Expression level of long noncoding RNA NKILAmiR103-miR107 inflammatory axis and its clinical significance as potential biomarker in patients with colorectal cancer.
Inflammatory cytokines have been observed in colorectal cancer (CRC) tissues and can promote the susceptibility to metastasis of CRC cells. Diverse regulatory mechanisms of long ncRNAs (lncRNAs) and microRNAs (miRNAs) involved in the inflammatory responses are associated with tumor progression. The aim of this research was to investigate the expression level of the nuclear factor-kappa B interacting lncRNA (NKILA)-miR103-miR107 regulatory axis and its clinical significance as a potential biomarker in patients with CRC. In the present study, we investigated the expression levels of miR103, miR107, and NKILA in 21 paired CRC tissues and corresponding adjacent tissues, using real-time polymerase chain reaction technique. Receiver operating characteristic (ROC) curve was used to analyze the prognostic value of biomarkers and to compare their predictive value. It was found that the expression level of miR103 was significantly increased with the development of CRC (cancerous vs. corresponding normal tissues; 2.29 ± 1.65 vs. 1.16 ± 0.64, P = 0.003). Moreover, miR107 was upregulated in CRC tissues compared with paired normal tissues (2.1 ± 1.4 vs. 1.25 ± 0.83, P = 0.005), while NKILA displayed an opposite expression pattern versus miR103/107, but it was not statistically significant (3.69 ± 5.2 vs. 4.35 ± 5.99, P > 0.05). The ROC analysis demonstrated that miR103 had the best diagnostic ability performance with area under curve of 0.723 (0.545-0.901). We identified miR103/107 as tumor-promoting miRNAs with diagnostic value in cancer patients and presumptive negative regulators of NKILA, a potential cancer metastatic suppressor. Strategies that disrupt this regulatory axis might block CRC progression.


[Clinical and therapeutic approaches in angina pectoris of esophageal origin].
The authors, on a basis of experience acquisted since 1984 on two groups of patients, respectively 55 and 174 subjects with angina like chest-pain, individuated in the first group 45%, and 66.1% in the second group, the presence of GER-EMD with the execution of functional stationary manometric and 24 hour pH-metrical exams, without undergoing chemical, pharmacological, mechanical stimulation. They make note that 43 patients out of the second group, underwent, after a certain time, another cardiological study (negative for heart disease when recluted) due to graveness of the symptoms and 33 risulted holders of heart disease, 24 of whom also affected with EMD. The treatment with anti-H2 and procinethycs had succes in 39 patients out of 59, with GER; 10 patients underwent, with success, Nissen-Rossetti funduplication. Medical treatment with sublingual nifedipine was successful in 17 cases out of 56, with EMD; 19 underwent esophageal miotomy surgery commisurated on manometrical dates, with excellent results; 8 patients with hypertension of LES underwent pneumatic dilation with good results; 12 patients live, tolleratig angina like chest-pain. The final considerations are the following: it is not indispensable to look for contemperaly EMD and pain to afferm that pain is of esophageal origin; EMD must be clearly defined; the exclusion primarily of heart pathology must not exclude the possibility of the insorgence of heart desease, in the presence of EMD; the medical therapy, satisfactory in GER, is scarsely efficent in EMD, the decision for surgery must be taken on the gravity of pain associated with an esophageal pathology well defined with numerous diagnostic exams.


The brainweb: phase synchronization and large-scale integration.
The emergence of a unified cognitive moment relies on the coordination of scattered mosaics of functionally specialized brain regions. Here we review the mechanisms of large-scale integration that counterbalance the distributed anatomical and functional organization of brain activity to enable the emergence of coherent behaviour and cognition. Although the mechanisms involved in large-scale integration are still largely unknown, we argue that the most plausible candidate is the formation of dynamic links mediated by synchrony over multiple frequency bands.


LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma.
Chronic lymphocytic B cell leukaemia (CLL)/small lymphocytic B cell lymphoma (SLL) has proven to be not a uniform entity but to consist of various disease subtypes. CLL might also pose diagnostic challenges by demonstrating an uncommon immunohistochemical profile. Recently, the role of lymphocyte enhancer-binding factor 1 (LEF1) in CLL was elucidated being highly expressed and seeming to have a prognostic value. Our aim was to test the applicability of LEF1 as marker for CLL in a diagnostic setting. We investigated LEF1 expression in lymphomas by immunohistochemistry on tissue microarrays containing several lymphoma entities (altogether 720 cases, including 61 CLL cases). We also separated CLL cases by zeta-chain-associated protein kinase 70 (ZAP70) and CD38 stainings and fluorescence in situ hybridisation analyses for TP53 deletions and trisomy 12 into respective groups and correlated data with LEF1 expression. The area under the receiver operating characteristic curve for LEF1 as a diagnostic marker for CLL was 0.815 (95% CI 0.742 to 0.888). The relevant diagnostic cut-off value for LEF1 positivity determined by the Youden's index was 10% (specificity 92%, sensitivity 70%). The majority of CLL cases (70%) expressed LEF1. Eighteen per cent of (transformed) diffuse large B cell lymphoma cases also expressed LEF1. In most other lymphoma entities, LEF1 was negative. There was a positive correlation of LEF1 staining with ZAP70 expression (Spearman's rho: 0.438, p<0.001), but not with CD38 expression, TP53 deletions or trisomy 12. LEF1 is a useful marker in the differential diagnosis of CLL in difficult cases. It shows a high specificity (92%) and a reasonable sensitivity (70%) for this entity.


Tooth movement alterations by different low level laser protocols: a literature review.
Low-Level Laser Therapy (LLLT) provides several benefits for patients receiving orthodontic treatment. According to some literatures, Orthodontic Tooth Movement (OTM) can be enhanced but some investigators have reported contradictory results. This article reviews the literature regarding the different aspects of the use of LLLT on OTM and its alterations. The general data regarding the study design, sample size, wavelength (nm), power (mW), and duration were extracted and recorded independently. Electronic databases of PubMed and ScienceDirect from January 2009 to August 2014 were searched. Also Google Scholar and grey literature was searched for relevant references. Some investigators found that the amount of tooth movement in the Low-Energy Laser Irradiation (LELI) group was significantly greater than in the nonirradiation group by the end of the experimental period. Low-level laser irradiation accelerates the bone remodeling process by stimulating osteoblastic and osteoclastic cell proliferation and function during orthodontic tooth movement. But some researchers have reported that no statistical differences in the mean rate of tooth movement were noted between low energy and high energy experimental sides and their controls. Some evidence shows that low-level laser irradiation accelerates the bone remodeling process and some evidence shows that LLLT has not effect on OTM. In some investigations no statistical differences in the mean rate of tooth movement can be seen between low energy and high energy experimental sides and their controls. It has been shown by authors that laser irradiation can reduce the amount of OTM and a clinical usage for the inhibitory role of low level laser irradiation is enforcing the anchorage unit.


Changes in Insulin Requirements From the Onset of Continuous Subcutaneous Insulin Infusion (CSII) Until Optimization of Glycemic Control.
The aim was to evaluate changes in insulin requirements from onset of continuous subcutaneous insulin infusion (CSII) until glucose optimization in type 1 diabetes and to determine patient characteristics to be considered when CSII is implemented. We retrospectively analyzed 74 type 1 diabetic patients over a follow-up of 5 months after starting CSII. Patients without a decrease in HbA1c levels at the end of follow-up were excluded. We compared total daily doses (TDD), basal/bolus distribution, basal diurnal/nocturnal proportion, number of basal segments, and HbA1c levels in relation to sex, age, body mass index (BMI), diabetes duration, and indication for CSII. At follow-up, HbA1c decreased by 0.75%, TDD decreased by 18%, basal rate was 60% of TDD, and diurnal basal rate was 60% of total basal rate. Insulin requirements were higher in males and in obese patients. Female patients and patients with longer diabetes duration showed a higher percentage of basal insulin. The number of basal segments was 4.9 ± 2.9. Basal requirements were higher in the second half of the nocturnal period. The dawn phenomenon was more relevant in men. Improvements in glycemic control were more marked in younger patients, in patients with higher HbA1c, in patients using more basal segments, and in patients initiating CSII for glucose control before pregnancy. Sex, diabetes duration, and BMI should be considered when initiating CSII. Our findings may help clinicians in clinical decision making regarding CSII therapy.


