Genome regulation by long noncoding RNAs.
The central dogma of gene expression is that DNA is transcribed into messenger RNAs, which in turn serve as the template for protein synthesis. The discovery of extensive transcription of large RNA transcripts that do not code for proteins, termed long noncoding RNAs (lncRNAs), provides an important new perspective on the centrality of RNA in gene regulation. Here, we discuss genome-scale strategies to discover and characterize lncRNAs. An emerging theme from multiple model systems is that lncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators and then target these enzymatic activities to appropriate locations in the genome. Consistent with this notion, lncRNAs can function as modular scaffolds to specify higher-order organization in RNP complexes and in chromatin states. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs for proper gene control across all kingdoms of life.


Scapular kinematics during transfers in manual wheelchair users with and without shoulder impingement.
Scapular function during humeral elevation has been reported in groups with and without shoulder impingement pathology. To date, no one has assessed scapular kinematics during upper extremity loaded tasks that manual wheelchair users must perform on a daily basis. Therefore, the objective of this study was to compare scapular kinematics and muscle activation patterns during two different wheelchair transfers in groups of manual wheelchair users with and without shoulder impingement. A case controlled study of manual wheelchair users, with and without shoulder impingement was performed. Twenty-three male manual wheelchair users (13 without shoulder impingement, 10 with shoulder impingement) performed transfers toward the involved or dominant limb (lead limb transfer) and away from the instrumented limb (trail limb transfer). Position and orientation measures of the thorax, scapula and humerus were obtained using an electromagnetic tracking system. Muscle activity data were collected using telemetered electromyography. Each subject performed three trials of wheelchair transfers to each side. Manual wheelchair users with impingement performed transfers with reduced thoracic flexion, increased scapular internal rotation, and increased humeral internal rotation as compared to those without impingement. Differences were found between the tasks in the scapular motions and EMG amplitude. Trail limb transfer presented with reduced scapular upward rotation and posterior tip as compared to the lead limb transfer task. Increased muscle activity for the lower trapezius and serratus anterior muscles was demonstrated in the trail limb transfer. This study provides the first kinematic description of scapular kinematics during transfer tasks. Shoulder impingement and direction of transfer does affect transfer task performance in manual wheelchair users. Scapular kinematics and muscle patterns during transfers may predispose manual wheelchair users to the development of shoulder pathology.


FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands.
Murine lacrimal, harderian and meibomian glands develop from the prospective conjunctival and eyelid epithelia and produce secretions that lubricate and protect the ocular surface. Sox9 expression localizes to the presumptive conjunctival epithelium as early as E11.5 and is detected in the lacrimal and harderian glands as they form. Conditional deletion showed that Sox9 is required for the development of the lacrimal and harderian glands and contributes to the formation of the meibomian glands. Sox9 regulates the expression of Sox10 to promote the formation of secretory acinar lobes in the lacrimal gland. Sox9 and FGF signaling were required for the expression of cartilage-associated extracellular matrix components during early stage lacrimal gland development. Fgfr2 deletion in the ocular surface epithelium reduced Sox9 and eliminated Sox10 expression. Sox9 deletion from the ectoderm did not affect Fgf10 expression in the adjacent mesenchyme or Fgfr2 expression in the epithelium, but appeared to reduce FGF signaling. Sox9 heterozygotes showed a haploinsufficient phenotype, in which the exorbital branch of the lacrimal gland was absent in most cases. However, enhancement of epithelial FGF signaling by expression of a constitutively active FGF receptor only partially rescued the lacrimal gland defects in Sox9 heterozygotes, suggesting a crucial role of Sox9, downstream of FGF signaling, in regulating lacrimal gland branching and differentiation.


Cell recognition in plants: Determinants of the stigma surface and their pollen interactions.
The interaction between compatible pollen grains and the female stigma of Gladiolus gandavensis has been used as a model system for investigation of cell recognition in plants. The molecular architecture of the receptive stigma surface has been investigated, and determinants binding to both concanavalin A and beta-glucosyl artificial carbohydrate antigen, as well as esterase activity, have been characterized, and conditions for their isolation have been established. The stigma surface, before and after modification, was found to bind (125)I-labeled proteins nonspecifically. Pollen tube penetration of the papillar cuticle is prevented when the receptor sites for concanavalin A are occupied. The concanavalin-A-binding determinants of the stigma surface have been fractionated to reveal several glycoproteins in the molecular weight range 43,000-93,000 and a group of glycolipids of molecular weight approximately 22,000. These results are interpreted in terms of two major recognition events regulating pollination.


Effects of electroacupuncture on the glucose-lipid metabolism and the expression of ZAG and GLUT4 in the femoral quadriceps and adipose tissue in the rats with type 2 diabetes mellitus.
To observe the effects on the glucose-lipid metabolism and the expression of zinc-α2-glycoprotein (ZAG) and glucose transporter 4 (GLUT4) in the femoral quadriceps and adipose tissue after electroacupuncture (EA) at "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) in the rats with diabetes mellitus type 2 (T2DM), so as to explore the effect mechanism of EA in treatment of T2DM. Twelve ZDF male rats were fed with high-sugar and high-fat fodder, Purina #5008 for 4 weeks to induce T2DM model. After successfully modeled, the rats were randomly divided into a model group and an EA group, with 6 rats in each one. Additionally, 6 ZL male rats of the same months age were collected as the blank group. The rats in the EA group were treated with EA at bilateral "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6), with continuous wave, 15 Hz in frequency, and 2 mA in intensity. The electric stimulation lasted 20 min each time. EA was delivered once daily, 6 times a week for 4 weeks. Separately, the levels of fasting blood glucose (FBG) was measured before modeling, before and after intervention, and the body mass of each rat was weighted before and after intervention. After intervention, the levels of the total cholesterol (TC), triacylglycerol (TG) and free fatty acid (FFA) in serum were detected using enzyme colorimetric method; and the levels of the serum insulin (INS) and ZAG were detected by ELISA. Besides, the insulin sensitivity index (HOMA-ISI) was calculated. With Western blot technique adopted, the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue were determined. After intervention, compared with the blank group, the levels of FBG and body mass, and the levels of serum TC, TG, FFA and INS increased (P<0.01), while HOMA-ISI decreased (P<0.01); the level of ZAG in the serum and the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue dropped (P<0.01) in the model group. In the EA group, compared with the model group, the levels of FBG and body mass, and the levels of serum TC, TG, FFA and INS were reduced (P<0.01), and HOMA-ISI increased (P<0.01); the level of ZAG in the serum and the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue increased (P<0.01, P<0.05). Electroacupuncture can effectively regulate glucose-lipid metabolism, improve insulin resistance and sensitivity in the rats with T2DM, which is associated with the modulation of ZAG and GLUT4 expression in the skeletal muscle and adipose tissue.


Quorum-sensing control of matrix protein production drives fractal wrinkling and interfacial localization of Vibrio cholerae pellicles.
Bacterial cells at fluid interfaces can self-assemble into collective communities with stunning macroscopic morphologies. Within these soft, living materials, called pellicles, constituent cells gain group-level survival advantages including increased antibiotic resistance. However, the regulatory and structural components that drive pellicle self-patterning are not well defined. Here, using Vibrio cholerae as our model system, we report that two sets of matrix proteins and a key quorum-sensing regulator jointly orchestrate the sequential mechanical instabilities underlying pellicle morphogenesis, culminating in fractal patterning. A pair of matrix proteins, RbmC and Bap1, maintain pellicle localization at the interface and prevent self-peeling. A single matrix protein, RbmA, drives a morphogenesis program marked by a cascade of ever finer wrinkles with fractal scaling in wavelength. Artificial expression of rbmA restores fractal wrinkling to a ΔrbmA mutant and enables precise tuning of fractal dimensions. The quorum-sensing regulatory small RNAs Qrr1-4 first activate matrix synthesis to launch pellicle primary wrinkling and ridge instabilities. Subsequently, via a distinct mechanism, Qrr1-4 suppress fractal wrinkling to promote fine modulation of pellicle morphology. Our results connect cell-cell signaling and architectural components to morphogenic patterning and suggest that manipulation of quorum-sensing regulators or synthetic control of rbmA expression could underpin strategies to engineer soft biomaterial morphologies on demand.


Concentration of halothane in veterinary operating and treatment rooms.
Fourteen operating rooms and 3 treatment rooms in veterinary facilities were monitored for ambient halothane. All rooms except 1 were in private practices, Regularly scheduled surgical or dental procedures were monitored under routine working situations of each facility. The mean maximal steady halothane value for all rooms was 4.7 ppm, with a range of 1.1. to 18 ppm. In 10 of the 17 rooms, concentrations exceeded the recommended maximum of 2 ppm. Rooms that had scavenging devices averaged 1.4 ppm whereas rooms without scavenging devices averaged 5.2 ppm. The average room volume for the 17 rooms was 39.7 m3, with a range of 21.6 to 79 m3. The average ventilation or air movement for 11 rooms was 6 rooms air exchanges/hour. The average time spent in the rooms during halothane usage was 1.8 hours.


