. One patient required evacuation of a cervical haematoma and there were two transient XII nerve palsies.ConclusionCombined CEA/CABG can be performed safely with acceptable morbidity and mortality in patients selected in accordance with strict criteria in a centre with a large experience of both cardiac and carotid surgery.     

Traumatic central cord syndrome: neurologic recovery after surgical management

The purpose of this study was to evaluate neurologic recovery following an acute, traumatic central cord syndrome (TCCS) injury. We retrospectively reviewed 69 patients who were treated surgically following an acute TCCS injury. The American Spinal Injury Association (ASIA) motor scores (AMS) were obtained from the time of presentation, from the time of hospital discharge, and from the most recent follow-up visit. The mean AMS was 63.2±25.8 at presentation and 89.9±14.6 at final follow-up (P<.001). Overall, 74% of the patients improved at least one ASIA impairment scale grade. Surgery was performed at a mean of 2.9 days (range, 0.25-24 days) following the injury using a posterior approach in 33 patients (48%), anterior approach in 22 patients (32%), and combined anterior-posterior approach in 14 patients (20%). Neither surgical timing nor approach appears to affect motor recovery. Adverse events were encountered in 24.6% of the patients. There were no deaths. A history of a loss of consciousness, decreased rectal tone at presentation, the presence of a fracture, the timing of surgery, and surgical approach did not have a significant impact on motor recovery.     

Up to 9-day survival and control of thrombocytopenia following alpha1,3-galactosyl transferase knockout swine liver xenotransplantation in baboons

Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, Smith RN, Robson SC, Cosimi AB, Sachs DH, Hertl M. Up to 9‐day survival and control of thrombocytopenia following GalT‐KO swine liver xenotransplantation in baboons. Xenotransplantation 2012; 19: 256–264.. © 2012 John Wiley & Sons A/S. Abstract: Background:  With standard miniature swine donors, survivals of only 3 days have been achieved in primate liver‐transplant recipients. The recent production of alpha1,3‐galactosyl transferase knockout (GalT‐KO) miniature swine has made it possible to evaluate xenotransplantation of pig organs in clinically relevant pig‐to‐non‐human primate models in the absence of the effects of natural anti‐Gal antibodies. We are reporting our results using GalT‐KO liver grafts. Methods:  We performed GalT‐KO liver transplants in baboons using an immunosuppressive regimen previously used by our group in xeno heart and kidney transplantation. Post‐operative liver function was assessed by laboratory function tests, coagulation parameters and histology. Results:  In two hepatectomized recipients of GalT‐KO grafts, post‐transplant liver function returned rapidly to normal. Over the first few days, the synthetic products of the donor swine graft appeared to replace those of the baboon. The first recipient survived for 6 days and showed no histopathological evidence of rejection at the time of death from uncontrolled bleeding, probably caused by transfusion‐refractory thrombocytopenia. Amicar treatment of the second and third recipients led to maintenance of platelet counts of over 40 000 per μl throughout their 9‐ and 8‐day survivals, which represents the longest reported survival of pig‐to‐primate liver transplants to date. Both of the last two animals nevertheless succumbed to bleeding and enterococcal infection, without evidence of rejection. Conclusions:  These observations suggest that thrombocytopenia after liver xenotransplantation may be overcome by Amicar therapy. The coagulopathy and sepsis that nevertheless occurred suggest that additional causes of coagulation disturbance must be addressed, along with better prevention of infection, to achieve long‐term survival.     

Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early osteoarthritic synovial fluid

ABSTRACT: BACKGROUND: Osteoarthritis (OA) and Rheumatoid arthritis (RA) are diseases which result in the degeneration of the joint surface articular cartilage. Matrix Metalloproteinases (MMPs) are enzymes that aid in the natural remodelling of tissues throughout the body including cartilage. However, some MMPs have been implicated in the progression of OA and RA as their expression levels and activation states can change dramatically with the onset of disease. Yet, it remains unknown if normal and arthritic joints demonstrate unique MMPs expression profiles, and if so, can the MMP expression profile be used to identify patients with early OA. In this study, the synovial fluid protein expression levels for MMPs 1, 2, 3, 7, 8, 9, 12 & 13, as well as those for the Tissue Inhibitors of MMPs (TIMPs) 1, 2, 3, & 4 were examined in highly characterized normal knee joints, and knee joints with clinically diagnosed OA (early and advanced) or RA. The purpose of this study was to determine if normal, OA, and RA patients exhibit unique expression profiles for a sub-set of MMPs, and if early OA patients have a unique MMP expression profile that could be used as an early diagnostic marker. METHODS: Synovial fluid was aspirated from stringently characterized normal knee joints, and in joints diagnosed with either OA (early and advanced) or RA. Multiplexing technology was employed to quantify protein expression levels for 8 MMPs and 4 TIMPs in the synovial fluid of 12 patients with early OA, 17 patients diagnosed with advanced OA, 15 with RA and 25 normal knee joints. Principle component analysis (PCA) was used to reveal which MMPs were most influential in the distinction between treatment groups. K - means clustering was used to verify the visual grouping of subjects via PCA. RESULTS: Significant differences in the expression levels of MMPs and TIMPs were observed between normal and arthritic synovial fluids (with the exception of MMP 12). PCA demonstrated that MMPs 2, 8 & 9 can be used to effectively separate individuals diagnosed with advanced arthritis from early osteoarthritic and normal individuals, however, these MMP profiles do not separate early OA from normal synovial fluid. An apparent separation between advanced OA and RA subjects was also revealed through PCA. K-means clustering verified the presence of 3 clusters: normal joints clustered with early OA, and separate clusters of advanced OA or RA. CONCLUSIONS: This study demonstrates that unique MMP and TIMP expression profiles are present within normal, advanced OA and RA synovial fluid. These MMP profiles can be used to distinguish advanced OA & RA synovial fluid from early OA & normal synovial fluid, and even between synovial fluid samples from OA and RA joints. Although this methodology cannot be used for the diagnosis of early OA, high throughput multiplex technology of MMPs and TIMPs in synovial fluid may prove useful in determining the severity of the disease state, and/or quantifying the response of individuals to disease interventions.