Cytochalasans and Their Impact on Actin Filament Remodeling.
The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners (actin-binding proteins, ABPs). This gives rise to a temporally and spatially controlled, dynamic network, eliciting a plethora of motility-associated processes. To interfere with the complex inter- and intracellular interactions the actin cytoskeleton confers, small molecular inhibitors have been used, foremost of all to study the relevance of actin filaments and their turnover for various cellular processes. The most prominent inhibitors act by, e.g., sequestering monomers or by interfering with the polymerization of new filaments and the elongation of existing filaments. Among these inhibitors used as tool compounds are the cytochalasans, fungal secondary metabolites known for decades and exploited for their F-actin polymerization inhibitory capabilities. In spite of their application as tool compounds for decades, comprehensive data are lacking that explain (i) how the structural deviances of the more than 400 cytochalasans described to date influence their bioactivity mechanistically and (ii) how the intricate network of ABPs reacts (or adapts) to cytochalasan binding. This review thus aims to summarize the information available concerning the structural features of cytochalasans and their influence on the described activities on cell morphology and actin cytoskeleton organization in eukaryotic cells.


Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy.
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta cell-like phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K(ATP) channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K(ATP) channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K(ATP) channel activity, and as a result of changes in intracellular Ca(2+) homeostasis ([Ca(2+)](i)) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus.


Baseline left atrial low-voltage area predicts recurrence after pulmonary vein isolation: WAVE-MAP AF results.
Electro-anatomical mapping may be critical to identify atrial fibrillation (AF) subjects who require substrate modification beyond pulmonary vein isolation (PVI). The objective was to determine correlations between pre-ablation mapping characteristics and 12-month outcomes after a single PVI-only catheter ablation of AF. This study enrolled paroxysmal AF (PAF), early persistent AF (PsAF; 7 days-3 months), and non-early PsAF (>3-12 months) subjects undergoing de novo PVI-only radiofrequency catheter ablation. Sinus rhythm (SR) and AF voltage maps were created with the Advisor HD Grid™ Mapping Catheter, Sensor Enabled™ for each subject, and the presence of low-voltage area (LVA) (low-voltage cutoffs: 0.1-1.5 mV) was investigated. Follow-up visits were at 3, 6, and 12 months, with a 24-h Holter monitor at 12 months. A Cox proportional hazards model identified associations between mapping data and 12-month recurrence after a single PVI procedure. The study enrolled 300 subjects (113 PAF, 86 early PsAF, and 101 non-early PsAF) at 18 centres. At 12 months, 75.5% of subjects were free from AF/atrial flutter (AFL)/atrial tachycardia (AT) recurrence. Univariate analysis found that arrhythmia recurrence did not correlate with AF diagnosis, but LVA was significantly correlated. Low-voltage area (<0.5 mV) >28% of the left atrium in SR [hazard ratio (HR): 4.82, 95% confidence interval (CI): 2.08-11.18; P = 0.0003] and >72% in AF (HR: 5.66, 95% CI: 2.34-13.69; P = 0.0001) was associated with a higher risk of AF/AFL/AT recurrence at 12 months. Larger extension of LVA was associated with an increased risk of arrhythmia recurrence. These subjects may benefit from substrate modification beyond PVI.


A Virtual Agent to Support Individuals Living With Physical and Mental Comorbidities: Co-Design and Acceptability Testing.
Individuals living with long-term physical health conditions frequently experience co-occurring mental health problems. This comorbidity has a significant impact on an individual's levels of emotional distress, health outcomes, and associated health care utilization. As health care services struggle to meet demand and care increasingly moves to the community, digital tools are being promoted to support patients to self-manage their health. One such technology is the autonomous virtual agent (chatbot, conversational agent), which uses artificial intelligence (AI) to process the user's written or spoken natural language and then to select or construct the corresponding appropriate responses. This study aimed to co-design the content, functionality, and interface modalities of an autonomous virtual agent to support self-management for patients with an exemplar long-term condition (LTC; chronic pulmonary obstructive disease [COPD]) and then to assess the acceptability and system content. We conducted 2 co-design workshops and a proof-of-concept implementation of an autonomous virtual agent with natural language processing capabilities. This implementation formed the basis for video-based scenario testing of acceptability with adults with a diagnosis of COPD and health professionals involved in their care. Adults (n=6) with a diagnosis of COPD and health professionals (n=5) specified 4 priority self-management scenarios for which they would like to receive support: at the time of diagnosis (information provision), during acute exacerbations (crisis support), during periods of low mood (emotional support), and for general self-management (motivation). From the scenario testing, 12 additional adults with COPD felt the system to be both acceptable and engaging, particularly with regard to internet-of-things capabilities. They felt the system would be particularly useful for individuals living alone. Patients did not explicitly separate mental and physical health needs, although the content they developed for the virtual agent had a clear psychological approach. Supported self-management delivered via an autonomous virtual agent was acceptable to the participants. A co-design process has allowed the research team to identify key design principles, content, and functionality to underpin an autonomous agent for delivering self-management support to older adults living with COPD and potentially other LTCs.


Clinical potential relevance of metabolic properties of SGLT2 inhibitors in patients with heart failure.
Introduction: Heart failure (HF) affects approximately 2% of the population worldwide, remaining a major cause of hospitalization and mortality despite innovative therapeutic approaches introduced in the past few decades. Type 2 diabetes mellitus (T2DM) contributes significantly to end-organ damage and HF-related complications and is associated with worse clinical status and increased all-cause and cardiovascular mortality in patients with HF with reduced (HFrEF) or with preserved ejection fraction (HFpEF), compared to HF patients without T2DM. Recently, a novel class of antidiabetic drugs has been introduced: sodium glucose co-trasport-2 inhibitors (SGLT2i). Initially designed for patients with T2DM to reduce kidney blood glucose resorption, SGLT2i rapidly gained attention among HF specialists since they were able to show a beneficial prognostic impact in patients affected by HF and T2DM, even independently from the glycemic control as suggested by the EMPA-REG OUTCOME and CANVAS trials. Areas covered: The present review focuses on the mechanisms and the current clinical evidence supporting the use of SGLT2i in HF patients with T2DM. Moreover, the SGLT2i pharmacokinetic and pharmacodynamic properties will be presented in order to better understand the rationale and the design of the ongoing clinical trials investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM. Expert opinion: SGLT2i are emerging as an effective and safe therapy for the treatment of T2DM and current evidence has unexpectedly demonstrated a robust cardiovascular protection in HF patients with T2DM. Therefore, ongoing clinical trials are investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM. However, it is methodologically disappointing that the mechanisms underlying the encouraging results in cardiovascular protection of this drug class are still not fully understood. A better understanding of the pharmacokinetic and pharmacodynamic properties of SGLT2i is necessary in order to better determine the effect of this new class of drugs in patients with HF.


Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapy.
Neonatal abstinence syndrome (NAS) occurs in more than 50% of infants exposed to intrauterine opiates. Maternal opiate dosing has been investigated with conflicting results. The aims of this study were to correlate maternal methadone dose and other risk factors with the development of NAS requiring pharmacological treatment by using easily accessible clinical parameters. Retrospective medical record review of data from 228 opioid dependent pregnant women who delivered 232 live-born infants. Logistic regression analysis was performed on maternal, perinatal and neonatal parameters to identify risk factors for NAS requiring treatment. A prediction model was developed and validated on a separate independent cohort of 188 infants. Of the 232 infants, 172 (74%) infants were treated for NAS. The risk of withdrawal increased by 17% per 5 mg increment of the last maternal methadone dose. The risk was lower for younger gestational ages and for those delivered by Caesarean section compared to those delivered by normal vaginal delivery. Through predictive modeling, gestational age, mode of delivery and last methadone dose were established as risk factors for withdrawal. The model was validated by other statistical measures and its diagnostic performance confirmed on the separate independent cohort. Our data suggests that timing and mode of delivery as well as last maternal methadone dose are significant risk factors for the development of NAS requiring treatment. Based on these clinical parameters, risk stratification for perinatal management of pregnancies associated with opioid dependency and risk prediction for the neonate might now be possible.


Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council.
To test the equivalence of three versus four cycles of bleomycin, etoposide, and cisplatin (BEP) and of the 5-day schedule versus 3 days per cycle in good-prognosis germ cell cancer. The study was designed as a 2 x 2 factorial trial. The aim was to rule out a 5% decrease in the 2-year progression-free survival (PFS) rate. The study included the assessment of patient quality of life. A cycle of BEP consisted of etoposide 500 mg/m(2), administered at either 100 mg/m(2) days 1 through 5 or 165 mg/m(2) days 1 through 3, cisplatin 100 mg/m(2), administered at either 20 mg/m(2) days 1 through 5 or 50 mg/m(2) days 1 and 2. Bleomycin 30 mg was administered on days 1, 8, and 15 during cycles 1 through 3. The randomization procedure allowed some investigators to participate only in the comparison of three versus four cycles. From March 1995 until April 1998, 812 patients were randomly assigned to receive three or four cycles: of these, 681 were also randomly assigned to the 5-day or the 3-day schedule. Histology, marker values, and disease extent are well balanced in the treatment arms of the two comparisons. The projected 2-year PFS is 90.4% on three cycles and 89.4% on four cycles. The difference in PFS between three and four cycles is -1.0% (80% confidence limit [CL], -3.8%, +1.8%). Equivalence for three versus four cycles is claimed because both the upper and lower bounds of the 80% CL are less than 5%. In the 5- versus 3-day comparison, the projected 2-year PFS is 88.8% and 89.7%, respectively (difference, -0.9%, (80% CL, -4.1%, +2.2%). Hence, equivalence is claimed in this comparison also. Frequencies of hematologic and nonhematologic toxicities were essentially similar. Quality of life was maintained better in patients receiving three cycles; no differences were detected between 3 and 5 days of treatment. We conclude that three cycles of BEP, with etoposide at 500 mg/m(2), is sufficient therapy in good-prognosis germ cell cancer and that the administration of the chemotherapy in 3 days has no detrimental effect on the effectiveness of the BEP regimen.


Ruby fluorescence-enabled ultralong lock-on time high-gain gallium arsenic photoconductive semiconductor switch.
We report a new type of photoconductive semiconductor switch (PCSS), consisting of a semi-insulating gallium arsenic (GaAs) substrate and a front-bonded ruby crystal. The 532 nm laser pulses from an Nd-YAG laser incident on the front surface of the ruby crystal. A portion of the laser pulse passes through the crystal and reaches the GaAs substrate, and the remaining portion of the laser pulse is absorbed by the ruby crystal. This results in the emission of 694 nm fluorescent light. Furthermore, a portion of emitted fluorescent light also reaches the GaAs substrate. The high-fluence 532 nm short laser pulse with a pulse width around several nanoseconds is used to trigger the PCSS entering the high-gain nonlinear mode, whereas the low-fluence long-lifetime (on the order of a millisecond) 694 nm fluorescent light is used to maintain the lock-on time. Thus, an ultralong lock-on time on the order of millisecond is achieved, which is 3 orders of magnitude longer than a typical lock-on time of high-gain GaAs PCSS.


Cardiac safety of donepezil in elderly patients with Alzheimer disease.
Donepezil is a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease (AD), however its cholinergic adverse side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the adverse side effects caused by donepezil on cardiac rhythm and postural blood pressure changes in elderly patients with Alzheimer Disease. The ECG parameters including heart rate, PR, QT, QTc interval and QRS duration and postural blood pressure changes were recorded at the baseline and at each donepezil dose level (5 and 10 mg/d). Patients Seventy-one consecutive patients who were referred by primary care centers to a Geriatric Clinic were enrolled and underwent comprehensive geriatric assessment. Fifty-two subjects completed the study. There were no significant changes relative to the baseline in any of the ECG parameters or arterial blood pressure at any of the investigated dosages of donepezil. It was demonstrated that donepezil was not associated with increased negative chronotropic, arrhythmogenic or hypotensive effects for elderly patients with Alzheimer's disease.


Investigation of adolescents and their mothers in terms of nomophobia.
Nomophobia (NoMP) is the fear of being unable to interact with others via mobile phones and is a current topic in adolescents` mental health. The purpose of this study was to investigate the association between NoMP in adolescents and their mothers` level of NoMP. The levels of depression, anxiety, attention deficit/hyperactivity-impulsivity symptoms, NoMP, and perceived parental emotional availability were examined. One hundred fifty-five adolescents (60% girls) were included in the study with their mothers. Ninetythree (60%) adolescents (67.7% girls) and 64 (41.3%) mothers were classified as nomophobic. There was a positive correlation between the NoMP levels of adolescents and their mothers. Nomophobic girls perceived less paternal support. All psychopathologic symptoms were higher in the nomophobic mothers. There was no difference between nomophobic and non-nomophobic adolescents in terms of maternal psychopathologies. We suggest that parental effects should be investigated during the assessment of NoMP, especially in adolescent girls. The phone usage habits of mothers and their relationship with their adolescent children were closely associated with adolescent NoMP.


Velamentous Umbilical Cord Insertion and Ruptured Fetal Vessel: A Cause of Fetal-Maternal Hemorrhage: A Case Report.
Fetal hemorrhage is rare but can result in rapid fetal compromise. Abnormally located fetal vessels within the membranes increase the risk for their rupture and subsequent hemorrhage. The classic example of this is vasa previa. We present a case of acute fetal hemorrhage resulting from a ruptured fetal vessel. During induction of labor, significant fetal heart rate deceleration occurred, coinciding with acute vaginal bleeding and amniotomy. A depressed, live female neonate was delivered by emergency cesarean section. Examination of the placenta revealed a velamentous cord insertion and a ruptured fetal vessel coursing through the chorioamniotic membranes. Neonatal resuscitation included red blood cell transfusion for hypotension and low hematocrit. The neonate made a full recovery. Acute fetal hemorrhage from the rupture of aberrant fetal vessels often coincides with rupture of membranes. Identifying ruptured fetal vessels abnormally coursing through the chorioamniotic membranes on examination of the placenta provides supporting evidence for suspected fetal hemorrhage.


A case report: the use of ketamine and midazolam intravenous sedation for a child undergoing radiotherapy.
The combination of ketamine hydrochloride and midazolam was used to successfully provide intravenous sedation for a child requiring daily radiation treatments. During the radiation therapy treatments, the anesthesia provider was not in direct contact with the patient. Traditional monitoring was complemented by the addition of closed-circuit television monitoring. The drug combination provided consistent cardiac and respiratory stability, as well as patient immobility, for each radiation treatment.


Risk for affective disorders is associated with greater prefrontal gray matter volumes: A prospective longitudinal study.
Major depression and bipolar disorders aggregates in families and are linked with a wide range of neurobiological abnormalities including cortical gray matter (GM) alterations. Prospective studies of individuals at familial risk may expose the neural mechanisms underlying risk transmission. We used voxel based morphometry to investigate changes in regional GM brain volume, over a seven-year period, in 37 initially healthy individuals having a mono- or di-zygotic twin diagnosed with major depression or bipolar disorder (high-risk group; mean age 41.6 yrs.) as compared to 36 individuals with no history of affective disorders in the index twin and first-degree relatives (low-risk group; mean age 38.5 yrs.). Groups did not differ in regional GM volume changes over time. However, independent of time, high-risk twins had significantly greater GM volumes in bilateral dorsal anterior cingulate, inferior frontal gyrus and temporoparietal regions as compared to low-risk twins. Further, individuals who developed an affective disorder at follow-up (n = 12), had relatively the largest GM volumes, both at baseline and follow-up, in the right dorsal anterior cingulate cortex and right inferior frontal cortex compared to high- and low-risk twins who remained well at follow-up. This pattern of apparently stable grater regional GM volume may constitute a neural marker of an increased risk for developing an affective disorder in individuals at familial risk.


TransforLearn: Interactive Visual Tutorial for the Transformer Model.
The widespread adoption of Transformers in deep learning, serving as the core framework for numerous large-scale language models, has sparked significant interest in understanding their underlying mechanisms. However, beginners face difficulties in comprehending and learning Transformers due to its complex structure and abstract data representation. We present TransforLearn, the first interactive visual tutorial designed for deep learning beginners and non-experts to comprehensively learn about Transformers. TransforLearn supports interactions for architecture-driven exploration and task-driven exploration, providing insight into different levels of model details and their working processes. It accommodates interactive views of each layer's operation and mathematical formula, helping users to understand the data flow of long text sequences. By altering the current decoder-based recursive prediction results and combining the downstream task abstractions, users can deeply explore model processes. Our user study revealed that the interactions of TransforLearn are positively received. We observe that TransforLearn facilitates users' accomplishment of study tasks and a grasp of key concepts in Transformer effectively.


