The Lisbon Agreement on Femoroacetabular Impingement Imaging-part 3: imaging techniques.
Imaging diagnosis of femoroacetabular impingement (FAI) remains controversial due to a lack of high-level evidence, leading to significant variability in patient management. Optimizing protocols and technical details is essential in FAI imaging, although challenging in clinical practice. The purpose of this agreement is to establish expert-based statements on FAI imaging, using formal consensus techniques driven by relevant literature review. Recommendations on the selection and use of imaging techniques for FAI assessment, as well as guidance on relevant radiographic and MRI classifications, are provided. The Delphi method was used to assess agreement and derive consensus among 30 panel members (musculoskeletal radiologists and orthopedic surgeons). Forty-four questions were agreed on and classified into five major topics and recent relevant literature was circulated, in order to produce answering statements. The level of evidence was assessed for all statements and panel members scored their level of agreement with each statement during 4 Delphi rounds. Either "group consensus," "group agreement," or "no agreement" was achieved. Forty-seven statements were generated and group consensus was reached for 45. Twenty-two statements pertaining to "Imaging techniques" were generated. Eight statements on "Radiographic assessment" and 12 statements on "MRI evaluation" gained consensus. No agreement was reached for the 2 "Ultrasound" related statements. The first international consensus on FAI imaging was developed. Researchers and clinicians working with FAI and hip-related pain may use these recommendations to guide, develop, and implement comprehensive, evidence-based imaging protocols and classifications. • Radiographic evaluation is recommended for the initial assessment of FAI, while MRI with a dedicated protocol is the gold standard imaging technique for the comprehensive evaluation of this condition. • The MRI protocol for FAI evaluation should include unilateral small FOV with radial imaging, femoral torsion assessment, and a fluid sensitive sequence covering the whole pelvis. • The definite role of other imaging methods in FAI, such as ultrasound or CT, is still not well defined.


Update and review of anorexia nervosa.
Anorexia nervosa is not a new disease but it has become increasingly recognized and occurs more frequently in adolescent girls and young women. Among older women, its incidence has remained constant. Scientific evidence suggests that dieting triggers a process of catastrophic weight loss in persons who are psychologically and physiologically vulnerable. Long-term studies are demonstrating diverse outcomes ranging from full recovery to chronicity and death. Treatment is often based on unproven theory and on short-term goals. Research studies comparing the effects of different treatment regimens are needed.


"Trying" times: Medicalization, intent, and ambiguity in the definition of infertility.
Researchers studying infertility from the perspective of anthropology and other the social sciences seldom examine the assumptions embedded in the biomedical definition of infertility. Implicit in the biomedical definition is the assumption that people can be divided straightforwardly into those who are trying to conceive and those who are not trying to conceive. If being infertile implies "intent to conceive," we must recognize that there are various degrees of intent and that the line between the fertile and the infertile is not as sharp as is usually imagined. Drawing on structured interview data collected from a random sample of Midwestern U.S. women and from qualitative interviews, we demonstrate that that there is a wide range of intent among those classified as infertile according to the biomedical definition. We explore the implications of this for research.


SF-KDM2A binds to ribosomal RNA gene promoter, reduces H4K20me3 level, and elevates ribosomal RNA transcription in breast cancer cells.
Regulation of rRNA transcription is an important factor for control of cell proliferation. We previously found that the JmjC domain-containing demethylase KDM2A reduces H3K36me2 in the rRNA gene promoter and rRNA transcription under starvation, which results in suppression of cell proliferation. The KDM2A gene also produces another protein product, SF-KDM2A, which lacks a JmjC domain and has no demethylase activity. As yet, the function of SF-KDM2A is not clear. Recently, it was reported that KDM2A was frequently amplified and that elevated expression of KDM2A was significantly associated with short survival of breast cancer patients. SF-KDM2A was more abundant than full-length KDM2A in a subset of breast cancers. In the present study, we report that SF-KDM2A localized in nucleoli and bound to the rRNA gene promoter in breast cancer cells. Overexpression of SF-KDM2A stimulated the transcription of rRNA. While the zf-CXXC domain was required for SF-KDM2A binding to the rRNA gene promoter, SF-KDM2A with mutations in the zf-CXXC domain lost the binding to the rRNA gene promoter and did not stimulate rRNA transcription. Knockdown of SF-KDM2A reduced rRNA transcription and cell proliferation. When SF-KDM2A was overexpressed, a transcriptionally repressive mark, H4K20me3, in the rRNA gene promoter was specifically reduced in a zf-CXXC domain-dependent manner, and knockdown of SF-KDM2A increased the H4K20me3 level. Taken together, these results demonstrate that SF-KDM2A binds to the rRNA gene promoter, reduces the H4K20me3 level, and activates rRNA transcription, suggesting that the stimulation of rRNA transcription by SF-KDM2A may contribute to tumorigenesis in breast cancer.


Molecular Classification of Neuroendocrine Tumors of the Thymus.
The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems. One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features. Whole-genome sequencing data fell into three clusters: CNIlow, CNIint, and CNIhigh. CNIlow and CNIint comprised not only TC and AC, but also six LCNECs. CNIhigh contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). TNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a morphomolecular grading system, Thy-NET G1-G3, instead of histologic classification for patient stratification and prognostication.


Location is everything when it comes to megakaryocyte function.
Megakaryocytes (MKs) give rise to platelets, which are blood cells that are essential to prevent hemorrhage. Although the majority of MKs localize to the bone marrow, there is a distinct population of lung-residing MKs (MKL). In this issue of the JCI, Pariser et al. examined gene expression patterns of MKs collected from murine and nonhuman primate bone marrow or lung. This Commentary explores the premise that environmental factors from the lung determine the genetic and phenotypic similarity of MKL to lung dendritic cells, distinguishing MKL from bone marrow MKs. Indeed, while MKL retain the ability to make platelets, they also process and present antigens that activate CD4+ lymphocytes. These data suggest that MKL may play an important role in immune processes beyond platelet production.


Cyclic AMP regulates the proportion of functional acetylcholine receptors on chicken ciliary ganglion neurons.
Previous studies have shown that the number of functional acetylcholine receptors (AcChoRs) on chicken ciliary ganglion neurons in culture is considerably smaller than the total number of AcChoRs detected on the neurons by labeled receptor probes. Here we use patch-clamp recording to show that a cAMP-dependent process enhances the AcCho response of the neurons by a mechanism likely to involve an increase in the number of functional AcChoRs. The increase occurs without requiring protein synthesis and without involving a detectable increase in the total number of AcChoRs on the cell surface measured with a labeled receptor probe. The results imply that the neurons have functional and nonfunctional pools of AcChoRs and that functional receptors can be recruited from intracellular receptors or from nonfunctional receptors on the cell surface by a cAMP-dependent process. A cAMP-dependent regulation of the number of functional neurotransmitter receptors would provide a reversible mechanism by which cell-cell interactions could modulate synaptic transmission in the nervous system.


Role of the zinc-finger and basic motifs of chrysanthemum virus B p12 protein in nucleic acid binding, protein localization and induction of a hypersensitive response upon expression from a viral vector.
The genomes of carlaviruses encode cysteine-rich proteins (CRPs) of unknown function. The 12 kDa CRP of chrysanthemum virus B (CVB), p12, has been shown previously to induce a hypersensitive response (HR) when expressed from potato virus X (PVX). This study demonstrated that a p12-induced HR was preceded by induction of a number of genes related to pathogenesis, stress and systemic acquired resistance. p12 localized predominantly to the nucleus. Interestingly, it was found that p12 bound both RNA and DNA in vitro, but notably exhibited a preference for DNA in the presence of Zn(2+) ions. Mutational analysis of the p12 conserved sequence motifs demonstrated that the basic motif is required for p12 translocation to the nucleus, thus representing part of the protein nuclear localization signal, whereas the predicted zinc finger motif is needed for both Zn(2+)-dependent DNA binding and eliciting an HR in PVX-infected leaves. Collectively, these results link, for the first time, nuclear localization of the protein encoded by a cytoplasmically replicating virus and its DNA-binding capacity with HR induction. Furthermore, these data suggest that p12 may mediate induction of the host genes by binding to the plant genomic DNA, and emphasize that CVB p12 is functionally distinct from other known nuclear-localized proteins encoded by the plant positive-stranded RNA viruses.


Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction.
Protein-protein interactions occurring via the recognition of short peptide sequences by modular interaction domains play a central role in the assembly of signalling protein complexes and larger protein networks that regulate cellular behaviour. In addition to spatial and temporal factors, the specificity of signal transduction is intimately associated with the specificity of many co-operative, pairwise binding events upon which various pathways are built. Although protein interaction domains are usually identified via the recognition code, the consensus sequence motif, to which they selectively bind, they are highly versatile and play diverse roles in the cell. For example, a given interaction domain can bind to multiple sequences that exhibit no apparent identity, and, on the other hand, domains of the same class or different classes may favour a given consensus motif. This promiscuity in ligand selection is typified by the SH3 (Src homology 3) domain and several other interaction modules that commonly recognize proline-rich sequences. Furthermore, interaction domains are highly adaptable, a property that is essential for the evolution of novel pathways and modulation of signalling dynamics. The ability of certain interaction domains to perform multiple tasks, however, poses a challenge for the cell to control signalling specificity when cross-talk between pathways is undesired. Extensive structural and biochemical analysis of many interaction domains in recent years has started to shed light on the molecular basis underlying specific compared with diverse binding events that are mediated by interaction domains and the role affinity plays in affecting domain specificity and regulating cellular signal transduction.


