The natural history of resectable metastatic melanoma (Stage IVA melanoma).
One-hundred-two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease-free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty-five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease-free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease-free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft-tissue metastases appeared to benefit most from BCG in prolonging the disease-free interval. Only 1/10 treated by surgery alone had a disease-free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft-tissue disease may benefit significantly from treatment with BCG.


CDC4/FBXW7 and the 'just enough' model of tumourigenesis.
There is good evidence to show that cancer-causing mutations are not always simple gain- and loss-of-function changes. One example is the APC gene, where the combination of mutations produces a 'just-right' level of Wnt signalling. A recent article by Berger and colleagues posited a 'continuum model' in which increasing or decreasing gene expression of function was linearly associated with tumourigenesis. Berger also proposed an 'obligate haploinsufficiency' or 'fail-safe' model, whereby heterozygous mutations produce sufficient derangement for tumourigenesis, yet homozygous mutations are cell-lethal or senescence-causing. One gene highlighted by Berger and colleagues as an example of a gene following a 'continuum' or 'fail-safe' model was FBXW7/CDC4, a gene mutated in several different types of malignancy. We have analysed the COSMIC FBXW7 data. FBXW7 does not obviously follow a 'continuum' or 'fail-safe' model and the most common mutant genotypes are mono-allelic missense changes that affect critical arginine residues involved in interactions with substrates. There is no strong selection for complete loss of FBXW7 protein function, but bi-allelic inactivating mutations do occur. For FBXW7, we suggest a variant of 'just right' which we call 'just enough'. For FBXW7 mutations that occur away from the propellor tips, the heterozygote may have some effect on tumourigenesis, but there is selective pressure for a 'second hit'. For propellor tip mutations, by contrast, there is weak pressure for a 'second hit' because they usually provide sufficient functional derangement on their own.


MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C.
Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could provide therapeutic opportunities that are more effective and less toxic than current treatments. Here, we employed an in vivo shRNA screen and identified jumonji domain-containing protein JMJD1C as an important driver of MLL-AF9 leukemia. Using a conditional mouse model, we showed that loss of JMJD1C substantially decreased LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias. We determined that JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program. In contrast, loss of JMJD1C led to only minor defects in blood homeostasis and modest effects on HSC self-renewal. Together, these data establish JMJD1C as an important mediator of MLL-AF9- and HOXA9-driven LSC function that is largely dispensable for HSC function.


Compartmentalized Cerebral Metabolism of [1,6-(13)C]Glucose Determined by in vivo (13)C NMR Spectroscopy at 14.1 T.
Cerebral metabolism is compartmentalized between neurons and glia. Although glial glycolysis is thought to largely sustain the energetic requirements of neurotransmission while oxidative metabolism takes place mainly in neurons, this hypothesis is matter of debate. The compartmentalization of cerebral metabolic fluxes can be determined by (13)C nuclear magnetic resonance (NMR) spectroscopy upon infusion of (13)C-enriched compounds, especially glucose. Rats under light α-chloralose anesthesia were infused with [1,6-(13)C]glucose and (13)C enrichment in the brain metabolites was measured by (13)C NMR spectroscopy with high sensitivity and spectral resolution at 14.1 T. This allowed determining (13)C enrichment curves of amino acid carbons with high reproducibility and to reliably estimate cerebral metabolic fluxes (mean error of 8%). We further found that TCA cycle intermediates are not required for flux determination in mathematical models of brain metabolism. Neuronal tricarboxylic acid cycle rate (V(TCA)) and neurotransmission rate (V(NT)) were 0.45 ± 0.01 and 0.11 ± 0.01 μmol/g/min, respectively. Glial V(TCA) was found to be 38 ± 3% of total cerebral oxidative metabolism, accounting for more than half of neuronal oxidative metabolism. Furthermore, glial anaplerotic pyruvate carboxylation rate (V(PC)) was 0.069 ± 0.004 μmol/g/min, i.e., 25 ± 1% of the glial TCA cycle rate. These results support a role of glial cells as active partners of neurons during synaptic transmission beyond glycolytic metabolism.


Use of OmpU porins for attachment and invasion of Crassostrea gigas immune cells by the oyster pathogen Vibrio splendidus.
OmpU porins are increasingly recognized as key determinants of pathogenic host Vibrio interactions. Although mechanisms remain incompletely understood, various species, including the human pathogen Vibrio cholera, require OmpU for host colonization and virulence. We have shown previously that OmpU is essential for virulence in the oyster pathogen Vibrio splendidus LGP32. Here, we showed that V. splendidus LGP32 invades the oyster immune cells, the hemocytes, through subversion of host-cell actin cytoskeleton. In this process, OmpU serves as an adhesin/invasin required for β-integrin recognition and host cell invasion. Furthermore, the major protein of oyster plasma, the extracellular superoxide dismutase Cg-EcSOD, is used as an opsonin mediating the OmpU-promoted phagocytosis through its RGD sequence. Finally, the endocytosed bacteria were found to survive intracellularly, evading the host defense by preventing acidic vacuole formation and limiting reactive oxygen species production. We conclude that (i) V. splendidus is a facultative intracellular pathogen that manipulates host defense mechanisms to enter and survive in host immune cells, and (ii) that OmpU is a major determinant of host cell invasion in Vibrio species, used by V. splendidus LGP32 to attach and invade oyster hemocytes through opsonisation by the oyster plasma Cg-EcSOD.


Ras/ERK1/2 pathway regulates the self-renewal of dairy goat spermatogonia stem cells.
Spermatogonia stem cells (SSCs), also named the male germline stem cells (mGSCs), which is located at the base of the seminiferous tubules of testis, is the basis for generating sperm steadily in male animals. Currently, there are some preliminary study on the self-renewal and differentiation of SSCs, but further mechanism, especially in large animals, has not been clearly understood. Ras/ERK1/2 pathway is widely distributed in multiple cells in vivo. It plays an important role in cell proliferation, differentiation and so on. However, the study on the function for the self-renewal of dairy goats SSCs has not been investigated. In this study, the dairy goat SSCs characterization were evaluated by semi-RT-PCR, alkaline phosphatase (AP) staining, and immunofluorescence staining. Then, Ras/ERK1/2 pathway was blocked by specific MEK1/2 inhibitor PD0325901. We analyzed the proliferation by cell number, cell growth curve, Brdu incorporation assay, and cell cycle analysis. The results showed that the proliferation was significantly inhibited by PD0325901. Cell apoptosis induced by blocking the Ras/ERK1/2 pathway was analyzed by TUNEL. The expression of ETV5 and BCL6B, the downstream gene of Ras/ERK1/2 pathway, was downregulated. This study suggest that the Ras/ERK1/2 pathway plays a critical role in maintaining the self-renewal of dairy goat SSCs via regulation of ETV5 and BCL6B. This study laid a foundation for insights into the mechanism of SSCs self-renewal comprehensively.


Quantitative study on the effects of chronic ethanol administration on the testis of adult male rat.
Considering the possibility that alcoholism induces gonadal dysfunction, the present work was designed to investigate the morphophysiology of rat testes submitted to experimental alcoholism. Male Sprague-Dawley rats weighing 150+/-5 gm were chronically given 40% ethanol solution at a dose of 3 g/kg body weight for 30 days. (3)H-thymidine autoradiographic investigations and histological studies were carried out to determine the proliferative activity and/or different stages of spermatogenesis in the seminiferous tubule cycle and Leydig cells. The 3H-thymidine autoradigraphic investigation revealed that there was a significant inhibition in the proliferative activity of the spermatogonia in all stages of the seminiferous tubule cycle in the alcohol-treated rats versus controls as indicated by the values of (3)H-labelling indices. The histological and numerical investigations indicated that the alcohol-treated rats presented testicular lesions including a significant decrease in the diameter of the seminiferous tubules, the number of different germ cells in all stages of the seminiferous tubule cycle and the presence of degenerative germ cells. In addition, there was a significant decrease in the number of Leydig cells. The present work suggests the deleterious effects of alcohol on the testes. These effects may be due to the effect of alcohol on the gonadotrophic cells of the pituitary gland and/or directly on the seminiferous tubules and Leydig cells.


Activation helix orientation of the estrogen receptor is mediated by receptor dimerization: evidence from molecular dynamics simulations.
In recent years, the nuclear receptors (NR) dynamics have been studied extensively by various approaches. However, the transition path of helix 12 (H12) to an agonist or an antagonist conformation and the exchange pathway between these states is not clear yet. A number of accelerated molecular dynamics (aMD) runs were performed on both an ERα monomer and a homodimer with a total length of 2.2 μs. We have been able to sample reasonably well the H12 conformational landscape to reproduce precisely both the agonist and the antagonist conformations, starting from an unfolded position, and to describe the transition path between them, even in the presence of an agonist ligand. These conformations were the most prevalent, suggesting that the extended H12 state is not likely to exist and that the natural ERα H12 position might exist in both the agonist and antagonist states. Remarkably, the H12 transition occurs and is regulated only in a dimer form and the proper agonist or antagonist H12 conformation can be achieved solely in one of the dimer subunits. These results clearly demonstrate that clusters of the two well-known H12 states exist by themselves in the protein free energy landscape, i.e. they are not constituted directly by the ligands, and dimerization favors the switch between them. Conversely, in a monomer, no transitions have been observed. Thus, the dimer formation helps the constitution of populations of discrete H12 conformational states and reshapes the conformational landscape. Further analyses have shown that these observations can be explained by specific interface and long range protein-protein interactions, resulting in conformational fluctuations in helices 5 and 11. Based on these results, a new ERα activation/deactivation mechanism and a sequence of binding events during receptor activity modulation have been suggested according to which ligands control the H12 conformation via alterations of the inter-dimer interactions. These findings agree with the HDX and fluorescence experiments and provide an explanation on a structural basis of these data, demonstrating that the dynamics of H12 are not altered greatly upon ligand binding and large fluctuations at the end of H11 are present.