Long-term survival of extensive amalgam restorations.
In cost-effectiveness analysis and contemporary treatment planning strategies, the postponement of placement of cast crowns plays an important role. Extensive amalgam restorations that involve the rebuilding of cusps and the provision of auxiliary retention are thought to make this postponement possible. This study reports the long-term survival (100 months) of extensive amalgam restorations in a randomized, controlled clinical trial. The operational hypothesis was that the type of retention and the operator have a long-term influence on the survival and clinical functioning of extensive amalgam restorations. Three hundred extensive amalgam restorations were placed by three operators in molar teeth in which one or more cusps were reconstructed. Five different auxiliary retention methods were used for retention of these restorations. Since the purpose of extensive amalgam restorations is considered to be two-fold (to restore a broken-down molar to function acceptably as an independent restoration and to create a substructure for subsequent crown construction), survival was assessed at different levels. The survival rate of extensive amalgam restorations as an independent restoration was 88+/-2%. The functional survival rate (as an independent restoration or as a substructure) was 92+/-2%. The influence of experimental variables ('retention method' and 'operator') and background variables ('tooth type', 'extension of extensive amalgam restorations', and 'age of patient') on the survival was analyzed by Log Rank and Breslow tests. The analyses revealed that there were no statistically significant influences on the survival rates except for the variable 'age of patient' (p < or = 0.05). Extensive amalgam restorations were more prone to failure in the group of older patients than in the group of younger ones. It is concluded that the clinical survival of extensive amalgam restorations is independent from several clinical variables in the study.


Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly altered genome: combined molecular and therapeutic studies.
Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well-characterized preclinical models for EMM are not available. Herein, a patient-derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events, and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of the tumor of the patient. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations (CNAs) were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF was already observed at the medullary stage and a new one, t(10;14)(p?11-12;q32), was observed only with extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact single nucleotide variants and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% versus non-treated tumors, whereas treatment with the anti-CD38 antibody daratumumab showed a reduction of 46%. The generation of PDOX from a small EMM biopsy allowed us to investigate in depth the molecular events associated with extramedullary disease in combination with drug testing.


Chromosome damage in human cells induced by UMTS mobile telephony radiation.
Environmental exposure to modern microwave telecommunication electromagnetic fields (EMFs) has increased to unprecedented levels with consequent health complaints and concerns. Many studies have already reported genotoxic effects on a variety of organisms and cell/tissue types. Human peripheral blood lymphocytes from six healthy donors were stimulated for mitosis and exposed to microwave EMF of Universal Mobile Telecommunications System (UMTS) or third generation (3G) mobile telephony (MT) EMF/radiation emitted by a commercially available mobile phone handset. Lymphocytes exposed during the G2 phase of the cell division cycle and observed at metaphase, exhibited chromatid-type aberrations (gaps and breaks) at highly significant percentages - up to 275% - compared to the control (sham-exposed) samples. Each subject exhibited a different sensitivity to the microwave exposure. Moreover, the percentages of aberrations in the control samples among subjects were different due to genetic and environmental factors. The MT EMF exposure induced mainly achromatic lesions (gaps), and secondarily terminal deletions (breaks) in a smaller degree. In conclusion, the present study shows that microwave 3G MT EMF/radiation - within the current exposure limits - has significant genotoxic action on human cells, and human exposure to this EMF/radiation should be kept at levels as low as possible.


[Aseptic osteonecrosis of the head of the metacarpal (Mauclaire's disease)--case report and review of the literature].
Aseptic osteonecrosis of the head of metacarpal is a rare disease with an unknown aetiology. It was first described by Mauclaire 1927. We now report on the treatment of 2 patients with Mauclaire's disease via transplantation of the calotte of the head of the 2nd metatarsal. At 26 and 30 months, respectively, after surgery both patients were free of complaints in activities of daily live and had free function of their fingers. There was no discomfort in the resection area at the 2nd metatarsal. Based on this experience, the method seems to be a recommendable option in young adults. A prerequisite is that the base of the proximal phalanx be intact.


Efficacy of Hip Arthroscopy for the Management of Septic Arthritis: A Systematic Review.
This systematic review assessed the role of hip arthroscopic irrigation and debridement for eradication of infection in native joints to ascertain outcomes and complications associated with this surgical approach. The Medline, Embase, and PubMed databases were searched on July 20, 2014, for English-language studies that addressed arthroscopic treatment of native septic hip arthritis. The studies were systematically screened and data abstracted in duplicate, with qualitative findings presented. There were 11 eligible studies (1 case-control study, 8 case series, and 2 case reports) reporting on 65 patients (65 hips) treated by arthroscopic irrigation and debridement for septic hip arthritis. The mean length of patient follow-up was 19.1 months (range, 6 to 84 months). The indications for surgery were as follows: pyrexia, anterior groin or hip pain with limited hip range of motion and an inability to bear weight, associated leukocytosis, an elevated erythrocyte sedimentation rate or C-reactive protein level, and/or hip imaging or aspiration results consistent with infection. Specific contraindications for surgery reported across studies included tuberculous of fungal infection, coexistence of osteomyelitis, immunocompromised individuals, and pre-existing surgery on the affected hip. The initial rate of infection eradication was 100%. All studies reported significant improvements in patient pain and function. Improvements were also observed in range of motion, as well as across both the Bennett radiographic and clinical assessments and Harris Hip Score. No complications, major or minor, were reported, and only 1 of 65 hips (1.5%) required revision arthroscopy for recurrence because of a methicillin-resistant Staphylococcus aureus infection. Arthroscopic native hip irrigation and debridement for septic arthritis appear to comprise a safe and effective treatment option for selected patients (e.g., no deformity, no bacterial infections, and not immunocompromised). Timely diagnosis and intervention, however, remain the most critical prognostic factors for successful outcomes. Level IV, systematic review of Level IV and V studies.


Characterization of trajectories of physical activity and cigarette smoking from early adolescence to adulthood.
Cigarette smoking and physical inactivity are two critical risk factors for noncommunicable diseases and all-cause mortality. However, few studies have compared the long-term trajectories of both behaviors, as well as multilevel factors associated with trajectory patterns. Using the National Longitudinal Study of Adolescent to Adult Health (Add Health) Wave I through V survey data, this study characterized distinct subgroups of the population sharing similar behavioral patterns from adolescence to adulthood, as well as predictors of subgroup membership for physical activity (PA) and cigarette smoking behavior respectively. Using the Add Health Wave I through V survey data, we identified the optimal number of latent classes and class-specific trajectories of PA and cigarette smoking from early adolescence to adulthood, fitting latent growth mixture models with standardized PA score and past 30-day cigarette smoking intensity as outcome measures and age as a continuous time variable. Associations of baseline sociodemographic factors, neighborhood characteristics, and sociopsychological factors with trajectory class membership were assessed using multinomial logistic regression. We identified three distinct subgroups of non-linear PA trajectories in the study population: moderately active group (N = 1067, 5%), persistently inactive group (N = 14,257, 69%) and worsening activity group (N = 5410, 26%). Foror cigarette smoking, we identified three distinct non-linear trajectory subgroups: persistent non-smoker (N = 14,939, 72%), gradual quitter (N = 2357, 11%), and progressing smoker (N = 3393, 16%). Sex, race/ethnicity, neighborhood environment and perceived peer support during adolescence were significant predictors of both physical activity and cigarette smoking trajectory subgroup membership from early adolescence to adulthood. There are three distinct subgroups of individuals sharing similar PA and cigarette smoking behavioral profile respectively from adolescence to adulthood in the Add Health study population. Behavioral interventions that focus on neighborhood environment (e.g. establish community-based activity center) and relationship to peers during adolescence (e.g. peer counseling) could be key to long-term PA promotion and cigarette smoking cessation.


Mapping the blood vessels with paracellular permeability in the retinas of diabetic rats.
Diabetic retinopathy increases the permeability of the blood-retinal barrier, but the specific vessels that become permeable have not been identified. Both transcellular and paracellular pathways of vascular solute flux have been proposed. This study was conducted to test the hypothesis that paracellular flux contributes to increased retinal vascular permeability after VEGF treatment or diabetes, and to map the types of vessels that became permeable. Regions of paracellular flux were identified by perfusion with fluorescent concanavalin A (ConA). Rats were injected intravitreally with VEGF or made diabetic with streptozotocin (STZ). After specified times, the rats were perfused with fixative followed by ConA, which binds to the basement membrane but not the luminal surface of endothelial cells. With this approach, ConA labels only blood vessels with paracellular permeability. Retinas were also labeled by immunofluorescence for the tight junction proteins occludin and claudin-5 and examined by confocal microscopy. ConA labeling increased in the superficial arterioles and postcapillary venules, 2 weeks after the onset of diabetes. After 1 month, ConA labeling dramatically increased and extended to the capillaries of the outer plexiform layer. There was an inverse relationship between occludin immunoreactivity and ConA binding, but no change in claudin-5 immunoreactivity was detected. Injection of VEGF gave similar results. Diabetes and VEGF increase paracellular vascular permeability in the retina, associated with redistribution of occludin. This permeability begins in the superficial arterioles and postcapillary venules and progresses to the capillary bed.


