Seton drainage prior to transanal advancement flap repair: useful or not?

Introduction: Transanal advancement flap repair (TAFR) provides a useful tool in the treatment of high transsphincteric fistulas. Recent studies indicate that TAFR fails in one out of three patients. Until now, no definite predictive factor for failure has been identified. Although some authors have reported that preoperative seton drainage might improve the outcome of TAFR, this could not be confirmed by others. We conducted the present study to assess the influence of preoperative seton drainage on the outcome of TAFR in a relatively large series. Methods: Between December 1992 and June 2008, a consecutive series of 278 patients [M/F = 179:99, median age 46 years (range, 19-73 years)] with cryptoglandular, transsphincteric fistula, passing through the upper or middle third of the external anal sphincter underwent TAFR. Patients were recruited from the colorectal units of two university hospitals (Erasmus Medical Center, Rotterdam, n = 211; and Leiden University Medical Center, Leiden, n = 67). Baseline characteristics did not differ between the two clinics. Sixty-eight of these patients underwent preoperative seton drainage for at least 2 months and until the day of the flap repair. Results: Median healing time was 2.2 months. In patients without preoperative seton drainage, the healing rate was 63%, whereas the healing rate was 67% in patients who underwent preoperative seton drainage. This difference was not statistically significant. No differences in healing rates were found between the series from Leiden and Rotterdam. Conclusion: Preoperative seton drainage does not improve the outcome of TAFR

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

Predictors of long-term pain and disability in patients with low back pain investigated by magnetic resonance imaging: A longitudinal study

<p>Abstract</p> <p>Background</p> <p>It is possible that clinical outcome of low back pain (LBP) differs according to the presence or absence of spinal abnormalities on magnetic resonance imaging (MRI), in which case there could be value in using MRI findings to refine case definition of LBP in epidemiological research. We therefore conducted a longitudinal study to explore whether spinal abnormalities on MRI for LBP predict prognosis after 18 months.</p> <p>Methods</p> <p>A consecutive series of patients aged 20-64 years, who were investigated by MRI because of mechanical LBP (median duration of current episode 16.2 months), were identified from three radiology departments, and those who agreed completed self-administered questionnaires at baseline and after a mean follow-up period of 18.5 months (a mean of 22.2 months from MRI investigation). MRI scans were assessed blind to other clinical information, according to a standardised protocol. Associations of baseline MRI findings with pain and disability at follow-up, adjusted for treatment and for other potentially confounding variables, were assessed by Poisson regression and summarised by prevalence ratios (PRs) with their 95% confidence intervals (CIs).</p> <p>Results</p> <p>Questionnaires were completed by 240 (74%) of the patients who had agreed to be followed up. Among these 111 men and 129 women, 175 (73%) reported LBP in the past four weeks, 89 (37%) frequent LBP, and 72 (30%) disabling LBP. In patients with initial disc degeneration there was an increased risk of frequent (PR 1.3, 95%CI 1.0-1.9) and disabling LBP (PR 1.7, 95%CI 1.1-2.5) at follow-up. No other associations were found between MRI abnormalities and subsequent outcome.</p> <p>Conclusions</p> <p>Our findings suggest that the MRI abnormalities examined are not major predictors of outcome in patients with LBP. They give no support to the use of MRI findings as a way of refining case definition for LBP in epidemiological research.</p

Looking ahead at the potential benefits of biotechnology-derived allergen therapeutics

While biotechnology-derived allergen therapeutics show promise in improving the safety of immunotherapy, they may prove to have additional benefits in comparison to conventional allergenic extracts that deserve commentary. These issues range from product stability and compatibility to medical practice issues, which will be the focus of this article

Large tunable valley splitting in edge-free graphene quantum dots on boron nitride

Coherent manipulation of binary degrees of freedom is at the heart of modern quantum technologies. Graphene offers two binary degrees: the electron spin and the valley. Efficient spin control has been demonstrated in many solid state systems, while exploitation of the valley has only recently been started, yet without control on the single electron level. Here, we show that van-der Waals stacking of graphene onto hexagonal boron nitride offers a natural platform for valley control. We use a graphene quantum dot induced by the tip of a scanning tunneling microscope and demonstrate valley splitting that is tunable from -5 to +10 meV (including valley inversion) by sub-10-nm displacements of the quantum dot position. This boosts the range of controlled valley splitting by about one order of magnitude. The tunable inversion of spin and valley states should enable coherent superposition of these degrees of freedom as a first step towards graphene-based qubits

Childhood traumatic experiences and mental health problems in sexually offending and non-sexually offending juveniles

OBJECTIVE: To examine the relationship between a history of childhood abuse and mental health problems in juveniles who sexually offended (JSOs) over and above general offending behavior. METHODS: A sample of 44 JSOs incarcerated in two juvenile detention centers in the Netherlands between May 2008 and March 2014 were examined for childhood abuse history (Childhood Trauma Questionnaire-Short Form) and mental health problems (Massachusetts Youth Screening Instrument-Version 2). Furthermore, the connection between childhood abuse and mental health problems in JSOs was compared to a sample of 44 propensity score matched juveniles who offended non-sexually (non-JSOs). RESULTS: In JSOs, sexual abuse was related to anger problems, suicidal ideation, and thought disturbance. These associations were significantly stronger in JSOs than in non-JSOs. CONCLUSIONS: Our results suggest that the relationship between childhood abuse and both internalizing and externalizing mental health problems is of more salience for understanding sexual offending than non-sexual offending, and should, therefore, be an important focus in the assessment and treatment of JSOs

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

Probabilistic downscaling of remote sensing data with applications for multi-scale biogeochemical flux modeling

Upscaling ecological information to larger scales in space and downscaling remote sensing observations or model simulations to finer scales remain grand challenges in Earth system science. Downscaling often involves inferring subgrid information from coarse-scale data, and such ill-posed problems are classically addressed using regularization. Here, we apply two-dimensional Tikhonov Regularization (2DTR) to simulate subgrid surface patterns for ecological applications. Specifically, we test the ability of 2DTR to simulate the spatial statistics of high-resolution (4 m) remote sensing observations of the normalized difference vegetation index (NDVI) in a tundra landscape. We find that the 2DTR approach as applied here can capture the major mode of spatial variability of the high-resolution information, but not multiple modes of spatial variability, and that the Lagrange multiplier (γ) used to impose the condition of smoothness across space is related to the range of the experimental semivariogram. We used observed and 2DTR-simulated maps of NDVI to estimate landscape-level leaf area index (LAI) and gross primary productivity (GPP). NDVI maps simulated using a γ value that approximates the range of observed NDVI result in a landscape-level GPP estimate that differs by ca 2% from those created using observed NDVI. Following findings that GPP per unit LAI is lower near vegetation patch edges, we simulated vegetation patch edges using multiple approaches and found that simulated GPP declined by up to 12% as a result. 2DTR can generate random landscapes rapidly and can be applied to disaggregate ecological information and compare of spatial observations against simulated landscapes