SAVoR: a server for sequencing annotation and visualization of RNA structures.
RNA secondary structure is required for the proper regulation of the cellular transcriptome. This is because the functionality, processing, localization and stability of RNAs are all dependent on the folding of these molecules into intricate structures through specific base pairing interactions encoded in their primary nucleotide sequences. Thus, as the number of RNA sequencing (RNA-seq) data sets and the variety of protocols for this technology grow rapidly, it is becoming increasingly pertinent to develop tools that can analyze and visualize this sequence data in the context of RNA secondary structure. Here, we present Sequencing Annotation and Visualization of RNA structures (SAVoR), a web server, which seamlessly links RNA structure predictions with sequencing data and genomic annotations to produce highly informative and annotated models of RNA secondary structure. SAVoR accepts read alignment data from RNA-seq experiments and computes a series of per-base values such as read abundance and sequence variant frequency. These values can then be visualized on a customizable secondary structure model. SAVoR is freely available at http://tesla.pcbi.upenn.edu/savor.


[Role of government in clinical trials].
The regulation of clinical trials by the Government is a process of continuous change and adaptation, current challenge is to ensure the safety of participants and get balance of administrative procedures. Development and regulation of clinical trials in different countries vary according to the situation, context national or international execution, determining the insufficiency of national regulation requiring review of international regulation. The aim of this publication is to present a comprehensive overview of the role of Government in the regulation of clinical trials in different realities. It includes a review of the regulation in The European Union, The United States and some Latin American countries and finally the regulation in Peru. Contemporary trends in the regulation of clinical trials, are characterized by increasing standards of quality, ensuring the safety of the participants, promote transparency, lower bureaucratic processes and strengthening ethics IRB committees in the framework of open democratic processes, involving all stakeholders in dynamic processes based on current knowledge and changing tendencies. The challenge is to promote the development of clinical trials from the government institutions (universities, research centers, institutes, hospitals, etc.) priorizing local needs including orphan drugs, prevalent and neglected diseases, and therapeutic use of active components of local native plants.


Peripheral nerve injuries in sports-related surgery: presentation, evaluation, and management: AAOS exhibit selection.
Peripheral nerve injuries during sports-related operative interventions are rare complications, but the associated morbidity can be substantial. Early diagnosis, efficient and effective evaluation, and appropriate management are crucial to maximizing the prognosis, and a clear and structured algorithm is therefore required. We describe the surgical conditions and interventions that are commonly associated with intraoperative peripheral nerve injuries. In addition, we review the common postoperative presentations of patients with these injuries as well as the anatomic structures that are directly injured or associated with these injuries during the operation. Some examples of peripheral nerve injuries incurred during sports-related surgery include ulnar nerve injury during ulnar collateral ligament reconstruction of the elbow and elbow arthroscopy, median nerve injury during ulnar collateral ligament reconstruction of the elbow, axillary nerve injury during Bankart repair and the Bristow transfer, and peroneal nerve injury during posterolateral corner reconstruction of the knee and arthroscopic lateral meniscal repair. We also detail the clinical and radiographic evaluation of these patients, including the utility and timing of radiographs, magnetic resonance imaging (MRI), ultrasonography, electromyography (EMG), and nonoperative or operative management. The diagnosis, evaluation, and management of peripheral nerve injuries incurred during sports-related surgical interventions are critical to minimizing patient morbidity and maximizing postoperative function. Although these injuries occur during a variety of procedures, common themes exist regarding evaluation techniques and treatment algorithms. Nonoperative treatment includes physical therapy and medical management. Operative treatments include neurolysis, transposition, neurorrhaphy, nerve transfer, and tendon transfer. This article provides orthopaedic surgeons with a simplified, literature-based algorithm for evaluation and management of peripheral nerve injuries associated with sports-related operative procedures.


The influence of personality disorder on outcome in adolescent self-harm.
Little is currently known about the presence and impact of personality disorder in adolescents who self-harm. To evaluate personality disorder in repeated self-harm in adolescence and its impact on self-harm psychopathology and adaptation outcomes over 1 year. A clinical referral sample (n = 366) of adolescents presenting with repeated self-harm aged 12-17 years, as part of a randomised controlled trial (Assessment of Treatment in Suicidal Teenagers study, ASSIST). Personality disorder was assessed using the Structured Clinical Interview for DSM-IV Axis II (SCID-II). One-year outcomes included frequency and severity of repeat self-harm, self-reported suicidality, mood and functional impairment. About 60% of the referred adolescents showed one or more forms of personality disorder. Personality disorder was associated with significantly greater severity of self-harm, overall psychopathology and impairment. There was a complex association with treatment adherence. Personality disorder predicted worse 1-year outcomes in relation to self-harm frequency and severity, as well as impairment, suicidality and depressive symptoms. Personality disorder can be reliably measured in adolescence and showed high prevalence in this clinical self-harm sample. Controlling for other variables, it showed a strong independent association with self-harm severity at referral and predicted adherence to treatment and clinical outcomes (independent of treatment) over 1 year. Consideration of personality disorder diagnosis is indicated in the assessment and management of adolescents who repeatedly self-harm.


Inhibition of agonist-induced vasocontraction and impairment of endothelium-dependent vasorelaxation by extract of motorcycle exhaust particles in vitro.
The in vitro effects of motorcycle exhaust particulate extract (MEPE) on blood vessels were studied in thoracic aorta isolated from Wistar rat. The MEPE relaxed the phenylephrine-precontracted aorta with an EC50 value of 0.05 +/- 0.004 mg/ml. This relaxing effect of MEPE persisted in endothelium-denuded aorta, suggesting that the relaxation induced by MEPE is endothelium-independent. The phenylephrine-induced vasocontraction and inositol 1,4,5-triphosphate formation were inhibited concentration dependently in aorta pretreated with MEPE. However, the high-K+-induced vasocontraction and the Ca2+ sensitivity of the contractile proteins were not significantly affected by MEPE. In addition to the inhibitory effects on agonist-induced contraction, the vasorelaxing effects both of acetylcholine and of sodium nitroprusside were impaired by MEPE. The inhibitory effects of MEPE on acetylcholine and sodium nitroprusside, but not phenylephrine, were reversed by cotreatment with superoxide dismutase. These results showed that the MEPE, added in vitro, inhibited the phenylephrine-induced, but not depolarization-induced, vasocontraction of aorta. The MEPE also impaired the vasorelaxation induced by acetylcholine in a superoxide anion-dependent manner.


Lighting design for globally illuminated volume rendering.
With the evolution of graphics hardware, high quality global illumination becomes available for real-time volume rendering. Compared to local illumination, global illumination can produce realistic shading effects which are closer to real world scenes, and has proven useful for enhancing volume data visualization to enable better depth and shape perception. However, setting up optimal lighting could be a nontrivial task for average users. There were lighting design works for volume visualization but they did not consider global light transportation. In this paper, we present a lighting design method for volume visualization employing global illumination. The resulting system takes into account view and transfer-function dependent content of the volume data to automatically generate an optimized three-point lighting environment. Our method fully exploits the back light which is not used by previous volume visualization systems. By also including global shadow and multiple scattering, our lighting system can effectively enhance the depth and shape perception of volumetric features of interest. In addition, we propose an automatic tone mapping operator which recovers visual details from overexposed areas while maintaining sufficient contrast in the dark areas. We show that our method is effective for visualizing volume datasets with complex structures. The structural information is more clearly and correctly presented under the automatically generated light sources.


An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers.
Up to 30% stage I lung cancer patients suffer recurrence within 5 years of curative surgery. We sought to improve existing protein-coding gene and microRNA expression prognostic classifiers by incorporating epigenetic biomarkers. Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed by Cox regression and Kaplan-Meier survival analysis in both cohorts. Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. The HOXA9 locus was methylated de novo in stage I tumors (p < 0.0005). High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB. Four protein-coding gene (XPO1, BRCA1, HIF1α, and DLC1), miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome (HR, 2.8; p = 0.002; HR, 2.3; p = 0.01; and HR, 2.4; p = 0.005, respectively), and when combined, identified high-risk, therapy naive, stage I patients (HR, 10.2; p = 3 × 10). All associations were confirmed in two independently collected cohorts. A prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung cancer patients at high risk of recurrence.


