A new technique for solving puzzles.
This paper proposes a new technique for solving jigsaw puzzles. The novelty of the proposed technique is that it provides an automatic jigsaw puzzle solution without any initial restriction about the shape of pieces, the number of neighbor pieces, etc. The proposed technique uses both curve- and color-matching similarity features. A recurrent procedure is applied, which compares and merges puzzle pieces in pairs, until the original puzzle image is reformed. Geometrical and color features are extracted on the characteristic points (CPs) of the puzzle pieces. CPs, which can be considered as high curvature points, are detected by a rotationally invariant corner detection algorithm. The features which are associated with color are provided by applying a color reduction technique using the Kohonen self-organized feature map. Finally, a postprocessing stage checks and corrects the relative position between puzzle pieces to improve the quality of the resulting image. Experimental results prove the efficiency of the proposed technique, which can be further extended to deal with even more complex jigsaw puzzle problems.


Evaluation of corneal morphologic and functional parameters after use of topical cyclosporine-a 0.05% in dry eye.
To report the effect of topical Cyclosporine-A (CsA) 0.05% on corneal morphologic and functional parameters in patients with dry eye. In this prospective and observational study 30 eyes of 30 patients who received topical CsA 0.05% for treatment of dry eye were evaluated. Each clinical examination included a routine Schirmer I test and tear film break-up time (TBUT) was performed at baseline and after 1, 2, 3, and 6 months of treatment. All participants also underwent central corneal thickness (CCT) measurements with ultrasound pachymetry, endothelial cell density (ECD) with specular microscopy, corneal topographical evaluation with Orbscan II, and corneal biomechanical parameters with Ocular Response Analyzer measurements at baseline and after treatment. The Schirmer I test and TBUT were significantly improved after treatment (for both; P<0.01). The CCT, topographical findings, ECD, and corneal biomechanical parameters were not significantly different at baseline and follow-up visits (P>0.05). No serious adverse effects were seen at follow up visits. The study showed that Topical CsA 0.05% caused no changes on corneal morphology and function.


Compulsory substance abuse treatment: an overview of recent findings and issues.
An overview of research trends and issues in the area of compulsory substance abuse treatment is presented, using a sample of 170 English-language articles obtained from a search of 4 databases (Medline, PubMed, Embase, PsychINFO, supplemented by a manual search). About half (51%) of these articles were non-empirical (i.e. literature reviews, policy proposals, legal and ethical commentaries on compulsory treatment). A subsample of empirical studies published since 1988 (n = 71) was coded to summarize research trends in relation to 3 key issues: (1) how compulsory treatment was studied (country of origin; type of compulsory treatment; treatment population), (2) the evidence base for judging effectiveness of compulsory treatment (research design; sampling; type, timing and results of outcome measures), and (3) the relationship between compulsory treatment and coercion (measurement strategies). Directions for future research are discussed.


IgE-mediated triggering signals for mediator release from human mast cells and basophils.
Human basophils were developed in suspension culture of mononuclear cells of cord blood in the presence of conditioned medium of phytohemagglutinin-stimulated human T cells, from which interleukin 2 had been eliminated. Approximately 50-90% of cells recovered after 2-4 wk of culture were basophil granulocytes, which bear receptors with high affinity for human IgE. Sensitization of the cells with human IgE followed by challenge with anti-IgE resulted in the release of histamine and arachidonic acid (AA). In both the cultured basophils and human lung mast cells, bridging of cell-bound IgE with anti-IgE induced a transient increase in phospholipid methylation and intracellular cyclic AMP (cAMP), and these processes were followed by Ca2+ uptake and release of both histamine and AA. As demonstrated in rat mast cells, evidence was obtained that the activation of a proteolytic enzyme and phospholipid methylation induced by the bridging of IgE receptors are involved in the subsequent increase in AMP, and are an essential step for transduction of triggering signals for mediator release.


HIV, syphilis infection, and risky sexual behaviors among male university students who have sex with men in Beijing, China: a cross-sectional study.
Young male university students who have sex with men are at high risk of HIV and sexually transmitted infections (STIs). We conducted a cross-sectional survey to assess the prevalence of risky sexual behaviors, HIV, and syphilis among male university students who have sex with men in Beijing, China; and to identify risk factors for unprotected anal intercourse (UAI). Among 157 study participants, HIV and syphilis prevalence were 2.5% and 7.0%, respectively. We found a high prevalence of UAI in our study population. Multiple logistic regression analysis revealed two significant predictors of UAI: believing it is not necessary to use a condom with a regular sex partner and not feeling anxious about being gay. Not using a condom during first sexual experience with a man was a marginally significant predictor of UAI. Male university students who have sex with men are especially vulnerable to HIV and STIs. Intensified education and HIV testing programs are needed to reduce risk in this population.


Training Neural Networks by Lifted Proximal Operator Machines.
We present the lifted proximal operator machine (LPOM) to train fully-connected feed-forward neural networks. LPOM represents the activation function as an equivalent proximal operator and adds the proximal operators to the objective function of a network as penalties. LPOM is block multi-convex in all layer-wise weights and activations. This allows us to develop a new block coordinate descent (BCD) method with convergence guarantee to solve it. Due to the novel formulation and solving method, LPOM only uses the activation function itself and does not require any gradient steps. Thus it avoids the gradient vanishing or exploding issues, which are often blamed in gradient-based methods. Also, it can handle various non-decreasing Lipschitz continuous activation functions. Additionally, LPOM is almost as memory-efficient as stochastic gradient descent and its parameter tuning is relatively easy. We further implement and analyze the parallel solution of LPOM. We first propose a general asynchronous-parallel BCD method with convergence guarantee. Then we use it to solve LPOM, resulting in asynchronous-parallel LPOM. For faster speed, we develop the synchronous-parallel LPOM. We validate the advantages of LPOM on various network architectures and datasets. We also apply synchronous-parallel LPOM to autoencoder training and demonstrate its fast convergence and superior performance.


Update on prostate cancer in black men within the UK.
There is a wealth of evidence which can be traced back to the African transatlantic slave trade indicating that black men have a higher risk of prostate cancer compared to other ethnic groups. Migration to Westernised countries may have had little effect on the incidence of prostate cancer in this ethnic group; however, current evidence indicates that there are several complex factors that may contribute to this risk. Studies in the UK quote that black men are at 2-3 times the risk of prostate cancer in comparison to their Caucasian counterparts, with a 30% higher mortality rate. Caution should be taken prior to the interpretation of these results due to a paucity of research in this area, limited accurate ethnicity data, and lack of age-specific standardisation for comparison. Cultural attitudes towards prostate cancer and health care in general may have a significant impact on these figures, combined with other clinico-pathological associations. This update summarises new contributory research on this subject, highlighting the need to increase awareness and understanding of prostate cancer amongst high-risk communities and to support further robust research in this area by nominating a lead in cancer and ethnicity studies within the National Health Service.


Counting adolescents in: the development of an adolescent health indicator framework for population-based settings.
Changing realities in low- and middle-income countries (LMICs) in terms of inequalities, urbanization, globalization, migration, and economic adversity shape adolescent development and health, as well as successful transitions between adolescence and young adulthood. It is estimated that 90% of adolescents live in LMICs in 2019, but inadequate data exist to inform evidence-based and concerted policies and programs tailored to address the distinctive developmental and health needs of adolescents. Population-based data surveillance such as Health and Demographic Surveillance Systems (HDSS) and school-based surveys provide access to a well-defined population and provide cost-effective opportunities to fill in data gaps about adolescent health and well-being by collecting population-representative longitudinal data. The Africa Research Implementation Science and Education (ARISE) Network, therefore, systematically developed adolescent health and well-being indicators and a questionnaire for measuring these indicators that can be used in population-based LMIC settings. We conducted a multistage collaborative and iterative process led by network members alongside consultation with health-domain and adolescent health experts globally. Seven key domains emerged from this process: socio-demographics, health awareness and behaviors; nutrition; mental health; sexual and reproductive health; substance use; and healthcare utilization. For each domain, we generated a clear definition; rationale for inclusion; sub-domain descriptions, and a set of questions for measurement. The ARISE Network will implement the questionnaire longitudinally (i.e., at two time-points one year apart) at ten sites in seven countries in sub-Saharan Africa and two countries in Asia. Integrating the questionnaire within established population-based data collection platforms such as HDSS and school settings can provide measured experiences of young people to inform policy and program planning and evaluation in LMICs and improve adolescent health and well-being.


Direct and Base Excision Repair-Mediated Regulation of a GC-Rich cis-Element in Response to 5-Formylcytosine and 5-Carboxycytosine.
Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2'-deoxy-(5-fC/5-caC) or their BER-resistant 2'-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5'-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5'-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches.


Immediate glycosylation of Sindbis virus membrane proteins.
The mechanism by which the membrane proteins of Sindbis virus are initially glycosylated during growth of the virus in chick cells was studied. The experiments suggest strongly that the two viral glycoproteins are glycosylated before release from the polysome, and that this glycosylation involves transfer of a large 1800 dalton oligosaccharide to the polypeptide chains. The donor of the oligosaccharide is most probably a lipid.


Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy.
This study was designed to assess the effect of differential leukocyte depletion during chemotherapy by monitoring the levels of exhaled hydrogen peroxide H2O2 and nitric oxide (F(eNO)) present. In 39 patients with lung cancer (chronic obstructive pulmonary disorder up to stage II, median forced expiratory volume in one second 78% predicted), measurements were performed before a cycle of therapy (day 1), at least once during the cycle (day 8: n = 34; day 15: n = 19), and afterwards (days 21-29). There were significant changes in the level of H2O2, F(eNO) and peripheral blood cell differentials over the visits. The level of H2O2 was decreased only on day 15, with a median (difference between the upper and lower quartiles) fall of 31 (57)%, while F(eNO) was reduced only on day 8, by 22 (40)%. Neutrophil numbers were unchanged on day 8 and decreased by 59 (48)% on day 15, while monocyte numbers were decreased on day 8 by 87 (39)%. On days 21-29, values had returned to baseline. Taken together with previous findings, the parallel course of levels of exhaled hydrogen peroxide and neutrophil counts suggests that a major part of exhaled hydrogen peroxide is due to neutrophils via the conducting airways. In contrast, the production of exhaled nitric oxide seems to be primarily associated with monocytes.