The oronasal speculum.
The oronasal speculum is a standard nasal speculum with a metal tongue depressor incorporated into one of the handles. It permits the physician to examine the oral cavity and pharynx immediately after examination of the nose without changing instruments.


Seasonal Occurrence and Interspecific Interactions of Egg Parasitoids of Megacopta cribraria (Heteroptera: Plataspidae) in Japan.
We conducted a field study to determine seasonal egg parasitism rates of the kudzu bug Megacopta cribraria (F.) on the kudzu plant, Pueraria montana (Lour.) Merr. var. lobata (Willd.) Maesen et Almeida ex Sanjappa and Pradeep, in Tokyo, Japan, during the period from May 2014 to September 2014. The eggs of M. cribraria per 1 m2 of kudzu at four locations in Tokyo were collected weekly and parasitism rates were assessed. Eggs of M. cribraria were laid on the kudzu plant from May to September. Megacopta cribraria eggs were parasitized by two parasitoid species, Paratelenomus saccharalis (Dodd) and Ooencyrtus nezarae Ishii. Paratelenomus saccharalis first appeared in May, and its parasitism rates peaked in July and September. Ooencyrtus nezarae first appeared in June and its parasitism rates peaked in July. Except for one location which could not be statistically analyzed because of the small sample size, occurrence of parasitism by P. saccharalis and O. nezarae in M. cribraria egg masses was independent at one location and positively associated at two locations, suggesting that the use of host egg masses by P. saccharalis and O. nezarae is not mutually exclusive. Parasitism rates by P. saccharalis and O. nezarae were significantly lower for egg masses parasitized by both species than for those parasitized by a single species. The proportion of males among O. nezarae progeny was significantly higher for egg masses parasitized by O. nezarae together with P. saccharalis than for those parasitized by O. nezarae alone. These results suggest that parasitism of host egg masses by the two species is influenced by their interspecific interactions.


Results of a three-year trial of arterial hypertension prevention in a population of children aged 11-15 years by overweight control.
As part of a study of prevention of atherosclerosis precursors mass examinations were performed in two districts of Moscow. In the intervention district, the sample included 1123 pupils aged 11-12 years (544 boys, 579 girls), in the control district 1963 pupils (963 boys, 1000 girls) were examined. Repeat checks were performed one, 2 and 3 years after initial examination (blood pressure, body mass and height, skinfold thickness above m. triceps and below the scapula). The prevention programme addressed the whole population, with special emphasis on obese children (instruction about diet and correct feeding habits, body mass control) and their social microenvironment. Favourable results were registered, in terms of blood pressure and skinfold thickness reduction, during the first 2 years in boys; in girls diastolic BP dropped in the 1st year only, skinfold thickness was reduced in the first 2 years. Multiple regression analysis confirmed that the observed changes could be ascribed to the effect of the preventive programme.


Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention.
Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.


Native and Polyubiquitinated Forms of Dihydroceramide Desaturase Are Differentially Linked to Human Embryonic Kidney Cell Survival.
There is controversy concerning the role of dihydroceramide desaturase (Degs1) in regulating cell survival, with studies showing that it can both promote and protect against apoptosis. We have therefore investigated the molecular basis for these opposing roles of Degs1. Treatment of HEK293T cells with the sphingosine kinase inhibitor SKi [2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole] or fenretinide, but not the Degs1 inhibitor GT11 {N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octan-amide}, induced the polyubiquitination of Degs1 (Mr = 40 to 140 kDa) via a mechanism involving oxidative stress, p38 mitogen-activated protein kinase (MAPK), and Mdm2 (E3 ligase). The polyubiquitinated forms of Degs1 exhibit "gain of function" and activate prosurvival pathways, p38 MAPK, c-Jun N-terminal kinase (JNK), and X-box protein 1s (XBP-1s). In contrast, another sphingosine kinase inhibitor, ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], at concentrations of 25 to 50 μM failed to induce formation of the polyubiquitinated forms of Degs1. In contrast to SKi, ABC294640 (25 μM) promotes apoptosis of HEK293T cells via a Degs1-dependent mechanism that is associated with increased de novo synthesis of ceramide. These findings are the first to demonstrate that the polyubiquitination of Degs1 appears to change its function from proapoptotic to prosurvival. Thus, polyubiquitination of Degs1 might provide an explanation for the reported opposing functions of this enzyme in cell survival/apoptosis.


Heart rate variability is associated with survival in patients with brain metastasis: a preliminary report.
Impaired heart rate variability (HRV) has been demonstrated as a negative survival prognosticator in various diseases. We conducted this prospective study to evaluate how HRV affects brain metastasis (BM) patients. Fifty-one BM patients who had not undergone previous brain operation or radiotherapy (RT) were recruited from January 2010 to July 2012, and 40 patients were included in the final analysis. A 5-minute electrocardiogram was obtained before whole brain radiotherapy. Time domain indices of HRV were compared with other clinical factors on overall survival (OS). In the univariate analysis, Karnofsky performance status (KPS) <70 (P = 0.002) and standard deviation of the normal-to-normal interval (SDNN) <10 ms (P = 0.004) significantly predict poor survival. The multivariate analysis revealed that KPS <70 and SDNN <10 ms were independent negative prognosticators for survival in BM patients with hazard ratios of 2.657 and 2.204, respectively. In conclusion, HRV is associated with survival and may be a novel prognostic factor for BM patients.


Central and peripheral components of short latency vestibular responses in the chicken.
Far-field recordings of short latency vestibular responses to pulsed cranial translation are composed of a series of positive and negative peaks occurring within 10 ms following stimulus onset. In the bird, these vestibular evoked potentials (VsEPs) can be recorded noninvasively and have been shown in the chicken and quail to depend strictly upon the activation of the vestibular component of the eighth nerve. The utility of the VsEP in the study of vestibular systems is dependent upon a clear understanding of the neural sources of response components. The primary aim of the current research in the chicken was to critically test the hypotheses that 1) responses are generated by both peripheral and central neurons and 2) peaks P1 and N1 originate from first order vestibular neurons, whereas later waves primarily depend on activity in higher order neurons. The principal strategy used here was to surgically isolate the eighth nerve as it enters the brainstem. Interruption of primary afferents of the eighth nerve in the brainstem substantially reduced or eliminated peaks beyond P2, whereas P1 and N1 were generally spared. Surgical sections that spared vestibular pathways had little effect on responses. The degree of change in response components beyond N1 was correlated with the extent of damage to central vestibular relays. These findings support the conclusion that responses are produced by both peripheral and central elements of the vestibular system. Further, response peaks later than N1 appear to be dependent upon central relays, whereas P1 and N1 reflect activity of the peripheral nerve. These findings clarify the roles of peripheral and central neurons in the generation of vestibular evoked potentials and provide the basis for a more useful and detailed interpretation of data from vestibular response testing.


Relative contributions of biological and chemical reactions to the overall rate of pyrite oxidation at temperatures between 30 degrees C and 70 degrees C.
The stoichiometry and kinetics of the spontaneous, chemical reaction between pyrite and ferric iron was studied at 30, 45, and 70 degrees C in shake flasks at pH 1.5 by monitoring the ferrous iron, total iron, elemental sulfur, and sulfate concentration profiles in time. It was found that the sulfur moiety of pyrite was oxidized completely to sulfate. Elemental sulfur was not produced in detectable amounts. The iron moiety of pyrite was released as ferrous iron. All observed initial reaction rates could be fitted into an empirical equation. This equation includes the concentrations of ferric iron and pyrite, and a constant which is dependent on the temperature and the nature of the main anion present. It was observed that ferrous iron formed during the reaction slowed down the oxidation of pyrite by ferric iron. The extent of this effect decreased with increasing temperature. With the aid of the empirical equation, the contribution of the chemical oxidation of pyrite by ferric iron to the overall oxidation in a hypothetical plug-flow reactor, in which biologically mediated oxdidation of pyrite and ferrous iron by oxygen also takes place, can be assessed. At 30, 45, and 70 degrees C, respectively, 2, 8-17, and 43% of the pyrite was oxidized chemically by ferric iron. Therefore, it is expected that only in reactors operating at high temperatures with extremely thermophilic bacteria, will chemical oxidation cause a significant deviation from the apparent first order overall kinetics of biological pyrite oxidation.