The protein kinase Ire1 impacts pathogenicity of Candida albicans by regulating homeostatic adaptation to endoplasmic reticulum stress.
The unfolded protein response (UPR), crucial for the maintenance of endoplasmic reticulum (ER) homeostasis, is tied to the regulation of multiple cellular processes in pathogenic fungi. Here, we show that Candida albicans relies on an ER-resident protein, inositol-requiring enzyme 1 (Ire1) for sensing ER stress and activating the UPR. Compromised Ire1 function impacts cellular processes that are dependent on functional secretory homeostasis, as inferred from transcriptional profiling. Concordantly, an Ire1-mutant strain exhibits pleiotropic roles in ER stress response, antifungal tolerance, cell wall regulation and virulence-related traits. Hac1 is the downstream target of C. albicans Ire1 as it initiates the unconventional splicing of the 19 bp intron from HAC1 mRNA during tunicamycin-induced ER stress. Ire1 also activates the UPR in response to perturbations in cell wall integrity and cell membrane homeostasis in a manner that does not necessitate the splicing of HAC1 mRNA. Furthermore, the Ire1-mutant strain is severely defective in hyphal morphogenesis and biofilm formation as well as in establishing a successful infection in vivo. Together, these findings demonstrate that C. albicans Ire1 functions to regulate traits that are essential for virulence and suggest its importance in responding to multiple stresses, thus integrating various stress signals to maintain ER homeostasis.


Aggressive angiomyxoma in men. A report of two cases associated with inguinal hernias.
Aggressive angiomyxoma is a rare, locally invasive, but nonmetastasizing soft-tissue tumor that most commonly occurs in the pelvis or perineum of premenopausal women. In this article, we report two cases of aggressive angiomyxoma that occurred in middle-aged men. Although both patients initially presented with inguinal hernias, in other respects the two cases were significantly different. In one case, the tumor was small and found only incidentally at the time of surgery. In the other case, the tumor was extremely large, primarily involved the scrotal soft tissue, and was clinically thought to represent a testicular tumor.


Delayed appearance of pseudotypes between vesicular stomatitis virus influenza virus during mixed infection of MDCK cells.
In intact Madin-Darby canine kidney (MDCK) cell monolayers, vesicular stomatitis virus (VSV) matures only at basolateral membranes beneath tight junctions, whereas influenza virus buds from apical cell surfaces. Early in the growth cycle, the viral glycoproteins are restricted to the membrane domain from which each virus buds. We report here that phenotypic mixing and formation of VSV pseudotypes occurred when influenza virus-infected MDCK cells were superinfected with VSV. Up to 75% of the infectious VSV particles from such experiments were neutralized by antiserum specific for influenza virus, and a smaller proportion (up to 3%) were resistant to neutralization with antiserum specific for VSV. The latter particles, which were neutralized by antiserum to influenza A/WSN virus, are designated as VSV(WSN) pseudotypes. During mixed infections, both wild-type viruses were detected 1 to 2 h before either phenotypically mixed VSV or VSV(WSN) pseudotypes. Coincident with the appearance of cytopathic effects in the monolayer, the yield of pseudotypes rose dramatically. In contrast, in doubly infected BHK-21 cells, which do not show polarity in virus maturation sites and are not connected by tight junctions, VSV(WSN) pseudotypes were detected as soon as VSV titers rose to the minimum levels which allowed detection of pseudotypes, and the proportion observed remained relatively constant at later times. Examination of thin sections of doubly infected MDCK monolayers revealed that polarity in maturation sites was preserved for both viruses until approximately 12 h after inoculation with influenza virus, when disruption of junctional complexes was evident. Even at later periods, the majority of each virus type was associated with its normal membrane domain, suggesting that the sorting mechanisms responsible for directing the glycoproteins of VSV and influenza virus to separate surface domains continue to operate in doubly infected MDCK cells. The time course of VSV(WSN) pseudotype formation and changes in virus maturation sites are compatible with progressive mixing of viral glycoproteins at either intracellular or plasma membranes of doubly infected cells.


MdmX regulates transformation and chromosomal stability in p53-deficient cells.
The cellular homologues Mdm2 and MdmX play critical roles in regulating the activity of the p53 tumor suppressor in damaged and non-damaged cells and during development in mice. Recently, we have utilized genetically defined primary cells and mice to reveal that endogenous levels of MdmX can also suppress multipolar mitosis and transformation in hyperploid p53-deficient cells and tumorigenesis in p53-deficient mice. These MdmX functions are not shared by Mdm2, and are distinct from the well-established ability of MdmX to complex with and inhibit p53 activity. Here we discuss some of the ramifications of MdmX loss in p53-deficient cells and mice, and we explore further the fate of MdmX/p53-double null embryonic fibroblasts undergoing multi-polar cell division using time-lapse video microscopy. We also discuss the relationship between chromosomal loss, cell proliferation, and the tumorigenic potential of p53-deficient cells lacking MdmX.


Facial expression coding in children and adolescents with autism: Reduced adaptability but intact norm-based coding.
Individuals with autism spectrum disorder (ASD) can have difficulty recognizing emotional expressions. Here, we asked whether the underlying perceptual coding of expression is disrupted. Typical individuals code expression relative to a perceptual (average) norm that is continuously updated by experience. This adaptability of face-coding mechanisms has been linked to performance on various face tasks. We used an adaptation aftereffect paradigm to characterize expression coding in children and adolescents with autism. We asked whether face expression coding is less adaptable in autism and whether there is any fundamental disruption of norm-based coding. If expression coding is norm-based, then the face aftereffects should increase with adaptor expression strength (distance from the average expression). We observed this pattern in both autistic and typically developing participants, suggesting that norm-based coding is fundamentally intact in autism. Critically, however, expression aftereffects were reduced in the autism group, indicating that expression-coding mechanisms are less readily tuned by experience. Reduced adaptability has also been reported for coding of face identity and gaze direction. Thus, there appears to be a pervasive lack of adaptability in face-coding mechanisms in autism, which could contribute to face processing and broader social difficulties in the disorder.


Scalable Enrichment of Immunomodulatory Human Acute Myeloid Leukemia Cell Line-Derived Extracellular Vesicles.
Acute myeloid leukemia (AML) cells can secrete trophic factors, including extracellular vesicles (EVs), instructing the stromal leukemic niche. Here, we introduce a scalable workflow for purification of immunomodulatory AML-EVs to compare their phenotype and function to the parental AML cells and their secreted soluble factors. AML cell lines HL-60, KG-1, OCI-AML3, and MOLM-14 released EVs with a peak diameter of approximately 80 nm in serum-free particle-reduced medium. We enriched EVs >100x using tangential flow filtration (TFF) and separated AML-derived soluble factors and cells in parallel. EVs were characterized by electron microscopy, immunoblotting, and flow cytometry, confirming the double-membrane morphology, purity and identity. AML-EVs showed significant enrichment of immune response and leukemia-related pathways in tandem mass-tag proteomics and a significant dose-dependent inhibition of T cell proliferation, which was not observed with AML cells or their soluble factors. Furthermore, AML-EVs dose-dependently reduced NK cell lysis of third-party K-562 leukemia targets. This emphasizes the peculiar role of AML-EVs in leukemia immune escape and indicates novel EV-based targets for therapeutic interventions.


Gender Differences in Prevalence and Patterns of Dietary Supplement Use in Elite Athletes.
Purpose: Dietary supplement use by athletes has been the topic of previous research; however, the lack of homogeneity among published studies makes it difficult to analyze the differences, if any, in the patterns of use between male and female athletes. The aim of this study was to determine gender differences in the patterns of dietary supplement use by elite athletes. Methods: A total of 504 elite athletes (329 males and 175 females) participating in individual and team sports completed a validated questionnaire on dietary supplement use during the preceding season. The dietary supplements were categorized according to the latest IOC consensus statement. Results: A higher proportion of male versus female athletes (65.3 versus 56.5%, p < .05) consumed dietary supplements. Both male and female athletes reported a similar mean consumption of dietary supplements (3.2 ± 2.1 versus 3.4 ± 2.3 supplements/season, respectively; p = .45). Protein supplements were the most commonly consumed supplements in male athletes (49.8%) and their prevalence was higher than in female athletes (29.3%, p < .01). In females, multivitamins (39.4%) and branched-chain amino acids (39.4%) were the most commonly consumed supplements and iron supplementation was more prevalent than in males (22.2% versus 10.2%, p = .01). A higher proportion of male athletes relied on themselves to plan dietary supplements use (48.0%), while female appeared to rely more on doctors (34.0%, p < .01). Conclusion: In summary, male athletes had a slightly higher prevalence in the use of supplements than their female counterparts, specifically regarding protein supplements, and were more involved in the self-prescription of supplements.


Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE trial). A multicenter, prospective, randomized, controlled clinical registry trial based on the Swedish angiography and angioplasty registry (SCAAR) platform. Study design and rationale.
In ST-elevation myocardial infarction (STEMI), distal embolization of thrombus material often precludes restoration of normal coronary artery flow. Small-scaled studies have demonstrated that intracoronary thrombus aspiration improves flow and myocardial perfusion, but only one larger randomized single-center study has suggested a survival benefit. Thrombus aspiration is widely used in clinical practice and is recommended by international guidelines despite limited evidence. The Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia is a multicenter, prospective, randomized, controlled, clinical open-label trial based on the Swedish angiography and angioplasty registry (SCAAR) platform with blinded evaluation of end points. A total of 5,000 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) will randomly be assigned either to conventional PCI or to thrombus aspiration followed by PCI. SCAAR will be used as the platform for randomization, allowing a broad population of all-comers in the registry network to be enrolled. All follow-up will also be done in SCAAR and other national registries. The primary end point is time to all-cause death at 30 days. The Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia trial is the largest trial to date to evaluate the effect of thrombus aspiration on death following PCI in patients with STEMI. We propose the term randomized clinical registry trial to describe the novel entity of using an online national registry as platform for case records, randomization, and follow-up.