Craniofacial morphology of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is the second most common neuromuscular disease of childhood. It is the most common fatal recessive neuromuscular disease. This study is the first to evaluate the craniofacial growth of SMA patients. The results pertain to a sample of 25 SMA patients, between 5 and 32 y of age, who were case matched with unaffected normal controls. Group differences for 25 measures, derived from tracings of standardized cephalometric radiographs, were evaluated using multivariate analysis of variance. The SMA group showed excessive vertical development, particularly of the lower face. They demonstrated relatively larger anterior than posterior facial heights, due in part to a smaller cranial base angulation and a more anteriorly positioned mandibular ramus. Anteroposterior skeletal discrepancies of SMA patients, due to the combined effects of a protrusive maxilla and a retrusive mandible, were moderate. The interincisal angle of the SMA group was smaller than normal, due primarily to proclined maxillary incisors. Relative to palatal length, the SMA group had smaller anterior cranial base and mandibular corpus lengths. These results suggest abnormal craniofacial growth patterns of SMA patients. The etiology of the observed abnormalities seems to be complex and multifaceted, but attention to the treatment of malocclusion may be important for optimal nutrition and respiratory function.


Modeling combined ultrasound and photoacoustic imaging: Simulations aiding device development and artificial intelligence.
Combined ultrasound and photoacoustic (USPA) imaging has attracted several pre-clinical and clinical applications due to its ability to simultaneously display structural, functional, and molecular information of deep biological tissue in real time. However, the depth and wavelength dependent optical attenuation and the unknown optical and acoustic heterogeneities limit the USPA imaging performance in deep tissue regions. Novel instrumentation, image reconstruction, and artificial intelligence (AI) methods are currently being investigated to overcome these limitations and improve the USPA image quality. Effective implementation of these approaches requires a reliable USPA simulation tool capable of generating US based anatomical and PA based molecular contrasts of deep biological tissue. Here, we developed a hybrid USPA simulation platform by integrating finite element models of light (NIRFast) and ultrasound (k-Wave) propagations for co-simulation of B-mode US and PA images. The platform allows optimization of different design parameters for USPA devices, such as the aperture size and frequency of both light and ultrasound detector arrays. For designing tissue-realistic digital phantoms, a dictionary-based function has been added to k-Wave to generate various levels of ultrasound speckle contrast. The feasibility of modeling US imaging combined with optical fluence dependent multispectral PA imaging is demonstrated using homogeneous as well as heterogeneous tissue phantoms mimicking human organs (e.g., prostate and finger). In addition, we also demonstrate the potential of the simulation platform to generate large scale application-specific training and test datasets for AI enhanced USPA imaging. The complete USPA simulation codes together with the supplementary user guides have been posted to an open-source repository (https://github.com/KothapalliLabPSU/US-PA_simulation_codes).


Redox properties of alluaudite sodium cobalt manganese sulfates as high-voltage electrodes for rechargeable batteries.
Alluaudite sulfates are predicted to be high-voltage electrodes for lithium- and sodium-ion batteries. Herein, we provide the first experimental evidence for the operation of sodium cobalt-manganese sulfate, Na2+2δ(Co0.63Mn0.37)2-δ(SO4)3, at potentials higher than 4.0 V vs. Li/Li+. This fact comes as a result of the reduced cationic deficiency, redox properties of Co and Mn and stability of the alluaudite structure during alkali ion intercalation.


Islet transplantation 30 years after the first transplants.
First clinical islet allotransplantation in patients affected by type 1 diabetes mellitus was performed about 30 years ago. Despite the progressive improvement of the success rate, the clinical indication to the islet allotransplantation remains limited to selected patients affected by brittle type 1 diabetes mellitus. The burden of the immunosuppression therapy still represents the main critical issue but other areas might be subject to further improvements, such as the islet production, islet engraftment and long-term function. Several strategies have been proposed to increase the success rate of pancreas digestion and islet purification or to facilitate islet engraftment by reducing islet hypoxia and the inflammatory reaction occurring in the site of transplantation. The co-transplantation of progenitors of beta cell together with the islets has expected to contribute to prolong graft function. Clinical trials are expected soon. Scientific advances, as well as economical efforts, are required to make this procedure a real therapeutical option for patients with type 1 diabetes mellitus.


Genetic structure among morphotypes of the endangered Brazilian palm Euterpe edulis Mart (Arecaceae).
Euterpe edulis (Arecaceae) Mart has high ecological and economic importance providing food resources for more than 58 species of birds and 20 species of mammals, including humans. E. edulis is the second most exploited nontimber product from Brazilian Atlantic Forest. Due to overexploitation and destruction of habitats, E. edulis is threatened by extinction. Euterpe edulis populations have large morphological variations, with individuals having green, red, or yellow leaf sheath. However, no study has related phenotypic distinctions between populations and their levels of genetic structure. Thus, this study aimed to evaluate the diversity and genetic structure of different E. edulis morphotypes. We sampled 250 adult individuals in eight populations with the different morphotypes. Using 14 microsatellite markers, we access genetic diversity through population genetic parameters calculated in the GenAlex program and the diveRsity package in R. We used the Wilcoxon test to verify population bottlenecks and the genetic distance of Nei and Bayesian analysis for genetic clusters. The eight populations showed low allele richness, low observed heterozygosity, and high inbreeding values (f). In addition, six of the eight populations experienced genetic bottlenecks, which would partly explain the low genetic diversity in populations. Cluster analysis identified two clusters (K = 2), with green morphotype genetically distinguishing from yellow and red morphotypes. Thus, we show, for the first time, a strong genetic structure among E. edulis morphotypes even for geographically close populations.


Immunity, inflammation, and cancer: an eternal fight between good and evil.
Cancer development and its response to therapy are strongly influenced by innate and adaptive immunity, which either promote or attenuate tumorigenesis and can have opposing effects on therapeutic outcome. Chronic inflammation promotes tumor development, progression, and metastatic dissemination, as well as treatment resistance. However, cancer development and malignant progression are also associated with accumulation of genetic alterations and loss of normal regulatory processes, which cause expression of tumor-specific antigens and tumor-associated antigens (TAAs) that can activate antitumor immune responses. Although signals that trigger acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation, chronic inflammation can be immunosuppressive. This antagonism between inflammation and immunity also affects the outcome of cancer treatment and needs to be considered when designing new therapeutic approaches.


Influence of Temperament As a Risk Indicator for Early Childhood Caries.
Purpose: To evaluate the association between temperament and caries. Methods: A total of 408 primary caregiver-child pairs were followed for 36 months; they completed the Early Childhood Behavior Questionnaire Very Short-Form (ECBQ-VSF) at age four years. Demographic, behavioral, and clinical data were obtained at ages one, two-and-a-half, and four years, with caries experience assessed each time using the International Caries Detection and Assessment System (ICDAS). The ECBQ-VSF (36 items) was used to measure three child temperament domains: (1) surgency; (2) negative affect; and (3) effortful control. The associations between cavitated carious lesion experience by age four years (decayed, missing, and filled primary surfaces [dmfs] score greater than zero; d equals ICDAS score greater than or equal to three) and the three ECBQ-VSF temperament domains were analyzed using generalized estimating equation models. Results: Temperament domains predicted the number of carious surfaces (dmfs). After adjusting for covariates, every one-point increase in surgency and one-point increase in negative affect were associated with 77 percent and 31 percent increases in dmfs, respectively (P<0.05), and every one-point increase in effortful control was associated with a 39 percent decrease in dmfs (P<0.05). Conclusions: By age four years, children with higher levels of surgency and negative affect have a higher caries experience, whereas children with greater effortful control have a lower caries experience.


[Sclerosing mesenteritis: a disease of malignant appearance].
Sclerosing mesenteritis is a rare benign disorder of unknown etiology that often resembles a neoplasm. Numerous terms have been used in the past to describe this entity which has a variable clinical presentation and is characterized by thickening of the intestinal mesentery. Accurate information regarding the epidemiology, natural course and therapeutic response of the disease is sparse. Herein we present a review of the literature and a brief discussion of relevant concepts for the diagnosis and treatment of patients with sclerosing mesenteritis.


The longitudinal relationship between changes in body weight and changes in medial tibial cartilage, and pain among community-based adults with and without meniscal tears.
Meniscal tears are commonly found on MRI and increase the risk for radiographic knee osteoarthritis (OA). While meniscectomy is recommended when knee pain is severe or functionally disabling, it is unclear how to best treat meniscal tears without these symptoms. The aim of this longitudinal study was to examine the effect of weight change on knee cartilage and pain in a cohort of community-based adults with and without meniscal tears detected by MRI. 250 adults with no history of knee OA or knee injury were recruited from the general community and weight-loss clinics. MRI of the knee, Western Ontario and McMaster University Osteoarthritis Index (WOMAC), weight and height were measured at baseline and again at follow-up approximately 2 years later. Medial meniscal tears were present in 36 (18%) of the cohort. In those with medial meniscal tears, after adjustment for confounders, percentage weight change was significantly associated with percentage change in medial tibial cartilage volume (β 0.2% 95% CI 0.08% to 0.3% p=0.002) and knee pain (β 11.6% 95% CI 2.1% to 21.1% p=0.02). That is, for every 1% gain in weight, there was an associated 0.2% increased loss of medial tibial cartilage volume and 11.6% increase in pain. In those with no medial meniscal tear, neither change in medial tibial cartilage volume (β 0.02% 95% CI -0.01% to 0.10% p=0.53) or pain (β 1.9% 95% CI -2.2% to 6.1% p=0.36) were significantly associated with change in weight. This study demonstrated that among adults with medial meniscal tears, weight gain is associated with increased cartilage loss and pain, while weight loss is associated with the converse. This suggests attention to weight is particularly important in the management of people with medial meniscal tears.