Infant gaze following and pointing predict accelerated vocabulary growth through two years of age: a longitudinal, growth curve modeling study.
We found that infant gaze following and pointing predicts subsequent language development. At ages 0;10 or 0;11, infants saw an adult turn to look at an object in an experimental setting. Productive vocabulary was assessed longitudinally through two years of age. Growth curve modeling showed that infants who gaze followed and looked longer at the target object had significantly faster vocabulary growth than infants with shorter looks, even with maternal education controlled; adding infant pointing strengthened the model. We highlight the role of social cognition in word learning and emphasize the communicative-referential functions of early gaze following and pointing.


A phylogenetic hot spot for evolutionary novelty in Middle American treefrogs.
Among the various types of evolutionary changes in morphology, the origin of novel structures may be the most rare and intriguing. Here we show statistically that the origins of different novel structures may be correlated and phylogenetically clustered into "hot spots" of evolutionary novelty, in a case study involving skull elements in treefrogs. We reconstruct phylogenetic relationships within a clade of Middle American treefrogs based on data from 10 nuclear and four mitochondrial genes and then analyze morphological evolution across this tree. New cranial elements are rare among anurans and tetrapods in general, but three novel elements have evolved within this clade, with a 40% increase in the number of skull roof elements in some species. Two of these elements also evolved in a related clade of treefrogs, and these two novel elements may have each evolved repeatedly within one or both clades. The molecular phylogeny suggests striking homoplasy in cranial morphology and shows that parsimony and Bayesian analyses of the morphological data have produced misleading results with strong statistical support. The origins of the novel elements are associated with an overall increase in the ossification of dermal skull roof elements (suggesting peramorphosis) and with the evolution of a novel adaptive behavior. Our study may be the first to statistically document significant phylogenetic clustering and correlation in the origins of novel structures, and to demonstrate the strongly misleading effects of peramorphosis on phylogenetic analysis.


An 18-case outbreak of drug-resistant Pseudomonas aeruginosa bacteriemia in hematology patients.
We retrospectively identified an outbreak of 18 episodes of P. aeruginosa bacteriemia in 17 patients with hematologic malignancies in 2004. All strains were ticarcillin I/R, 77% ciprofloxacin I/R, 72% ceftazidime I/R, 72% amikacin I/R and 50% imipenem I/R. The outbreak was multiclonal. Colistin was employed for documented therapy in ten cases including seven in which it was the only active drug. Outcomes were resolution of infection in 12 out of 18 episodes (67%), and death in six cases, five (25%) of which were attributable to the infection. Colistin was useful even in highly resistant strains and the efficacy of antibacterial therapy was similar (57%)in bacteriemia due to strains only susceptible to colistin.


'A hidden disorder until the pieces fall into place'--a qualitative study of vaginal prolapse.
Vaginal prolapse affects quality of life negatively and is associated with urinary, bowel, and sexual symptoms. Few qualitative studies have explored women's experiences of vaginal prolapse. The objective of the study was to elucidate the experiences of living with prolapse and its impact on daily life, prior to surgical intervention. In-depth interviews were conducted with 14 women with vaginal prolapse, prior to surgical treatment. Recruitment of the informants was according to 'purposive sampling'. An interview guide was developed, including open-ended questions addressing different themes, which was processed and revised during the data collection and constituted part of a study-emergent design. Data were collected until 'saturation' was achieved, that is, when no significant new information was obtained by conducting further interviews. Interviews were audiotaped, transcribed verbatim, and analyzed according to manifest and latent content analysis. The theme defining the process of living with prolapse and women's experiences was labelled 'process of comprehension and action'. The findings constitute two categories: obstacles and facilitators to seeking health care. The category obstacles comprises six subcategories that define the factors restraining women from seeking health care: absence of information, blaming oneself, feeling ignored by the doctor, having a covert condition, adapting to successive impairment, and trivializing the symptoms and de-prioritizing own health. The category facilitators include five subcategories that define the factors promoting the seeking of health care: confirmation and support by others, difficulty in accepting an ageing body, feeling sexually unattractive, having an unnatural body, and reaching the point of action. The main theme identified was the 'process of comprehension and action'. This process consisted of factors functioning as either obstacles or facilitators to seeking health care. The main obstacles described by the participants were lack of information and confirmation. The main facilitators constituted feeling sexually unattractive and impaired physical ability due to prolapse. Information on prolapse should be easily accessible, to improve the possibility for women to gain knowledge about the condition and overcome obstacles to seeking health care. Health care professionals have a significant role in facilitating the process by confirming and informing women about available treatment.


Modeling Inhibitory Interneurons in Efficient Sensory Coding Models.
There is still much unknown regarding the computational role of inhibitory cells in the sensory cortex. While modeling studies could potentially shed light on the critical role played by inhibition in cortical computation, there is a gap between the simplicity of many models of sensory coding and the biological complexity of the inhibitory subpopulation. In particular, many models do not respect that inhibition must be implemented in a separate subpopulation, with those inhibitory interneurons having a diversity of tuning properties and characteristic E/I cell ratios. In this study we demonstrate a computational framework for implementing inhibition in dynamical systems models that better respects these biophysical observations about inhibitory interneurons. The main approach leverages recent work related to decomposing matrices into low-rank and sparse components via convex optimization, and explicitly exploits the fact that models and input statistics often have low-dimensional structure that can be exploited for efficient implementations. While this approach is applicable to a wide range of sensory coding models (including a family of models based on Bayesian inference in a linear generative model), for concreteness we demonstrate the approach on a network implementing sparse coding. We show that the resulting implementation stays faithful to the original coding goals while using inhibitory interneurons that are much more biophysically plausible.


Oxyradical Stress, Endocannabinoids, and Atherosclerosis.
Atherosclerosis is responsible for most cardiovascular disease (CVD) and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox) produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS) have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB) is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ) is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG). Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS) in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.


Effects of an Advocacy Trial on Food Industry Salt Reduction Efforts-An Interim Process Evaluation.
The decisions made by food companies are a potent factor shaping the nutritional quality of the food supply. A number of non-governmental organizations (NGOs) advocate for corporate action to reduce salt levels in foods, but few data define the effectiveness of advocacy. This present report describes the process evaluation of an advocacy intervention delivered by one Australian NGO directly to food companies to reduce the salt content of processed foods. Food companies were randomly assigned to intervention (n = 22) or control (n = 23) groups. Intervention group companies were exposed to pre-planned and opportunistic communications, and control companies to background activities. Seven pre-defined interim outcome measures provided an indication of the effect of the intervention and were assessed using intention-to-treat analysis. These were supplemented by qualitative data from nine semi-structured interviews. The mean number of public communications supporting healthy food made by intervention companies was 1.5 versus 1.8 for control companies (p = 0.63). Other outcomes, including the mean number of news articles, comments and reports (1.2 vs. 1.4; p = 0.72), a published nutrition policy (23% vs. 44%; p = 0.21), public commitment to the Australian government's Food and Health Dialogue (FHD) (41% vs. 61%; p = 0.24), evidence of a salt reduction plan (23% vs. 30%; p = 0.56), and mean number of communications with the NGO (15 vs. 11; p = 0.28) were also not significantly different. Qualitative data indicated the advocacy trial had little effect. The absence of detectable effects of the advocacy intervention on the interim markers indicates there may be no impact of the NGO advocacy trial on the primary outcome of salt reduction in processed foods.


Beneficial effects of TQRF and TQ nano- and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Aβ levels in high fat-cholesterol diet-induced rats.
The study determined the effect of thymoquinone rich fraction (TQRF) and thymoquinone (TQ) in the forms of nano- and conventional emulsions on learning and memory, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble β-amyloid (Aβ) levels in rats fed with a high fat-cholesterol diet (HFCD). The TQRF was extracted from Nigella sativa seeds using a supercritical fluid extraction system and prepared into nanoemulsion, which later named as TQRF nanoemulsion (TQRFNE). Meanwhile, TQ was acquired commercially and prepared into thymoquinone nanoemulsion (TQNE). The TQRF and TQ conventional emulsions (CE), named as TQRFCE and TQCE, respectively were studied for comparison. Statin (simvastatin) and non-statin (probucol) cholesterol-lowering agents, and a mild-to-severe Alzheimer's disease drug (donepezil) were served as control drugs. The Sprague Dawley rats were fed with HFCD for 6 months, and treated with the intervention groups via oral gavage daily for the last 3 months. As a result, HFCD-fed rats exhibited hypercholesterolaemia, accompanied by memory deficit, increment of lipid peroxidation and soluble Aβ levels, decrement of total antioxidant status and down-regulation of antioxidants genes expression levels. TQRFNE demonstrated comparable effects to the other intervention groups and control drugs in serum biomarkers as well as in the learning and memory test. Somehow, TQRFNE was more prominent than those intervention groups and control drugs in brain biomarkers concomitant to gene and protein expression levels. Supplementation of TQRFNE into an HFCD thus could ameliorate memory deficit, lipid peroxidation and soluble Aβ levels as well as improving the total antioxidant status and antioxidants genes expression levels.


Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer.
Epidermal growth factor receptor (EGFR) is a validated target in different human malignancies. EGFR tyrosine kinase inhibitors (TKIs) are known to contribute considerably to the extension of progression-free survival in EGFR-mutant non-small cell lung cancer and monoclonal antibodies (mAbs) targeting EGFR have also improved the efficacy outcomes in KRAS wild-type colorectal cancer. Nevertheless, a significant percentage of lung and colorectal cancer patients do not respond to anti-EGFR agents and secondary resistance after initial benefit is a challenging reality faced by clinicians. Extensive preclinical work on the potential mechanisms of resistance to EGFR inhibitors in different disease settings has guided the development of second-generation irreversible EGFR TKIs, more efficient anti-EGFR mAbs, and combination strategies with agents targeting other receptors and downstream effectors. In order to elucidate the role of the multiple therapeutic strategies under investigation to overcome EGFR inhibitors-resistance, rational drug development based on stringent preclinical data, biomarker validation and proper selection of patients in the ongoing clinical trials are of paramount importance. Preliminary results of clinical trials evaluating these approaches will be discussed in this manuscript, with emphasis on TKIs in lung cancer and mAbs in advanced colorectal cancer.