Stochastic behavior analysis of complex repairable industrial systems utilizing uncertain data.
The purpose of this paper is to present a novel technique for analyzing the behavior of an industrial system stochastically by utilizing vague, imprecise, and uncertain data. In the present study two important tools namely Lambda-Tau methodology and particle swarm optimization are combinedly used to present a novel technique named as particle swarm optimization based Lambda-Tau (PSOBLT) for analyzing the behavior of a complex repairable system stochastically up to a desired degree of accuracy. Expressions of reliability indices like failure rate, repair time, mean time between failures (MTBF), expected number of failures (ENOF), reliability and availability for the system are obtained by using Lambda-Tau methodology and particle swarm optimization is used to construct their membership function. The interaction among the working units of the system is modeled with the help of Petri nets. The feeding unit of a paper mill situated in a northern part of India, producing approximately 200ton of paper per day, has been considered to demonstrate the proposed approach. Sensitivity analysis of system's behavior has also been done. The behavior analysis results computed by PSOBLT technique have a reduced region of prediction in comparison of existing technique region, i.e. uncertainties involved in the analysis are reduced. Thus, it may be a more useful analysis tool to assess the current system conditions and involved uncertainties.


eckol enhances heme oxygenase-1 expression through activation of Nrf2/JNK pathway in HepG2 cells.
Eckol isolated from Ecklonia stolonifera was previously reported to exhibit cytoprotective activity with its intrinsic antioxidant activity in in vitro studies. In this study, we characterized the mechanism underlying the eckol-mediated the expression of heme oxygenase-1 (HO-1). Eckol suppressed the production of intracellular reactive oxygen species and increased glutathione level in HepG2 cells. Eckol treatment enhanced the expression of HO-1 at the both level of protein and mRNA in HepG2 cells. Enhanced expression of HO-1 by eckol was presumed to be the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2) demonstrated by its nuclear translocation and increased transcriptional activity. c-Jun NH2-terminal kinases (JNKs) and PI3K/Akt contributed to Nrf2-mediated HO-1 expression. These results demonstrate that the eckol-mediated expression of HO-1 in HepG2 cells is regulated by Nrf2 activation via JNK and PI3K/Akt signaling pathways, suggesting that eckol may be used as a natural antioxidant and cytoprotective agent.


Peri-implant marginal bone loss: an academic controversy or a clinical challenge?
The aim of this narrative review was to explore and discuss marginal bone loss around transmucosal oral implants and the related incidence of this biologic complication. Treatment with osseointegrated implants is most often successful and improves the quality of life for the patient. At present only limited data are available to evaluate long-term technical and biological complications. When peri-implant tissue destruction occurs, little is known about the initiating process. Possible factors of relevance for the initiation and progression of peri-implantitis are discussed. Periodontitis, smoking and a variety of local factors are among the most plausible putative reported risk factors. Also, oral hygiene and the inability to clean the reconstruction were reported. The unit for reporting incidence of peri-implant bone loss varies in different studies between implants and patients. Since there seems to be a clustering effect, and implants in the same mouth cannot be considered independent from each other, it is recommended to use the patient as a unit. The different cut-off values for clinical parameters reported in different studies will exert a significant influence on the magnitude of the reported incidence of peri-implantitis. It is suggested that the composite variables including bone loss > or =2 mm, compared to initial radiographs at delivery of the prosthetic device, in combination with bleeding on probing should be interpreted as a 'red flag' for the clinician to critically evaluate if any intervention is indicated in the individual case. Until more solid scientific evidence has been made available, it is likely that the academic controversy in relation to peri-implant bone loss and peri-implantitis will continue.


Immortalization of rat middle ear epithelial cells by adeno 12-SV40 hybrid virus.
Rat middle ear epithelial cells were infected with the adeno 12-SV40 hybrid virus. The cell line thus obtained displays features of primary cultured epithelial cells in both light microscopic and ultrastructural examinations. The immortalized cells have been in continuous proliferation for 40 passages and more than 17 months. Immunohistochemical analysis of the immortalized cells was positive for the SV40 T antigen and the tumor suppressor protein p53. The cells also stained positive for cytokeratin, an epithelial cell marker, and negative for vimentin, a fibroblast marker. These results, together with karyotype analysis, indicate that this cell line originated from rat middle ear epithelial cells and retains the characteristics of epithelial cells. This cell line will be useful for studying the normal cellular biology of middle ear epithelial cells, as well as the cellular and molecular mechanisms involved in the bacteria-middle ear epithelial cell interaction.


Towards a Sustainable Natural Resource Management of Tribal Communities: Findings from a Study of Swidden and Wetland Cultivation in Remote Hill Regions of Eastern India.
/ Environmental degradation in many hill forest regions of Asia, inhabited by indigenous/tribal communities is growing at an unprecedented rate. The case of Orissa State in eastern India is no exception. The government is of the view that the local population is responsible for forest degradation as they practice swidden cultivation and forest gathering indiscriminately to sustain their livelihoods. Based on economic merit alone, the government has undertaken some policy initiatives. Such initiatives that are meant to stop swidden cultivation have not been successful. This study recommends an integrated framework for developing a sustainable natural resource management practice for tribal communities. The framework has taken into consideration both economic and noneconomic factors in evaluating various alternatives. Furthermore, it has been applied to two tribal communities in Orissa (Juang and Saora). Based on an economic analysis comparing returns from swidden as well as wetland cultivation, it is observed that where forest degradation is not serious, wetland cultivation does not have a significant economic merit vis-à-vis swidden cultivation. However, in view of the long-term sustainability issue within ecological limits, swidden cultivation may be phased out in favor of wetland cultivation with an appropriate transition period. During this transition, government must adopt suitable policy initiatives to provide tribals tenurial rights to land, help financially in creating settled lands through terracing, introduce certain improved agroforestry techniques and train tribal people in other income-generating activities. Furthermore, all such interventions made by the government should have a strong sociocultural component in order to attract the tribal people to give up swidden cultivation.


Closure of patent foramen ovale: when and how?
Percutaneous closure of a patent foramen ovale (PFO) was performed in 98 consecutive patients (mean age 52.5 +/- 13 years, 61 women). Indications included recurrent transient ischaemic attack (47%), cryptogenic stroke (34%), peripheral embolism (11%), disabling migraine with aura (4%), professional scuba diving (1 pt) and severe platypnea-orthodeoxia syndrome (1 pt). Each PFO was characterized by transesophageal echocardiography (TEE) according to anatomy, degree of shunt (1-mild, 2-moderate, 3-severe), right atrial anatomical features relevant for PFO closure (such as presence of an Eustachian valve, Chiari network, lipomatosis or absence of septum secundum) with a new classification scheme. According to this classification successful device delivery was obtained in 100% of pts. Major complications included heparin-induced thrombocytopenia in 1 pt and device dislodgment in 1 pt; minor complications were mostly related to the catheter introduction site (2 pts) and mild immediate shunt (2 pts). In conclusion, percutaneous PFO closure based on strict anatomic criteria is a safe procedure with minimal periprocedural complications.


Estimates of Intraclass Correlation Coefficients From Longitudinal Group-Randomized Trials of Adolescent HIV/STI/Pregnancy Prevention Programs.
Group-randomized trials (GRTs) are one of the most rigorous methods for evaluating the effectiveness of group-based health risk prevention programs. Efficiently designing GRTs with a sample size that is sufficient for meeting the trial's power and precision goals while not wasting resources exceeding them requires estimates of the intraclass correlation coefficient (ICC)-the degree to which outcomes of individuals clustered within groups (e.g., schools) are correlated. ICC estimates vary widely depending on outcome, population, and setting, and small changes in ICCs can have large effects on the sample size needed to estimate intervention effects. This study addresses a gap in the literature by providing estimates of ICCs for adolescent sexual risk-taking outcomes under a range of study conditions. Multilevel regression analyses were applied to existing data from four federally funded GRTs of school-based HIV/STI/pregnancy prevention programs to obtain a variety of ICC estimates. ICCs ranged from 0 to 0.15, with adjustment for covariates and repeated measurements reducing the ICC in the majority of cases. Minimum detectable effect sizes with 80% power and 0.05 significance levels ranged from small to medium Cohen's d (0.13 to 0.53) assuming 20 schools of 100 students each. This study provides the first known set of ICC estimates for investigators to use when planning studies of school-based programs to prevent sexual risk behaviors in youth. The results provide further evidence of the importance of using the appropriate adjusted ICC estimate at the design stage to maximize resources in costly GRTs.