Triple RNA-Seq characterizes aphid gene expression in response to infection with unequally virulent strains of the endosymbiont Hamiltonella defensa.
Secondary endosymbionts of aphids provide benefits to their hosts, but also impose costs such as reduced lifespan and reproductive output. The aphid Aphis fabae is host to different strains of the secondary endosymbiont Hamiltonella defensa, which encode different putative toxins. These strains have very different phenotypes: They reach different densities in the host, and the costs and benefits (protection against parasitoid wasps) they confer to the host vary strongly. We used RNA-Seq to generate hypotheses on why four of these strains inflict such different costs to A. fabae. We found different H. defensa strains to cause strain-specific changes in aphid gene expression, but little effect of H. defensa on gene expression of the primary endosymbiont, Buchnera aphidicola. The highly costly and over-replicating H. defensa strain H85 was associated with strongly reduced aphid expression of hemocytin, a marker of hemocytes in Drosophila. The closely related strain H15 was associated with downregulation of ubiquitin-related modifier 1, which is related to nutrient-sensing and oxidative stress in other organisms. Strain H402 was associated with strong differential regulation of a set of hypothetical proteins, the majority of which were only differentially regulated in presence of H402. Overall, our results suggest that costs of different strains of H. defensa are likely caused by different mechanisms, and that these costs are imposed by interacting with the host rather than the host's obligatory endosymbiont B. aphidicola.


Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts.
Hematopoietic cytokine receptor signaling pathways involve activation of signal transducers and activators of transcription (STAT) proteins, which are postulated to be involved in cellular differentiation. Aberrant STAT isoforms (beta forms rather than the normal alpha forms) have been described and have been found to block the normal signaling pathway from the receptor. Bcr/Abl proteins have been suggested to directly activate STATs, without exposure to growth factors. We asked whether STATs play a role in leukemogenesis. We analyzed constitutive and induced patterns of STAT activity in pretreatment blasts from 36 newly diagnosed acute myeloid leukemia (AML) patients and studied protein tyrosine kinases (PTKs) that may be involved in STAT activity, using in vitro and in-gel kinase assays. The beta forms were expressed in 21 of 27 samples (78%). Constitutive STAT3 and STAT5 activity was found in samples from 28 and 22% of patients, respectively. Response to exogenous cytokines identified two groups. STAT activity in one group was modulated by exogenous cytokines: constitutive STAT activity increased in some patients but decreased or disappeared in response to cytokines in others. The second group was cytokine insensitive. Additionally, we found constitutive PTK activity in two patients whose blasts demonstrated constitutive STAT activity, suggesting that PTKs use cytokine receptor signal pathways to activate STATs in AML blasts without exposure to exogenous cytokines. Our data suggest that (a) constitutive expression of aberrant STATs may be involved in blocking differentiation of AML blasts, (b) exogenous cytokines may activate STAT-inhibitory pathways, and (c) STATs may be activated by PTKs in some AML blasts.


Breast cancers with EGFR and HER2 co-amplification favor distant metastasis and poor clinical outcome.
ErbB signaling serves essential roles in invasive ductal carcinoma (IDC). The aim of the present study was to assess gene amplification in ErbB family members in IDC with clinical implications. Quantitative polymerase chain reaction and fluorescence in situ hybridization were performed on formalin-fixed paraffin-embedded tumor samples for gene amplification detection. The clinical and histopathological characteristics, as well as the prognostic significance, were analyzed. Among the 119 IDC patients evaluated, epidermal growth factor receptor [EGFR; also known as human epidermal growth factor receptor (HER)1], HER2, HER3 and HER4 gene amplification was observed in 30 (25.2%), 44 (36.9%), 0 (0.0%) and 1 (0.8%) patients, respectively. EGFR amplification was associated with estrogen receptor status (P=0.028) and higher possibilities of recurrence (P=0.015) and distant metastasis (following initial surgery) (P=0.011). In survival analysis, EGFR amplification was also associated with disease-free survival (DFS) (P=0.001) and overall survival (OS) (P=0.003). HER2 amplification was associated with larger tumor size (P=0.006), later clinical stage (P=0.003) and distant metastasis (following initial surgery) (P=0.006). In survival analysis, HER2 amplification was also associated with DFS (P=0.011). Notably, the present study identified a group of patients in whom EGFR and HER2 were co-amplified. This group of patients appeared to have a higher possibility of metastasis (when diagnosed) (P=0.014) and distant metastasis (following initial surgery) (P<0.001). In survival analysis, these patients were noticed to be associated with DFS (P<0.001) and OS (P=0.002). With respect to treatment regimen, this was also true for the DFS association with chemotherapy (P<0.001), radiotherapy (P<0.001) and hormonal therapy (P=0.001). The present results suggest that EGFR and HER2 amplification favor distant metastasis following initial surgery and are significantly associated with poor clinical outcome in breast cancer patients.


Utility of 5-ALA for resection of CNS tumours other than high-grade gliomas: a protocol for a systematic review.
5-aminolevulinic acid (5-ALA) is a proagent developed for fluorescent-guided surgery for high-grade glioma patients associated with a significant increase in resection conferring survival. 5-ALA was shown to penetrate the blood-brain barrier accumulating in malignant glioma cells with high selectivity, sensitivity and positive predictive value. However, those have yet to be explored aiding diagnosis for tumours of the central nervous system (CNS) other than high-grade gliomas (HGG). No up-to-date systematic review exists reporting the major surgical outcomes and diagnostic accuracy. We sought to conduct a systematic review of the literature summarising surgical outcomes, evaluate the quality of diagnostic accuracy reported in the literature and qualitatively assess the evidence to inform future studies. We will search electronic databases (Medline, Embase) with subsequent interrogation of references lists of articles reporting the use of 5-ALA for brain tumours other than high-grade glioma adult patients, which also report the extent of resection and/or survival. Prospective and retrospective cohort and case-control studies with more than five patients will be included. Two independent reviewers will screen the abstracts and full articles, with a third reviewer resolving any conflicts. The data will be extracted in a standardised template and outcomes will be reported using descriptive statists. The quality of non-randomised studies will be appraised. The study will summarise the available evidence on the effect of the clinical utility of 5-ALA in achieving resection and improving survival and its diagnostic accuracy for tumours of the CNS other than HGG. The data will be presented nationally and internationally and the manuscript will be published in a peer-reviewed journal. No ethical approvals were needed. The aim is to inform prospective studies minimising reporting bias allowing for more reliable, reproducible and generalisable results. The study has been registered in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.PROSPERO registration numberCRD42021260542.


Splicing of many human genes involves sites embedded within introns.
The conventional model for splicing involves excision of each intron in one piece; we demonstrate this inaccurately describes splicing in many human genes. First, after switching on transcription of SAMD4A, a gene with a 134 kb-long first intron, splicing joins the 3' end of exon 1 to successive points within intron 1 well before the acceptor site at exon 2 is made. Second, genome-wide analysis shows that >60% of active genes yield products generated by such intermediate intron splicing. These products are present at ∼15% the levels of primary transcripts, are encoded by conserved sequences similar to those found at canonical acceptors, and marked by distinctive structural and epigenetic features. Finally, using targeted genome editing, we demonstrate that inhibiting the formation of these splicing intermediates affects efficient exon-exon splicing. These findings greatly expand the functional and regulatory complexity of the human transcriptome.


Outcomes From Lateral Eyelid Coupling for Facial Paralysis Using the Modified Tarsoconjunctival Flap.
In the setting of facial paralysis, inadequate eyelid closure and lower eyelid ectropion can lead to corneal exposure and impaired quality of life. Repair of paralytic ectropion is challenging, and an ideal surgical approach for all cases has not been identified. To assess the patient-reported outcomes and eyelid position improvement in patients with flaccid facial paralysis undergoing lateral eyelid coupling with a tarsal strip canthoplasty and modified tarsoconjunctival flap to correct eyelid malposition. Review of medical records of adults with flaccid facial paralysis who underwent a single-stage tarsal strip canthoplasty and modified tarsoconjunctival flap at a tertiary academic center. Inclusion criteria included a minimum of 3 months of follow-up. The lateral upper and lower eyelid are coupled with the hybrid tarsoconjunctival flap. Patient-reported outcome measures and objective photograph analysis. Preoperative and postoperative Facial Clinimetric Evaluation (FaCE) scores and Moe Ectropion Grading Scale scores were compared. The relationship between radiation therapy (RT) and outcomes was analyzed. Sixteen patients (8 [50%] female; mean [SD] age at surgery, 71.5 [9.6] years) were identified between January 2014 and August 2017. Twelve (75%) had paralysis from facial nerve sacrifice during cancer ablation. The mean time between paralysis and referral for surgical repair of ectropion was 23 months (range, 0-151 months) and mean follow-up after surgery was 9.8 months (range, 3-39 months). The most common symptom was epiphora, which was significantly reduced after surgery (75% vs 25%; P = .01). Median Moe Ectropion Grading Scale score improved from 3 (interquartile range, 2-3) to 0 (interquartile range, 0-1; P < .001). Quality of life measured using the FaCE scale demonstrated a significant improvement in mean eye comfort (from 18.8 [95% CI, 2.3-35.2] to 47.9 [95% CI, 31.9-63.9]; P = .01) and lacrimal control scores (from 12.5 [95% CI, 0-29.2] to 45.8 [95% CI, 29.3-62.3]; P = .03) in the 6 patients in the RT group, but no difference in the 4 patients in the non-RT group. Ocular symptoms, eyelid appearance, and quality of life were improved after lateral eyelid coupling among patients with flaccid facial paralysis and paralytic ectropion. The tarsoconjunctival flap does limit peripheral vision, but is reversible if dynamic eyelid closure is returned with nerve grafting. 4.