High-accuracy translation-rotation encoder with two gratings in a Littrow mount.
A new type of translation-rotation encoder that makes use of two identical transparent dielectric gratings lighted in a -1-order Littrow mount is proposed. The correct choice of the wavelength-to-groove-spacing ratio produces only two transmitted beams, which interfere with the highest possible visibility in a large range of experimental conditions. Thus this mounting permits high-accuracy encoders to be produced by the use of cheap photoresist or plastic gratings and opens the way to industrial applications in high-precision mechanics, information processing, etc.


C-terminal region of outer surface protein C binds borreliacidal antibodies in sera from patients with Lyme disease.
Borreliacidal antibodies specific for outer surface protein C (OspC) are induced shortly after infection with Borrelia burgdorferi. In this study, we identified the region of OspC recognized by immunoglobulin M (IgM) and IgG borreliacidal antibodies. Sera from patients with early Lyme disease were screened for borreliacidal activity specific for B. burgdorferi 50772 and OspC antibodies. Seven sera that contained similarly high titers of each response were then chosen randomly and adsorbed with OspC or a truncated OspC (OspC-Dra) containing the 50 amino acids nearest the carboxy terminus. Adsorption with OspC or OspC-Dra completely eliminated the borreliacidal activity in six (86%) of seven sera and significantly decreased the activity in the remaining serum (titer of 10,240 to 1,280). Moreover, OspC antibodies were no longer detected by OspC enzyme-linked immunosorbent assay or in a Western blot that contained native OspC. The findings confirmed that sera from patients with early Lyme disease contain high concentrations of IgM or IgG borreliacidal antibodies that bind a conserved region of OspC.


Impaired Action Control in Patients With Functional Movement Disorders.
Despite being a major cause of neurological disability, the neural mechanisms of functional movement disorders (FMDs) remain poorly understood. Recent studies suggest that FMD is linked to dysfunctional motor and prefrontal regions that could lead to motor and cognitive impairments. The aim of this study was to investigate different components of action control in FMD by using choice-reaction, stop-signal, and Simon tasks. Thirty patients with an FMD were prospectively recruited from the University of Louisville Movement Disorders Clinic and compared with 53 healthy control subjects, recruited from the Vanderbilt University Medical Center Movement Disorders Clinic. FMD motor symptom severity was rated with the Simplified Functional Movement Disorder Rating Scale (S-FMDRS). By using a computer and handheld response grips, participants completed three action-control tasks (choice-reaction task, stop-signal task, and Simon task) that tested action initiation, action cancelation, and interference control over actions. Action-control measures were compared between groups with analyses of variance. Patients with FMD were less proficient in suppressing incorrect response impulses on the Simon task and were slower to stop on the stop-signal task compared with healthy control subjects. No significant correlation with neuropsychological measurements, S-FMDRS scores, and action-control measurements was observed. These results suggest that two forms of inhibitory control, selective impulse inhibition and global action cancelation, are impaired in patients with FMD, independent of slowing on go reaction times. Improved understanding of action control in FMD may help in the development of new diagnostic and therapeutic strategies.


Immunobiology and the future of myoblast transfer therapy.
Myoblast transfer therapy (MTT) is a cell-mediated gene transfer method aimed at the restoration of normal dystrophin expression in Duchenne muscular dystrophy (DMD). Initial clinical MTT trials were conducted amid much controversy, as they were based on very few animal studies. Unfortunately, the trials were of little therapeutic benefit. As a result, there has been a renaissance of interest in experimental studies in animal models. In MTT, myoblasts are obtained by muscle biopsy from normal, i.e., dystrophin-positive, donors, expanded in culture, and injected directly into the muscles of dystrophic recipients. The major requirement for successful MTT is the survival of injected donor myoblasts in the host environment. However, a vast majority of donor cells fail to survive for more than 1 h after injection, and very few last beyond the first week. This review on the immunological aspects of MTT focuses in particular on the roles of specific components of the host immune response, the effects of tissue culture on donor cells, and strategies under development to circumvent the problem of donor myoblast death after injection in vivo.


Defining racial and ethnic disparities in THA and TKA.
For minority populations in the United States, especially African Americans, Hispanics, and Native Americans, healthcare disparities are a serious problem. The literature documents racial and ethnic utilization disparities with regard to THA and TKA. We therefore (1) defined utilization disparities for total joint arthroplasty in racial and ethnic minorities, (2) delineated patient and provider factors contributing to the lower total joint arthroplasty utilization, and (3) discussed potential interventions and future research that may increase total joint arthroplasty utilization by racial and ethnic minorities. We searched the MEDLINE database and identified 67 articles, 21 of which we excluded. By searching Google and Google Scholar and reference lists of the included articles, we identified 40 articles for this review. Utilization disparities were defined by documented lower utilization of THA or TKA in specific racial or ethnic groups. Lower utilization of THA and TKA among some racial and ethnic minority groups (African Americans, Hispanics) is not explained by decreased disease prevalence or disability. At least some utilization disparities are independent of income, geographic location, education, and insurance status. Causal factors related to racial and ethnic disparities may be related in part to patient factors such as health literacy, trust, and preferences. Provider unconscious or conscious biases or beliefs also play a role in at least some healthcare disparities. Racial and ethnic THA and TKA utilization disparities exist. These disparities are not explained by lower disease prevalence. The existing data suggest patient education, improved health literacy regarding THA and TKA, and a patient-provider relationship leading to improved trust would be beneficial. Research providing a better understanding of the root causes of these disparities is needed.


PCR detection of Toxoplasma gondii DNA in CSF for the differential diagnosis of AIDS-related focal brain lesions.
To evaluate whether the detection of Toxoplasma gondii DNA in CSF could contribute to the differential diagnosis of AIDS-related focal brain lesions, CSF samples from 88 HIV-infected patients (56 with focal brain lesions and 32 without) were tested prospectively by a nested PCR for the B1 gene of T. gondii. The assay had a detection limit of 10 trophozoite equivalents. Six of 18 patients with toxoplasmic encephalitis, but none of the 70 patients with other disorders, were PCR-positive (33.3% sensitivity and 100% specificity). Considering only those patients with cerebral toxoplasmosis from whom CSF was collected before or during the first week of antitoxoplasmic therapy, sensitivity rose to 50%. This was higher than the sensitivity in patients whose CSF was collected after the first week of treatment (odds ratio (OR) of 7.0; 95% CI: 0.46-218.2). The administration of antitoxoplasmic prophylaxis did not affect the PCR results. Patients with a poor response to therapy had a higher probability of detectable T. gondii DNA in their CSF (OR of 5.0; 95% CI: 0.37-86.6). All patients with other central nervous system disorders were PCR-negative. Despite the moderate sensitivity, the high specificity and positive predictive value (100%) make this assay a useful tool in the differential diagnosis of AIDS-related focal brain lesions as part of a series of CSF and neuroradiological examinations.


Treatment duration and gingival inflammation in Angle's Class I malocclusion patients treated with the conventional straight-wire method and the Damon technique: a single-centre, randomised clinical trial.
To compare the duration of orthodontic treatment and Gingival Index (GI) scores in Class I malocclusion patients treated with a conventional straight-wire method (CG) or the Damon technique (DT). Two-arm, parallel, randomised clinical trial Setting: A postgraduate orthodontic clinic Participants: Patients with a balanced facial profile, a full permanent dentition and Angle's Class I malocclusion with moderate crowding. The primary outcome was the duration of orthodontic treatment in months. GI scores throughout treatment were secondary outcomes and the PAR index was also assessed. Randomisation was accomplished using a table of random numbers and the allocation was concealed in sequentially numbered and opened, opaque, sealed envelopes. Blinding was applicable for PAR assessment only. Comparison of data between groups was performed with appropriate tests for independent samples. Twenty-two patients were randomly allocated to treatment in a 1:1 ratio to either CG or DT group. Age at the start of treatment, initial PAR index and GI scores were similar between groups. All patients completed the study, but the total duration of orthodontic treatment was almost half of the initial assumption. No statistically significant differences were observed in treatment duration (CG: Mean ([Formula: see text]) = 14.5 months, Standard Deviation (SD) = ±3.03; DT: [Formula: see text] months, SD = ±2.93; 95% Confidence Interval: -0.40 to 4.90; P = 0.093; t-test). The two groups did not differ statistically regarding the GI scores during the observational period. No serious harms were observed other than gingival inflammation associated with oral biofilm accumulation. The present study did not reveal statistically significant differences between the compared, conventional straight-wire method and Damon technique-treated, Angle's Class I malocclusion groups regarding total treatment duration and GI scores.


Use of in vivo two-dimensional MR spectroscopy to compare the biochemistry of the human brain to that of glioblastoma.
To develop an in vivo two-dimensional localized correlation spectroscopy technique with which to monitor the biochemistry of the human brain and the pathologic characteristics of diseases in a clinically applicable time, including ascertainment of appropriate postprocessing parameters with which to allow diagnostic and prognostic molecules to be measured, and to investigate how much of the chemical information, known to be available from malignant cultured cells, could be recorded in vivo from human brain. The study was approved by the institutional review board and was compliant with HIPAA. With use of a 3.0-T clinical magnetic resonance (MR) unit and a 32-channel head coil, localized correlation spectroscopy was performed in six healthy control subjects and six patients with glioblastoma multiforme (GBM) with an acquisition time of 11 minutes. Two-dimensional spectra were processed and analyzed and peak volume ratios were tabulated. The data used were proved to be normally distributed by passing the Shapiro-Wilk normality test. The first row of the spectra was extracted to examine diagnostic features. The pathologic characteristics and grade of each GBM were determined after biopsy or surgery. Statistically significant differences were assessed by using a t test. The localized correlation spectroscopy method assigned biochemical species from the healthy human brain. The correlation spectra of GBM were of sufficiently high quality that many of the cross peaks, recorded previously from malignant cell models in vitro, were observed, demonstrating a statistically significant difference (P < .05) between the cross peak volumes measured for healthy subjects and those with GBM (which include lipid, alanine, N-acetylaspartate, γ-aminobutyric acid, glutamine and glutamate, glutathione, aspartate, lysine, threonine, total choline, glycerophosphorylcholine, myo-inositol, imidazole, uridine diphosphate glucose, isocitrate, lactate, and fucose). The first row of the spectra was found to contain diagnostic features. Localized correlation spectroscopy of the human brain at 3.0 T with use of a 32-channel head coil was performed in 11 minutes and provided information about neurotransmitters, metabolites, lipids, and macromolecules. The method was able to help differentiate healthy brain from the biochemical signature of GBM in vivo. This method may, in the future, reduce the need for biopsy and is now applicable for the study of selected neurologic diseases.