Improved Deformation-Driven Element Packing with RepulsionPak.
We present a method to fill a container shape with deformable instances of geometric elements selected from a library, creating a 2D artistic composition called an element packing. Each element is represented as a mass-spring system, allowing it to deform to achieve a better fit with its neighbours and the container. We start with an initial placement of small elements and gradually transform them using a physics simulation that trades off between the evenness of the packing and the deformations of the individual elements. Unlike previous work, elements can be given preferred orientations, and we can use shape matching to control the initial placement of elements in tight convex corners. We also explore the creation of tileable packings, and validate our approach using statistical measurements of the distributions of positive and negative space in packings. Our method produces compositions in which the negative space between elements is approximately uniform in width, similar to real-world examples created by artists.


Perioperative Near-Infrared Spectroscopy Monitoring in Neonates With Congenital Heart Disease: Relationship of Cerebral Tissue Oxygenation Index Variability With Neurodevelopmental Outcome.
To evaluate the value of perioperative cerebral near-infrared spectroscopy monitoring using variability analysis in the prediction of neurodevelopmental outcomes in neonates undergoing surgery for congenital heart disease. Retrospective cohort study. Urban, academic, tertiary-care children's hospital. Neonates undergoing surgery with cardiopulmonary bypass for congenital heart disease. Perioperative monitoring of continuous cerebral tissue oxygenation index by near-infrared spectroscopy and subsequent neurodevelopmental testing at 6, 15, and 21 months of age. We developed a new measure, cerebral tissue oxygenation index variability, using the root mean of successive squared differences of averaged 1-minute cerebral tissue oxygenation index values for both the intraoperative and first 24-hours postoperative phases of monitoring. There were 62 neonates who underwent cerebral tissue oxygenation index monitoring during surgery for congenital heart disease and 44 underwent subsequent neurodevelopmental testing (12 did not survive until testing and six were lost to follow-up). Among the 44 monitored patients who underwent neurodevelopmental testing, 20 (45%) had abnormal neurodevelopmental indices. Patients with abnormal neurodevelopmental indices had lower postoperative cerebral tissue oxygenation index variability when compared with patients with normal indices (p = 0.01). Adjusting for class of congenital heart disease and duration of deep hypothermic circulatory arrest, lower postoperative cerebral tissue oxygenation index variability was associated with poor neurodevelopmental outcome (p = 0.02). We found reduced postoperative cerebral tissue oxygenation index variability in neonatal survivors of congenital heart disease surgery with poor neurodevelopmental outcomes. We hypothesize that reduced cerebral tissue oxygenation index variability may be a surrogate for impaired cerebral metabolic autoregulation in the immediate postoperative period. Further research is needed to investigate clinical implications of this finding and opportunities for using this measure to drive therapeutic interventions.


The role of T cells in the regulation of B cell tolerance.
The study of conventional models of B cell tolerance has suggested that self-tolerance is imposed on B cells at an early stage in their development due to a peculiar sensitivity of immature B cells to tolerance induction. While this concept accounts for some aspects of central B cell tolerance, it is inconsistent with recent reports of tolerance induction in mature splenic B cells from immunoglobulin transgenic mice. We present an alternative model, the hierarchical model (Aust. N. Z. J. Med. 25, 761-767, 1995), in which regulation of naive B cell reactivity is a function of antigen signal strength and availability of T cell help, but is independent of B cell maturation stage. In turn, the development of tolerance or memory in the T cell compartment is dependent on a combination of antigen-MHC recognition by T cells and antigen-nonspecific signalling by antigen-presenting cells. Using a transgenic model of T-B collaboration, we have shown that both immature and mature self-reactive B cells can be rescued and induced to secrete auto-antibody if the B cell determinant is linked to a carrier protein bearing a foreign T cell determinant.


A Comparison of Oxygenation Efficacy between High-Flow Nasal Cannulas and Standard Facemasks during Elective Tracheal Intubation for Patients with Obesity: A Randomized Controlled Trial.
Obese patients are predisposed to rapid oxygen desaturation during tracheal intubation. We aimed to compare the risk of desaturation between high-flow nasal oxygenation (HFNO) and classical facemask oxygenation (FMO) during rapid sequence intubation for elective surgery in obese patients. Adults with a body mass index ≥30 kg·m−2 undergoing laparoscopic sleeve gastrectomy at a medical center were randomized into the HFNO group (n = 40) and FMO group (n = 40). In the HFNO group, patients used a high-flow nasal cannula to receive 30 to 50 L·min−1 flow of heated and humidified 100% oxygen. In the FMO group, patients received a fitting facemask with 15 L·min−1 flow of 100% oxygen. After 5-min preoxygenation, rapid sequence intubation was performed. The primary outcome was arterial desaturation during intubation, defined as a peripheral capillary oxygen saturation (SpO2) <92%. The risk of peri-intubation desaturation was significantly lower in the HFNO group compared to the FMO group; absolute risk reduction: 0.20 (95% confidence interval: 0.05−0.35, p = 0.0122); number needed to treat: 5. The lowest SpO2 during intubation was significantly increased by HFNO (median 99%, interquartile range: 97−100) compared to FMO (96, 92−100, p = 0.0150). HFNO achieved a higher partial pressure of arterial oxygen (PaO2) compared to FMO, with medians of 476 mmHg (interquartile range: 390−541) and 397 (351−456, p = 0.0010), respectively. There was no difference in patients' comfort level between groups. Compared with standard FMO, HFNO with apneic oxygenation reduced arterial desaturation during tracheal intubation and enhanced PaO2 among patients with obesity.


Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture.
Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.


Semiautomated head-and-neck IMRT planning using dose warping and scaling to robustly adapt plans in a knowledge database containing potentially suboptimal plans.
Prior work by the authors and other groups has studied the creation of automated intensity modulated radiotherapy (IMRT) plans of equivalent quality to those in a patient database of manually created clinical plans; those database plans provided guidance on the achievable sparing to organs-at-risk (OARs). However, in certain sites, such as head-and-neck, the clinical plans may not be sufficiently optimized because of anatomical complexity and clinical time constraints. This could lead to automated plans that suboptimally exploit OAR sparing. This work investigates a novel dose warping and scaling scheme that attempts to reduce effects of suboptimal sparing in clinical database plans, thus improving the quality of semiautomated head-and-neck cancer (HNC) plans. Knowledge-based radiotherapy (KBRT) plans for each of ten "query" patients were semiautomatically generated by identifying the most similar "match" patient in a database of 103 clinical manually created patient plans. The match patient's plans were adapted to the query case by: (1) deforming the match beam fluences to suit the query target volume and (2) warping the match primary/boost dose distribution to suit the query geometry and using the warped distribution to generate query primary/boost optimization dose-volume constraints. Item (2) included a distance scaling factor to improve query OAR dose sparing with respect to the possibly suboptimal clinical match plan. To further compensate for a component plan of the match case (primary/boost) not optimally sparing OARs, the query dose volume constraints were reduced using a dose scaling factor to be the minimum from either (a) the warped component plan (primary or boost) dose distribution or (b) the warped total plan dose distribution (primary + boost) scaled in proportion to the ratio of component prescription dose to total prescription dose. The dose-volume constraints were used to plan the query case with no human intervention to adjust constraints during plan optimization. KBRT and original clinical plans were dosimetrically equivalent for parotid glands (mean/median doses), spinal cord, and brainstem (maximum doses). KBRT plans significantly reduced larynx median doses (21.5 ± 6.6 Gy to 17.9 ± 3.9 Gy), and oral cavity mean (32.3 ± 6.2 Gy to 28.9 ± 5.4 Gy) and median (28.7 ± 5.7 Gy to 23.2 ± 5.3 Gy) doses. Doses to ipsilateral parotid gland, larynx, oral cavity, and brainstem were lower or equivalent in the KBRT plans for the majority of cases. By contrast, KBRT plans generated without the dose warping and dose scaling steps were not significantly different from the clinical plans. Fast, semiautomatically generated HNC IMRT plans adapted from existing plans in a clinical database can be of equivalent or better quality than manually created plans. The reductions in OAR doses in the semiautomated plans, compared to the clinical plans, indicate that the proposed dose warping and scaling method shows promise in mitigating the impact of suboptimal clinical plans.


Lesbian, gay, and bisexual (LGB) youth within in welfare: Prevalence, risk and outcomes.
The purpose of this study was to estimate the population of sexual minority or LGB (lesbian, gay and bisexual) children and youth involved with the child welfare system, and to compare their health, mental health, placement and permanency outcomes to those of non-LGB youth. Data were drawn from the Second National Survey of Child and Adolescent Well-Being (NSCAW-II), a nationally representative sample of children who were referred to child welfare due to a report of abuse or neglect over a fifteen month period. This sample included youth ages eleven and older who self-identified their sexual orientation (n = 1095). Results indicate that approximately 15.5% of all system involved youth identified as lesbian, gay or bisexual, and that lesbian and bisexual females, and LGB youth of color are both overrepresented within child welfare systems. Although no substantive difference in risk factors, permanency and placement were found between LGB and Non-LGB youth, LGB youth were significantly more likely to meet the criteria for adverse mental health outcomes. Implications for child welfare practice and policy are presented, along with recommendations for future research in this area.