Role of ALAD and VDR genotypes on the association of low blood lead level with serum uric acid and blood pressure in automobile paint workers of Karachi, Pakistan.
Lead is an environmental pollutant having nephrotoxic effects even at low level. Its continuous exposure is associated with increased serum uric acid level that resulting in renal insufficiency. This research was conducted to see the effects of delta-aminolevulinic acid dehydratase (ALAD) and vitamin D receptor (VDR) genotypes on biochemical parameters and blood pressure (BP) of automobile workers having low blood lead level (BLL) with continuous lead exposure. Automobile paints workers with ALAD 1-2 genotype showed the positive association of BLL with diastolic BP (p<0.05) whereas, a genotypic combination of ALAD 1-2/VDR BB showed the negative association of serum uric acid with BLL (p<0.05). Similarly negative effects of VDR BB genotype (p<0.01) and ALAD 1-2 genotype (p<0.05) were observed in the association of serum uric acid with BLL at the mean age ≥30 years. This suggests that automobile paint workers having ALAD 1-2 genotypes are at the risk of increased diastolic BP. The research also foretells that combination of ALAD 1-2/VDR BB may play a significant role against lead induced nephrotoxicity at low BLL with continuous lead exposure.


Matrix-assisted ultraviolet laser desorption/ionization mass spectrometry applied to multiple forms of lipases.
Matrix-assisted ultraviolet laser desorption/ionization mass spectrometry was used to investigate heterogeneous patterns and molecular masses of microbial lipases from Penicillium camembertii, Geotrichum candidum, and Pseudomonas sp. Mass spectral peaks of the native, glycosylated lipases from P. camembertii and G. candidum were broader than those of the corresponding deglycosylated enzymes, indicative of heterogeneous glycosylations. The broader peaks in the mass spectra were caused by an overlapping of unresolved peaks, derived from single glycoprotein species. Molecular masses determined for the deglycosylated proteins were in excellent agreement with those deduced from amino acid composition and sequence data, whereas with conventional biochemical methods (gelfiltration, sodium dodecyl sulfate-polyacrylamide gel electrophoresis) only very rough estimations of molecular masses were possible. By mass spectrometric analysis of the four fractions of chromatographically separated P. camembertii lipase molecular masses of 29,990, 34,030, 31,990, and 32,140 Da were found before and 29,960, 29,980, 29,990 and 30,010 Da, respectively, after deglycosylation. Thus from the four native fractions of P. camembertii lipase three were glycoproteins. G. candidum lipase showed an average molecular mass of 63,500 Da for the heterogeneously deglycosylated native form and a molecular mass of 59,650 Da for the deglycosylated enzyme. For the Pseudomonas lipase, which could only be isolated with lipids firmly attached, a molecular mass of 32,890 Da was determined, in close agreement with that derived from the cDNA sequence.


[Reversible precipitation of the glucocorticoid receptor from rat liver by La3+ ions].
It was shown that La3+ ions are capable of precipitating the glucocorticoid receptor from rat liver. Treatment of cytosol containing either free receptor or the hormonereceptor complex with 0,005 M La(NO3)3 results in recptor precipitation. The pellet is readily dissolved in buffer with EDTA. Transcortin and transcortin-like proteins are not affected by La3+ ions. The lanthanium-treated receptor does not lose its ability to bind DNA and chromatin in vitro. It is suggested that precipitation by La3+ ions can be used for separation of the receptor from transcortin and transcortin-like proteins as well as for evaluation of binding parameters for steroid-receptor complexes in rat liver cytosol.


Interventions for preventing oral mucositis for patients with cancer receiving treatment.
Treatment of cancer is increasingly more effective but is associated with short and long-term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers). To evaluate the effectiveness of prophylactic agents for oral mucositis in patients with cancer receiving treatment, compared with other potentially active interventions, placebo or no treatment. The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Date of most recent searches: April 2004. Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancer receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes - prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life. Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group statistical guidelines were followed and risk ratios (RR) calculated using random-effects models. Two hundred and two studies were eligible. One hundred and thirty two were excluded for various reasons, usually as there was no useable information on mucositis. Of the 71 useable studies all had data for mucositis comprising 5217 randomised patients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, aloe vera, amifostine, antibiotic pastille or paste, benzydamine, beta carotene, calcium phosphate, camomile, chlorhexidine, clarithromycin, folinic acid, glutamine, GM-CSF, honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte GF, misonidazole, oral care, pentoxifylline, povidone, prednisone, propantheline, prostaglandin, sucralfate, traumeel and zinc sulphate. Of the 29 interventions included in trials, 10 showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial in the meta-analysis finding a significant difference when compared with a placebo or no treatment were: amifostine which provided minimal benefit in preventing moderate and severe mucositis RR = 0.84 (95% confidence interval (CI) 0.75 to 0.95) and 0.60 (95% CI 0.37 to 0.97), antibiotic paste or pastille demonstrated a moderate benefit in preventing mucositis RR = 0.87 (95% CI 0.79 to 0.97), hydrolytic enzymes reduced moderate and severe mucositis with RRs = 0.52 (95% CI 0.36 to 0.74) and 0.17 (95% CI 0.06 to 0.52), and ice chips prevented mucositis at all levels RR = 0.63 (95% CI 0.44 to 0.91), 0.43 (95% CI 0.23 to 0.81), 0.27 (95% CI 0.11 to 0.68). Other interventions showing some benefit with only one study were: benzydamine, calcium phosphate, honey, oral care protocols, povidone and zinc sulphate. The number needed to treat (NNT) to prevent one patient experiencing moderate or severe mucositis over a baseline incidence of 60% for amifostine is 10 (95% CI 7 to 33), antibiotic paste or pastille 13 (95% CI 8 to 56), hydrolytic enzyme 4 (95% CI 3 to 6) and ice chips 5 (95% CI 3 to 19). When the baseline incidence is 40%/90% the NNTs for amifostine are 16/7, for antibiotic paste or pastille 19/7, for hydrolytic enzyme 5/3 and for ice chips 7/3. The general reporting of RCTs was poor. However, the assessments of the quality of the randomisation improved when the authors provided additional information. Several of the interventions were found to have some benefit at preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specific for certain cancer types and treatment. There is a need for well designed and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.


Combining angiotensin II blockade and renin receptor inhibition results in enhanced antifibrotic effect in experimental nephritis.
The limited antifibrotic effect of therapeutic angiotensin blockade, the fact that angiotensin blockade dramatically elevates renin levels, and recent evidence that renin has an angiotensin-independent, receptor-mediated profibrotic action led us to hypothesize that combining renin receptor inhibition and ANG II blockade would increase the antifibrotic effect of angiotensin blockade alone. Using cultured nephritic glomeruli from rats with anti-Thy-1-induced glomerulonephritis, the maximally effective dose of enalaprilate was determined to be 10(-4) M, which reduced mRNAs for transforming growth factor (TGF)-β1, fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1) by 49, 65, and 56% and production of TGF-β1 and FN proteins by 60 and 49%, respectively. Disease alone caused 6.8-fold increases in ANG II levels that were reduced 64% with enalaprilate. In contrast, two- and threefold disease-induced increases in renin mRNA and activity were further increased 2- and 3.7-fold with 10(-4) M enalaprilate treatment. Depressing the renin receptor by 80% with small interfering (si) RNA alone reduced fibrotic markers in a manner remarkably similar to enalaprilate alone but had no effect on glomerular renin expression. Enalaprilate and siRNA combination therapy further reduced disease markers. Notably, elevated TGF-β1 and FN production was reduced by 73 and 81%, respectively. These results support the notion of a receptor-mediated profibrotic action of renin, suggest that the limited effectiveness of ANG II blockade may be due, at least in part, to the elevated renin they induce, and support our hypothesis that adding renin receptor inhibitor to ANG II blockade in patients may have therapeutic potential.


Telemetric study of sleep architecture and sleep homeostasis in the day-active tree shrew Tupaia belangeri.
In this study the authors characterized sleep architecture and sleep homeostasis in the tree shrew, Tupaia belangeri, a small, omnivorous, day-active mammal that is closely related to primates. Adult tree shrews were individually housed under a 12-hr light/12-hr dark cycle in large cages containing tree branches and a nest box. The animals were equipped with radio transmitters to allow continuous recording of electroencephalogram (EEG), electromyogram (EMG), and body temperature without restricting their movements. Recordings were performed under baseline conditions and after sleep deprivation (SD) for 6 hr or 12 hr during the dark phase. Under baseline conditions, the tree shrews spent a total of 62.4 ± 1.4% of the 24-hr cycle asleep, with 91.2 ± 0.7% of sleep during the dark phase and 33.7 ± 2.8% sleep during the light phase. During the dark phase, all sleep occurred in the nest box; 79.6% of it was non-rapid eye movement (NREM) sleep and 20.4% was rapid eye movement (REM) sleep. In contrast, during the light phase, sleep occurred almost exclusively on the top branches of the cage and only consisted of NREM sleep. SD was followed by an immediate increase in NREM sleep time and an increase in NREM sleep EEG slow-wave activity (SWA), indicating increased sleep intensity. The cumulative increase in NREM sleep time and intensity almost made up for the NREM sleep that had been lost during 6-hr SD, but did not fully make up for the NREM sleep lost during 12-hr SD. Also, only a small fraction of the REM sleep that was lost was recovered, which mainly occurred on the second recovery night. The day-active tree shrew shares most of the characteristics of sleep structure and sleep homeostasis that have been reported for other mammalian species, with some peculiarities. Because the tree shrew is an established laboratory animal in neurobiological research, it may be a valuable model species for studies of sleep regulation and sleep function, with the added advantage that it is a day-active species closely related to primates.