Finding FMR1 mosaicism in Fragile X syndrome.
Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism. Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR). Four patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of FMR1 gene. The presence of a 2-3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions. The authors data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated.


Dynamic measurements of cervical neural foramina during neck movements in asymptomatic young volunteers.
Neural foraminal dimensions are considered important in nerve root compression and development of cervical radiculopathy, but baseline data regarding their range during normal motion are not available. An in vivo study of cervical foraminal motion was conducted to characterize normal 3D dynamic foraminal dimensions during physiological neck motion and compare between different tasks and intervertebral segments. Biplane X-ray imaging and computed tomography-based markerless tracking were used to measure foraminal height (FH) and width (FW) from five asymptomatic subjects during neck axial rotation and extension. FH and FW were quantified as the minimum (SI.Min and AP.Min), range (SI.Range and AP.Range), and median (SI.Med and AP.Med) of superoinferior (SI) and anteroposterior (AP) dimensions for each trial and as the coefficient of variation of these variables from three trials (SI.Med.CV and AP.Med.CV, SI.Range.CV and AP.Range.CV) at C3-4 through C6-7 levels for each subject. Differences were analyzed using mixed model ANOVA. AP.Range and AP.Med.CV were greater (P < 0.0001) while AP.Min and AP.Range.CV were smaller (P < 0.0006 and P < 0.0005) during neck extension than rotation. SI.Range and SI.Med.CV were greater for extension than rotation at C5-6 (P < 0.002 and P < 0.03), whereas SI.Med.CV was greater for rotation than extension at C3-4 (P < 0.03). AP.Range (P < 0.02), AP.Med.CV (P < 0.05), SI.Range (P < 0.0004), and SI.Med.CV (P < 0.02) were different between cervical levels, the latter two being during extension only. Patterns of FH and FW during normal motion are different between tasks and cervical levels. These findings are expected to provide a basis for future studies of spinal degeneration and surgical efficacy.


[Cause and surgical management of local recurrence of rectal cancer following radical resection retaining the anus].
Of seventy-one patients with rectal cancer after radical resection retaining the anus, 15 developed local recurrence with a recurrence rate of 21.1%. Local recurrence was correlated with improper safety margin from the lower edge of cancer to the anal end. There was statistical significant difference between 3 cm or more and 2 cm or less. The local recurrence was also related to the pathologic stage, histologic differentiation and implant of free cancer cells. It is suggested that the surgical indication of saving the anus be strict and without stretching, the safety margin from the lower edge of cancer to the anal end should not be less than 2 cm in early rectal cancer and not less than 4 cm in advanced lesions. During the operation, no touching tumor technique, thorough rinsing of the peritoneal cavity and pre- or post-operative radiotherapy are important for prevention of local recurrence. Early local recurrent rectal cancer can be detected by periodic examinations.


A dual encapsulation strategy to generate anion-responsive luminescent lanthanide hydrogels.
We report a new method to generate ion-responsive luminescent hydrogels, involving encapsulation of a luminescent lanthanide probe within crosslinked amphiphilic polymer particles and subsequent entrapment within a hydrogel. The resulting hydrogels are capable of reversible bicarbonate sensing, exhibit no leaching, and can be tuned for a range of sensing applications.


Making Evidence Actionable: Interactive Dashboards, Bayes, and Health Care Innovation.
The results of many large-scale federal or multi-site evaluations are typically compiled into long reports which end up sitting on policymaker's shelves. Moreover, the information policymakers need from these reports is often buried in the report, may not be remembered, understood, or readily accessible to the policymaker when it is needed. This is not a new challenge for evaluators, and advances in statistical methodology, while they have created greater opportunities for insight, may compound the challenge by creating multiple lenses through which evidence can be viewed. The descriptive evidence from traditional frequentist models, while familiar, are frequently misunderstood, while newer Bayesian methods provide evidence which is intuitive, but less familiar. These methods are complementary but presenting both increases the amount of evidence stakeholders and policymakers may find useful. In response to these challenges, we developed an interactive dashboard that synthesizes quantitative and qualitative data and allows users to access the evidence they want, when they want it, allowing each user a customized, and customizable view into the data collected for one large-scale federal evaluation. This offers the opportunity for policymakers to select the specifics that are most relevant to them at any moment, and also apply their own risk tolerance to the probabilities of various outcomes.


Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis.
Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.


alphaII-Spectrin breakdown product cerebrospinal fluid exposure metrics suggest differences in cellular injury mechanisms after severe traumatic brain injury.
Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI. To further understand these biomarkers, the present study examined (1) the exposure and kinetic characteristics of SBDPs in cerebrospinal fluid (CSF) of adults with severe TBI, and (2) the relationship between these exposure and kinetic metrics and severity of injury. This clinical database study analyzed CSF concentrations of 150-, 145-, and 120-kDa SBDPs in 38 severe TBI patients. Area under the curve (AUC), mean residence time (MRT), maximum concentration (C(max)), time to maximum concentration (T(max)), and half-life (t(1/2)) were determined for each SBDP. Markers of calpain proteolysis (SBDP150 and SBDP145) had a greater median AUC and C(max) and a shorter MRT than SBDP120, produced by caspase-3 proteolysis in the CSF in TBI patients ( p < 0.001). AUC and MRT for SBDP150 and SBDP15 were significantly greater in patients with worse Glasgow Coma Scale (GCS) scores at 24 h after injury compared to those whose GCS scores improved (AUC p=0.013, MRT p=0.001; AUC p=0.009, MRT p=0.021, respectively). A positive correlation was found between patients with longer elevations in intracranial pressure (ICP) measurements of 25mmHg or higher and those with a greater AUC and MRT for all three biomarkers. This is the first study to show that the biomarkers of proteolysis differentially associated with calpain and caspase-3 activity have distinct CSF exposure profiles following TBI that suggest a prominent role for calpain activity. Further studies are being conducted to determine if exposure and kinetic metrics for biofluid-based biomarkers can predict clinical outcome.


MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.
Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.


Hepatobiliary manifestations of inflammatory bowel disease.
Patients with inflammatory bowel diseases (IBDs) may present with several hepatic abnormalities. Some of these liver diseases are benign and only require observation, whereas others may cause liver failure and require liver transplantation. The aim of this review was to present and summarize the latest evidence on the most common liver diseases seen in patients with IBD. These manifestations can be divided in to 3 groups: those that are seen in association with IBD, those that are due to metabolic and physiologic changes induced by the IBD and those that are secondary to the drugs used in the treatment of IBD. Primary sclerosing cholangitis is one of the most common hepatobiliary manifestations of IBD that is more prevalent in patients with ulcerative colitis. There is no approved medical treatment for primary sclerosing cholangitis and about 50% of patients will require liver transplantation within 10 to 15 years from the time of diagnosis. Among the drugs that are commonly used in the treatment of IBD, thiopurines and methotrexate impose the higher risk of hepatotoxicity. In most cases, dose adjustment and avoidance of hepatotoxins will normalize the liver tests and discontinuation of the drug is required in a minority of cases. Reactivation of hepatitis B virus during immunosuppressive therapy is a major concern and adequate screening and vaccination is warranted. The approach to a patient with IBD who presents with abnormal liver chemistries can be challenging not only because 2 or more conditions can co-exist but also because management must be individualized.


Effects of medium and temperature on cellular responses in the superficial zone of hypo-osmotically challenged articular cartilage.
Osmotic loading of articular cartilage has been used to study cell-tissue interactions and mechanisms in chondrocyte volume regulation in situ. Since cell volume changes are likely to affect cell's mechanotransduction, it is important to understand how environmental factors, such as composition of the immersion medium and temperature affect cell volume changes in situ in osmotically challenged articular cartilage. In this study, chondrocytes were imaged in situ with a confocal laser scanning microscope (CLSM) through cartilage surface before and 3 min and 120 min after a hypo-osmotic challenge. Samples were measured either in phosphate buffered saline (PBS, without glucose and Ca(2+)) or in Dulbecco's modified Eagle's medium (DMEM, with glucose and Ca(2+)), and at 21 °C or at 37 °C. In all groups, cell volumes increased shortly after the hypotonic challenge and then recovered back to the original volumes. At both observation time points, cell volume changes as a result of the osmotic challenge were similar in PBS and DMEM in both temperatures. Our results indicate that the initial chondrocyte swelling and volume recovery as a result of the hypo-osmotic challenge of cartilage are not dependent on commonly used immersion media or temperature.