Genetically permissive recognition of adjacent epitopes from the 19-kDa antigen of Mycobacterium tuberculosis by human and murine T cells.
The specificity of the T cell-immune repertoire at the level of individual antigenic determinants could play a fundamental role in the immunopathogenesis of tuberculous infections. Therefore, we analyzed the immunogenicity, genetic restriction, and epitope core structure of two adjacent, yet distinct, immunodominant T cell determinants from the 19-kDa Ag of Mycobacterium tuberculosis. After immunization with two peptides comprising residues 45 to 64 and 61 to 80, vigorous in vitro proliferative responses to the homologous peptide were elicited in five different strains of C57BL/10 mice (H-2b,k,d,s,f), indicating that both epitopes were recognized in a genetically permissive manner. When immunized with intact 19-kDa protein, lymph node cells from the same mouse strains responded to both peptides, with the exception of H-2b mice, which did not respond to p45-64. Delayed-type hypersensitivity responses in C57BL/10 (H-2b) mice were elicited by p61-80 only, whereas in H-2d mice both peptides were delayed-type hypersensitivity negative, despite eliciting pronounced proliferative responses. Analysis of the proliferative responses of human PBMC in purified protein derivative-positive healthy subjects and tuberculosis patients revealed significant differences in the antigenicity to the two peptides. All purified protein derivative-positive healthy and diseased individuals manifested strong responses to p45-64, indicating HLA permissive recognition. In contrast, pronounced responses to p61-80 were detected only in patients with lymphatic tuberculosis. Epitope core structures, composed of 6 or 7 residues within each peptide, have been mapped with peptides of overlapping sequence. Significantly, for both epitopes, the core sequences recognized by both human and murine T cells were almost identical. We conclude that despite many similarities between murine and human T cell epitope recognition, distinct differences in the responsiveness of the infected host could play a role in pathogenesis. Furthermore, the genetically permissive nature of the identified epitopes is a potentially important attribute for the development of peptide-based diagnostic reagents and vaccines.


Prolonged enhancement of anterior thalamic synaptic responsiveness by stimulation of a brain-stem cholinergic group.
This study describes the effects of brain-stem cholinergic laterodorsal tegmental (LDT) stimulation on the synaptic responsiveness of anterior thalamic (AT) neurons. A sample of AT cells, physiologically identified by their short-latency (less than 6.5 msec) response to mammillary body (MB) stimulation, was recorded in unanesthetized, chronically implanted cats and in urethane-anesthetized cats. In chronic experiments, LDT stimulation evoked a short-latency (10-20 msec) excitation in most AT cells. Moreover, brief LDT trains (3 shocks at 300 Hz, every 3 sec) enhanced the responsiveness of AT cells to both MB (orthodromic) and cortical (ortho- and antidromic) stimuli. This effect did not vary as a function of the interval between LDT conditioning and MB or cortical testing shocks, but as a function of the number of trials. The effects of LDT stimuli resisted reserpine treatment (0.75 mg/kg), suggesting that they were not dependent on the coactivation of monoaminergic fibers. Finally, LDT trains did not suppress inhibitory processes in AT neurons when conditioning-testing intervals were longer than 60 msec. Intracellular recordings performed in urethane-anesthetized cats revealed that LDT stimulation induced a short-latency depolarization which increased with membrane hyperpolarization and was associated with an increase in apparent membrane conductance. Usually, isolated LDT trains did not evoke lasting changes in membrane potential or conductance. However, when LDT trains were applied every 3 sec, they gradually decreased the apparent membrane conductance without altering the membrane potential. This conductance change had a time course similar to the LDT-induced potentiation of responsiveness observed in the chronic experiments. In some neurons, LDT conditioning trains also induced a marked increase in the probability of fast prepotentials being triggered by subthreshold MB or cortical orthodromic volleys. In order to distinguish the cumulative effects of repeated LDT trains from the possibly slow time course of LDT influences, we studied the effects of a unique 1 sec LDT train (at 30 Hz) on the synaptic responsiveness of AT cells recorded extracellularly in reserpine-treated, urethane-anesthetized animals. Such LDT trains induced a 2.9-fold increase in synaptic responsiveness, reaching its peak 40-50 sec after the LDT train and lasting up to 4 min. Iontophoretic application of the muscarinic blocker scopolamine blocked these long-lasting potentiating effects of LDT stimuli. Removal of cortical and basal forebrain inputs to the AT nuclear complex by appropriate transections did not abolish the potentiating effects of LDT trains.(ABSTRACT TRUNCATED AT 400 WORDS)


Resource allocation in metabolic networks: kinetic optimization and approximations by FBA.
Based on recent theoretical results on optimal flux distributions in kinetic metabolic networks, we explore the congruences and differences between solutions of kinetic optimization problems and results obtained by constraint-based methods. We demonstrate that, for a certain resource allocation problem, kinetic optimization and standard flux balance analysis (FBA) give rise to qualitatively different results. Furthermore, we introduce a variant of FBA, called satFBA, whose predictions are in qualitative agreement with kinetic optimization.


Selective bond dissociation and rearrangement with optimally tailored, strong-field laser pulses.
We used strong-field laser pulses that were tailored with closed-loop optimal control to govern specified chemical dissociation and reactivity channels in a series of organic molecules. Selective cleavage and rearrangement of chemical bonds having dissociation energies up to approximately 100 kilocalories per mole (about 4 electron volts) are reported for polyatomic molecules, including (CH3)2CO (acetone), CH3COCF3 (trifluoroacetone), and C6H5COCH3 (acetophenone). Control over the formation of CH(3)CO from (CH3)2CO, CF3 (or CH3) from CH3COCF3, and C6H5CH3 (toluene) from C6H5COCH3 was observed with high selectivity. Strong-field control appears to have generic applicability for manipulating molecular reactivity because the tailored intense laser fields (about 10(13) watts per square centimeter) can dynamically Stark shift many excited states into resonance, and consequently, the method is not confined by resonant spectral restrictions found in the perturbative (weak-field) regime.


Management of ionizing radiation injuries and illnesses, part 5: local radiation injury.
This final article in the series on the medical management of ionizing radiation injuries and illnesses focuses on the effects of acute ionizing radiation exposure to one of the largest organ systems of the body-the skin. These injuries may extend beyond the skin into deeper tissues and cause local radiation injury. There are numerous causes of these injuries, ranging from industrial incidents to medical procedures. In the present article, the authors characterize the clinical course, pathophysiologic process, sources of injury, diagnosis, and management of local radiation injury and describe a clinical scenario. This information is important for primary care physicians, to whom patients are likely to initially present with such injuries.


Opsonizing properties of rat ficolin-A in the defence against Cryptococcus neoformans.
Cryptococcus neoformans is a pathogenic fungus causing life threatening infections in humans. The present in vitro study aimed to investigate the opsonizing properties of a well characterized serum ficolin (rat ficolin-A), a member of carbohydrate-recognition molecules of the innate immune system, in the defence against this fungal pathogen. Using flow cytometric analysis we have been able to demonstrate that ficolin-A readily binds to two different acapsular C. neoformans serotypes (representative of the primary infectious form of this fungus) whereas the encapsulated forms are not being recognized. The ficolin-A binding was concentration dependent and inhibited by the acetylated sugars N-acetyleglucosamine and N-acetylegalactosamine but less so by galactose, glucose and mannan. The binding was enhanced at acidic pHs (5.7 and 4.7) compared to physiological pH (7.4) which may indicate that the carbohydrate recognizing fibrinogen-like domains of ficolins undergo conformational changes providing more efficient binding at sites of inflammation where the pH is much lower than normal. We further assessed the biological consequence of the ficolin-A recognition of acapsular C. neoformans by investigating their interaction with lung epithelial cells (type II pneumocytes cell line A549). Flow cytometric analysis demonstrated that ficolin-A opsonized acapsular C. neoformans showed significantly increased adherence to A549 cells when exposed to acidic conditions compared to the unopsonized controls (p=0.04). We conclude that ficolin-A binds acapsular C. neoformans via their carbohydrate recognizing fibrinogen-like domains leading to enhanced uptake by lung epithelial cells in vitro.


Prolotherapy: An effective therapy for Tietze syndrome.
To compare the short-term effect of prolotherapy and conservative terapy for the Tietze syndrome. From 2013 to 2014, twenty-one patients underwent prolotherapy (group 1) and thirteen underwent conservative therapy with analgesics (group 2). A visual analogue score (VAS) was recorded for measurement of pain intensity in all patients before (Pre VAS) and after injection first day (VAS1), first week (VAS2) and fourth week (VAS3). Group 2 were received systemic nonsteroidal anti-inflammatory drug. VAS score was recorded similarly at the same times (Pre VAS, VAS1, VAS2, VAS3), and clinical affects were compared between the two groups. The mean VAS score (mm) before prolotherapy was 7.10 in patients who received prolotherapy, and 7.14 mm in patients who treated nonsteroidal anti-inflammatory drug. The mean VAS after the fist injection was 2.19 mm and dropped to 1.52 mm after the third injection. The mean VAS after the nonsteroidal anti-inflammatory drug treatment dropped 2.62 mm and during the same scores to 3 weeks later. There was no significant difference between the group 1 and group 2 in the age, sex and comorbidity. Also there was no significant difference between the group 1 and group 2 in clinical and radiological evidence. The prolotherapy group showed a faster recovery, including significantly reduced clinic findings (p: 0.001). Third VAS is significant finding for the prolotherapy group. Prolotherapy could be performed safely and is a method with a favorable long term treatments for Tietze Syndrome. It may be the ideal procedure for patients with drugs side effects and advers events especially for those with limited liver and kidney reserve or significant comorbidities.