Survey and Exposure Assessment of Biogenic Amines in Fish Species Commonly Consumed in Korea.
Because of the increased awareness of the health benefits of fish, fish consumption has increased each year in several countries, including Korea. However, fish consumption is associated with acute toxicity owing to the presence of biogenic amines in rapidly spoiling fish. Several food safety agencies have established standards for acceptable histamine concentrations in some restrictive fish and fishery products; however, such standards are not available for other species. We aimed to generate data from biogenic amine monitoring to evaluate the safety of fish commonly consumed in Korea. We monitored the biogenic amine concentrations in 609 fish samples from 19 commonly consumed species. Of these 609 samples, several had amine concentrations higher than the maximums allowed. An age-specific exposure assessment based on human biogenic amine exposure per serving revealed that persons 1 to 3 years of age had the highest exposure to total biogenic amines, although no significant differences were found between the age groups analyzed. The analysis also revealed that the exposure in some fish species, such as Japanese jack mackerel, Konoshiro gizzard shad, and brown sole, exceeded the standard limits established in some countries. These results suggest that more fish species should be included to establish standards for exposure to various biogenic amines. Parameters such as age-specific consumption and data for populations with maximum consumption should be considered because the current standards are limited to histamine and do not account for the differences in histamine sensitivity associated with these variables. Our results provide important data on limits for biogenic amines in various fish species that could be used to minimize potential health risks.


GENESiS: creating a composite index of the vulnerability to anxiety and depression in a community-based sample of siblings.
There is considerable evidence for a unitary and dimensional view of the genetic vulnerability to symptoms of anxiety and depression. The GENESiS (Genetic Environmental-Nature of Emotional States in Siblings) Study aims to use a multivariate approach to detect genetic loci that contribute to individual differences in this vulnerability dimension. The study used the UK General Practice Research Framework to generate a community-based sample of siblings. Questionnaire measures of anxiety/depression included the short form of the neuroticism scale from the revised Eysenck Personality Questionnaire (EPQ-N), the General Health Questionnaire (GHQ-12), and the anxious arousal and high positive affect subscales from the Mood and Anxiety Symptoms Questionnaire (MASQ-AA and MASQ-HPA). Genetic model-fitting of 2658 unselected sibships provided evidence for a single common genetic (familial) factor that accounted for a substantial proportion of the genetic variances and covariances of these four measures. Using the parameter estimates of this model, we constructed a composite index of this common genetic factor. This index, which has a sib correlation of 0.22, will be used as a quantitative phenotype in the molecular genetic phase of GENESiS.


Fundamental study on non-invasive blood glucose sensing.
Diabetes is a disease which severely threatens the health of human beings. Unfortunately, current monitoring techniques with finger sticks discourage the regular use. Noninvasive spectroscopic measurement of blood glucose is a simple and painless technique, and reduces the long-term health care costs of diabetic patients due to no reagents. It is suitable for home use. Moreover, the establishment of the methodology not only applies to blood glucose noninvasive measurement, but also can be extended to noninvasive measurement of other analytes in body fluid, which will be of important significance for the development of the technique of clinical analysis. In this paper, some fundamental researches, which have been achieved in our laboratory in the field of non-invasive blood glucose measurement, were introduced. 1. Fundamental research was done for the glucose concentrations from simple to complex samples with near and middle infrared spectroscopy: (1) the relationship between the instrument precision and prediction accuracy of the glucose measurement; (2) the change of the result of the quantitative measurement with the change of the complexity of samples; (3) the attempt of increasing the prediction accuracy of the glucose measurement by improving the methods of modeling. The research results showed that it is feasible for non-invasive blood glucose measurement with near and middle infrared spectroscopy in theory, and the experimental results, from simple to complex samples, proved that it is effective for the methodology consisting of hardware and software. 2. According to the characteristics of human body measurement, the effects of measuring conditions on measurement results, such as: (1) the effect of measurement position; (2) the effect of measurement pressure; (3) the effect of measurement site; (4) the effect of measured individual, were investigated. With the fundamental researches, the special problems of human body measurement were solved. In addition, the practical and effective method of noninvasive human blood glucose measurement was proposed.


Generation of superoxide and singlet oxygen from alpha-tocopherolquinone and analogues.
Three potential routes to generation of reactive oxygen species (ROS) from alpha-tocopherolquinone (alpha-TQ) have been identified. The quinone of the water-soluble vitamin E analogue Trolox C (Trol-Q) is reduced by hydrated electron and isopropanol alpha-hydroxyalkyl radical, and the resulting semiquinone reacts with molecular oxygen to form superoxide with a second order rate constant of 1.3 x 10(8) dm(3)/mol/s, illustrating the potential for redox cycling. Illumination (UV-A, 355 nm) of the quinone of 2,2,5,7,8-pentamethyl-6-hydroxychromanol (PMHC-Q) leads to a reactive short-lived (ca. 10(- 6) s) triplet state, able to oxidise tryptophan with a second order rate constant greater than 10(9) dm(3)/mol/s. The triplet states of these quinones sensitize singlet oxygen formation with quantum yields of about 0.8. Such potentially damaging reactions of alpha-TQ may in part account for the recent findings that high levels of dietary vitamin E supplementation lack any beneficial effect and may lead to slightly enhanced levels of overall mortality.


DNA Walker-Regulated Cancer Cell Growth Inhibition.
We demonstrate a DNAzyme-based walker system as a controlled oligonucleotide drug AS1411 release platform for breast cancer treatment. In this system, AS1411 strands are released from fuel strands as a walker moves along its carbon nanotube track. The release rate and amount of anticancer oligonucleotides are controlled by the walker operation. With a walker system embedded within the collagen extracellular matrix, we show that this drug release system can be used for in situ cancer cell growth inhibition.


Canadian Cytogenetic Emergency network (CEN) for biological dosimetry following radiological/nuclear accidents.
To test the ability of the cytogenetic emergency network (CEN) of laboratories, currently under development across Canada, to provide rapid biological dosimetry using the dicentric assay for triage assessment, that could be implemented in the event of a large-scale radiation/nuclear emergency. A workshop was held in May 2004 in Toronto, Canada, to introduce the concept of CEN and recruit clinical cytogenetic laboratories at hospitals across the country. Slides were prepared for dicentric assay analysis following in vitro irradiation of blood to a range of gamma-ray doses. A minimum of 50 metaphases per slide were analyzed by 41 people at 22 different laboratories to estimate the exposure level. Dose estimates were calculated based on a dose response curve generated at Health Canada. There were a total of 104 dose estimates and 96 (92.3%) of them fell within the expected range using triage scoring criteria. Half of the laboratories analyzed 50 metaphases in </= 1 hour and the time to score them was proportional to dose. The capacity and scoring expertise of the various participating laboratories were found to be generally acceptable. The dose estimates generated through triage scoring by this network were acceptable for emergency biological dosimetry. When this network is fully operational, it will be the first of its kind in Canada able to respond to radiological/nuclear emergencies by providing triage quality biological dosimetry for a large number of samples. This network represents an alternate expansion of existing international emergency biological dosimetry cytogenetic networks.


Carboxy-terminal analysis of nine proteins specified by the flavivirus Kunjin: evidence that only the intracellular core protein is truncated.
Nine proteins specified by Kunjin virus were labelled with [3H]lysine and digested with carboxypeptidase B which specifically cleaves carboxy-terminal Lys or Arg. The theoretical amount of [3H]lysine was released from the non-structural (ns) proteins NS2A, NS2B, NS3 and NS4B, which have a common carboxy terminus Lys-Arg deduced from cleavage sites established in the viral polyprotein by previous N-terminal amino acid analyses. This is a flavivirus consensus site, always followed by Gly, Ala or Ser. These results indicate that no truncations had occurred despite anomalous electrophoretic migrations of NS2A, NS2B and NS4B observed in some gel systems. No [3H]lysine was released from NS4A or NS5 which terminate in Ala and Leu, respectively, thus establishing that NS5 (observed Mr 98,000, theoretical Mr 103,600) was not cleaved post-translationally at any internal Lys-Arg site. Unexpectedly, [3H]lysine residues were apparently released from P14(C), the intracellular equivalent of virion C protein which terminates in Ala (adjacent to the established N-terminus of prM). However, a putative internal cleavage site (Lys-Arg decreases Gly) exists 18 residues upstream from the carboxy terminus of C, prior to the transmembrane spanning domain. Apparent internal cleavage in the cytosol at this site to produce P14(C) would expose [3H]lysine residues to carboxypeptidase B, and account for the previously observed differences in size and composition between C and P14(C).