Treatment of mixed cryoglobulinemia: a rheumatology perspective.
The treatment of the cryoglobulinemic syndrome or vasculitis (CV) must be targeted to the individual patient, and requires clinical expertise and knowledge of the disease biology. In general, the treatment is suggested by the clinical picture, but biologic issues should also be considered. Both immunosuppressive and antiviral approaches deserve equal attention based on the wide clinical spectrum and on disease biology, where the viral trigger and the downstream autoimmune response may play a different role in different disease stages. The severity of the disease, previous history and therapies administered, comorbidities and other individual factors should be analysed in the single case. Acute and life-threatening conditions usually require high dose steroids, plasmapheresis and/or cyclophosphamide. Rituximab often represents the best option for severe CV. Antiviral therapy is a cornerstone for the management of CV in hepatitis-related cases, and has the strongest biologic rationale, in general, in this disease and should be always considered in stabilised patients. A multispecialistic approach is needed to better define treatment strategies in different subsets of patients.


Using Tablet for visual exploration of second-generation sequencing data.
The advent of second-generation sequencing (2GS) has provided a range of significant new challenges for the visualization of sequence assemblies. These include the large volume of data being generated, short-read lengths and different data types and data formats associated with the diversity of new sequencing technologies. This article illustrates how Tablet-a high-performance graphical viewer for visualization of 2GS assemblies and read mappings-plays an important role in the analysis of these data. We present Tablet, and through a selection of use cases, demonstrate its value in quality assurance and scientific discovery, through features such as whole-reference coverage overviews, variant highlighting, paired-end read mark-up, GFF3-based feature tracks and protein translations. We discuss the computing and visualization techniques utilized to provide a rich and responsive graphical environment that enables users to view a range of file formats with ease. Tablet installers can be freely downloaded from http://bioinf.hutton.ac.uk/tablet in 32 or 64-bit versions for Windows, OS X, Linux or Solaris. For further details on the Tablet, contact firstname.lastname@example.com.


The normal fundus. VI. The variation of fundus elements in relation to age and sex assessed by colour and filter fundus photography in clinically healthy subjects without ophthalmoscopical changes.
In 185 clinically healthy subjects ranging in age from 10 to 71 years with apparently normal ophthalmoscopy, colour and interference filter photographs of the one eye revealed one or more distinctly outlined yellowish elements in 126 eyes (68%) and a single red spot in 3 eyes (2%). The frequency of eyes with one or more fundus elements correlated positively (P less than 0.01) with age and predominated in males with an age greater than or equal to 25 years. A thinning of the pigment epithelium in the posterior pole of the fundus without concomitant myopia was associated (P less than 0.01) to the age group above 50 years (19 of 22 eyes) compared with the age group below 50 years (3 of 12 eyes). The fundus elements seen in 126 of 162 colour photographs with corresponding interference filter photographs of sufficient quality were recognized with the green filter in 98%, with the blue filter in 91% and the red filter photographs in 61% of the eyes.


Muscle mechanical properties of adult and older rats submitted to exercise after immobilization.
To describe the effects of immobilization, free remobilization and remobilization by physical exercise about mechanical properties of skeletal muscle of rats of two age groups. 56 Wistar rats divided into two groups according to age, an adult group (five months) and an older group (15 months). These groups were subdivided in: control, immobilized, free remobilized and remobilized by physical exercise. The pelvic limb of rats was immobilized for seven days. The exercise protocol consisted of five swimming sessions, once per day and 25 minutes per session. The gastrocnemius muscle was subjected to tensile tests, and evaluated the properties: load at the maximum limit, stretching at the maximum limit and stiffness. The immobilization reduced the values of load at the maximum limit and the remobilization protocols were not sufficient to restore control levels in adult group and older rats. The stretching at the maximum limit differs only in the older group. The immobilization reduces the muscle's ability to bear loads and exercise protocol tends to restore the default at control values in adult and older rats. The age factor only interfered in the stretching at the maximum limit, inducing a reduction of this property in the post-immobilization. Level of Evidence II, Investigating the Results of Treatment.


In vitro and in vivo antioxidant and anti-inflammatory capacities of an antioxidant-rich fruit and berry juice blend. Results of a pilot and randomized, double-blinded, placebo-controlled, crossover study.
This study investigated the in vitro and in vivo antioxidant and anti-inflammatory properties of a juice blend (JB), MonaVie Active, containing a mixture of fruits and berries with known antioxidant activity, including acai, a palm fruit, as the predominant ingredient. The phytochemical antioxidants in the JB are primarily in the form of anthocyanins, predominantly cyanidin 3-rutoside, cyanidin 3-diglycoside, and cyanidin 3-glucoside. The cell-based antioxidant protection of erythrocytes (CAP-e) assay demonstrated that antioxidants in the JB penetrated and protected cells from oxidative damage ( p < 0.001), whereas polymorphonuclear cells showed reduced formation of reactive oxygen species ( p < 0.003) and reduced migration toward three different pro-inflammatory chemoattractants: fmlp ( p < 0.001), leukotriene B4 ( p < 0.05), and IL-8 ( p < 0.03). A randomized, double-blinded, placebo-controlled, crossover trial with 12 healthy subjects examined the JB's antioxidant activity in vivo. Blood samples at baseline, 1 h, and 2 h following consumption of the JB or placebo were tested for antioxidant capacity using several antioxidant assays and the TBARS assay, a measure of lipid peroxidation. A within subject comparison showed an increase in serum antioxidants at 1 h ( p < 0.03) and 2 h ( p < 0.015), as well as inhibition of lipid peroxidation at 2 h ( p < 0.01) postconsumption.


Value of surface counting in predicting response to splenectomy in haemolytic anaemia.
The value of surface counting with (51)Cr-labelled red cells in predicting response to splenectomy in haemolytic anaemia has been analysed in 18 cases. The cases included six patients with congenital haemolytic anaemias, four with primary autoimmune haemolytic anaemias, and eight patients with secondary haemolytic anaemias (four with a positive antiglobulin test). All patients showed evidence of splenic accumulation of labelled cells and in 16 of the cases this was confined to the spleen. Improvement followed splenectomy in 17 of the cases although there was no close correlation between the magnitude of accumulation of radioactivity as measured by excess counts and the degree of response. The reasons for these discrepancies are discussed, The only patient who completely failed to respond to splenectomy had a sideroblastic element to the anaemia. It has been concluded that surface counting is of value in selecting patients for splenectomy but should not be depended upon without reference to other clinical and haematological factors, which are likely to influence the prognosis.


Informant agreement in the assessment of disruptive behavior disorders in detained minors in Belgium: a diagnosis-level and symptom-level examination.
Because diagnostic assessment of children emphasizes information from multiple informants, the reliability of findings in detained and incarcerated samples may be hampered. The objective of the current study was to examine parent-child agreement with regard to disruptive behavior disorders (with or without impairment) and disorder-related symptoms in detained male youths. Between January 2005 and February 2007, a representative sample of 150 detainees, 12 to 17 years old, from the 3 Youth Detention Centers for boys in Flanders, Belgium, and 1 parent of each were interviewed with the Diagnostic Interview Schedule for Children, Version IV (DISC-IV). Interviewees were selected consecutively on the basis of Belgian origin for practical, financial, and time-related reasons. Of the 150 participants, 9 were excluded and the parents of 26 could not be included for various reasons, and thus full data were obtained for 115 parents. Overall poor parent-child agreement at the disorder and symptom level was found, which is consistent with previous studies. Parents reported significantly more unique information on attention-deficit/hyperactivity disorder (ADHD) (p < .001) and oppositional defiant disorder (ODD) (p < .001), while youths reported significantly more unique conduct disorder (CD)-related information (p = .01). The large proportion of parents uniquely reporting ADHD and ODD supports previous concerns about the reliability of self-reported ADHD and ODD and suggests an essential contribution by parents to the accurate assessment of these disorders in adolescent detainees. With regard to CD, it may be appropriate to rely on youth self-report.


Effects of progesterone on protein metabolism in chicken oviduct tissue pretreated with oestrogen.
1. The effect of simultaneous injections of oestrogen benzoate and progesterone (0.5mg/day each) on immature chicken oviduct tissue pretreated with oestrogen benzoate (0.5mg/day) was studied. 2. After 3 days of treatment with both hormones, the weight of the tissue doubles as compared with tissue treated only with oestradiol benzoate. 3. The progesterone-induced weight increase had no effect on total DNA content of the tissue, but greatly increased the protein/DNA and RNA/DNA ratios. 4. Amino acid incorporation in vivo after progesterone treatment was elevated as measured by using 2h pulses of amino acids; this effect could be accounted for by observed alterations in the concentrations of free amino acids in the tissue. 5. With longer pulses of amino acid the specific radioactivity of total protein remained high in tissue treated with progesterone, at times when specific radioactivity of protein in oestrogen-treated animals was diminishing. 6. From a knowledge of the specific radioactivity of labelled amino acids in the free amino acid pool and in newly synthesized protein, the rate of protein synthesis was estimated in differently treated tissues. 7. The results suggest that progesterone treatment does not cause an increase in protein synthesis. It is concluded that the observed accumulation of oviduct protein is achieved via an effect of progesterone on protein catabolism.


Randomised controlled trial of acetate in preterm neonates receiving parenteral nutrition.
To determine whether by partly replacing chloride with acetate in parenteral nutrition, hyperchloraemia, metabolic acidosis, and the subsequent use of interventions such as colloid infusion, alkali treatment, increased assisted ventilation, would be reduced. Fifty eight neonates of less than 32 weeks gestation, receiving parenteral nutrition from days 3 to 10, were given either standard parenteral nutrition or a novel formulation with replacement of any chloride dose > 3 mmol/kg/day as acetate. Acetate (0 to 14.2 mmol/kg/day) reduced the incidence of hyperchloraemia from 77% to 25%, and caused an increase in base excess from day 5 onwards (mean intergroup difference 3.6 to 9.9 mmol/l), an increased pH (day 8, 7.34 vs 7.26), with an increased pCO2 (1 kPa). The acetate group received less bicarbonate (median 0 mmol vs 4.8 mmol) and less colloid (41 ml/kg vs 204 ml/kg). There was no difference in any parameter of assisted ventilation. Acetate in neonatal parenteral nutrition reduces metabolic acidosis and hyperchloraemia.