Live or heat-killed probiotic administration reduces anxiety and central cytokine expression in BALB/c mice, but differentially alters brain neurotransmitter gene expression.
While the potential for probiotic supplements to act as adjunctive treatments for mood disorders has been widely demonstrated, the precise mode of action remains unclear. To investigate the psychotropic effects of a multi-species probiotic on emotional behaviour in male BALB/c mice, we explored the potential mechanisms of action relating to the temporal changes in the mRNA expression of brain cytokines, BDNF, central 5HT receptor and serotonin transporter (SERT) and GABA receptor in the context of probiotic induced behavioural changes. The effects of a heat-killed probiotic, independent of microbial metabolic processes were also evaluated on the same outcomes to understand whether the host response to the bacteria is more or less important than the contribution of the metabolic activity of the bacteria themselves. Results showed that probiotic supplementation reduced anxiety-like behaviours, increased time spent in the light area of the light-dark box, and decreased the expression of pro-inflammatory cytokines in the brain. Furthermore, probiotic administration elevated hippocampal BDNF and decreased GABAB1β expression. Interestingly, the heat-killed probiotic and its membrane fraction had similar effects on emotional behaviours and gene expression in the brain. The ingestion of live and heat-killed probiotic preparations also reduced TLR2 expression in the gut. Thus, the present study reveals that the anxiolytic action of a multispecies probiotic in BALB/c mice is independent of bacterial viability. This suggests that it is the host response to probiotics, rather than microbial metabolism that facilitates the molecular changes in the brain and downstream behaviours. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".


Search for relevant indications for selenium supplementation in thyroid diseases.
Selenium plays a significant role in the thyroid function and its deficiency is considered by some authors to be a cause of thyroid disorders. The potential therapeutic influence of selenium supplementation in thyroid disease was investigated in several studies and some results were encouraging, however results were inconsistent and did not allow conclusion to be drawn. For that reason, we have performed a review study on relevance of selenium supplementation in thyroid disease. Till now, there is no strong evidence that selenium supplementation leads to clinical improvement in the course of autoimmune thyroiditis, nodular goitre or thyroid cancer. On the other hand, there is some evidence that selenium is effective in the treatment of orbitopathy; thus, the European Group on Graves' Orbitopathy (EUGOGO) recommends selenium administration in mild active orbitopathy.


Designing Awe in Virtual Reality: An Experimental Study.
Awe is a little-studied emotion with a great transformative potential. Therefore, the interest toward the study of awe's underlying mechanisms has been increased. Specifically, researchers have been interested in how to reproduce intense feelings of awe within laboratory conditions. It has been proposed that the use of virtual reality (VR) could be an effective way to induce awe in controlled experimental settings, thanks to its ability of providing participants with a sense of "presence," that is, the subjective feeling of being displaced in another physical or imaginary place. However, the potential of VR as awe-inducing medium has not been fully tested yet. In the present study, we provided an evidence-based design and a validation of four immersive virtual environments (VEs) involving 36 participants in a within-subject design. Of these, three VEs were designed to induce awe, whereas the fourth VE was targeted as an emotionally neutral stimulus. Participants self-reported the extent to which they felt awe, general affect and sense of presence related to each environment. As expected, results showed that awe-VEs could induce significantly higher levels of awe and presence as compared to the neutral VE. Furthermore, these VEs induced significantly more positive than negative affect. These findings supported the potential of immersive VR for inducing awe and provide useful indications for the design of awe-inspiring virtual environments.


Body composition and hematological changes following ascents of Mt. Aconcagua and Mt. Everest.
Both Mt. Aconcagua (22,841.2 ft/6962 m) and Mt. Everest (29,035.4 ft/ 8850 m) are highly prized summits by mountaineers, yet there are no published studies comparing the physiological adaptations that occur from climbing both peaks. This case study compares the changes in body composition and hematology of a mountaineer who ascended both peaks. The male subject was 41 yr of age during the Aconcagua ascent and 43 yr of age during the Everest ascent, and had a history of ascents above 19,685 ft (6000 m). Baseline body composition measurements and blood draws were done within a few days of departure for both expeditions. Body composition was assessed by air displacement plethysmography and the blood draw consisted of a complete blood count (CBC). Post-expedition measurements were taken 10-14 d after reaching the summits. The ascent of Aconcagua resulted in a 2.0-kg drop in body mass and a reduction in body fat (15.5% to 12.1%), but blood chemistry remained within +/- 2% of baseline values. Body mass was reduced from 65.0 kg to 60.5 kg during the Everest expedition with a drop in body fat from 17.3% to 10.2%. Despite no change in RBCs there were increases in hemoglobin and mean corpuscular hemoglobin of 12.7% and 13.7%, respectively. It took the subject 12 d to reach the summit of Aconcagua, whereas it took 50 d to reach the summit of Everest. The longer duration at higher altitude for the Everest expedition resulted in more dramatic physiological changes.


Isolation and expression of the xynB gene and its product, XynB, a consistent component of the Clostridium cellulovorans cellulosome.
The nucleotide sequence of the Clostridium cellulovorans xynB gene, which encodes the XynB xylanase, consists of 1,821 bp and encodes a protein of 607 amino acids with a molecular weight of 65,976. XynB contains a typical N-terminal signal peptide of 29 amino acid residues, followed by a 147-amino-acid sequence that is homologous to the family 4-9 (subfamily 9 in family 4) carbohydrate-binding domain. Downstream of this domain is a family 10 catalytic domain of glycosyl hydrolase. The C terminus separated from the catalytic domain by a short linker sequence contains a dockerin domain responsible for cellulosome assembly. The XynB sequence from mass spectrometry and N-terminal amino acid sequence analyses agreed with that deduced from the nucleotide sequence. XynB was highly active toward xylan, but not active toward carboxymethyl cellulose. The enzyme was optimally active at 40 degrees C and pH 5.0. Northern hybridizations revealed that xynB is transcribed as a monocistronic 1.9-kb mRNA. RNA ligase-mediated rapid amplification of 5' cDNA ends by PCR (RLM-5'RACE PCR) analysis of C. cellulovorans RNA identified a single transcriptional start site of xynB located 47 bp upstream from the first nucleotide of the translation initiation codon. Alignment of the xynB promoter region provided evidence for highly conserved sequences that exhibited strong similarity to the sigmaA consensus promoter sequences of gram-positive bacteria. Expression of xynB mRNA increased from early to middle exponential phase and decreased during the early stationary phase when the cells were grown on cellobiose. No alternative promoter was observed by RLM-5'RACE PCR and reverse transcriptase PCR analyses during expression. The analysis of the products from xylan hydrolysis by thin-layer chromatography indicated its endoxylanase activity. The results suggest that XynB is a consistent and major cellulosomal enzyme during growth on cellulose or xylan.


nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors.
Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570). Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis. Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred. nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.


Degradation of Acetonitrile by Pseudomonas putida.
A bacterium capable of utilizing high concentrations of acetonitrile as the sole source of carbon and nitrogen was isolated from soil and identified as Pseudomonas putida. This bacterium could also utilize butyronitrile, glutaronitrile, isobutyronitrile, methacrylonitrile, propionitrile, succinonitrile, valeronitrile, and some of their corresponding amides, such as acetamide, butyramide, isobutyramide, methacrylamide, propionamide, and succinamide as growth substrates. Acetonitrile-grown cells oxidized acetonitrile with a K(m) of 40.61 mM. Mass balance studies with [C]acetonitrile indicated that nearly 66% of carbon of acetonitrile was released as CO(2) and 14% was associated with the biomass. Metabolites of acetonitrile in the culture medium were acetic acid and ammonia. The acetate formed in the early stages of growth completely disappeared in the later stages. Cell extracts of acetonitrile-grown cells contained activities corresponding to nitrile hydratase and amidase, which mediate the breakdown of actonitrile into acetic acid and ammonia. Both enzymes were intracellular and inducible and hydrolyzed a wide range of substrates. The specific activity of amidase was at least 150-fold higher than the activity of the enzyme nitrile hydratase.


A modified per os double contrast examination of the colon in the elderly.
A modified per os double contrast examination of the colon was used in 62 elderly patients in whom conventional barium enema had been unsuccessful. We created endogenous gas generation instead of air insufflation by per os administration of a special mixture containing barium sulfate, lactulose and gastrografin. Good quality double contrast images of the colon were obtained after 12 hours in 59 of the 62 patients. The sensitivity of the method was 100% in 6 patients suffering from carcinoma and in 15 patients suffering from diverticular disease. However, the method failed to demonstrate small solitary polyps in 5 patients and it was also negative in another 27 patients. 7 of these had negative endoscopy and in the remaining a definite diagnosis was not established by any other method. It seems that this method may become an alternative for investigation of suspected colonic pathology in the elderly patients with difficulty in retaining the barium enema.