JAZF1, A Novel p400/TIP60/NuA4 Complex Member, Regulates H2A.Z Acetylation at Regulatory Regions.
Histone variants differ in amino acid sequence, expression timing and genomic localization sites from canonical histones and convey unique functions to eukaryotic cells. Their tightly controlled spatial and temporal deposition into specific chromatin regions is accomplished by dedicated chaperone and/or remodeling complexes. While quantitatively identifying the chaperone complexes of many human H2A variants by using mass spectrometry, we also found additional members of the known H2A.Z chaperone complexes p400/TIP60/NuA4 and SRCAP. We discovered JAZF1, a nuclear/nucleolar protein, as a member of a p400 sub-complex containing MBTD1 but excluding ANP32E. Depletion of JAZF1 results in transcriptome changes that affect, among other pathways, ribosome biogenesis. To identify the underlying molecular mechanism contributing to JAZF1's function in gene regulation, we performed genome-wide ChIP-seq analyses. Interestingly, depletion of JAZF1 leads to reduced H2A.Z acetylation levels at > 1000 regulatory sites without affecting H2A.Z nucleosome positioning. Since JAZF1 associates with the histone acetyltransferase TIP60, whose depletion causes a correlated H2A.Z deacetylation of several JAZF1-targeted enhancer regions, we speculate that JAZF1 acts as chromatin modulator by recruiting TIP60's enzymatic activity. Altogether, this study uncovers JAZF1 as a member of a TIP60-containing p400 chaperone complex orchestrating H2A.Z acetylation at regulatory regions controlling the expression of genes, many of which are involved in ribosome biogenesis.


'Research is the last thing on our minds, we are in crisis': Experiences of Lagos state nurses towards research and scholarly endeavours.
To explore the experiences of Nigerian nurses in research and scholarly endeavours. Descriptive phenomenological qualitative study design. In-depth interviews were conducted among 30 nurses until data saturation was reached. Data were analysed using the thematic analysis method, and consolidated criteria for reporting qualitative research guidelines (COREQ) were adhered to in reporting this study. Three themes emerged: (1) challenges of nurses with research; (2) the state of nursing research in Lagos state; (3) strategies to improve the state of nursing research in Lagos state. Some challenges nurses in Lagos State encounter with research include heavy workload and nursing shortage due to brain drain, faulty research foundation, lack of continuing education in research and the stressful nature of conducting research in Lagos. As research is essential in addressing healthcare challenges, policymakers are encouraged to employ more nurses to reduce the workload and provide time for research activities. Training and continuing education in research can be incorporated into professional development programmes. Lagos State will benefit from nursing research units in the hospitals, and a coordinating centre for the units should be provided with adequate funding. Support could be obtained from the Institute of Nursing Research Nigeria in establishing these structures. Hospital management should embrace and welcome research output from nurses and ensure such results are implemented to improve patients' care. Nurses who excel in research might be recognised with awards and other incentives to inspire their peers.


Desmoid tumors: diagnostic and therapeutic considerations.
A literature review on desmoid tumors was carried out, which are tumors that affect soft tissues with a locally aggressive behavior and are unable to metastasize. Sporadic cases are located on the extremities and chest wall; hereditary cases have an intra-abdominal predilection, and those associated with pregnancy occur on the abdominal wall. Imaging techniques assess disease extension. Trucut biopsy is the study of choice for diagnosis. Mutations in the CTNNB1 or APC genes cause an abnormal accumulation of b-catenin within the cell. In this review, an emphasis is made on therapeutic strategies' evolution and change, and current tools for decision making are analyzed, as well as clinical outcomes. Radiation therapy can play a therapeutic or adjuvant role. Advances in the understanding of the disease have allowed establishing better targeted treatments with lower morbidity; however, there are still unanswered questions regarding the choice of the ideal candidate for surveillance and/or early treatment. Data related to quality of life are also presented, as well as the uncertainty generated by this diagnosis for both doctor and patient.


Contrasted demographic responses facing future climate change in Southern Ocean seabirds.
1. Recent climate change has affected a wide range of species, but predicting population responses to projected climate change using population dynamics theory and models remains challenging, and very few attempts have been made. The Southern Ocean sea surface temperature and sea ice extent are projected to warm and shrink as concentrations of atmospheric greenhouse gases increase, and several top predator species are affected by fluctuations in these oceanographic variables. 2. We compared and projected the population responses of three seabird species living in sub-tropical, sub-Antarctic and Antarctic biomes to predicted climate change over the next 50 years. Using stochastic population models we combined long-term demographic datasets and projections of sea surface temperature and sea ice extent for three different IPCC emission scenarios (from most to least severe: A1B, A2, B1) from general circulation models of Earth's climate. 3. We found that climate mostly affected the probability to breed successfully, and in one case adult survival. Interestingly, frequent nonlinear relationships in demographic responses to climate were detected. Models forced by future predicted climatic change provided contrasted population responses depending on the species considered. The northernmost distributed species was predicted to be little affected by a future warming of the Southern Ocean, whereas steep declines were projected for the more southerly distributed species due to sea surface temperature warming and decrease in sea ice extent. For the most southerly distributed species, the A1B and B1 emission scenarios were respectively the most and less damaging. For the two other species, population responses were similar for all emission scenarios. 4. This is among the first attempts to study the demographic responses for several populations with contrasted environmental conditions, which illustrates that investigating the effects of climate change on core population dynamics is feasible for different populations using a common methodological framework. Our approach was limited to single populations and have neglected population settlement in new favourable habitats or changes in inter-specific relations as a potential response to future climate change. Predictions may be enhanced by merging demographic population models and climatic envelope models.


Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models.
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corresponding 8-hydroperoxide is formed by mouse Alox15b (Alox8). This functional difference impacts the biosynthetic capacity of the two enzymes for creating pro- and anti-inflammatory eicosanoids. To explore the functional consequences of the humanization of the reaction specificity of mouse Alox15b in vivo, we tested Alox15b knock-in mice that express the arachidonic acid 15-lipoxygenating Tyr603Asp and His604Val double mutant of Alox15b, instead of the arachidonic acid 8-lipoxygenating wildtype enzyme, in two different animal inflammation models. In the dextran sodium sulfate-induced colitis model, female Alox15b-KI mice lost significantly more bodyweight during the acute phase of inflammation and recovered less rapidly during the resolution phase. Although we observed significant differences in the colonic levels of selected pro- and anti-inflammatory eicosanoids during the time-course of inflammation, there were no differences between the two genotypes at any time-point of the disease. In Freund's complete adjuvant-induced paw edema model, Alox15b-KI mice were less susceptible than outbred wildtype controls, though we did not observe significant differences in pain perception (Hargreaves-test, von Frey-test) when the two genotypes were compared. our data indicate that humanization of the reaction specificity of mouse Alox15b (Alox8) sensitizes mice for dextran sodium sulfate-induced experimental colitis, but partly protects the animals in the complete Freund's adjuvant-induced paw edema model.


The three-dimensional structure of peptide-MHC complexes.
The ability of MHC molecules to present a broad spectrum of peptide antigens for T cell recognition requires a compromise between high affinity and broad specificity. Three-dimensional atomic structures of several class I and class II MHC molecules reveal a unique structural solution to this problem: Tight binding to the peptide main chain is supplemented by more or less restrictive interactions with peptide side chains. In spite of these contacts, peptide side-chain and conformational variability ensures that the resulting peptide-MHC complex presents an antigenically unique surface to T cell receptors. Extension of this understanding to other peptide-MHC complexes, including agonist/antagonist peptides and the identification of antigenic peptides within protein sequences, however, requires a detailed analysis of the interactions that determine both peptide-MHC binding affinity and the conformations of bound peptides. While many of these interactions can be modeled by homology with known structures, their specificity can depend sensitively on subtle and long-range structural effects. Structurally and immunologically important distinctions are also found between the class I and class II peptide-binding strategies. Taken together, these interactions ultimately determine the ability of an individual to respond successfully to immune challenges.


Is diet quality associated with early childhood caries in preschool children? A descriptive study.
Limited evidence about the role of diet quality, an important component of nutritional status, in the etiology of dental caries has been reported. The aim of this study was to examine the association between diet and dental caries in children by using the dietary intake data, anthropometrical measurements and dental examination. A total of 395 children (52.7% boys and 42.8% girls) who were 36-71 months of age (mean age 58.7±8.6 months) and attended one of the eleven preschools within a district of Ankara participated in this descriptive study. Dental examinations were performed in the schools under day-light by a pediatric dentist; decayed, missing and filled teeth as well as surfaces were recorded. Data related to socio-demographic characteristics and 24-hour dietary recall of children were gathered via a structured, pre-tested questionnaire which was conducted by the research dietitian. The Healthy Eating Index-2010 (HEI-2010) and Mediterranean Diet Quality Index for children and adolescents (KIDMED) were used to assess dietary intake. Anthropometric measurements including weight, height, upper arm circumference and head circumference were taken by the same researcher. The percentage of Early Childhood Caries (ECC) was increased by age (p < 0.001) whereas no significant difference was observed by sex, socioeconomic status, tooth brushing frequency and body mass index (p > 0.05). Although children who had bad KIDMED scores had slightly higher mean values of decayed missing and filled teeth (dmft) (5.39± 4.6) and decayed missing and filled surface (dmfs) (8.45± 8.69), compared to the scores of children with good or medium KIDMED scores, the differences were not statistically significant (p > 0.05). On the contrary to the KIDMED findings, the mean value of tooth decay was significantly higher among children with bad HEI-2010 score (4.2±4.3) compared to children with medium HEI-2010 score (2.47±2.9) (p=0.043). It is concluded that a healthy eating pattern and high diet quality is essential for the prevention of early childhood caries in preschool children. Further studies are required to develop dietary strategies for the prevention of dental caries.


Atypical Presentation of Hashimoto's Disease in an Adolescent: Thyroid-Associated Ophthalmopathy.
Hashitoxicosis is generally differentiated from Graves' hyperthyroidism by its shorter course and absence of ophthalmopathy. In this case report, we describe an adolescent girl who presented with significant clinical findings of hyperthyroidism, a diffuse goiter with homogenously increased uptake in scintigraphy, and with ocular findings of ophthalmopathy. The thyroid stimulating hormone receptor antibody test was positive, and the family history revealed thyroid-associated ophthalmopathy. Clinical findings supported the diagnosis of Hashimoto's disease (HD) in the follow-up period. Radioactive iodine uptake investigation was found to be a reliable method for differential diagnosis. Attention was drawn to the rarity of pediatric cases of HD who present with ophthalmopathy.