Gene expression profile in white alpaca (Vicugna pacos) skin.
A cDNA library from white alpaca (Vicugna pacos) skin was constructed using SMART technology to investigate the global gene expression profile in alpaca skin and identify genes associated with physiology of alpaca skin and pigmentation. A total of 5359 high-quality EST (expressed sequence tag) sequences were generated by sequencing random cDNA clones from the library. Clustering analysis of sequences revealed a total of 3504 unique sequences including 739 contigs (assembled from 2594 ESTs) and 2765 singletons. BLAST analysis against GenBank nr database resulted in 1287 significant hits (E-value < 10(-10)), of which 863 were annotated through gene ontology analysis. Transcripts for genes related to fleece quality, growth and coat color (e.g. collagen types I and III, troponin C2 and secreted protein acidic and rich in cysteine) were abundantly present in the library. Other genes, such as keratin family genes known to be involved in melanosome protein production, were also identified in the library. Members (KRT10, 14 and 15) of this gene family are evolutionarily conserved as revealed by a cross-species comparative analysis. This collection of ESTs provides a valuable resource for future research to understand the network of gene expression linked to physiology of alpaca skin and development of pigmentation.


Diffuse cerebral vasospasm after resection of schwannoma: a case report.
The etiology of vasospasm after brain tumor resection remains unclear. This is the first report of diffuse cerebral vasospasm following resection of a schwannoma located in the left portion/part of the ventral medulla oblongata. A 16-year-old boy presented with dizziness and projectile vomiting without apparent cause three months before admission. Magnetic resonance imaging revealed a space-occupying lesion in the left portion of the ventral medulla oblongata. The tumor was completely resected. Pathological examination was consistent with diagnosis of schwannoma. Three days after surgery, the patient was in an unconscious state. Magnetic resonance angiography revealed the occurrence of cerebral vasospasm, with ischemic infarction and segmental cerebrovascular stenosis. Seven days after surgery, dehydration therapy was carried out and decompressive craniectomy was performed in the frontal and temporal areas. Despite treatments, the patient was in a persistent vegetative state after surgery, with normal vital signs. This was an uncommon occurrence of diffuse cerebral vasospasm following the resection of schwannoma. Appropriate management of this condition is uncertain, but aggressive treatments including expansion of blood volume and relief of spasm should be performed to treat postsurgery vasospasm.


Mutational effects on the clonal interference phenomenon.
We study the process of fixation of beneficial mutations in an asexual population by means of a theoretical model. Particularly, we wish to investigate how the supply of deleterious and beneficial mutations influences the dynamics of the adaptive process of an evolving population. It is well known that the deleterious mutations drastically affect the fate of beneficial mutations. In addition, an increasing supply of favorable mutations, to compensate the decay of the fitness due to the accumulation of deleterious mutations, produces the clonal interference phenomenon where advantageous mutations in distinct lineages compete to reach fixation. This competition imposes a limit to the speed of adaptation of the population. Intuitively, we would expect that the interplay of the two mechanisms would conspire to ensure fixation of only large-effect beneficial mutations. Our results, however, show that beneficial mutations of small effect have an increased probability of fixation when both beneficial and deleterious mutations rates are increased.


A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity.
Pathogen recognition through Toll-like receptors (TLRs) is crucial in order to mount an appropriate immune response against microorganisms. On the basis of a lack of evidence indicating that Caenorhabditis elegans uses TLRs to elicit an immune response and on the absence of genes encoding Rel-like transcription factors in its genome, it is believed that TLR-mediated immunity arose after coelomates split from pseudocoelomates and acoelomates. Here, we show that C. elegans tol-1(nr2033) mutants are killed by the human pathogen Salmonella enterica, which causes a significant pharyngeal invasion in the absence of TOL-1-mediated immunity. We also show that TOL-1 is required for the correct expression of ABF-2, which is a defensin-like molecule expressed in the pharynx, and heat-shock protein 16.41, which is also expressed in the pharynx and is part of a HSP family of proteins required for C. elegans immunity. The results indicate that TOL-1 has a direct role in defence response to certain Gram-negative bacteria and indicate that part of the TLR-mediated immunity might be evolutionarily conserved.


Phosphorylation-induced conformational changes of cystic fibrosis transmembrane conductance regulator monitored by attenuated total reflection-Fourier transform IR spectroscopy and fluorescence spectroscopy.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ABC protein superfamily. Phosphorylation of a regulatory domain of this protein is a prerequisite for activity. We analyzed the effect of protein kinase A (PKA) phosphorylation on the structure of purified and reconstituted CFTR protein. 1H/2H exchange monitored by attenuated total reflection Fourier transform IR spectroscopy demonstrates that CFTR is highly accessible to aqueous medium. Phosphorylation of the regulatory (R) domain by PKA further increases this accessibility. More specifically, fluorescence quenching of cytosolic tryptophan residues revealed that the accessibility of the cytoplasmic part of the protein is modified by phosphorylation. Moreover, the combination of polarized IR spectroscopy with 1H/2H exchange suggested an increase of the accessibility of the transmembrane domains of CFTR. This suggests that CFTR phosphorylation can induce a large conformational change that could correspond either to a displacement of the R domain or to long range conformational changes transmitted from the phosphorylation sites to the nucleotide binding domains and the transmembrane segments. Such structural changes may provide better access for the solutes to the nucleotide binding domains and the ion binding site.


Comprehensive Surgical Treatment as the Mainstay of Management in Retroperitoneal Sarcomas: Retrospective Study from Two Non-sarcoma Specialist Centers.
Complete resection, surgical expertise and individualization of patient management in comprehensive oncology centres result in better clinical outcomes in patients presenting with retroperitoneal sarcomas. Clinical outcomes of primary and recurrent retroperitoneal sarcoma resections performed between January 2002 and December 2016 in two large surgical oncology, but non-sarcoma specialist centers, were reviewed to determine the efficacy of complete surgical resection as the principle instrument for treatment. The histological type, tumor size and grade, as well as organ resection, were recorded and subsequently reviewed. Our study included 108 cases of sarcoma resection (60 first-time, 38 second-time and 10 third-time laparotomies) in 60 patients (35 males and 25 females). Most patients had complete resection: 57 had a macroscopically complete (R0/R1) resection and three had R2 resection. The 90-day mortality rate was zero and morbidity was minimal. Five- and 10-year overall survival (OS) rates were 88% and 79%, respectively, whereas the corresponding disease-free survival (DFS) rates were 65% and 59%, respectively. High-grade tumors were associated with decreased DFS (hazard ratio(HR)=3.35; 95% confidence interval(CI)=1.23-9.10; p=0.018) and decreased OS (HR=7.18; 95% CI=1.50-34.22; p=0.013). Complete surgical resection of retroperitoneal sarcomas combined with individualized patient management when offered by experienced surgical oncology teams, adhering to international guidelines, can succeed in providing patients with good long-term outcomes, comparable to those achieved at sarcoma-specialist centers.


fMRI and its interpretations: an illustration on directional selectivity in area V5/MT.
fMRI is a tool to study brain function noninvasively that can reliably identify sites of neural involvement for a given task. However, to what extent can fMRI signals be related to measures obtained in electrophysiology? Can the blood-oxygen-level-dependent signal be interpreted as spatially pooled spiking activity? Here we combine knowledge from neurovascular coupling, functional imaging and neurophysiology to discuss whether fMRI has succeeded in demonstrating one of the most established functional properties in the visual brain, namely directional selectivity in the motion-processing region V5/MT+. We also discuss differences of fMRI and electrophysiology in their sensitivity to distinct physiological processes. We conclude that fMRI constitutes a complement, not a poor-resolution substitute, to invasive techniques, and that it deserves interpretations that acknowledge its stand as a separate signal.


Arthroscopic ligamentum teres reconstruction using semitendinosus tendon: surgical technique and an unusual outcome.
Although the exact biomechanical function of the ligamentum teres (LT) remains unclear, an important role in hip stability has been suggested. In some patients, perhaps because of their specific anatomy or physical activity, it seems to have a major function as a hip stabilizer. Therefore, after a complete LT tear, this group of patients may have persistent hip pain and mechanical symptoms probably related to microinstability and subtle subluxation. We present the case of a female patient with a complete LT tear. This had been treated by debridement and anterior capsule tightening, followed by prolonged rehabilitation. However, she had persistent symptoms. An LT reconstruction with a novel surgical technique was performed. The LT was reconstructed with double-stranded semitendinosus graft. The acetabular end was fixed with 2 anchors, and the femoral end was passed into a bone tunnel and fixed with an interference screw. After surgery, the patient's modified Harris Hip Score and Non-Arthritic Hip Score improved from 53 and 73 to 100 and 95, respectively, at 12 months of follow-up. At repeat arthroscopy 15 months after surgery, it was observed that the graft had resorbed, although the 2 Ticron stitches (Covidien, Mansfield, MA) remained firmly attached and were still acting as a small synthetic ligament.