Clinical outcome of early-stage endometroid adenocarcinoma: a tertiary cancer center experience.
Endometrial cancer (EC) outcome data from developing countries are sparse. We undertook this retrospective analysis to report outcome in our patient population. Two hundred forty-nine patients with stage I and II and type I histology ECs referred/treated at our institution from 1998 to 2004 were analyzed. All the details including demographic profile, surgical and histopathological details, as well as International Federation of Gynecology and Obstetrics stage and adjuvant therapy were compiled. The 1988 International Federation of Gynecology and Obstetrics staging and risk stratification were performed on the basis of PORTEC risk groups. With a median age of 54 years (26-72 years), 136 patients (55%) underwent surgery elsewhere; 118 (47.3%) underwent a complete surgical staging. There were 60 (24.1%), 124 (49.8%), 65 (26.1%) patients in the low-risk (LR), intermediate-risk (IR), and high-risk (HR) groups, respectively. Adjuvant radiation was given in 160 patients (LR, 18; IR, 85; and HR, 57). With a median follow-up of 36 months (mean, 40 months), 10 patients had vault recurrences, (LR, 3; IR, 4; and HR, 3), 11 had nodal (5 also had local recurrence; LR, 2; IR, 4; and HR, 5), and 16 had distant recurrences (3 also had nodal; LR, 4; IR, 5; HR, 7). The 5-year disease-free survival (DFS) and overall survival (OAS) rates were 80% and 95%, respectively. The DFS and OAS rates at 5 years were 84% and 97%, 85% and 98%, and 60% and 85% for the LR, IR, and HR groups, respectively. On multivariate analysis, grade (P = 0.002) and type of radiation (P = 0.027) had significant impact on DFS and OAS. Late toxicities (grade 3/4) were vaginal stenosis in 4 (1%) and radiation proctitis in 3 (1%) patients. In our study, ECs are seen in relatively younger population. There is a trend toward incomplete staging surgery outside the oncological referral network. However, the clinical outcome for early-stage type I histology ECs within our population are similar to those reported in the literature.


The influence of social deprivation as measured by the CNI on psychiatric admissions.
The purpose of this study was to examine the importance of social deprivation for psychiatric admissions and its correlation with two different deprivation scores. Care Need Index (CNI) and Townsend scores were calculated at the small area level in Malmö, a city in southern Sweden. Admission rates for all psychiatric inpatients from Malmö aged 20-79 years, admitted to the psychiatric and alcohol clinics from 1 January 1991 to 31 December 1994, were calculated. The relationship between the CNI and psychiatric admissions was analysed by applying a Poisson regression model. The results are shown as incidence density ratios (IDR) with 95% confidence intervals (CI). From the most deprived areas, the first psychiatric admission rate was more than four times higher than in the most affluent areas. The rates of second and third admission were even higher. Admissions to the alcohol clinic were similar to psychiatric admissions, but the most deprived areas had first admission rates about ten times higher than in the most affluent areas. About 27% of first admissions, including patients from both psychiatric and alcohol clinics, had a diagnosis of psychosis, and 43% were substance abusers. There were differences between the patients' diagnoses in different areas. The correlation between the CNI and Townsend scores was very high. The most important finding of this study is the strong correlation between social deprivation, based on different deprivation indices, and first admissions to psychiatric and alcohol clinics.


[Regional features of obesity-associated gene polymorphism (rs9939609 FTO gene and gene Trp64Arg ADRB3) in Russian population].
Recent studies have shown a significant association with obesity polymorphisms: rs9939609 gene due to fat mass and obesity FTO in European and some Asian and African American populations Trp64Arg ADRB3 gene in several European populations. Association of variants rs9939609 and Trp64Arg obesity was studied in 1244 the inhabitants of Moscow and Sverdlovsk regions. Genotyping was performed using allele-specific amplification, detection results in real time using TaqMan-probes complementary DNA polymorphic sites. The frequency of the mutant allele of the FTO gene in the population of Moscow and Sverdlovsk region was 45.1%, with the TT genotype was detected in 30.2% of cases, AT--49.5%, AA--20.3%. Women had the presence of the mutant allele more likely than men (48.4 vs. 42.5%). People with obesity were more genotypes AA (26.3%) and AT (52.8%) compared to the surveyed with a BMI of less than 30 kg/m2 (respectively 18.1 and 50.7%). A significantly higher incidence of risk allele A was found in individuals with obesity (52.6 and 43.4%). The presence of the mutant allele of the gene ADRB3 among the population of Moscow and Sverdlovsk regions was noted in 7.4% of cases. While 15.5% of patients had a heterozygous genotype Trp64Arg ADRB3, that is consistent with international research. The frequency of the risk allele and genotype Arg64 Trp64Arg in women (9.3 and 18.5%) was significantly higher than men (6.2 and 12.2%). The presence of the mutant allele and genotype Trp64Arg ADRB3 (respectively, 9.1 and 18.1%) were significantly more marked in the examined obese compared with those with a body mass index less than 30 kg/m2 (7.4 and 14.9%), but these differences were not statistically significant. The results of these studies suggest that genetic variants of the FTO gene rs9939609 genotype and Trp64Arg ADRB3 contribute to the development of obesity among residents of Moscow and Sverdlovsk Region of Russia. The risk of obesity increases in the case of combined polymorphisms in both genes.


Effectiveness of Virtual Reality-Based Interventions for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis.
This review aims to evaluate the effectiveness of virtual reality-based interventions (VR-based interventions) on cognitive deficits in children with attention deficit hyperactivity disorder (ADHD). A systematic review and meta-analysis were performed according to the PRISMA statement and the Cochrane Handbook guidelines for conducting meta-analyses. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used to assess the quality of the evidence. Clinical trials published up to 29 October 2020, were included. The meta-analysis included four studies, with a population of 125 participants with ADHD. The magnitude of the effect was large for omissions (SMD = -1.38; p = 0.009), correct hits (SMD = -1.50; p = 0.004), and perceptual sensitivity (SMD = -1.07; p = 0.01); and moderate for commissions (SMD = -0.62; p = 0.002) and reaction time (SMD = -0.67; p = 0.03). The use of VR-based interventions for cognitive rehabilitation in children with ADHD is limited. The results showed that VR-based interventions are more effective in improving sustained attention. Improvements were observed in attentional vigilance measures, increasing the number of correct responses and decreasing the number of errors of omission. No improvements were observed in impulsivity responses.


Epithelioid Hemangioendothelioma of the Bowel in Crohn's Disease: The First Reported Case.
Epithelioid hemangioendothelioma (EHE) is an uncommon malignant endothelial neoplasm that most commonly arises in soft tissue, bone, lung, and liver. Crohn's disease (CD) is an inflammatory bowel disease of unknown etiology that is frequently associated with complications including strictures, fistulas/fissures, and neoplasms. A 43-year-old woman with a 6-year history of severe CD presented with anal pain and bleeding. She had prior partial colectomy for a stricture and a diverting ileostomy for perianal fissures and stricture. Colonoscopy showed severe chronic active colitis, stricture at 30 cm of anal verge, and a perianal fistula. The patient underwent total proctocolectomy. The colonic mucosa exhibited segmental ulceration and irregular thickening of the colon wall. Beneath an ulcer of the anal canal within the muscularis propria was a 1.2-cm poorly circumscribed, firm, white-tan mass. The mass was composed of cords and groups of large epithelioid endothelial cells with intracytoplasmic vacuoles enmeshed in a myxohyaline stroma. Immunohistochemically, the tumor cells were positive for ERG, CD31, and CAMTA1 and focally positive for keratin and SMA. Next-generation sequencing revealed a WWTR1-CMATA1 fusion. The morphology, immunoprofile, and molecular genetics were diagnostic of EHE. Long-standing inflammatory bowel disease is associated with significant risk for developing neoplasms, usually carcinomas, which can be indistinguishable radiologically and clinically from nonneoplastic complications. These tumors are often identified as an incidental finding in specimens resected for clinically severe disease. This is the first report of EHE arising in the bowel affected by CD, and it mimicked mural fibrosis and fissures.


Epidemic characteristics of hand, foot, and mouth disease in Shanghai from 2009 to 2010: Enterovirus 71 subgenotype C4 as the primary causative agent and a high incidence of mixed infections with coxsackievirus A16.
Enterovirus 71 (EV71) has been the main causative agent of hand, foot, and mouth disease (HFMD) outbreaks in recent years. A significant increase in the number of HFMD cases in China over the last 3 y has made the public prevention and therapy of this disease a critical issue. A total of 3208 HFMD patients in Shanghai during the period 2009 to 2010 were analyzed; 437 clinical specimens were collected for the determination of causative pathogens. Eight of the isolated EV71 strains were sequenced and phylogenetically analyzed. The widespread outbreak of HFMD in Shanghai was caused predominantly by EV71 (86.5%), and in part by coxsackievirus A16 (CA16) (6.9%). The high incidence of mixed infections with EV71 and CA16 (17.6% of the total CA16-infected cases) has never before been observed in China. Most HFMD patients (76.9%) were aged 1-4 y. Boys showed a higher HFMD prevalence rate (65.3%) than girls (34.7%). Phylogenetic analysis on the basis of the VP1 gene and the complete genome sequences revealed that the EV71 strains that circulated in Shanghai belonged to the C4 subgenotype. EV71 subgenotype C4 was the major causative agent of the HFMD outbreak in Shanghai. A high incidence of mixed infections with EV71 and CA16 was also observed.