Review of the patient-centered communication landscape in multiple myeloma and other hematologic malignancies.
To identify factors limiting and facilitating patient-centered communication (PCC) in the United States hematology-oncology setting, with a focus on multiple myeloma (MM), given the limited attention to PCC and rapid pace of change that has taken place in this setting. A literature search was performed from 2007 to 2017 to identify published articles and congress abstracts related to clinician-patient communication and treatment decision-making in oncology. Search results were evaluated by year of publication and disease area. A thematic assessment was performed to identify factors limiting and promoting PCC for patients with MM and other hematologic malignancies. Of the 6673 publications initially retrieved, 18 exclusively reported findings in patients with hematologic malignancies and were included in this review. We identified three critical, but modifiable, barriers to PCC in the hematologic malignancy setting, including insufficient information exchange, treatment goal misalignment, and discordant role preferences in treatment decision-making. Factors that enhanced interaction quality included educational programs for clinicians and patients. Patients with MM and other hematologic malignancies experience a distinct set of challenges that may affect PCC. Clinicians have the opportunity to improve patient care by proactively addressing the identified barriers and implementing strategies demonstrated to improve PCC.


Outsourcing punishment to God: beliefs in divine control reduce earthly punishment.
The sanctioning of norm-transgressors is a necessary--though often costly--task for maintaining a well-functioning society. Prior to effective and reliable secular institutions for punishment, large-scale societies depended on individuals engaging in 'altruistic punishment'--bearing the costs of punishment individually, for the benefit of society. Evolutionary approaches to religion suggest that beliefs in powerful, moralizing Gods, who can distribute rewards and punishments, emerged as a way to augment earthly punishment in large societies that could not effectively monitor norm violations. In five studies, we investigate whether such beliefs in God can replace people's motivation to engage in altruistic punishment, and their support for state-sponsored punishment. Results show that, although religiosity generally predicts higher levels of punishment, the specific belief in powerful, intervening Gods reduces altruistic punishment and support for state-sponsored punishment. Moreover, these effects are specifically owing to differences in people's perceptions that humans are responsible for punishing wrongdoers.


Blood derived stem cells: an ameliorative therapy in veterinary ophthalmology.
Stem cell technology has evoked considerable excitement among people interested in the welfare of animals, as it has suggested the potential availability of new tools for several pathologies, including eye disease, which in many cases is considered incurable. One such example is ulcerative keratitis, which is very frequent in horses. Because some of these corneal ulcers can be very severe, progress rapidly and, therefore, can be a possible cause of vision loss, it is important to diagnose them at an early stage and administer an appropriate treatment, which can be medical, surgical, or a combination of both. The therapeutic strategy should eradicate the infection in order to reduce or stop destruction of the cornea. In addition, it should support the corneal structures and control the uveal reaction, and the pain associated with it, in order to minimize scarring. In this study, we address how stem cells derived from peripheral blood can be used also in ophthalmological pathologies. Our results demonstrate that this treatment protocol improved eye disease in four horse cases, including corneal ulcers and one case of retinal detachment. In all cases, we detected a decrease in the intense inflammatory reaction as well as the restoration of the epithelial surface of the central cornea.


Headaches during war: analysis of presentation, treatment, and factors associated with outcome.
Headache is often associated with physical trauma and psychological stress. The aim of this study is to evaluate the impact of headache on personnel deployed in war zones and to identify factors associated with return to duty (RTD). Outcome data were prospectively collected on 985 personnel medically evacuated out of Operations Iraqi and Enduring Freedom for a primary diagnosis of headache between 2004 and 2009. Electronic medical records were reviewed to examine clinical and treatment patterns and the effect that myriad factors had on RTD. 33.6% of evacuees returned to duty. The most common headaches were post-concussion (34.1%) and migraine (30.0%). Headaches typically associated with trauma such as post-concussion (18.7%), occipital neuralgia (23.1%), and cervicogenic headache (29.7%) had the lowest RTD rates, whereas tension headache (49.6%) was associated with the best outcome. Other variables associated with negative outcome included presence of aura (OR 0.51, 95% CI 0.30-0.88; p = 0.02), traumatic brain injury (OR 0.50, 95% CI 0.29-0.87; p = 0.01), opioid (OR 0.41, 95% CI 0.26-0.63; p < 0.001), and beta-blocker (OR 0.26, 95% CI 0.12-0.61; p = 0.002) use, and co-existing psychopathology (p < 0.001 in univariable analysis). Headaches represent a significant cause of unit attrition in personnel deployed in military operations, with physical trauma and co-existing psychopathology associated with poorer outcomes.


Association of Second Allogeneic Hematopoietic Cell Transplant vs Donor Lymphocyte Infusion With Overall Survival in Patients With Acute Myeloid Leukemia Relapse.
The optimal treatment approach to patients with acute myeloid leukemia (AML) who relapse after an allogeneic hematopoietic cell transplant (allo-HCT) remains elusive. No randomized clinical trial comparing survival outcomes of a second allo-HCT (allo-HCT2) vs donor lymphocyte infusion (DLI) has been conducted to date. To compare overall survival (OS) after an allo-HCT2 or DLI in relapsed AML after a first allo-HCT. A retrospective registry study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation involving 418 adults who received an allo-HCT2 (n = 137) or DLI (n = 281) for postallograft-relapsed AML. Analysis was assessed on the principle of intent-to-first received intervention. The data were collected from November 21, 2015, to May 15, 2017, and analysis was performed June 1, 2017. Number of patients with relapsed AML who are alive after 2 years and 5 years from receiving an allo-HCT2 or DLI. Of the 418 patients, 228 (54.5%) were men; mean age was 46.2 years (interquartile range, 36.5-56.9 years). There was no apparent difference in OS whether an allo-HCT2 or DLI was prescribed (2-year OS with allo-HCT2, 26%; 5-year OS with allo-HCT2, 19%; 2-year OS with DLI, 25%; 5-year OS with DLI, 15%; P = .86). Overall survival was better if either of these procedures was offered when the patient was in complete remission (hazard ratio, 0.55; 95% CI, 0.41-0.74; P < .001). Conversely, OS was low for patients relapsing within less than 6 months after an allo-HCT1, regardless of the treatment prescribed (5-year OS: allo-HCT2, 9%; 95% CI, 1%-17% vs DLI, 4%; 95% CI, 1%-8%; P = .86). Heterogeneity of the patient-, disease-, and treatment-related characteristics limit the ability to recommend one approach over another. Findings of this study highlight that best outcomes seem to be achieved in patients relapsing 6 or more months from an allo-HCT1 or those in complete remission at the time of either allo-HCT2 or DLI.


Relapse of Plasmablastic Lymphoma With Cutaneous Involvement in an Immunocompetent Male.
Plasmablastic lymphoma (PBL) is a rare type of non-Hodgkin lymphoma frequently found in the context of immunosuppression and infection with human immunodeficiency virus (HIV) and/or Epstein-Barr virus (EBV). A 33-year-old immunocompetent male presented with recurrent episodes of epistaxis and a growing intranasal mass. Excisional biopsy of the mass revealed an immunohistochemical profile diagnostic of PBL. Upon completion of chemoradiation, he underwent a transnasal endoscopic mucosal flap tissue rearrangement to restore patency for both functional and surveillance purposes. There was no endoscopic evidence of residual or recurrent disease. However, 8 months later, he was found to have a relapse involving the skin. The nasal cavity is one of the most common sites affected by PBL. Involvement of the nasal cavity may present with symptoms of persistent epistaxis accompanied by an enlarging mass. A plasmablastic immunophenotype in combination with HIV or EBV positivity can aid diagnosis.


Sequence and structural analysis of surface protein antigen I/II (SpaA) of Streptococcus sobrinus.
Streptococcal antigen I/II or the surface protein antigen A (SpaA) of Streptococcus sobrinus is an adhesin which mediates binding of the organism to tooth surfaces. The complete sequence of the gene which encodes SpaA has been determined. The gene consists of 4,584 bp and encodes a protein of 1,528 amino acid residues. The deduced amino acid sequence shows extensive homology with those of the cell surface adhesins from Streptococcus mutans serotypes c and f and from Streptococcus sanguis. Structural analysis of the N-terminal region (residues 50 to 550), which is rich in alanine and includes four tandem repeats of an 82-residue sequence, suggests that it adopts an alpha-helical coiled-coil conformation. Cell surface hydrophobicity may be associated with this region. The C-terminal region is more conserved and includes two tandem repeats of a 39-residue proline-rich sequence. A further proline-rich sequence in this region is predicted to span the cell wall. Although a hydrophobic sequence is present in the C-terminal region, it appears to be too short to span the cell membrane. Anchoring of SpaA in the cell membrane may therefore require some form of posttranslational modification or association with another membrane protein.