Late emergence of the vibrissa direction selectivity map in the rat barrel cortex.
In the neocortex, neuronal selectivities for multiple sensorimotor modalities are often distributed in topographical maps thought to emerge during a restricted period in early postnatal development. Rodent barrel cortex contains a somatotopic map for vibrissa identity, but the existence of maps representing other tactile features has not been clearly demonstrated. We addressed the issue of the existence in the rat cortex of an intrabarrel map for vibrissa movement direction using in vivo two-photon imaging. We discovered that the emergence of a direction map in rat barrel cortex occurs long after all known critical periods in the somatosensory system. This map is remarkably specific, taking a pinwheel-like form centered near the barrel center and aligned to the barrel cortex somatotopy. We suggest that this map may arise from intracortical mechanisms and demonstrate by simulation that the combination of spike-timing-dependent plasticity at synapses between layer 4 and layer 2/3 and realistic pad stimulation is sufficient to produce such a map. Its late emergence long after other classical maps suggests that experience-dependent map formation and refinement continue throughout adult life.


dbl-1/TGF-β and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest.
Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.


High-Throughput Multiplexed Quantitation of Protein Aggregation and Cytotoxicity in a Huntington's Disease Model.
A hallmark of Huntington's disease is the presence of a large polyglutamine expansion in the first exon of the Huntingtin protein and the propensity of protein aggregation by the mutant proteins. Aberrant protein aggregation also occurs in other polyglutamine expansion disorders, as well as in other neurodegenerative diseases including Parkinson's, Alzheimer's, and prion diseases. However, the pathophysiological role of these aggregates in the cell death that characterizes the diseases remains unclear. Identification of small molecule probes that modulate protein aggregation and cytotoxicity caused by aggregated proteins may greatly facilitate the studies on pathogenesis of these diseases and potentially lead to development of new therapies. Based on a detergent insoluble property of the Huntingtin protein aggregates, we have developed a homogenous assay to rapidly quantitate the levels of protein aggregates in a cellular model of Huntington's disease. The protein aggregation assay has also been multiplexed with a protease release assay for the measurement of cytotoxicity resulting from aggregated proteins in the same cells. Through a testing screen of a compound library, we have demonstrated that this multiplexed cytotoxicity and protein aggregation assay has ability to identify active compounds that prevent cell death and/or modulate protein aggregation in cells of the Huntington's disease model. Therefore, this multiplexed screening approach is also useful for development of high-throughput screening assays for other neurodegenerative diseases involving protein aggregation.


Psoriasis Severity, Health-Related Quality of Life, Work Productivity, and Activity Impairments Among Patients With Moderate to Severe Psoriasis Receiving Systemic Treatment: Real-World Data From Clinical Practice in Spain.
The treatment of psoriasis should not only focus on skin affectations but also weigh the parameters for health-related quality of life (HRQoL), thereby tackling the concept of cumulative life course impairment (CLCI) and treating the patient from a holistic perspective. The CRYSTAL study aimed to characterize psoriasis with real-word data from Spanish clinical practice in patients with moderate to severe disease who received continuous systemic treatment for at least 24 weeks by using the absolute Psoriasis Area and Severity Index (PASI) score and its correlation to HRQoL. This was a non-interventional, cross-sectional study conducted in 30 centers in Spain, with 301 patients between the ages of 18 and 75 years. The study collected data regarding current treatment and absolute PASI and their relationship to HRQoL using the Dermatology Life Quality Index (DLQI), to activity impairment using the Work Productivity and Activity Impairment (WPAI) questionnaire, and to treatment satisfaction. The mean (SD) age was 50.5 (12.5) years, with a duration of disease of 14 (14.1) years. The mean (SD) absolute PASI reported was 2.3 (3.5), with 28.7% of patients presenting with PASI from >1 to ≤3 and 22.6% with PASI>3. Higher PASI scores were associated with higher DLQI (p<0.001) and WPAI scores and lower levels of treatment satisfaction (p<0.001). These data indicate that achieving lower absolute PASI values may correlate not only with better HRQoL but also with better work productivity and treatment satisfaction.


Activation of the lac repressor in the transgenic mouse.
We have introduced sequences encoding the lac repressor of Escherichia coli into the genome of the mouse. One sequence was derived from the bacterial lac operon and the other was created by re-encoding the amino acid sequence of lacI with mammalian codons. Both versions are driven by an identical promoter fragment derived from the human beta-actin locus and were microinjected into genetically identical pronuclear stage embryos. All transgenes utilizing the bacterial coding sequence were transcriptionally silent in all somatic tissues tested. The sequence re-encoded with mammalian codons was transcriptionally active at all transgene loci and expressed ubiquitously. Using methylation-sensitive enzymes, we have determined the methylation status of lac repressor transgenes encoded by either the bacterial or mammalian sequence. The highly divergent bacterial sequence was hypermethylated at all transgene loci, while the mammalian sequence was only hypermethylated at a high copy number locus. This may reflect a normal process that protects the genome from acquiring new material that has an abnormally divergent sequence or structure.


A morphoelastic model for dermal wound closure.
We develop a model of wound healing in the framework of finite elasticity, focussing our attention on the processes of growth and contraction in the dermal layer of the skin. The dermal tissue is treated as a hyperelastic cylinder that surrounds the wound and is subject to symmetric deformations. By considering the initial recoil that is observed upon the application of a circular wound, we estimate the degree of residual tension in the skin and build an evolution law for mechanosensitive growth of the dermal tissue. Contraction of the wound is governed by a phenomenological law in which radial pressure is prescribed at the wound edge. The model reproduces three main phases of the healing process. Initially, the wound recoils due to residual stress in the surrounding tissue; the wound then heals as a result of contraction and growth; and finally, healing slows as contraction and growth decrease. Over a longer time period, the surrounding tissue remodels, returning to the residually stressed state. We identify the steady state growth profile associated with this remodelled state. The model is then used to predict the outcome of rewounding experiments designed to quantify the amount of stress in the tissue, and also to simulate the application of pressure treatments.


Long-term follow-up of bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones.
It is unknown whether long term cross-sex hormone treatment affects the human skeleton. We monitored bone mineral density and biochemical markers of bone turnover for 28-63 months in 20 male-to-female transsexuals (M-->F) treated with anti-androgens and oestrogens, and 19 female-to-male transsexuals (F-->M) treated with androgens. They underwent gonadectomy 13-35 months after the start of cross-sex hormone administration. Bone mineral density (BMD) and the markers of bone turnover osteocalcin, alkaline phosphatase, fasting urinary calcium/creatinine and hydroxyproline/creatinine, were measured at baseline, after 1 year and after 28-63 months of cross-sex hormone administration. In oestrogen-treated M-->F, variables of bone turnover decreased significantly with consecutive measurements. BMD had increased significantly after 1 year, but decreased again to baseline levels after 28-63 months of cross-sex hormones. In F-->M, alkaline phosphatase levels increased during the first year. BMD did not change during the first year but had decreased significantly after 28-63 months following ovariectomy. In both M-->F and F-->M, the change of BMD correlated inversely with serum LH and FSH levels. Of all biochemical variables LH levels appeared to be the best predictor of loss of BMD; in the long-term LH levels were more elevated in testosterone-treated F-->M than in oestrogen-treated M-->F transsexuals. In M-->F, oestrogen treatment prevented bone loss after testosterone deprivation. In F-->M the testosterone dosage used, associated with a decline in serum oestradiol levels, was unable to maintain bone mass fully in all subjects in the longer term. The inverse relationship between BMD and serum LH levels suggests that the dose of hormone replacement has been too low in subjects with a decline in their BMD. Its cause might be underdosing or non-compliance in some patients. We propose that serum LH levels may be used as a measure of the adequacy of replacement with sex steroids.


Tissue engineering in plastic surgery: a review.
Novel tissue- and organ-engineering strategies are needed to address the growing need for replacement biological parts. Collective progress in stem cell technology, biomaterials, engineering, and molecular medicine has advanced the state of regenerative medicine, yet many hurdles to clinical translation remain. Plastic surgeons are in an ideal position to capitalize on emerging technologies and will be at the forefront of transitioning basic science research into the clinical reconstructive arena. This review highlights fundamental principles of bioengineering, recent progress in tissue-specific engineering, and future directions for this exciting and rapidly evolving area of medicine.


Genetic signatures of a demographic collapse in a large-bodied forest dwelling primate (Mandrillus leucophaeus).
It is difficult to predict how current climate change will affect wildlife species adapted to a tropical rainforest environment. Understanding how population dynamics fluctuated in such species throughout periods of past climatic change can provide insight into this issue. The drill (Mandrillus leucophaeus) is a large-bodied rainforest adapted mammal found in West Central Africa. In the middle of this endangered monkey's geographic range is Lake Barombi Mbo, which has a well-documented palynological record of environmental change that dates to the Late Pleistocene. We used a Bayesian coalescent-based framework to analyze 2,076 base pairs of mitochondrial DNA across wild drill populations to infer past changes in female effective population size since the Late Pleistocene. Our results suggest that the drill underwent a nearly 15-fold demographic collapse in female effective population size that was most prominent during the Mid Holocene (approximately 3-5 Ka). This time period coincides with a period of increased dryness and seasonality across Africa and a dramatic reduction in forest coverage at Lake Barombi Mbo. We believe that these changes in climate and forest coverage were the driving forces behind the drill population decline. Furthermore, the warm temperatures and increased aridity of the Mid Holocene are potentially analogous to current and future conditions faced by many tropical rainforest communities. In order to prevent future declines in population size in rainforest-adapted species such as the drill, large tracts of forest should be protected to both preserve habitat and prevent forest loss through aridification.