Probing the wurtzite conduction band structure using state filling in highly doped InP nanowires.
We have grown InP nanowires doped with hydrogen sulfide, which exhibit sulfur concentrations of up to 1.4%. The highest doped nanowires show a pure wurtzite crystal structure, in contrast to bulk InP which has the zinc blende structure. The nanowires display photoluminescence which is strongly blue shifted compared with the band gap, well into the visible range. We find evidence of a second conduction band minimum at the gamma point about 0.23 eV above the band edge, in excellent agreement with recent theoretical predictions. Electrical measurements show high conductivity and breakdown currents of 10(7) A/cm(2).


Thermal field formation during wIRA-hyperthermia: temperature measurements in skin and subcutis of piglets as a basis for thermotherapy of superficial tumors and local skin infections caused by thermosensitive microbial pathogens.
Purpose: The temporal and spatial formation of the temperature field and its changes during/upon water-filtered infrared-A (wIRA)-irradiation in porcine skin and subcutis were investigated in vivo in order to get a detailed physical basis for thermotherapy of superficial tumors and infections caused by thermosensitive microbial pathogens (e.g., Mycobacterium ulcerans causing Buruli ulcer). Methods: Local wIRA-hyperthermia was performed in 11 anesthetized piglets using 85.0 mW cm-2, 103.2 mW cm-2 and 126.5 mW cm-2, respectively. Invasive temperature measurements were carried out simultaneously in 1-min intervals using eight fiber-optical probes at different tissue depths between 2 and 20 mm, and by an IR thermometer at the skin surface. Results: Tissue temperature distribution depended on incident irradiance, exposure time, tissue depths and individual 'physiologies' of the animals. Temperature maxima were found at depths between 4 and 7 mm, exceeding skin surface temperatures by about 1-2 K. Tissue temperatures above 37 °C, necessary to eradicate M. ulcerans at depths <20 mm, were reached reliably. Conclusions: wIRA-hyperthermia may be considered as a novel therapeutic option for treatment of local skin infections caused by thermosensitive pathogens (e.g., in Buruli ulcer). To ensure temperatures required for heat treatment of superficial tumors deeper than 4 mm, the incident irradiance needed can be controlled either by (a) invasive temperature measurements or (b) control of skin surface temperature and considering possible temperature increases up to 1-2 K in underlying tissue.


Overexpression of T-LAK cell-originated protein kinase predicts poor prognosis in patients with stage I lung adenocarcinoma.
Tumor recurrence is the most common cause of disease failure after surgical resection in early-stage lung adenocarcinoma. Identification of clinically relevant prognostic markers could help to predict patients with high risk of disease recurrence. A meta-analysis of available lung adenocarcinoma microarray datasets revealed that T-LAK cell-originated protein kinase (TOPK), a serine/threonine protein kinase, is overexpressed in lung cancer. Using stable cell lines with overexpression or knockdown of TOPK, we have shown that TOPK can promote cell migration, invasion, and clonogenic activity in lung cancer cells, suggesting its crucial role in lung tumorigenesis. To evaluate the prognostic value of TOPK expression in resected stage I lung adenocarcinoma, a retrospective analysis of 203 patients diagnosed with pathological stage I lung adenocarcinoma was carried out to examine the expression of TOPK by immunohistochemistry (IHC). The prognostic significance of TOPK overexpression was examined. Overexpression of TOPK (IHC score >3) was detected in 67.0% of patients, and these patients were more frequently characterized with disease recurrence and angiolymphatic invasion. Using multivariate analysis, patient age (>65 years old; P = 0.002) and TOPK overexpression (IHC score >3; P < 0.001) significantly predicted a shortened overall survival. Moreover, TOPK overexpression (IHC score >3; P = 0.005) also significantly predicted a reduced time to recurrence in the patients. Our results indicate that overexpression of TOPK could predetermine the metastatic capability of tumors and could serve as a significant prognostic predictor of shortened overall survival and time to recurrence.


Experimental production of osteogenic sarcoma of the mandible in rabbits with 4-nitroquinoline 1-oxide.
A single intramedullary administration of 4-nitroquinoline 1-oxide (4-NQO) into the mandible in 32 rabbits induced 21 cases of osteogenic sarcoma (65.6%), 5 chondrosarcoma (15.6%), 2 fibrosarcomas, and 3 cementoblastomas. None of the tumors appeared until the 3rd month after the treatment. From the 4th to 6th month, early stages of osteogenic tumors were seen. In the late stadium, from 7th to 12th month, tumors showed prominent proliferation and invasion to the oral cavity and surrounding areas. Metastasis to the lung and liver was found in 2 cases of osteogenic sarcoma.


A Caliber Persistent Artery (Dieulafoy's Lesion) which is Associated with an Early-Stage Gastric Stump Cancer Following a Distal Gastrectomy.
A 75-years old man was hospitalized with symptoms which suggested gastric cancer. Thirty-eight years ago, he had undergone a Billroth-II gastric reconstruction for a peptic ulcer. At the present admission, he had presented with an eight-month history of recurrent haematemesis, epigastric pain, vomiting, and fatigue. The emergent endoscopy showed a type 0-IIc (superficial depressed) early gastric stump cancer in the anastomotic area and total removal of the gastric remnant and the jejunal segment was performed. The histological examination of the surgical specimen showed a gastric adenocarcinoma that invaded the mucosa and the submucosa, without lymph node metastases (pT1bN0 stage). Besides the tumour, enlarged vessels were observed in the submucosa and the muscularis propria, some of which were thrombotic. The surrounding normal gastric wall also presented submucosal oversized vascular spaces, some of which were protruding through the muscularis mucosae in the mucosal layer. Based on these characteristics and the recurrent haematemesis, a final diagnosis of early gastric stump carcinoma which was associated with Dieulafoy's lesion was made. This association has not yet been reported in the literature and it allowed us to diagnose the gastric stump cancer in a very early stage.


Voluntary exercise ameliorates the progression of atherosclerotic lesion formation via anti-inflammatory effects in apolipoprotein E-deficient mice.
A sedentary lifestyle with insufficient exercise is associated with cardiovascular disease. Previous studies have demonstrated that endurance exercise benefits atherosclerosis and cardiovascular disorders; however, the mechanisms by which physical activity, such as voluntary exercise (Ex), produces these effects are not fully understood. Eight-week-old male apolipoprotein (ApoE)-deficient mice were fed a standard diet (STD) or high fat diet (HFD) for 10 weeks. The HFD+Ex group mice performed Ex on a running wheel for 10 weeks. No significant differences in lipid profiles were observed between the HFD and HFD+Ex groups. Although changes in body and brown adipose tissue weights were comparable between the HFD and HFD+Ex groups, white adipose tissue weight was significantly lower in the HFD+Ex group than in the HFD group. The areas of atherosclerotic lesions in the aortic sinus and thoracoabdominal aorta were significantly reduced in the HFD+Ex group than in the HFD group (p<0.001). There was a strong negative correlation between atherosclerotic areas and the mean running distance per day in the HFD+Ex group (r=-0.90, p=0.01). Endothelial function was significantly preserved in the HFD+Ex group (p<0.05). Serum interleukin-6 and macrophage chemoattractant protein-1 levels were significantly lower and those of adiponectin were significantly higher in the HFD+Ex group than in the HFD group (p<0.05). These results suggest that Ex ameliorates the progression of endothelial dysfunction and atherosclerotic lesion formation through anti-inflammatory effects, despite continued consumption of HFD.


Association of obstructive sleep apnea risk with asthma control in adults.
Unrecognized obstructive sleep apnea (OSA) may lead to poor asthma control despite optimal therapy. Our objective was to evaluate the relationship between OSA risk and asthma control in adults. Patients with asthma seen routinely at tertiary-care clinic visits completed the validated Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ) and Asthma Control Questionnaire (ACQ). An ACQ score of >or= 1.5 defined not-well-controlled asthma, and an SA-SDQ score of >or= 36 for men and >or= 32 for women defined high OSA risk. Logistic regression was used to model associations of high OSA risk with not-well-controlled asthma (ACQ full version and short versions). Among 472 subjects with asthma, the mean +/- SD ACQ (full version) score was 0.87 +/- 0.90, and 80 (17%) subjects were not well controlled. Mean SA-SDQ score was 27 +/- 7, and 109 (23%) subjects met the definition of high OSA risk. High OSA risk was associated, on average, with 2.87-times higher odds for not-well-controlled asthma (ACQ full version) (95% CI, 1.54-5.32; P = .0009) after adjusting for obesity and other factors known to worsen asthma control. Similar independent associations were seen when using the short ACQ versions. High OSA risk is significantly associated with not-well-controlled asthma independent of known asthma aggravators and regardless of the ACQ version used. Patients who have difficulty achieving adequate asthma control should be screened for OSA.


Volume Law and Quantum Criticality in the Entanglement Entropy of Excited Eigenstates of the Quantum Ising Model.
Much has been learned about universal properties of entanglement entropies in ground states of quantum many-body lattice systems. Here we unveil universal properties of the average bipartite entanglement entropy of eigenstates of the paradigmatic quantum Ising model in one dimension. The leading term exhibits a volume-law scaling that we argue is universal for translationally invariant quadratic models. The subleading term is constant at the critical field for the quantum phase transition and vanishes otherwise (in the thermodynamic limit); i.e., the critical field can be identified from subleading corrections to the average (over all eigenstates) entanglement entropy.