Canadian Helicobacter Study Group Consensus Conference on the Approach to Helicobacter pylori Infection in Children and Adolescents.
Gastric infection with Helicobacter pylori is common in both children and adults, but children are considerably less susceptible to peptic ulcers and other pathological sequelae. As a result, the risk to benefit ratio of diagnostic studies and therapeutic regimens for H pylori in adults are likely different from those in pediatric populations. These guidelines for the management of pediatric H pylori infection, developed by the Canadian Helicobacter Study Group, are designed to identify when the diagnosis and treatment of H pylori may improve patient care. Given the low prevalence of this infection in Canada, it is important to recognize that indiscriminate testing and treatment programs in children are not recommended, and indeed may threaten the optimal care of children. Diagnostic tests should be employed judiciously and be reserved for children who are most likely to derive measurable benefit, such as those likely to have peptic ulcer disease. At this time a test and treat strategy in children cannot be considered prudent, evidence based or cost effective. It is appropriate to limit diagnosis and treatment to children and adolescents in whom H pylori has been identified during endoscopic investigation.


Biomedical data analysis by supervised manifold learning.
Biomedical data analysis is usually carried out by assuming that the information structure embedded into the biomedical recordings is linear, but that statement actually does not corresponds to the real behavior of the extracted features. In order to improve the accuracy of an automatic system to diagnostic support, and to reduce the computational complexity of the employed classifiers, we propose a nonlinear dimensionality reduction methodology based on manifold learning with multiple kernel representations, which learns the underlying data structure of biomedical information. Moreover, our approach can be used as a tool that allows the specialist to do a visual analysis and interpretation about the studied variables describing the health condition. Obtained results show how our approach maps the original high dimensional features into an embedding space where simple and straightforward classification strategies achieve a suitable system performance.


Platelet gel: applications in dental regenerative surgery.
Platelet growth factors obtained from platelet-rich plasma (PRP) are used in prosthetic and periodontal regenerative therapy in dentistry. Increased microvascular proliferation in the first 20 days is followed by enhanced osteoblast activity and immature osteoid formation within 3-6 weeks, improving the quality and quantity of newly formed bone tissue. The aim of this study was to evaluate, through three-dimensional X-ray monitoring, the amount of bone obtained after bone regeneration treatment with platelet gel from autologous PRP. Patients eligible for regenerative treatment of atrophic alveolar bone of the maxilla or mandible were studied. The patients' autologous whole blood was collected at the Department of Immunology and Transfusion of San Matteo Hospital for the preparation of platelet gel. The bone at the treated sites was analysed prior to and 4 months after the treatment using the three-dimensional X-ray system Galileos. Over a period of 6 years, 133 patients were treated: 304 implants were inserted and there were five cases of failure. The regenerated bone area consisted of histologically immature osteoid tissue composed of thin trabeculae of vital bone and nuclei of osteocytes, associated with fibro-connective tissue. This co-operative trial between the Transfusion Centre, for standardised production and validation of the platelet gel, and the Dental Surgery room for its application showed that the technique appears effective and safe. Although difficulties were encountered because of the small sample size and the inability to carry out long-term histological controls, the use of small amounts of PRP (5-10%) combined with autologous bone (15-20%) and alloplastic material appears to reduce the need for bone grafting.


Reconstruction of fingertip amputations with full-thickness perionychial grafts from the retained part and local flaps.
The treatment of fingertip amputations distal to the distal interphalangeal joint when the amputated part is saved is difficult and controversial. Both reattachment of the amputated portion as a composite graft and microvascular anastomosis are prone to failure in this distal location. The authors have evolved a reconstructive plan that uses the nail matrix, perionychium, and hyponychium of the amputated fingertip as a full-thickness graft when the amputation is between the midportion of the nail bed andjust proximal to the eponychial fold. Various flaps are used to lengthen and augment the finger pulp, and skeletal pinning is carried out as necessary. The charts of 15 patients who underwent this procedure over a 38 month period were evaluated retrospectively. Seven returned to the office for examination at least 1 year after the fingertip reconstruction described above; four others were interviewed by telephone. Nail deformity, fingertip sensation, and joint range of motion were evaluated, and the reconstructed fingertips were photographed in standardized views. In six of the seven patients seen in the office, aesthetic and functional results were judged as good by both patient and physician; one of the six had minimal nail curvature. The seventh patient had no nail growth, although finger length was retained and there was no functional disability. The four patients interviewed by phone reported normal fingertip use with no dysesthesias or cold intolerance; all had nail growth, although three patients described slight nail curvature that required care in trimming. The authors favor salvage of all perionychial parts when a distal fingertip amputation occurs. Reconstruction of the fingertip with grafting of the hyponychium, perionychium, and nail matrix from the amputated part combined with local flaps can provide a very satisfactory functional and aesthetic result.


Effects of p-aminohippurate and pyrazinoate on the renal excretion of salicylate in the rat: a micropuncture study.
The inhibitory effects of p-aminohippurate and pyrazinoate (PZA) on the transport of salicylate were studied by free-flow micropuncture in the rat. p-Aminohippurate (5, 10 or 25 mumol/kg X min) and PZA (10 or 25 mumol/kg X min) inhibited proximal tubular secretion of salicylate; they induced decreases in the fractional delivery of salicylate to the late proximal tubules. In alkalotic rats, the late proximal decrease in fractional delivery of salicylate was accompanied by a decreased fractional excretion of salicylate. In contrast, such a decrease in fractional excretion of salicylate was not observed in rats in normal acid-base balance. A greater rate of PZA infusion (25 mumol/kg X min) not only inhibited secretion, but also depressed a reabsorptive carrier-mediated transport of salicylate. Thus, in alkalotic rats, fractional delivery of salicylate to late proximal tubules were 1.90 +/- 0.15, 0.90 +/- 0.10 and 1.34 +/- 0.13, respectively, for control rats and rats infused with 10 or 25 mumol/kg X min of PZA. The corresponding values of fractional excretion of salicylate were 1.21 +/- 0.09, 0.61 +/- 0.05 and 0.08 +/- 0.09, respectively. The data suggest that salicylate is secreted as well as reabsorbed by carrier-mediated mechanisms and that there may be two secretory mechanisms.


Hepatitis viruses infection and risk of intrahepatic cholangiocarcinoma: evidence from a meta-analysis.
Studies investigating the association between Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and intrahepatic cholangiocarcinoma (ICC) have reported inconsistent findings. We conducted a meta-analysis of epidemiological studies to explore this relationship. A comprehensive search was conducted to identify the eligible studies of hepatitis infections and ICC risk up to September 2011. Summary odds ratios (OR) with their 95% confidence intervals (95% CI) were calculated with random-effects models using Review Manager version 5.0. Thirteen case-control studies and 3 cohort studies were included in the final analysis. The combined risk estimate of all studies showed statistically significant increased risk of ICC incidence with HBV and HCV infection (OR = 3.17, 95% CI, 1.88-5.34, and OR = 3.42, 95% CI, 1.96-5.99, respectively). For case-control studies alone, the combined OR of infection with HBV and HCV were 2.86 (95% CI, 1.60-5.11) and 3.63 (95% CI, 1.86-7.05), respectively, and for cohort studies alone, the OR of HBV and HCV infection were 5.39 (95% CI, 2.34-12.44) and 2.60 (95% CI, 1.36-4.97), respectively. This study suggests that both HBV and HCV infection are associated with an increased risk of ICC.


GUY1 confers complete female lethality and is a strong candidate for a male-determining factor in Anopheles stephensi.
Despite their importance in sexual differentiation and reproduction, Y chromosome genes are rarely described because they reside in repeat-rich regions that are difficult to study. Here, we show that Guy1, a unique Y chromosome gene of a major urban malaria mosquito Anopheles stephensi, confers 100% female lethality when placed on the autosomes. We show that the small GUY1 protein (56 amino acids in length) causes female lethality and that males carrying the transgene are reproductively more competitive than their non-transgenic siblings under laboratory conditions. The GUY1 protein is a primary signal from the Y chromosome that affects embryonic development in a sex-specific manner. Our results have demonstrated, for the first time in mosquitoes, the feasibility of stable transgenic manipulation of sex ratios using an endogenous gene from the male-determining chromosome. These results provide insights into the elusive M factor and suggest exciting opportunities to reduce mosquito populations and disease transmission.


[New aspects in drug therapy of ocular allergies].
Ophthalmic allergoses belong to highly prevalent ocular diseases. According to the records of the first center of allergic diseases of the eye set up in 1971 at Helmholtz Institute of Ocular Diseases in Moscow, the most prevalent clinical forms are seasonal pollenosis conjunctivitis, drug allergies, spring keratoconjunctivitis, large-papillary conjunctivitis, chronic allergic conjunctivitis, allergy associated with the "dry eye" syndrome, atopic keratoconjunctivitis, and ocular involvement in systemic immune diseases. Therapy of ocular allergies is based on the three main principles: removal of the allergen responsible for disease, immunotherapy, and symptomatic drug therapy. The main agents used in local antiallergic therapy are antihistaminic drugs (antasoline and acelastin), drugs inhibiting mast cell degranulation (chromoglycates and lodoxamide), and accessory drugs: corticosteroids (dexamethasone and deosonide), nonsteroid antiinflammatory agents (diclofenak), immunosuppressants (cyclosporin), and vasoconstrictors (tetrisoline). Antiallergic drugs can be used as monotherapy or in combinations, as they differ by the mechanism of action. Antiallergic drugs are used with good results in combined therapy of infectious conjunctivitis and keratitis.