Dam's infection progress and within-herd prevalence as predictors of Mycobacterium avium subsp. paratuberculosis ELISA response in Danish Holstein cattle.
Understanding the primary routes of transmission of Mycobacterium avium subsp. paratuberculosis (MAP) is pivotal to manage the pathogen in cattle herds. MAP is transmitted both vertically and horizontally, and both the dam's stage of infection and the prevalence in the population are therefore potentially important for MAP transmission control. The objective of this study was therefore to assess the dam's infection progress and the within-herd test-prevalence as predictors of MAP infection in Danish dairy cattle. MAP specific antibody ELISA records from 95,025 dam-offspring pairs were combined with test-prevalence estimates from 939 Danish Holstein herds. The odds of testing ELISA-positive given the within-herd test-prevalence and the time-period a dam had had MAP specific antibodies were estimated for the offspring. Both dams and offspring were tested as adults, and parity-group was used to correct for the effect of age. The results showed that both the within-herd test-prevalence and the dam's infection progress were significant predictors, while the dams that had tested positive when giving birth and up to 0.7 years after were more likely to have offspring that would test positive. The odds of testing positive were about 1.5 to 2.5 times higher for these offspring, compared to offspring of dams that never tested positive. Furthermore, offspring born in high (>5% ELISA-positive) and medium (2.5 to 5% ELISA-positive) prevalence herds had 9 and 3, respectively, times higher odds of testing positive, compared to animals born in a low prevalence herd. The variance heterogeneity reduced 81% through the included predictors. The results of this study suggest that irrespective of the prevalence, offspring of dams with MAP specific antibodies should be considered as high-risk animals when managing the infection in cattle herds, but both the prevalence and the dam's infection status are important in MAP control.


Serum anti-müllerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood.
Anti-müllerian hormone (AMH) is an accurate marker of ovarian reserve. However, sufficiently large sets of normative data from infancy to the end of reproductive life are scarce. This study was an assessment of serum AMH levels in healthy females. In 804 healthy females ranging from infancy until the end of the reproductive period, serum AMH levels were measured with an enzyme-linked immunometric assay. All adults had regular menstrual cycles. The majority was proven fertile and none of them had used oral contraceptive pills prior to study inclusion. In the total cohort, AMH was inversely correlated with age (r = -0.24; P < 0.001). The age at which the maximum AMH value was attained was at 15.8 yr. In girls younger than 15.8 yr, serum AMH and age were positively correlated (r = +0.18; P = 0.007). Thereafter AMH levels remained stable (r = -0.33; P = 0.66), whereas from the age of 25.0 yr onward, an inverse correlation between AMH and age (r = -0.47; P < 0.001) was observed. At any given age, considerable interindividual differences in serum AMH levels were observed. During infancy AMH levels increase, whereas during adolescence, a plateau until the age of 25 yr was observed. From the age of 25 yr onward, serum AMH levels correlate inversely with age, implying that AMH is applicable as a marker of ovarian reserve only in women of 25 yr old and older. Our nomogram may facilitate counseling women on their reproductive potential.


Outcome evaluation with signal activation of functional MRI in spinal cord injury.
The authors investigated the changes of cortical sensorimotor activity in functional MRI (fMRI) and functional recovery in spinal cord injury (SCI) patients who had been treated by bone marrow cell transplantation. Nineteen patients with SCI were included in this study; ten patients with clinical improvement and nine without. The cortical sensorimotor activations were studied using the proprioceptive stimulation during the fMRI. Diagnostic accuracy of fMRI with neurological improvement was 70.0% and 44.4% for sensitivity and specificity, respectively. Signal activation in the ipsilateral motor cortex in fMRI was commonly observed in the clinically neurological improved group (p-value=0.002). Signal activation in the contralateral temporal lobe and basal ganglia was more commonly found in the neurological unimproved group (p-value<0.001). Signal activation in other locations was not statistically different. In patients with SCI, activation patterns of fMRI between patients with neurologic recovery and those without varied. Such plasticity should be considered in evaluating SCI interventions based on behavioral and neurological measurements.


Rationale and design of the national emphysema treatment trial. A prospective randomized trial of lung volume reduction surgery. The national emphysema treatment trial research group
The National Emphysema Treatment Trial is a multicenter, randomized clinical trial of medical therapy vs medical therapy plus lung volume reduction surgery (LVRS) for the treatment of patients with severe bilateral emphysema. LVRS will be accomplished by bilateral stapled excision via median sternotomy or video-assisted thoracoscopic surgery. Every patient will complete 6 to 10 weeks of pulmonary rehabilitation prior to randomization and will participate in a maintenance program of pulmonary rehabilitation after randomization. The primary outcome to be assessed by the trial is survival. Additional outcomes to be assessed are maximum exercise capacity, pulmonary function, oxygen requirement, distance walked in 6 min, quality of life, respiratory symptoms, and health-care utilization and costs. In addition, selected clinics will evaluate lung mechanics and respiratory muscle function, partial and maximal flow-volume curves, gas exchange during maximal exercise, and right heart function. The trial is targeted to enroll patients with severe emphysema who have no significant comorbid conditions; each patient will be randomized to one of the two treatment groups. The study duration is 4.5 years with a close-out period of 6 months.


A quantitative evaluation of the AVITEWRITE model of handwriting learning.
Much sensory-motor behavior develops through imitation, as during the learning of handwriting by children. Such complex sequential acts are broken down into distinct motor control synergies, or muscle groups, whose activities overlap in time to generate continuous, curved movements that obey an inverse relation between curvature and speed. The adaptive vector integration to endpoint handwriting (AVITEWRITE) model of Grossberg and Paine (2000) [A neural model of corticocerebellar interactions during attentive imitation and predictive learning of sequential handwriting movements. Neural Networks, 13, 999-1046] addressed how such complex movements may be learned through attentive imitation. The model suggested how parietal and motor cortical mechanisms, such as difference vector encoding, interact with adaptively-timed, predictive cerebellar learning during movement imitation and predictive performance. Key psychophysical and neural data about learning to make curved movements were simulated, including a decrease in writing time as learning progresses; generation of unimodal, bell-shaped velocity profiles for each movement synergy; size scaling with isochrony, and speed scaling with preservation of the letter shape and the shapes of the velocity profiles; an inverse relation between curvature and tangential velocity; and a two-thirds power law relation between angular velocity and curvature. However, the model learned from letter trajectories of only one subject, and only qualitative kinematic comparisons were made with previously published human data. The present work describes a quantitative test of AVITEWRITE through direct comparison of a corpus of human handwriting data with the model's performance when it learns by tracing the human trajectories. The results show that model performance was variable across the subjects, with an average correlation between the model and human data of 0.89+/-0.10. The present data from simulations using the AVITEWRITE model highlight some of its strengths while focusing attention on areas, such as novel shape learning in children, where all models of handwriting and the learning of other complex sensory-motor skills would benefit from further research.


Current understanding of an Emerging Coronavirus using in silico approach: Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2).
Novel coronavirus (nCoV) namely "SARS-CoV-2" is being found responsible for current PANDEMIC commenced from Wuhan (China) since December 2019 and has been described with epidemiological linkage to China in about 221 countries and territories until now. In this study we have characterized the genetic lineage of SARS-CoV-2 and report the recombination within the genus and subgenus of coronaviruses. Phylogenetic relationship of thirty nine coronaviruses belonging to its four genera and five subgenera was analyzed by using the Neighbor-joining method using MEGA 6.0. Phylogenetic trees of full length genome, various proteins (spike, envelope, membrane and nucleocapsid) nucleotide sequences were constructed separately. Putative recombination was probed via RDP4. Our analysis describes that the "SARS-CoV-2" although shows great similarity to Bat-SARS-CoVs sequences through whole genome (giving sequence similarity 89%), exhibits conflicting grouping with the Bat-SARS-like coronavirus sequences (MG772933 and MG772934). Furthermore, seven recombination events were observed in SARS-CoV-2 (NC_045512) by RDP4. But not a single recombination event fulfills the high level of certainty. Recombination mostly housed in spike protein genes than rest of the genome indicating breakpoint cluster arises beyond the 95% and 99% breakpoint density intervals. Genetic similarity levels observed among "SARS-CoV-2" and Bat-SARS-CoVs advocated that the latter did not exhibit the specific variant that cause outbreak in humans, proposing a suggestion that "SARS-CoV-2" has originated possibly from bats. These genomic features and their probable association with virus characteristics along with virulence in humans require further consideration.