The overlapping relationship between emotion perception and theory of mind.
Socio-cognitive skills are crucial for successful interpersonal interactions. Two particularly important socio-cognitive processes are emotion perception (EP) and theory of mind (ToM), but agreement is lacking on terminology and conceptual links between these constructs. Here we seek to clarify the relationship between the two at multiple levels, from concept to neuroanatomy. EP is often regarded as a low-level perceptual process necessary to decode affective cues, while ToM is usually seen as a higher-level cognitive process involving mental state deduction. In information processing models, EP tends to precede ToM. At the neuroanatomical level, lesion study data suggest that EP and ToM are both right-hemisphere based, but there is also evidence that ToM requires temporal-cingulate networks, whereas EP requires partially separable regions linked to distinct emotions. Common regions identified in fMRI studies of EP and ToM have included medial prefrontal cortex and temporal lobe areas, but differences emerge depending on the perceptual, cognitive and emotional demands of the EP and ToM tasks. For the future, clarity of definition of EP and ToM will be paramount to produce distinct task manipulations and inform models of socio-cognitive processing.


Overexpression of AtEDT1/HDG11 in Chinese Kale (Brassica oleracea var. alboglabra) Enhances Drought and Osmotic Stress Tolerance.
Plants are constantly challenged by environmental stresses, including drought and high salinity. Improvement of drought and osmotic stress tolerance without yield decrease has been a great challenge in crop improvement. The Arabidopsis ENHANCED DROUGHT TOLERANCE1/HOMEODOMAIN GLABROUS11 (AtEDT1/HDG11), a protein of the class IV HD-Zip family, has been demonstrated to significantly improve drought tolerance in Arabidopsis, rice, and pepper. Here, we report that AtEDT1/HDG11 confers drought and osmotic stress tolerance in the Chinese kale. AtEDT1/HDG11-overexpression lines exhibit auxin-overproduction phenotypes, such as long hypocotyls, tall stems, more root hairs, and a larger root system architecture. Compared with the untransformed control, transgenic lines have significantly reduced stomatal density. In the leaves of transgenic Chinese kale plants, proline (Pro) content and reactive oxygen species-scavenging enzyme activity was significantly increased after drought and osmotic stress, particularly compared to wild kale. More importantly, AtEDT1/HDG11-overexpression leads to abscisic acid (ABA) hypersensitivity, resulting in ABA inhibitor germination and induced stomatal closure. Consistent with observed phenotypes, the expression levels of auxin, ABA, and stress-related genes were also altered under both normal and/or stress conditions. Further analysis showed that AtEDT1/HDG11, as a transcription factor, can target the auxin biosynthesis gene YUCC6 and ABA response genes ABI3 and ABI5. Collectively, our results provide a new insight into the role of AtEDT1/HDG11 in enhancing abiotic stress resistance through auxin- and ABA-mediated signaling response in Chinese kale.


Pulmonary tuberculosis in a BCG vaccinated area: relationship of disease severity with immunological and hematological parameters and drug resistance patterns.
Clinical hematological and immunological parameters were studied in a group of 145 pulmonary patients with active tuberculosis, from a defined area of Karachi (Kharadar) belonging to the lower socioeconomic strata. Although clinical symptomatology could not differentiate the extent of lung involvement, a majority (69.6%) of the patients were diagnosed radiologically as having moderately advanced pulmonary disease. The peak number of patients were in their second decade of life. No differences were observed in the extent of disease based on age or gender. All hematological parameters for the group were in the normal ranges except for low levels of hemoglobin (9.58 +/- 1.55 SD; normal range 12-14 mg/dl) and a high ESR (90 +/- 31 SD; normal range 0-13 mm/hour). A negative correlation of PPD skin test induration (r = 0.21, p = 0.02), and a positive correlation of total white blood cell (r = 0.20; p = 0.015) was observed with the amount of lung tissue involved. The resistance amongst the strains for the four first line anti-tuberculosis agents was found to be: isoniazid = 27.4%; ethambutol = 14.5%; rifampicin = 11.29% and streptomycin = 12.9%. Multi-drug resistance to the most commonly prescribed combination (rifampicin and ethambutol) was 8.06%. Drug resistance patterns to individual drugs were comparable with resistance patterns observed in strains from greater Karachi at The Aga Khan Hospital during the same period. Such studies should provide improved rationale for patients diagnosis and treatment.


Terahertz and mid-infrared plasmons in three-dimensional nanoporous graphene.
Two-dimensional (2D) graphene emerged as an outstanding material for plasmonic and photonic applications due to its charge-density tunability, high electron mobility, optical transparency and mechanical flexibility. Recently, novel fabrication processes have realised a three-dimensional (3D) nanoporous configuration of high-quality monolayer graphene which provides a third dimension to this material. In this work, we investigate the optical behaviour of nanoporous graphene by means of terahertz and infrared spectroscopy. We reveal the presence of intrinsic 2D Dirac plasmons in 3D nanoporous graphene disclosing strong plasmonic absorptions tunable from terahertz to mid-infrared via controllable doping level and porosity. In the far-field the spectral width of these absorptions is large enough to cover most of the mid-Infrared fingerprint region with a single plasmon excitation. The enhanced surface area of nanoporous structures combined with their broad band plasmon absorption could pave the way for novel and competitive nanoporous-graphene based plasmonic-sensors.


Mechanisms of plasminogen activator inhibitor 1 action in stromal remodeling and related diseases.
Plasminogen activator inhibitor type 1 (PAI-1) is the main physiologic inhibitor of fibrinolysis. However, it is also involved in many physiological processes such as extracellular matrix (ECM) proteolysis and remodeling, cell adhesion, motility, and apoptosis, angiogenesis, etc. The aim of the study was to summarize current knowledge and gain insights into the mechanisms of PAI-1 action in the processes of stromal remodeling and diseases with considerable matrix pathologies (atherosclerosis, tissue fibrosis, cancer metastasis, pregnancy related complications, etc). As a component of an early cellular response to injury, PAI-1 reacts with membrane surface proteins and participates in the initiation of intracellular signaling, specifically cytoskeletal reorganization and motility. Complexity of ECM homeostasis resides in varying relation of the plasminogen system components and other matrix constituents. Inflammatory mediators (transforming growth factor-β and interferon-γ) and hormones (angiotensin II) are in the close interdependent relation with PAI-1. Also, special attention is devoted to the role of increased PAI-1 concentrations due to the common 4G/5G polymorphism. Some of the novel mechanisms of ECM modification consider PAI-1 dependent stabilization of urokinase mediated cell adhesion, control of the vascular endothelial cadherin trafficking and interaction with endothelial cells proteasome, its relation to matrix metalloproteinase 2 and osteopontin, and oxidative inhibition by myeloperoxidase. Targeting and/or alteration of PAI-1 functions might bring benefit to the future therapeutic approaches in diseases where ECM undergoes substantial remodeling.


Thyroid consequences of the fukushima nuclear reactor accident.
A special report, 'The Fukushima Accident', was delivered at the 35th Annual Meeting of the European Thyroid Association in Krakow on September 11, 2011, and this study is the follow-up of the special report. To present a preliminary review of potential thyroid consequences of the 2011 Fukushima nuclear reactor accident. Numerous new data have been presented in Japanese, and most of them are available on the website from each research institute and/or from each municipality. The review was made using these data from the website. When individual radiation doses were expressed as values in more than 99% of residents, radiation doses by behavior survey in evacuation and deliberate evacuation areas were less than 10 mSv in the first 4 months, and internal radiation doses measured by whole body counters were less than 1 mSv/year. Individual thyroid radiation doses were less than 50 mSv (intervention levels) even in evacuation areas. As for health consequences, no one died and no one suffered from acute effects. The thyroid ultrasound examination is in progress and following examination of almost 40,000 children, 35% of them have nodules and/or cysts but no cancers. Countermeasures against radiation must consider current individual measured values, although every effort must be taken to reconstruct radiation doses as precisely as possible. At present, the difference of thyroid radiation dose between Chernobyl and Fukushima appears to be due to the strict control of milk started within a week after the accident in Fukushima. Since the iodine-131 plume moved around in wide areas and for a long time, the method of thyroid protection must be reconsidered.


Next-generation sequencing of cancer genomes: back to the future.
The systematic karyotyping of bone marrow cells was the first genomic approach used to personalize therapy for patients with leukemia. The paradigm established by cytogenetic studies in leukemia (from gene discovery to therapeutic intervention) now has the potential to be rapidly extended with the use of whole-genome sequencing approaches for cancer, which are now possible. We are now entering a period of exponential growth in cancer gene discovery that will provide many novel therapeutic targets for a large number of cancer types. Establishing the pathogenetic relevance of individual mutations is a major challenge that must be solved. However, after thousands of cancer genomes have been sequenced, the genetic rules of cancer will become known and new approaches for diagnosis, risk stratification and individualized treatment of cancer patients will surely follow.


A selection strategy in plant transformation based on antisense oligodeoxynucleotide inhibition.
Antisense oligodeoxynucleotide (asODN) inhibition was developed in the 1970s, and since then has been widely used in animal research. However, in plant biology, the method has had limited application because plant cell walls significantly block efficient uptake of asODN to plant cells. Recently, we have found that asODN uptake is enhanced in a sugar solution. The method has promise for many applications, such as a rapid alternative to time-consuming transgenic studies, and high potential for studying gene functionality in intact plants and multiple plant species, with particular advantages in evaluating the roles of multiple gene family members. Generation of transgenic plants relies on the ability to select transformed cells. This screening process is based on co-introduction of marker genes into the plant cell together with a gene of interest. Currently, the most common marker genes are those that confer antibiotic or herbicide resistance. The possibility that traits introduced by selectable marker genes in transgenic field crops may be transferred horizontally is of major public concern. Marker genes that increase use of antibiotics and herbicides may increase development of antibiotic-resistant bacterial strains or contribute to weed resistance. Here, we describe a method for selection of transformed plant cells based on asODN inhibition. The method enables selective and high-throughput screening for transformed cells without conferring new traits or functions to the transgenic plants. Due to their high binding specificity, asODNs may also find applications as plant-specific DNA herbicides.