Vocal emotion recognition by normal-hearing listeners and cochlear implant users.
The present study investigated the ability of normal-hearing listeners and cochlear implant users to recognize vocal emotions. Sentences were produced by 1 male and 1 female talker according to 5 target emotions: angry, anxious, happy, sad, and neutral. Overall amplitude differences between the stimuli were either preserved or normalized. In experiment 1, vocal emotion recognition was measured in normal-hearing and cochlear implant listeners; cochlear implant subjects were tested using their clinically assigned processors. When overall amplitude cues were preserved, normal-hearing listeners achieved near-perfect performance, whereas listeners with cochlear implant recognized less than half of the target emotions. Removing the overall amplitude cues significantly worsened mean normal-hearing and cochlear implant performance. In experiment 2, vocal emotion recognition was measured in listeners with cochlear implant as a function of the number of channels (from 1 to 8) and envelope filter cutoff frequency (50 vs 400 Hz) in experimental speech processors. In experiment 3, vocal emotion recognition was measured in normal-hearing listeners as a function of the number of channels (from 1 to 16) and envelope filter cutoff frequency (50 vs 500 Hz) in acoustic cochlear implant simulations. Results from experiments 2 and 3 showed that both cochlear implant and normal-hearing performance significantly improved as the number of channels or the envelope filter cutoff frequency was increased. The results suggest that spectral, temporal, and overall amplitude cues each contribute to vocal emotion recognition. The poorer cochlear implant performance is most likely attributable to the lack of salient pitch cues and the limited functional spectral resolution.


Prevalence and factors associated with the use of public health services for adult men.
The aim of this study was to identify prevalence and factors associated with use of public health services by adult males residing in the city of Maringá, Paraná. A household survey was carried out with 410 men aged 20 to 59 years old. Analysis was performed by means of descriptive statistics and multiple logistic regression models. The prevalence of use of public services stood at 56.3%. Men who used public health services most often were those with little education, no health plan, no partner, unemployed, who had more contact with nurses and other professionals, sought the services due to disease/symptoms/emergency, had difficulties with the service, rated health services as regular and chose attention and promptness as the most important aspects of health services - variables adjusted for family income, economic class and need for treatment. Men's health care should be reorganized according to factors linked to the use of health services by them, with the promotion of greater contact between health services and men and the centering of assistance on users, expanding men's participation in promotional and preventive practices.


Transcranial electrocortical stimulation to monitor the facial nerve motor function during cerebellopontine angle surgery.
This study was conducted to investigate the success rate of using the facial motor evoked potential (FMEP) of orbicularis oculi and oris muscles for facial nerve function monitoring with use of a stepwise protocol, and its usefulness in predicting facial nerve outcome during cerebellopontine angle (CPA) surgeries. FMEPs were recorded intraoperatively from 60 patients undergoing CPA surgeries. Transcranial electrocortical stimulation (TES) was performed using corkscrew electrodes positioned at hemispheric montage (C3/C4 and CZ). The contralateral abductor pollicis brevis muscle was used as the control response. Stimulation was always applied contralaterally to the affected side using 1, 3, or 5 rectangular pulses ranging from 200 to 600 V with 50 micros of pulse duration and an interstimulus interval of 2 ms. Facial potentials were recorded from needles placed in the orbicularis oculi and oris muscles. FMEP from the orbicularis oris and oculi muscles could be reliably monitored in 86.7% and 85% of the patients, respectively. The immediate postoperative facial function correlated significantly with the FMEP ratio in the orbicularis oculi muscle at 80% amplitude ratio (P = .037) and orbicularis oris muscle at 35% ratio (P = .000). FMEP loss was always related to postoperative facial paresis, although in different degrees. FMEPs can be obtained reliably by using TES with 3 to 5 train pulses. Stable intraoperative FMEPs can predict a good postoperative outcome of facial function. However, further refinements of this technique are necessary to minimize artifacts and to make this method more reliable.


Perceptions of Malawian nurses about nursing interventions for malnourished children and their parents.
In developing countries, malnutrition among children is a major public-health issue. The aim of the study was to describe perceptions of Malawian nurses about nursing interventions for malnourished children and their parents. A qualitative method was used. Data were collected and analyzed according to the phenomenographic research approach. Twelve interviews were performed with 12 nurses at a rural hospital in northern Malawi, Southeast Africa. Through the analysis, two major concepts, comprising four categories of description, emerged: managing malnutrition today and promotion of a favourable nutritional status. The categories of description involved identification and treatment of malnutrition, education during treatment, education during prevention, and assurance of food security. The participating nurses perceived education to be the most important intervention, incorporated in all areas of prevention and treatment of malnutrition. Identification and treatment of malnutrition, education during treatment, education to prevent malnutrition, and assurance of food security were regarded as the most important areas of intervention.


Pax genes in development.
The Pax gene family consists of nine members encoding nuclear transcription factors. Their temporally and spatially restricted expression pattern during embryogenesis suggests that they may play a key role during embryogenesis. Direct evidence for the important role of the Pax genes during embryonic development has been demonstrated by the correlation of mouse developmental mutants and human syndromes with mutations in some Pax genes. To date three Pax genes have been shown to be mutated in undulated, Splotch and small eye, respectively. In man, Pax-3 is mutated in the Waardenburg syndrome, while in aniridia Pax-6 is mutated.


Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial.
ICU discharge is often delayed by a requirement for intravenous vasopressor medications to maintain normotension. We hypothesised that the administration of midodrine, an oral α1-adrenergic agonist, as adjunct to standard treatment shortens the duration of intravenous vasopressor requirement. In this multicentre, randomised, controlled trial including three tertiary referral hospitals in the US and Australia, we enrolled adult patients with hypotension requiring a single-agent intravenous vasopressor for ≥ 24 h. Subjects received oral midodrine (20 mg) or placebo every 8 h in addition to standard care until cessation of intravenous vasopressors, ICU discharge, or occurrence of adverse events. The primary outcome was time to vasopressor discontinuation. Secondary outcomes included time to ICU discharge readiness, ICU and hospital lengths of stay, and ICU readmission rates. Between October 2012 and June 2019, 136 participants were randomised, of whom 132 received the allocated intervention and were included in the analysis (modified intention-to-treat approach). Time to vasopressor discontinuation was not different between midodrine and placebo groups (median [IQR], 23.5 [10-54] vs 22.5 [10.4-40] h; difference, 1 h; 95% CI - 10.4 to 12.3 h; p = 0.62). No differences in secondary endpoints were observed. Bradycardia occurred more often after midodrine administration (5 [7.6%] vs 0 [0%], p = 0.02). Midodrine did not accelerate liberation from intravenous vasopressors and was not effective for the treatment of hypotension in critically ill patients.


Protective Effects of Curcumin Against Alcoholic Fatty Liver.
Alcoholism is a global health concern. Due to its role as the principal site of ethanol metabolism, the liver endures the most significant amount of tissue damage from heavy drinking. Numerous liver lesions can result from chronic and heavy alcohol use, including steatosis, hepatitis, and fibrosis/cirrhosis. Fatty liver is caused by a redox shift from the oxidized to the reduced form of nicotinamide adenine dinucleotide (NAD+) caused by the ethanol oxidation reaction. The other molecular mechanisms related to the progression of alcohol-induced liver injury are increasing sterol regulatory element-binding protein-1 (SREBP-1) and decreasing PPAR-α activity, cell signaling pathway impairment, reactive oxygen species (ROS) accumulation, and lipid peroxidation. Curcuma longa L. rhizomes contain a substance called curcumin, which is naturally yellow in color and is also known as turmeric yellow. Curcumin has powerful biological and pharmacological properties, including antioxidant, anti-inflammatory, antifungal, antibacterial, antitumor, and anticancer effects. It's been employed as a hepatoprotective substance. Current studies have demonstrated the ability of curcumin to prevent the activation of NF-κB in Kupffer cells via endotoxins, to suppress the expression of various cytokines, chemokines, cyclooxygenase-2 (COX-2), and iNOS, as well as to modulate immune responses. The present study has shown the vital role of curcumin in a variety of hepatotoxic procedures, and summarizes those effects, focusing on the molecular insights they provide.


Digital pathology: a tool for 21st century neuropathology.
Digital pathology represents an electronic environment for performing pathologic analysis and managing the information associated with this activity. The technology to create and support digital pathology has largely developed over the last decade. The use of digital pathology tools is essential to adapt and lead in the rapidly changing environment of 21st century neuropathology. The utility of digital pathology has already been demonstrated by pathologists in several areas including consensus reviews, quality assurance (Q/A), tissue microarrays (TMAs), education and proficiency testing. These utilities notwithstanding, interface issues, storage and image formatting all present challenges to the integration of digital pathology into the neuropathology work environment. With continued technologic improvements, as well as the introduction of fluorescent side scanning and multispectral detection, future developments in digital pathology offer the promise of adding powerful analytic tools to the pathology work environment. The integration of digital pathology with biorepositories offers particular promise for neuropathologists engaged in tissue banking. The utilization of these tools will be essential for neuropathologists to continue as leaders in diagnostics, translational research and basic science in the 21st century.


Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats.
Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected into the fourth intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose sufficient to inhibit food intake. Nesfatin-1 (2 μg) inhibited dark-phase food intake, in a dose-dependent fashion, for >3 h. Gastric acid production was evaluated in urethane-anesthetized rats. Nesfatin-1 (2 μg) was introduced via the 4V following endocrine stimulation of gastric acid secretion by pentagastrin (2 μg·kg(-1)·h(-1) iv), vagal stimulation with 2-deoxy-D-glucose (200 mg/kg sc), or no stimulus. Gastric secretions were collected via gastric cannula and neutralized by titration to determine acid content. Nesfatin-1 did not affect basal and pentagastrin-stimulated gastric acid secretion, whereas 2-deoxy-D-glucose-stimulated gastric acid production was inhibited by nesfatin-1 in a dose-dependent manner. c-Fos immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by nesfatin-1 administered via the 4V. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold increase in the mean number of c-Fos-positive neurons in the dorsal motor nucleus of the vagus (DMNV) in nesfatin-1-treated animals vs. controls (P < 0.01). Finally, nesfatin-induced Ca(2+) signaling was evaluated in primary cultured DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent Ca(2+) increments in 95% of cultured DMNV neurons. These studies demonstrate that central administration of nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally stimulated secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers Ca(2+) signaling in cultured DMNV neurons.