Transient serum exposure regimes to support dual differentiation of human mesenchymal stem cells.
Human mesenchymal stem cells (MSCs), which can generate both osteoblasts and chondrocytes, represent an ideal resource for orthopaedic repair using tissue-engineering approaches. One major difficulty for the development of osteochondral constructs using undifferentiated MSCs is that serum is typically used in culture protocols to promote differentiation of the osteogenic component, whereas existing chondrogenic differentiation protocols rely on the use of serum-free conditions. In order to define conditions which could be compatible with both chondrogenic and osteogenic differentiation in a single bioreactor, we have analysed the efficiency of new biphasic differentiation regimes based on transient serum exposure followed by serum-free treatment. MSC differentiation was assessed either in serum-free medium or with a range of transient exposure to serum, and compared to continuous serum-containing treatment. Although osteogenic differentation was not supported in the complete absence of serum, marker expression and extensive mineralization analyses established that 5 days of transient exposure triggered a level of differentiation comparable to that observed when serum was present throughout. This initial phase of serum exposure was further shown to support the successful chondrogenic differentiation of MSCs, comparable to controls maintained in serum-free conditions throughout. This study indicates that a culture based on temporal serum exposure followed by serum-free treatment is compatible with both osteogenic and chondrogenic differentiation of MSCs. These results will allow the development of novel strategies for osteochondral tissue engineering approaches using MSCs for regenerative medicine.


Time-averaged image projection through a multimode fiber.
Many disciplines, ranging from lithography to opto-genetics, require high-fidelity image projection. However, not all optical systems can display all types of images with equal ease. Therefore, the image projection quality is dependent on the type of image. In some circumstances, this can lead to a catastrophic loss of intensity or image quality. For complex optical systems, it may not be known in advance which types of images pose a problem. Here we show a new method called Time-Averaged image Projection (TAP), allowing us to mitigate these limitations by taking the entire image projection system into account despite its complexity and building the desired intensity distribution up from multiple illumination patterns. Using a complex optical setup, consisting of a wavefront shaper and a multimode optical fiber illuminated by coherent light, we succeeded to suppress any speckle-related background. Further, we can display independent images at multiple distances simultaneously, and alter the effective sharpness depth through the algorithm. Our results demonstrate that TAP can significantly enhance the image projection quality in multiple ways. We anticipate that our results will greatly complement any application in which the response to light irradiation is relatively slow (one microsecond with current technology) and where high-fidelity spatial distribution of optical power is required.


Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma.
The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45-CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).


Relationship between binocular vision, visual acuity, and fine motor skills.
The aims of this study were to analyze the relationship between the performance on fine motor skills tasks and peripheral and bifoveal sensory fusion, phasic and tonic motor fusion, the level of visual acuity (VA) in the poorer seeing eye, and the interocular VA difference. Subjects aged 12 to 28 years with a range of levels of binocular vision and VA performed three tasks: Purdue pegboard (number of pegs placed in 30 s), bead threading task (with two sizes of bead to increase the difficulty, time taken to thread a fixed number of beads), and a water pouring task (accuracy and time to pour a fixed quantity into five glass cylinders). Ophthalmic measures included peripheral (Worth 4 dot) and bifoveal (4 prism diopter) sensory fusion, phasic (prism bar) and tonic (Risley rotary prism) motor fusion ranges, and monocular VA. One hundred twenty-one subjects with a mean age of 18.8 years were tested; 18.2% had a manifest strabismus. Performance on fine motor skills tasks was significantly better in subjects with sensory and motor fusion compared with those without for most tasks, with significant differences between those with and without all measures of fusion on the pegboard and bead task. Both the acuity in the poorer seeing eye (highest r value of all motor tasks = 0.43) and the interocular acuity difference were statistically significantly related to performance on the motor skill tasks. Both sensory and motor fusion and good VA in both eyes are of benefit in the performance of fine motor skills tasks, with the presence of some binocular vision being beneficial compared with no fusion on certain sensorimotor tasks. This evidence supports the need to maximize fusion and VA outcomes.


Insulin-like growth factor-I and insulin are associated with the presence and advancement of adenomatous polyps.
Insulin and insulin-like growth factor-I (IGF-I) affect proliferation, differentiation, and apoptosis and are potential risk factors for colorectal cancer (CRC). Visceral obesity, possibly via hyperinsulinemia, has also been linked to CRC risk. We evaluated the relationship of insulin, IGF-I, insulin-like growth factor binding protein (IGFBP) 3, and visceral adipose tissue (VAT) in subjects with adenomatous polyps, the precursor lesion of colorectal cancer. Participants were asymptomatic subjects who underwent screening flexible sigmoidoscopy (FSG) within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Subjects underwent single-slice, computerized tomography scanning to measure VAT and serum fasting insulin, IGF-I, and IGFBP-3 measurements. Four hundred fifty-eight subjects were enrolled, of which 202 subjects had an adenoma, 70 of which were an advanced adenoma. IGF-I (P = .02), IGF-I/IGFBP-3 ratio (P = .003), and insulin (P = .02) were significantly increased in subjects with adenomas compared with controls. In an unadjusted logistic regression analysis using sex-specific quartile cut points, subjects in quartile 4 in comparison with quartile 1 of IGF-I (odds ratio [OR] = 1.7; [95% CI: 1.0-2.9], Ptrend = .03), IGF-I/IGFBP-3 ratio (OR = 1.9 [95% CI: 1.1-3.3], Ptrend = .01), and insulin (OR = 2.1 [95% CI: 1.2-3.6], Ptrend = .04) were at increased risk of adenoma. When limiting the case group to advanced adenomas, the effect was more pronounced: IGF-I (OR = 2.8 [95% CI: 1.3-6.2], Ptrend = .006), IGF-I/IGFBP-3 ratio (OR = 2.3, [95% CI: 1.0-5.2], Ptrend = .04), and insulin (OR = 2.3 [95% CI: 1.1-4.9], Ptrend = .14). Visceral adipose tissue was not associated with adenoma risk. Levels of IGF-I, ratio of IGF-I/IGFBP-3, and insulin are associated with adenomas and even more so with advanced adenomas. These data support the hypothesis that insulin and IGF-I may contribute to the development and advancement of adenomatous polyps.


Poisson image reconstruction with Hessian Schatten-norm regularization.
Poisson inverse problems arise in many modern imaging applications, including biomedical and astronomical ones. The main challenge is to obtain an estimate of the underlying image from a set of measurements degraded by a linear operator and further corrupted by Poisson noise. In this paper, we propose an efficient framework for Poisson image reconstruction, under a regularization approach, which depends on matrix-valued regularization operators. In particular, the employed regularizers involve the Hessian as the regularization operator and Schatten matrix norms as the potential functions. For the solution of the problem, we propose two optimization algorithms that are specifically tailored to the Poisson nature of the noise. These algorithms are based on an augmented-Lagrangian formulation of the problem and correspond to two variants of the alternating direction method of multipliers. Further, we derive a link that relates the proximal map of an l(p) norm with the proximal map of a Schatten matrix norm of order p. This link plays a key role in the development of one of the proposed algorithms. Finally, we provide experimental results on natural and biological images for the task of Poisson image deblurring and demonstrate the practical relevance and effectiveness of the proposed framework.


5-Year Arthroscopy-Free Survivorship and Outcomes of Adolescents Undergoing Primary Hip Arthroscopy: A Comparison Between Traumatic and Atraumatic Injuries.
There is a paucity of literature evaluating the outcomes of adolescent patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS) with a discrete traumatic event related to an injury. (1) To evaluate 5-year outcomes of adolescents undergoing hip arthroscopy for FAIS with traumatic injuries (TIs) and (2) to compare the traumatic group with a propensity-matched control group of patients with atraumatic injuries. Cohort study; Level of evidence, 3. Data were reviewed for all adolescent patients (<18 years) undergoing primary hip arthroscopy for FAIS with a TI between November 2008 and March 2015. Patients were included if they had preoperative and minimum 5-year follow-up outcomes for the modified Harris Hip Score (mHHS), Nonarthritic Hip Score, Hip Outcome Score-Sport Specific Subscale, and visual analog scale for pain. The Patient Acceptable Symptom State (PASS), minimum clinically important difference (MCID), and maximum outcome improvement satisfaction threshold (MOIT) were also calculated for both groups. Adolescents with TI were propensity matched in a 1:2 ratio according to age at surgery, sex, and body mass index (BMI) to a control group of adolescents who reported atraumatic hip symptoms (AHSs). Survivorship was defined as having no secondary surgery on the ipsilateral hip. A total of 31 patients (32 hips) with TI, out of 39 total patients (40 hips) (80%), were included with a mean follow-up time of 72.2 ± 24.1 months and age of 15.8 ± 1.3 years. The TI group demonstrated significant improvement in all patient-reported outcomes (PROs) (P < .001) and demonstrated high rates of MCID (78.3%) and PASS (91.3%) for the mHHS. When compared with a propensity-matched control group of 64 AHS hips (57 patients), the TI group demonstrated similar rates of improvement in all PROs, as well as rates of achieving the MCID, PASS, and MOIT for all PROs; however, the TI group demonstrated significantly higher revision rates compared with controls (28.1% vs 6.3%; P = .008). Adolescent patients with TIs undergoing hip arthroscopy demonstrated favorable outcomes for all PROs (P < .001) and achieved high rates of MCID (78.3%) and PASS (91.3%) for the mHHS. When compared with a propensity-matched control group of adolescents with atraumatic injuries undergoing hip arthroscopy, they achieved similar levels of improvement, postoperative scores, and clinical benefit thresholds; however, reoperation rates were higher in the TI group compared with controls.