Sedentary and Trained Older Men Have Distinct Circulating Exosomal microRNA Profiles at Baseline and in Response to Acute Exercise.
Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men (n = 5) and age-matched sedentary males (n = 5) at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost). Following the isolation and enrichment of exosomes from plasma, exosome-enriched preparations were characterized and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed by comparing the baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost). Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. While further validation is needed, including measurements of IGF-1/IGF-1 signaling in blood or skeletal muscle, our results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.


A novel small RNA is important for biofilm formation and pathogenicity in Pseudomonas aeruginosa.
The regulation of biofilm development requires multiple mechanisms and pathways, but it is not fully understood how these are integrated. Small RNA post-transcriptional regulators are a strong candidate as a regulatory mechanism of biofilm formation. More than 200 small RNAs in the P. aeruginosa genome have been characterized in the literature to date; however, little is known about their biological roles in the cell. Here we describe the identification of the novel regulatory small RNA, SrbA. This locus was up-regulated 45-fold in P. aeruginosa strain PA14 biofilm cultures. Loss of SrbA expression in a deletion strain resulted in a 66% reduction in biofilm mass. Furthermore, the mortality rate over 72 hours in C. elegans infections was reduced to 39% when infected with the srbA deletion strain compared to 78% mortality when infected with the parental wild-type P. aeruginosa strain. There was no significant effect on culture growth or adherence to surfaces with loss of SrbA expression. Also loss of SrbA expression had no effect on antibiotic resistance to ciprofloxacin, gentamicin, and tobramycin. We conclude that SrbA is important for biofilm formation and full pathogenicity of P. aeruginosa.


Beyond Power Calculations: Assessing Type S (Sign) and Type M (Magnitude) Errors.
Statistical power analysis provides the conventional approach to assess error rates when designing a research study. However, power analysis is flawed in that a narrow emphasis on statistical significance is placed as the primary focus of study design. In noisy, small-sample settings, statistically significant results can often be misleading. To help researchers address this problem in the context of their own studies, we recommend design calculations in which (a) the probability of an estimate being in the wrong direction (Type S [sign] error) and (b) the factor by which the magnitude of an effect might be overestimated (Type M [magnitude] error or exaggeration ratio) are estimated. We illustrate with examples from recent published research and discuss the largest challenge in a design calculation: coming up with reasonable estimates of plausible effect sizes based on external information.


[The study of human pregnancy specific β1-glycoprotein immunomodulating effects].
Effect of human Pregnancy specific β1-glycoprotein (PSG) in physiological concentrations was analyzed against the expression of natural killer (NK)-, T-cells with natural killer functions (N KT-) and T-regulatory lymphocyte (Treg) markers, as well as on the activity of monocyte indolamine-2,3-dioxygenase (IDO) and lymphocyte apoptosis in vitro. It was revealed that PSG in high concentration (100 μg/mL) suppressed the CD16/56 expression by NK-cells, while inhibiting the cytolytic activity of these cells. Meanwhile, PSG in low concentrations (1 and 10 μg/mL) enhanced the CD16/56 expression by NKT-cells that was related to cytokine-producing activity. It was found that PSG increased the number of adaptive Tregs in culture (CD4+FOXP3+ and CD4+CD25(bright)FOXP3+). In addition, PSG promoted the IDO activity in peripheral monocytes, while further potentiating the Treg generation. In general, PSG rendered anti-apoptotic action on lymphocytes. Therefore, indicated effects can determine the PSG contribution to the development of immune tolerance in pregnancy.


[The effect of the plant growth stimulant bactozole on Rhizobium leguminosarum bv. viciae 250a and its nitrogen-tolerant mutant M-71 under varied nitrogen supply].
The effect of the plant growth stimulant bactozole on the growth of Rhizobium leguminosarum bv. viciae 250a and its nitrogen-tolerant mutant M-71 and the synthesis of extracellular carbohydrates was studied. At a low content of nitrate (6 mM) in the medium, all three bactozole concentrations tested (0.001, 0.01, and 0.1%) exerted similar stimulating effects on the growth of the parent strain 250a (about 1.5-fold) and the synthesis of extracellular carbohydrates (about 2-fold). At a high content of nitrate (20 mM) in the medium, when the growth of the parent strain and the synthesis of extracellular carbohydrates were inhibited, bactozole at all three concentrations exerted only a growth-stimulating effect. At the same time, mutant M-71 showed better growth at higher concentrations of bactozole, whereas the ability of the mutant to synthesize extracellular carbohydrates decreased with increasing bactozole concentration. The cell biomass of the mutant accumulated at 20 mM nitrate was 1.8-2.5 times greater than it was at 6 mM nitrate. Bactozole enhanced the symbiosis of legume plants with both parent and mutant strains, raising the mass of plants and enhancing nodulation and the nitrogen-fixing activity of root nodules. The symbiotic parameters of mutant M-71 were better (irrespective of whether bactozole was present or not) when its inoculum was grown at a high nitrogen content (20 mM nitrate), whereas the respective parameters of the parent strain were better when it was grown at 6 mM nitrate. The inference is made that the better physiological characteristics of the mutant in the high-nitrate medium is due to its higher nitrate reductase activity (as compared with the parent strain) in both the free-living state and in legume nodules.


Human homologue of yeast Rad23 protein A interacts with p300/cyclic AMP-responsive element binding (CREB)-binding protein to down-regulate transcriptional activity of p53.
The tumor suppressor protein p53 regulates various cellular responses to DNA damage and plays a significant role in DNA repair. The nuclear p300/cyclic AMP-responsive element binding (CREB)-binding protein (CBP) proteins act as coactivators in supporting the transcription function of p53. We examined the role of the human homologue of yeast Rad23 protein A (hHR23A), one of the two human homologues of the Saccharomyces cerevisiae nucleotide excision repair gene product Rad23, in the p300/CBP-associated regulation of p53 activity. Overexpression of wild-type hHR23A inhibits the p53 transcriptional activity and results in a decreased steady-state protein level of cellular p53. The inhibitory effect of hHR23A can be overcome by the concomitant expression of p300, CBP, and p300 segments harboring C/H1 domain and neutralized by the coexpression of HIV accessory protein Vpr, which binds COOH terminus of hHR23A/B. Additionally, hHR23A was shown to interact in vitro and in vivo with p300 segments harboring C/H1 domain. These studies provide evidence for the involvement of hHR23A in the regulation of p53 activity through p300/CBP. Although the precise direct role of hHR23 proteins in regulation of p53 and DNA repair remains to be elucidated, our data suggest that the interaction between hHR23A and p300/CBP has important implications in cross-talk between the p53 pathway and DNA repair.


Enhanced TLR4 reactivity following injury is mediated by increased p38 activation.
Severe injury primes the innate-immune system for increased Toll-like receptor 4 (TLR4)-induced proinflammatory cytokine production by macrophages. In this study, we examined changes in TLR4 signaling pathways in splenic macrophages from burn-injured or sham mice to determine the molecular mechanism(s) responsible for the increased TLR4 responsiveness. Using flow cytometry and specific antibodies, we first looked for injury-induced changes in the expression levels of several TLR-associated signaling molecules. We found similar levels of myeloid differentiation primary-response protein 88 (MyD88) and interleukin-1 receptor-associated kinase-M (IRAK-M) and somewhat lower levels of total p38, extracellular signal-regulated kinase (ERK), and stress-activated protein kinase (SAPK)/c-jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) in burn compared with sham macrophages. However, with the use of antibodies specific for the phosphorylated (activated) forms of the three MAPKs, we found that macrophages from burn mice showed a twofold increase in purified lipopolysaccharide (LPS)-stimulated p38 activation as compared with cells from sham mice on days 1 and 7 post-injury, whereas ERK and SAPK/JNK activation was increased by burn injury only on day 1. Using the specific p38 inhibitor (SB203580), we confirmed that the increase in tumor necrosis factor alpha production by LPS-stimulated burn macrophages requires p38 activation. Although we demonstrated that injury increases macrophage TLR4 mRNA expression and intracellular expression of TLR4-myeloid differentiation protein-2 (MD-2) protein, macrophage cell-surface expression of TLR4-MD-2 was not changed by burn injury. Our results suggest that the injury-induced increase in TLR4 reactivity is mediated, at least in part, by enhanced activation of the p38 signaling pathway.


Allocation Strategies of Carbon, Nitrogen, and Phosphorus at Species and Community Levels With Recovery After Wildfire.
Plant stoichiometry and nutrient allocation can reflect a plant's adaptation to environmental nutrient changes. However, the allocation strategies of carbon (C), nitrogen (N), and phosphorus (P) between leaf and fine root in response to wildfire have been poorly studied. Our primary objective was to elucidate the trade-off of elemental allocation between above- and belowground parts in response to the soil nutrient changes after a wildfire. We explored the allocation sloping exponents of C, N, and P between leaf and fine root at the species and community levels at four recovery periods (year 2, 10, 20, and 30) after moderately severe wildfire and one unburned treatment in boreal forests in Great Xing'an Mountains, northeast China. Compared with the unburned treatment, leaf C concentration decreased and fine root C increased at year 2 after recovery. The leaf N concentration at year 10 after recovery was higher than that of unburned treatment. Plant growth tended to be limited by P concentration at year 10 after recovery. Nutrient allocation between leaf and fine root differed between species and community levels, especially in the early recovery periods (i.e., 2 and 10 years). At the community level, the nutrient concentrations of the leaf changed more as compared to that of the fine root at year 2 after recovery when the fine root nutrients changed more than those of the leaf. The different C, N, and P allocation strategies advanced the understanding of plant adaptation to soil nutrient changes during the postfire ecosystem restoration.