Suppression of endotoxin-induced fever in near-term pregnant rats is mediated by brain nitric oxide.
Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (Tb) of near-term pregnant rats (day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 microg/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, NG-monomethyl-L-arginine citrate (L-NMMA; 280 microg), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle + IP LPS did not increase Tb, in contrast to the 1.0 +/- 0.2 degrees C rise in Tb in dams treated with ICV L-NMMA + IP LPS (P < 0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in Tb were 1.5 +/- 0.3 degrees C and 1.6 +/- 0.4 degrees C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5 h postinjection, Tb was 60-70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular L-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain.


Manifesto for the routine use of NMR for the liquid product analysis of aqueous CO2 reduction: from comprehensive chemical shift data to formaldehyde quantification in water.
CO2 reduction research is at a critical turnaround since it has the potential to partially or even substantially fulfil future clean energy needs. CO2-to-CO electrochemical conversion is getting closer from industrial implementation requirements. Efforts are now more and more directed to obtain highly reduced products such as methanol, methane, ethylene, ethanol, etc., most of them being liquids. Gas-phase products (e.g., CO, CH4) are typically detected and quantified by well-defined gas chromatography (GC and GC/MS) protocols. On the other hand, NMR, GC-MS, HPLC have been used for the liquid phase characterization, but no routine technique has yet been established, mainly due to lack of versatility of a single technique. Additionally, except NMR and GC-MS, classical techniques cannot distinguish 13C from 12C products, although it is a mandatory step to assess products origin. Herein, we show the efficiency and applicability of 1H NMR as routine technique for liquid phase products analysis and we address two previous shortcomings. We first established a comprehensive 1H and 13C NMR chemical shifts list for all 12CO2 and 13CO2 reduction products in water ranging from C1 to C3. Then we overcame the difficulty of identifying aqueous formaldehyde intermediate by 1H NMR through an efficient chemical trapping step, along with isotopic signature study. Formaldehyde can be reliably quantified in water with a concentration as low as 50 μM.


A Systematic Review of Self-Report Measures of Negative Self-Referential Emotions Developed for Non-Clinical Child and Adolescent Samples.
The crisis in child and adolescent mental health and wellbeing has prompted the development of school and community-based interventions to tackle negative emotions towards the self. Providing an evidence-base for such interventions is therefore a priority for policy makers and practitioners. This paper presents the first systematic review of self-referential and self-report measures of negative emotions for use with non-clinical child/adolescent populations, and evaluation of their psychometric properties. A systematic search of electronic databases and grey literature was conducted. Peer reviewed articles that introduced a new measure or included psychometric evaluation of a negative self-referential emotion for children and/or adolescents were identified. Study characteristics were extracted, and psychometric properties rated using internationally recognised quality criteria. Initially, 98 measures designed for evaluating children and adolescents' negative self-referential emotions were found. Measures were primarily excluded if they were intended for clinical diagnosis or did not focus on self-referential emotions. The remaining eight measures (Brief Shame and Guilt Questionnaire; Self-Consciousness Scale-Children; Shame and Guilt Scale for Adolescents; Test of Self-Conscious Affect- Adolescents; The Child-Adolescent Perfectionism Scale [CAPS]; Child and Adolescent Dysfunctional Attitudes Scale Revised; Children Automatic Thoughts Scale [CATS]; Negative Affect Self-Statement Questionnaire) were organised into domains consisting of self-conscious emotions, self-oriented perfectionism and negative self-cognitions. Psychometric quality ratings identified the CAPS (Flett et al. in J Psychoeduc Assess 34:634-652, 2016) and the CATS (Schniering and Rapee in Behav Res Ther 40:1091-1109, 2002) as having the strongest psychometric qualities. However, all reviewed measures lacked full evaluation of essential psychometric properties. Our review revealed a paucity of self-referential emotional measures suitable for assessing adverse negative self-referential emotions in general child and adolescent populations. Measures suitable for use in non-clinical samples were identified, but these require further evaluation and/or new scale developments are needed. The psychometric findings and methodological issues identified will guide researchers and practitioners to make evidence-based decisions in order to select optimal measures.


The intensive care medicine agenda on acute kidney injury.
Acute kidney injury (AKI) is a common complication in the critically ill. Current standard of care mainly relies on identification of patients at risk, haemodynamic optimization, avoidance of nephrotoxicity and the use of renal replacement therapy (RRT) in established AKI. The detection of early biomarkers of renal tissue damage is a recent development that allows amending the late and insensitive diagnosis with current AKI criteria. Increasing evidence suggests that the consequences of an episode of AKI extend long beyond the acute hospitalization. Citrate has been established as the anticoagulant of choice for continuous RRT. Conflicting results have been published on the optimal timing of RRT and on the renoprotective effect of remote ischaemic preconditioning. Recent research has contradicted that acute tubular necrosis is the common pathology in AKI, that septic AKI is due to global kidney hypoperfusion, that aggressive fluid therapy benefits the kidney, that vasopressor therapy harms the kidney and that high doses of RRT improve outcome. Remaining uncertainties include the impact of aetiology and clinical context on pathophysiology, therapy and prognosis, the clinical benefit of biomarker-driven interventions, the optimal mode of RRT to improve short- and long-term patient and kidney outcomes, the contribution of AKI to failure of other organs and the optimal approach for assessing and promoting renal recovery. Based on the established gaps in current knowledge the trials that must have priority in the coming 10 years are proposed together with the definition of appropriate clinical endpoints.


Using canine osteosarcoma as a model to assess efficacy of novel therapies: can old dogs teach us new tricks?
Since its domestication more than 10,000 years ago, the dog has been the animal that most intimately shares our work and homelife. Interestingly, the dog also shares many of our diseases including cancer such as osteosarcoma. Like the human, osteosarcoma is the most common bone malignancy of the dog and death from pulmonary metastasis is the most common outcome. The incidence of this spontaneous bone neoplasm occurs ten times more frequently that it does so in children with about 8,000-10,000 cases estimated to occur in dogs in the USA. Because there is no "standard of care" in veterinary medicine, the dog can also serve us by being a model for this disease in children. Although the most common therapy for the dog with osteosarcoma is amputation followed by chemotherapy, not all owners choose this route. Consequently, novel therapeutic interventions can be attempted in the dog with or without chemotherapy that could not be done in humans with osteosarcoma due to ethical concerns. This chapter will focus on the novel therapies in the dog that have been reported or are in veterinary clinical trials at the author's institution. It is hoped that collaboration between veterinary oncologists and pediatric oncologists will lead to the development of novel therapies for (micro- or macro-) metastatic osteosarcoma that improve survival and might ultimately lead to a cure in both species.


Two-photon fluorescence scanning near-field microscopy based on a focused evanescent field under total internal reflection.
We present two-photon fluorescence near-field microscopy based on an evanescent field focus produced by a ring beam under total internal reflection. The evanescent field produced by this method is focused by a high-numerical-aperture objective, producing a tightly confined volume that can effectively induce two-photon excitation. The imaging system is characterized by the two-photon-excited images of the nanocrystals, which show that the focused evanescent field is split into two lobes because of the enhancement of the longitudinal polarization component at the focus. This feature is confirmed by the theoretical prediction. Unlike other two-photon near-field probes, this method does not have the heating effect and requires no control mechanism of the distance between a sample and the probe.


[Atypical HHS-syndrome--a rare differential diagnosis of circulatory disorders of the hand].
We report on an acral circulatory disorder of the hand, representing a Hypothenar-Hammer-Syndrome (HHS) with atypical symptoms. The patient suffered from a radial circulatory disorder of his right hand, clinically representing a secondary M. Raynaud. The symptoms occurred after a single severe trauma of the right hand and after using both hands like a hammer. Angiography showed a cork-screw sign of the A. ulnaris at the typical area and an open Arcus palmaris superficialis as well as occlusions of multiple finger arteries. Symptoms improved significantly after lysis. The most important differential diagnosis is endangiitis obliterans according to angiography. If symptoms occur again, histology is recommended to exclude vasculitis. Surgery should be discussed if the HHS is confirmed, since a cork-screw morphology of the A. ulnaris exists as well as perfusion of the fingers mainly via the A. ulnaris. Also a radial circulatory disorder of the hand combined with typical anamnesis may represent a HHS.


Retention and risk factors for attrition in a large public health ART program in Myanmar: a retrospective cohort analysis.
The outcomes from an antiretroviral treatment (ART) program within the public sector in Myanmar have not been reported. This study documents retention and the risk factors for attrition in a large ART public health program in Myanmar. A retrospective analysis of a cohort of adult patients enrolled in the Integrated HIV Care (IHC) Program between June 2005 and October 2011 and followed up until April 2012 is presented. The primary outcome was attrition (death or loss-follow up); a total of 10,223 patients were included in the 5-year cumulative survival analysis. Overall 5,718 patients were analyzed for the risk factors for attrition using both logistic regression and flexible parametric survival models. The mean age was 36 years, 61% of patients were male, and the median follow up was 13.7 months. Overall 8,564 (84%) patients were retained in ART program: 750 (7%) were lost to follow-up and 909 (9%) died. During the 3 years follow-up, 1,542 attritions occurred over 17,524 person years at risk, giving an incidence density of 8.8% per year. The retention rates of participants at 12, 24, 36, 48 and 60 months were 86, 82, 80, 77 and 74% respectively. In multivariate analysis, being male, having high WHO staging, a low CD4 count, being anaemic or having low BMI at baseline were independent risk factors for attrition; tuberculosis (TB) treatment at ART initiation, a prior ART course before program enrollment and literacy were predictors for retention in the program. High retention rate of IHC program was documented within the public sector in Myanmar. Early diagnosis of HIV, nutritional support, proper investigation and treatment for patients with low CD4 counts and for those presenting with anaemia are crucial issues towards improvement of HIV program outcomes in resource-limited settings.