Role of epidermal growth factor receptor in the metastasis of intraocular melanomas.
To explore the expression and function of epidermal growth factor receptor (EGFR) expression on human uveal melanoma cells. Five human uveal melanoma cell lines were examined by flow cytometry for the expression of EGFR. The correlation between EGFR expression and metastasis of uveal melanoma cells was tested in a nude mouse model of intraocular melanoma. The effect of EGFR on liver homing of blood-borne uveal melanoma cells was tested by tracing the fate of radiolabeled cells treated with anti-EGFR monoclonal antibody. The capacity of EGFR to inhibit the cytotoxic effects of tumor necrosis factor-alpha (TNF-alpha) was determined in vitro. The role of EGFR in promoting metastatic disease was studied by infusing intraocular melanoma-bearing mice using a neutralizing antibody against EGFR. EGFR was expressed to varying degrees on all eight human uveal melanoma cell lines. Expression of EGFR correlated with metastatic potential and capacity of blood-borne uveal melanoma cells to localize in the liver. EGFR rendered uveal melanoma cells resistant to the cytolytic effects of TNF-alpha. Blocking EGFR with a neutralizing monoclonal antibody increased the susceptibility of uveal melanoma cells to TNF-mediated cytolysis, inhibited metastases, and prolonged host survival. The expression of EGFR on five human uveal melanoma cell lines is correlated with an increased capacity to localize in the liver, an increased resistance to TNF-mediated lysis, and decreased survival. Targeting EGFR expression and function may be a fruitful strategy for managing patients with uveal melanoma.


An ultra-high common-mode rejection ratio (CMRR) AC instrumentation amplifier for laplacian electrocardiographic measurement.
Laplacian electrocardiograms (LECGs) localize the moment of activation (MOA) of the heart noninvasively at a nearby point on the chest surface. Tripolar concentric ring (TCR) electrodes provide small, but well-defined, site-specific second spatial derivative signals of the potential on the chest surface for studying the activation sequence of the myocardium. A battery-powered, modified AC instrumentation amplifier (IA) was used as preamplifier to obtain signals with a high common-mode rejection ratio (CMRR). The authors' direct-coupled quasi-high-pass IA has high input impedance and high CMRR, without the need to match capacitors and resistors. The amplifier circuit and two lithium cells were integrated with the substrate for the TCR sensor to minimize inductive pickup by the leads. Combining the natural ability of the TCR electrodes to reject common-mode signals with the high CMRR of the IA made it possible to obtain LECG signals in real time with good signal-to-noise ratio (SNR). The authors observed and recorded the MOAs from 16 sites in a 4-by-4 matrix from the left side of the thorax of each subject. Beat-by-beat changes were observed from one subject showing episodes of bigeminal rhythm. The authors were able to obtain localized signals representing the right and left ventricles from surface TCR electrodes in real time.


Dietary phosphorus requirement of channel catfish.
Two experiments were conducted to reevaluate the dietary phosphorus requirement of fingerling channel catfish. Basal diets containing either casein with supplemental inorganic phosphorus and 0.5% total calcium or egg albumin with supplemental inorganic phosphorus and 0.75% total calcium yielded similar requirement data. Eleven-week growth, feed efficiency, serum phosphorus, bone ash, bone calcium and bon phosphorus data indicate that 0.33% apparent available dietary phosphorus is adequate for maximum growth and bone mineralization. Based on these data and previous findings, we would suggest a value of 0.4% apparent available phosphorus be used in formulating catfish feeds. The apparent availability of phosphorus from soybean meal, as determined by the chromic oxide indicator method, was 29% for channel catfish.


Aerotaxis in Salmonella typhimurium: role of electron transport.
Sensory transduction in aerotaxis required electron transport, in contrast to chemotaxis, which is independent of electron transport. Assays for aerotaxis were developed by employing spatial and temporal oxygen gradients imposed independently of respiration. By varying the step increase in oxygen concentration in the temporal assay, the dose-response relationship was obtained for aerotaxis in Salmonella typhimurium. A half-maximal response at 0.4 microM oxygen and inhibition by 5 mM KCN suggested that the "receptor" for aerotaxis is cytochrome o. The response was independent of adenosine triphosphate formation via oxidative phosphorylation but did correlate with changes in membrane potential monitored with the fluorescent cyanine dye diS-C3-(5). Nitrate and fumarate, which are alternative electron acceptors for the respiratory chain in S. typhimurium, inhibited aerotaxis when nitrate reductase and fumarate reductase were induced. These results support the hypothesis that taxis to oxygen, nitrate, and fumarate is mediated by the electron transport system and by changes in the proton motive force. Aerotaxis was normal in Escherichia coli mutants that were defective in the tsr, tar, or trg genes; in S. typhimurium, oxygen did not stimulate methylation of the products of these genes. A cheC mutant which shows an inverse response to chemoattractants also gave an inverse response to oxygen. Therefore, aerotaxis is transduced by a distinct and unidentified signally protein but is focused into the common chemosensory pathway before the step involving the cheC product. When S. typhimurium became anaerobic, the decreased proton motive force from glycolysis supported slow swimming but not tumbling, indicating that a minimum proton motive force was required for tumbling. The bacteria rapidly adapted to the anaerobic condition and resumed tumbling after about 3 min. The adaptation period was much shorter when the bacteria had been previously grown anaerobically.


Clinical Features and Treatment Outcomes of 81 Patients with Aggressive Type Adult T-cell Leukemia-lymphoma at a Single Institution over a 7-year Period (2006-2012).
Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL. We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyama's diagnostic criteria. Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that two-thirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index. In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice.


History of reconstructive rhinoplasty.
Amputation of the nose was practiced as a sign of humiliation to adulterers, thieves, and prisoners of war by certain ancient populations. To erase this disfigurement, numerous techniques were invented over the centuries. In India, where this injury was common, advancement cheek flaps were performed (around 600 BC). The forehead flap was introduced much later, probably around the 16th century. The Venetian adventurer Manuzzi, in writing a report about the Mughal Empire in the second half of the 17th century gave the description of the forehead rhinoplasty. Detailed information concerning the Indian forehead flap reached the Western world in 1794, thanks to a letter to the editor that appeared in the Gentleman's Magazine. From this episode, one can date the beginning of a widespread interest in rhinoplasty and in plastic surgery in general. In Europe, nasal reconstruction started in the 15th century in Sicily with the Brancas, initially with cheek flaps and then with arm flaps. At the beginning of the 16th century, rhinoplasty developed in Calabria (Southern Italy) with the Vianeos. In 1597, Gaspare Tagliacozzi, Professor of Surgery at Bologna, improved the arm flap technique and published a book entirely devoted to this art. He is considered the founder of plastic surgery.


Dynamic regulation of Emi2 by Emi2-bound Cdk1/Plk1/CK1 and PP2A-B56 in meiotic arrest of Xenopus eggs.
In vertebrates, unfertilized eggs are arrested at metaphase of meiosis II by Mos and Emi2, an inhibitor of the APC/C ubiquitin ligase. In Xenopus, Cdk1 phosphorylates Emi2 and both destabilizes and inactivates it, whereas Mos recruits PP2A phosphatase to antagonize the Cdk1 phosphorylation. However, how Cdk1 phosphorylation inhibits Emi2 is largely unknown. Here we show that multiple N-terminal Cdk1 phosphorylation motifs bind cyclin B1-Cdk1 itself, Plk1, and CK1δ/ε to inhibit Emi2. Plk1, after rebinding to other sites by self-priming phosphorylation, partially destabilizes Emi2. Cdk1 and CK1δ/ε sequentially phosphorylate the C-terminal APC/C-docking site, thereby cooperatively inhibiting Emi2 from binding the APC/C. In the presence of Mos, however, PP2A-B56β/ε bind to Emi2 and keep dephosphorylating it, particularly at the APC/C-docking site. Thus, Emi2 stability and activity are dynamically regulated by Emi2-bound multiple kinases and PP2A phosphatase. Our data also suggest a general role for Cdk1 substrate phosphorylation motifs in M phase regulation.


cDNA sequences for transcription factors and signaling proteins of the hemichordate Saccoglossus kowalevskii: efficacy of the expressed sequence tag (EST) approach for evolutionary and developmental studies of a new organism.
We describe a collection of expressed sequence tags (ESTs) for Saccoglossus kowalevskii, a direct-developing hemichordate valuable for evolutionary comparisons with chordates. The 202,175 ESTs represent 163,633 arrayed clones carrying cDNAs prepared from embryonic libraries, and they assemble into 13,677 continuous sequences (contigs), leaving 10,896 singletons (excluding mitochondrial sequences). Of the contigs, 53% had significant matches when BLAST was used to query the NCBI databases (< or = 10(-10)), as did 51% of the singletons. Contigs most frequently matched sequences from amphioxus (29%), chordates (67%), and deuterostomes (87%). From the clone array, we isolated 400 full-length sequences for transcription factors and signaling proteins of use for evolutionary and developmental studies. The set includes sequences for fox, pax, tbx, hox, and other homeobox-containing factors, and for ligands and receptors of the TGFbeta, Wnt, Hh, Delta/Notch, and RTK pathways. At least 80% of key sequences have been obtained, when judged against gene lists of model organisms. The median length of these cDNAs is 2.3 kb, including 1.05 kb of 3' untranslated region (UTR). Only 30% are entirely matched by single contigs assembled from ESTs. We conclude that an EST collection based on 150,000 clones is a rich source of sequences for molecular developmental work, and that the EST approach is an efficient way to initiate comparative studies of a new organism.


Lipid Trait Variants and the Risk of Non-Hodgkin Lymphoma Subtypes: A Mendelian Randomization Study.
Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10-8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.


Lupus and Perioperative Complications in Elective Primary Total Hip or Knee Arthroplasty.
The number of patients with systemic lupus erythematosus (herein, lupus) undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) is increasing. There is disagreement about the effect of lupus on perioperative complication rates. We hypothesized that lupus would be associated with higher complication rates in patients who undergo elective primary THA or TKA. Records of more than 6.2 million patients from the National Inpatient Sample who underwent elective primary THA or TKA from 2000 to 2009 were reviewed. Patients with lupus (n = 38,644) were compared with those without lupus (n = 6,173,826). Major complications were death, pulmonary embolism, myocardial infarction, stroke, pneumonia, and acute renal failure. Minor complications were wound infection, seroma, deep vein thrombosis, hip dislocation, wound dehiscence, and hematoma. Patient age, sex, duration of hospital stay, and number of Elixhauser comorbidities were assessed for both groups. Multivariate logistic regression models using comorbidities, age, and sex as covariates were used to assess the association of lupus with major and minor perioperative complications. The alpha level was set to 0.001. Among patients who underwent THA, those with lupus were younger (mean age, 56 vs. 65 years), were more likely to be women (87% vs. 56%), had longer hospital stays (mean, 4.0 vs. 3.8 days), and had more comorbidities (mean, 2.5 vs. 1.4) than those without lupus (all p < 0.001). In patients with THA, lupus was independently associated with major complications (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1 to 1.7) and minor complications (OR, 1.2; 95% CI, 1.0 to 1.5). Similarly, among patients who underwent TKA, those with lupus were younger (mean, 62 vs. 67 years), were more likely to be women (93% vs. 64%), had longer hospital stays (mean, 3.8 vs. 3.7 days), and had more comorbidities (mean, 2.8 vs. 1.7) than those without lupus (all p < 0.001). However, in TKA patients, lupus was not associated with greater odds of major complications (OR, 1.2; 95% CI, 0.9 to 1.4) or minor complications (OR, 1.1; 95% CI, 0.9 to 1.3). Lupus is an independent risk factor for major and minor perioperative complications in elective primary THA but not TKA.


Convection- and diffusion-dependent ventilation maldistribution in normal subjects.
We performed multiple-breath N2 washouts (MBNW) with tidal volumes of 1 liter at 8-16 breaths/min and constant flow rates in six normal subjects. For each breath we computed the slope of the alveolar plateau, normalized by the mean expired N2 concentration (Sn), the Bohr dead space (VDB), an index analogous to the Fowler dead space (V50), and the normalized slope of phase II (S2). In four subjects helium (He) and sulfur hexafluoride (SF6) were washed out after equilibration with a 5% gas mixture of each tracer. The Sn for He and SF6 increased in consecutive breaths, but the difference (delta Sn) increased only over the first five breaths, remaining constant thereafter. In all six subjects Sn, VDB, and V50 increased progressively in consecutive breaths of the MBNW, the increase in Sn being the greatest, approximately 290% from the first to the 23-25th breath. In contrast, S2 was unchanged initially and decreased after the sixth breath. The results indicate that after the fifth breath the increase in Sn during a MBNW is diffusion independent and may constitute a sensitive index of convection-dependent inhomogeneity (CDI). Subtraction of this component from the first breath suggests that Sn in a single-breath washout is largely due to a diffusion-dependent mechanism. The latter may reflect an interaction of convection and diffusion within the lung periphery, whereas CDI may comprise ventilation inequality among larger units, subtended by more centrally located branch points.


[The response of peripheral blood lymphocytes from lung cancer patients to in-vitro treatment with recombinant interleukin-2].
The cytotoxic activity of peripheral blood lymphocytes of 135 lung cancer patients was studied. A wide range of cytotoxicity values was shown--from 0 to 88%. During the randomized investigation of these patients no strong correlation was found between the levels of cytotoxicity and the cancer stages. A certain tendency of increasing the number of patients with weak cytotoxic activity upon progressing disease was followed. The lymphocytes with a strong natural killer activity did not react on the in vitro incubation with interleukin-2. The lymphocytes with a strong was obtained when the lymphocytes with the lowest cytotoxicity levels were incubated with this immunomodulator.


Tissue-specific heterogeneity in alpha-dystroglycan sialoglycosylation. Skeletal muscle alpha-dystroglycan is a latent receptor for Vicia villosa agglutinin b4 masked by sialic acid modification.
Because the polypeptide core of alpha-dystroglycan is encoded by a single gene, the difference in apparent molecular mass between alpha-dystroglycans expressed in various tissues is presumably due to differential glycosylation. However, little is presently known about the tissue-specific differences in alpha-dystroglycan glycosylation and whether these modifications may confer functional variability to alpha-dystroglycan. We recently observed that laminin-1 binding to skeletal muscle alpha-dystroglycan was dramatically inhibited by heparin, whereas the binding of commercial merosin to skeletal muscle alpha-dystroglycan was only marginally inhibited (Pall, E. A., Bolton, K. M., and Ervasti, J. M. (1996) J. Biol. Chem. 3817-3821). In contrast to 156-kDa skeletal muscle alpha-dystroglycan, both laminin-1 and merosin binding to 120-kDa brain alpha-dystroglycan were sensitive to heparin. We have now examined the laminin binding properties of 140-kDa alpha-dystroglycan purified from cardiac muscle and observed that like skeletal muscle alpha-dystroglycan, heparin inhibited cardiac alpha-dystroglycan binding to laminin-1, but not to merosin. On the other hand, cardiac and brain alpha-dystroglycans could be distinguished from skeletal muscle alpha-dystroglycan by their reactivity with the terminal GalNAc-specific lectin Vicia villosa agglutinin. Interestingly, skeletal muscle alpha-dystroglycan became reactive with V. villosa agglutinin upon digestion with sialidase from Clostridium perfringens, Arthrobacter neurofaciens, or Streptococcus, but not Vibrio cholerae or Newcastle disease virus sialidase. While none of the sialidase treatments affected the laminin binding properties of alpha-dystroglycan, the sum of our results suggests that skeletal muscle alpha-dystroglycan contains a novel sialic acid residue linked alpha2-6 to GalNAc. These properties are also consistent with the cellular characteristics of a GalNAc-terminated glycoconjugate recently implicated in neuromuscular synaptogenesis. Thus, variations in alpha-dystroglycan sialoglycosylation may prove as useful markers to further elucidate the role of alpha-dystroglycan glycoforms in different tissues and perhaps within a single cell type.


Modulation of aquaporin 4 and the amiloride-inhibitable sodium channel in perinatal rat lung epithelial cells.
During the perinatal period, a dramatic reversal of lung transepithelial ion and water transport occurs that involves the amiloride-inhibitable Na+ channel (ENaC). Aquaporin (AQP) water channel proteins facilitate cell membrane water transport. We now report that AQP-4, localized to basolateral membranes of airway epithelial cells, increases its mRNA expression in developing lung eightfold during the 2 days before birth to reach a peak on the first postnatal day in the lungs but not in brains or kidneys of neonatal rats. AQP-4 and the alpha-, beta-, and gamma-subunits of ENaC are both expressed by cultured rat fetal distal lung epithelial (FDLE) cells. AQP-4 and ENaC expression increase in FDLE cells cultured on uncoated permeant filters compared with matched control cells cultured on filters containing extracellular matrix derived from fetal lung epithelial cells. Similarly, AQP-4 expression increases in FDLE cells exposed to 21% O2 compared with cells exposed to 3% O2. These data demonstrate that AQP-4 expression is highest on the first day after birth in neonatal rat lungs. Exposure to ambient 21% O2 may contribute to increases in AQP-4 and ENaC expression to facilitate water transport across neonatal airway epithelia in the immediate postnatal period.


[Heterogeneity of virus-specific flavivirus proteins].
The polyacrylamide gel analysis of large intracellular virus-specific proteins NV5, NV4, and the intracellular form of structural protein V3 established differences in the electrophoretic mobility of each of these proteins formed in cells infected with tick-borne encephalitis, Powassan, Langat, and West Nile viruses. It is assumed that these differences in the electrophoretic mobility of NV5, NV4 proteins, and the intracellular form of V3 protein reflect the differences in the primary structure of each of these proteins in the viruses examined.


Balance in subjects with congenital or early onset strabismus: Influence of age.
Few studies have investigated the relationship between strabismus and balance, and those that do exist focused on patients within a limited age range, while no studies on possible age-related changes have yet been conducted. Therefore, the aim of our study was to investigate whether the balance strategies adopted by patients with congenital or early onset strabismus change with age. Forty strabismic patients and 36 healthy subjects were enrolled in the study. Both patients and healthy subjects were divided into three subgroups according to age (children, adolescents, and adults) and underwent a stabilometric evaluation. When we compared the whole group of strabismic patients with the group of healthy subjects, we found that the center of pressure area and the trunk oscillations in the former were significantly different from those in the latter; when we considered the three age groups separately, only values in children with strabismus were different from those in the age-matched control group of healthy subjects. Strabismus was found to affect balance in children by inducing a postural strategy characterized by a reduction in physiological trunk oscillations. Gaining a better insight into postural control in strabismic subjects and its evolution with age may be crucial to improving rehabilitation in such patients and planning tailored rehabilitation treatment.