Culture and psychiatric evaluation: operationalizing cultural formulation for DSM-5.
The Outline for Cultural Formulation (OCF) introduced with DSM-IV provided a framework for clinicians to organize cultural information relevant to diagnostic assessment and treatment planning. However, use of the OCF has been inconsistent, raising questions about the need for guidance on implementation, training, and application in diverse settings. To address this need, DSM-5 introduced a cultural formulation interview (CFI) that operationalizes the process of data collection for the OCF. The CFI includes patient and informant versions and 12 supplementary modules addressing specific domains of the OCF. This article summarizes the literature reviews and analyses of experience with the OCF conducted by the DSM-5 Cross-Cultural Issues Subgroup (DCCIS) that informed the development of the CFI. We review the history and contents of the DSM-IV OCF, its use in training programs, and previous attempts to render it operational through questionnaires, protocols, and semi-structured interview formats. Results of research based on the OCF are discussed. For each domain of the OCF, we summarize findings from the DCCIS that led to content revision and operationalization in the CFI. The conclusion discusses training and implementation issues essential to service delivery.


Digital blinding of radiographs to mask allocation in a randomized control trial.
To demonstrate the effectiveness of a digital radiographic altering technique in concealing treatment allocation to blind outcome assessment of distal femur fracture fixation. Digital postoperative anteroposterior and lateral radiographs from a sample of 33 randomly-selected patients with extra-articular distal femur fractures treated by surgical fixation at a Level 1 trauma center were included. Using commercially available digital altering software, we devised a technique to blind the radiographs by overlaying black boxes over the implant hardware while preserving an exposed fracture site for assessment of fracture healing. Three fellowship-trained surgeons evaluated a set of blinded radiographs twice and a control set of unblinded radiographs once. Each set of radiographs were reviewed independently and in a randomly-assigned order. The degrees of agreement and disagreement among evaluators in identifying implant type while reviewing both blinded and unblinded radiographs were assessed using the Bang Blinding Index and James Blinding Index. The degree of agreement in fracture union was assessed using kappa statistics. The assessment of blinded radiographs with both the Bang Blinding Index (BBI) and James Blinding Index (JBI) demonstrated a low degree of evaluator success at identifying implant type (Mean BBI, far cortical locking: -0.03, SD: 0.04; Mean BBI, standard screw: 0, SD: 0; JBI: 0.98, SD: 0), suggesting near perfect blinding. The assessment of unblinded radiographs with both blinding indices demonstrated a high degree of evaluator success at identifying implant type (Mean BBI, far cortical locking: 0.89, SD: 0.19; Mean BBI, standard screw: 0.87, SD: 0.04; JBI: 0.26, SD: 0.12), as expected. There was moderate agreement with regard to assessment of fracture union among the evaluators in both the blinded (Kappa: 0.38, 95%CI: 0.25-0.52) and unblinded (Kappa: 0.35, 95%CI: 0.25-0.45) arms of the study. There was no statistically significant difference in fracture union agreement between the blinded and unblinded groups. The digital blinding technique successfully masked the surgeons to the type of implant used for surgical treatment of distal femur fractures but did not interfere with the surgeons' ability to reliably evaluate radiographic healing at the fracture site.


Mineralogical analysis of the respiratory tract in aluminium oxide-exposed workers.
A retrospective study was conducted in order to characterize the retention of fibrous and nonfibrous mineral particles in the respiratory tract in subjects with previous occupational exposure in the aluminium industry. Bronchoalveolar lavage (BAL) fluid (three samples) or lung parenchyma (two samples) were studied using analytical transmission electron microscopy in five patients. A high concentration of aluminium fibres (> 10(7) fibres.g-1 dry lung) was identified in two lung tissue samples, and aluminium fibres were also identified in BAL fluid in three patients. All fibres were short (mean length: 1-2 microns), with no fibre longer than 5 microns. Some biopersistence of these fibres in the respiratory tract is suggested from these observations, since fibres were identified in biological samples collected more than 4 yrs after cessation of exposure in four out of five patients. Occupational physicians should be aware of possible exposure to short, thin aluminium fibres during primary aluminium production. Further studies are needed to assess the potential health effects of these fibres. Industrial hygiene measurements should also be performed to document the potential sources of exposure to aluminium fibres in this industry.


Social Determinants of Health and Associations With Outcomes in Pediatric Patients With Brain Tumors.
Social determinants of health (SDOH) are nonmedical factors that affect health outcomes. Limited investigation has been completed on the potential association of these factors to adverse outcomes in pediatric populations. In this study, the authors aimed to analyze the effects of SDOH disparities and their relationship with outcomes after brain tumor resection or biopsy in children. The authors retrospectively reviewed the records of their center's pediatric patients with brain tumor. Black race, public insurance, median household income, and distance to hospital were the investigated SDOH factors. Univariate analysis was completed between number of SDOH factors and patient demographics. Multivariate linear regression models were created to identify coassociated determinants and outcomes. A total of 272 patients were identified and included in the final analysis. Among these patients, 81 (29.8%) had no SDOH disparities, 103 (37.9%) had 1, 71 (26.1%) had 2, and 17 (6.2%) had 3. An increased number of SDOH disparities was associated with increased percentage of missed appointments (P = .002) and emergency room visits (P = .004). Univariate analysis demonstrated increased missed appointments (P = .01), number of postoperative imaging (P = .005), and number of emergency room visits (P = .003). In multivariate analysis, decreased median household income was independently associated with increased length of hospital stay (P = .02). The SDOH disparities are prevalent and impactful in this vulnerable population. This study demonstrates the need for a shift in research focus toward identifying the full extent of the impact of these factors on postoperative outcomes in pediatric patients with brain tumor.


Resting energy expenditures in Asian women measured by indirect calorimetry are lower than expenditures calculated from prediction equations.
Measured resting energy expenditure (REE) and REEs calculated using the Harris-Benedict equation, Food and Agriculture Organization/World Health Organization/United Nations University (FAO/WHO/UNU) equations (FAO equations), and the Liu equation were compared in Asian women. REEs were measured using indirect calorimetry in the morning after an overnight fast and compared with REEs calculated using the Harris-Benedict equation, the FAO equations, and the Liu equation. Height, weight, and 3-day diet records were also obtained. Thirty-six healthy, free-living Asian women aged 19 to 52 years and living in the United States were recruited from Washington State University, Pullman, and completed the study. Paired t tests, stepwise regression, one-way analysis of variance, and Pearson correlation coefficients were used for the statistical analyses. Significance was set at P < or = .05. A significant correlation was found between measured REE and REE derived from the Harris-Benedict equation (R = 0.67, P < .0001), the FAO equations (R = 0.70, P < .0001), and the Liu equation (R = 0.70, P < .0001). However, measured REE was significantly lower than REE calculated using the Harris-Benedict and FAO equations by 8.5% (P < .001) and 5.4% (P < .01), respectively. No significant difference was noted between measured REE and REE derived from the Liu equation. Caution must be taken when predicting REE of Asian women using the Harris-Benedict equation or the FAO equation. Indirect calorimetry or an equation specific to Asians, such as the Liu equation, is recommended when an accurate estimate is necessary.


Practical grantsmanship: the application process in health care research.
The creation of the Agency for Health Care Policy and Research presents expanded opportunities for research in primary care. This paper discusses the grant review process and includes section-by-section suggestions for successful proposal writing. Applicants should choose topics of their own interest, be aware of the funding agency's priorities, pick co-investigators who complement their own backgrounds and training, and perform at least some preliminary study of the topic which can be discussed in a proposal. Successful grantsmanship also requires patience, perseverance, and flexibility because several attempts may be necessary to receive funding.


Transcriptome profiling of peanut gynophores revealed global reprogramming of gene expression during early pod development in darkness.
After the zygote divides few times, the development of peanut pre-globular embryo and fruit is arrested under white or red light. Embryo development could be resumed in dark condition after gynophore is buried in soil. It is interesting to study the mechanisms of gynophore development and pod formation in peanut. In this study, transcriptome analysis of peanut gynophore was performed using Illumina HiSeq™ 2000 to understand the mechanisms of geocarpy. More than 13 million short sequences were assembled into 72527 unigenes with average size of 394 bp. A large number of genes that were not identified previously in peanut EST projects were identified in this study, including most genes involved in plant circadian rhythm, intra-cellular transportation, plant spliceosome, eukaryotes basal transcription factors, genes encoding ribosomal proteins, brassinosteriod biosynthesis, light-harvesting chlorophyll protein complex, phenylpropanoid biosynthesis and TCA cycle. RNA-seq based gene expression profiling results showed that before and after gynophore soil penetration, the transcriptional level of a large number of genes changed significantly. Genes encoding key enzymes for hormone metabolism, signaling, photosynthesis, light signaling, cell division and growth, carbon and nitrogen metabolism as well as genes involved in stress responses were high lighted. Transcriptome analysis of peanut gynophore generated a large number of unigenes which provide useful information for gene cloning and expression study. Digital gene expression study suggested that gynophores experience global changes and reprogram from light to dark grown condition to resume embryo and fruit development.


Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study.
Doripenem is a new carbapenem that has broad-spectrum activity against bacterial pathogens commonly responsible for nosocomial pneumonia (NP). It has several advantages over currently available carbapenems and other classes of drugs used in this indication. This prospective, randomized, open-label, multicenter study was designed to establish whether doripenem was noninferior to piperacillin/tazobactam in NP. Adults (n=448) with signs and symptoms of NP, including non-ventilated patients and those ventilated for <5 days, were stratified by ventilation mode, illness severity (Acute Physiology and Chronic Health Evaluation II score), and geographic region and then randomly allocated to treatment with doripenem 500 mg every 8 h by a 1-h intravenous (IV) infusion or piperacillin/tazobactam 4.5 g every 6 h by 30-min IV infusion. After receiving IV study drug for at least 72 h, eligible patients could be switched to oral levofloxacin 750 mg once daily. Antibiotic therapy was continued for a total of 7-14 days. The primary endpoint was the clinical cure rate, assessed 7-14 days after treatment completion, in clinically evaluable patients and in the clinical modified intent-to-treat population (cMITT). ClinicalTrials.gov, NCT00211003. Doripenem was noninferior to piperacillin/tazobactam. Clinical cure rates in clinically evaluable patients (n=253) were 81.3% in the doripenem arm and 79.8% in the piperacillin/tazobactam arm (between-treatment difference: 1.5%; 95% confidence interval [CI], -9.1 to 12.1%) and in the cMITT population 69.5% and 64.1%, respectively, (between-treatment difference: 5.4%; 95% CI, -4.1 to 14.8%). Baseline resistance of Klebsiella pneumoniae and Pseudomonas aeruginosa to piperacillin/tazobactam was 44% and 26.9%, respectively; a doripenem minimum inhibitory concentration (MIC) >8 mug/mL occurred in 0% and 7.7%, respectively. Favorable microbiological outcome rates against Gram-negative pathogens were numerically higher with doripenem than with piperacillin/tazobactam, but the difference was not statistically significant. Both study drugs were generally well tolerated, as only 16.1% and 17.6% of patients receiving doripenem and piperacillin/tazobactam, respectively, had a drug-related adverse event. Study limitations included the open-label design, the low rate of monotherapy (adjunctive use of aminoglycoside was required when P. aeruginosa was suspected), and the exclusion of the most critically ill and immunocompromized patients. Doripenem was clinically and microbiologically effective in patents with NP, including those with early-onset ventilator-associated pneumonia, and was therapeutically noninferior to piperacillin/tazobactam.


[Silicone ureteral prostheses: results of an experimental study of tolerance and surface conditions over six years, and clinical use for four years (author's transl)].
Two main points of interest are discussed more particularly in this report. Results of the experimental use of spiral prostheses in dogs are presented, studies having been conducted for a period extending over nearly six years, this being longer than any known previous study on this type of prosthesis. Those carried out by the Rhone Poulenc Centre lasted for three years. In this series, four prosthesis were studied for 30 months and two for 70 months. At the same time, the results of the use of straight prostheses in humans over a period of 4 years are also analyzed. Furthermore, the experimental study included a relatively complete ultrastructural study of these prostheses after they had been in contact with the dog's urine for six years, the surface being examined by electron microscopy, and the resulting lipidic deposits analyzed biochemically. The data obtained is used in an attempt to respond to two questions concerning ureteral replacement by silicone prostheses: the effect on the silicone of contact with urine after 6 years, and the possible extension or restriction of use of theses prostheses in humans as a result of the information obtained. The conclusions reached are that the quality of these prostheses has been confirmed and that their valid conception permits continuing clinical application. The indications are limited, however, by reflux and the alterations, even though minimal, appearing on their surface. Lipidic deposits are visible both macroscopically and by electron microscopy, and these could be the starting point for calcaneous incrustation after longer periods of use. Indications should be presently restricted, therefore, to patients with neoplastic lesions.


Ketanserin in the treatment of hypertension: a multicentre dose-finding study in China.
The effect of ketanserin at 5 mg, 10 mg and 20 mg twice daily for 3 months was studied in Chinese patients with hypertension. Both 10 mg and 20 mg doses twice daily effectively reduced systolic and diastolic pressures, while 5 mg twice daily was not effective. The 20 mg regimen was more effective than 10 mg in reducing diastolic, but not systolic pressures. Blood pressure reduction was progressive up to 1 month of treatment but not thereafter. Neither first-dose hypotension nor postural hypotension were seen. There were no effects on body weight or heart rate. A nominally significant 6 msec increase in QTc was seen with 10 mg, but not with 5 or 20 mg twice daily; this could be a chance finding. The side-effect burden was light, and decreased with time.


A study protocol for a randomised controlled trial evaluating the use of information communication technology (WhatsApp/WeChat) to deliver brief motivational interviewing (i-BMI) in promoting smoking cessation among smokers with chronic diseases.
The recent development of smoking cessation interventions for smokers with chronic diseases has focused heavily on brief interventions. However, these interventions are too brief to make an impact on these smokers, especially when most of them are without any intention to quit. Previous studies showed that smokers who did not want to quit might be interested in changing other health behaviours. Also, once people engage in a health behaviour, they are found more likely to change other unhealthy habits. Hence, a general health promotion approach could be a feasible approach to motivate smokers who do not want to quit to first engage in any desirable health behaviour, and later quit smoking when they intend to do so. This study aims to determine the potential efficacy and effect size of such intervention approach in promoting smoking cessation for smokers with chronic diseases. This is a randomized controlled trial. A convenience sample of 60 smokers with chronic diseases will be randomly assigned into either experimental (n = 30) or control group (n = 30). Smokers in the experimental group will receive an individual face-to-face brief motivational interviewing (MI) with generic advice on selected health behaviour. More brief MI messages will be delivered to them via WhatsApp/WeChat for 6 months. For subject in the control group, they will be asked to indicate their desirable health-related practice. However, no MI and booster interventions will be given. All subjects will complete a questionnaire at 1, 3, 6 and 12 months. Subjects abstinent from cigarettes at 12 months will perform a biochemical validation. The primary outcome is biochemically validated smoking abstinence at 12 months. Effect size of the intervention will be estimated by the odd ratios using intention-to-treat. This is the first study to determine the potential efficacy for the use of a personalized general health promotion approach in promoting smoking cessation for smokers with chronic diseases. If our proposed intervention is effective, we will able to assist smokers with chronic disease to quit smoking and change their health behaviour simultaneously. CinicalTrials.gov NCT03983330 (Prospectively registered), registered on June 12, 2019.


Genome-wide plasma DNA methylation features of metastatic prostate cancer.
Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.


Enhanced angiogenesis following allogeneic blood transfusion.
Blood transfusions are associated with recurrence of solid cancers. Angiogenesis is essential for cancer growth. Our aim was to determine for the first time in a prospective cohort study the effect of prestorage allogeneic leucodepleted SAGM (saline, adenine, glucose, mannitol) red cell transfusion on angiogenic factor levels and in vitro angiogenesis. Forty pretransfusion adult hospital inpatients were selected consecutively. Serum vascular endothelial growth factor (VEGF) and endostatin were measured in each patient before and after prestorage allogeneic leucodepleted SAGM red cell transfusion. All samples were exposed to an in vitro endothelial cell proliferation assay and 10 sample groups were also exposed to an in vitro whole angiogenesis assay. The median number of units transfused was 2 (minimum-maximum, 2-4). Twenty-nine (73%) patients had a rise in VEGF, with an overall increase of 118 pg/ml (quartiles -5, 306; P < 0.01). Twenty-eight (70%) patients had a decrease in endostatin, with an overall reduction of 1.2 ng/ml (quartiles 4.0, 0.0; P = 0.017). There was an overall 33% increase in endothelial cell proliferation (P < 0.01) and a 9.4% increase in in vitro whole assay angiogenesis (P < 0.01). Prestorage allogeneic leucodepleted SAGM red cell transfusions are associated with a favourable angiogenic factor imbalance and an elevation in in vitro angiogenesis.


The parenting hub of the hypothalamus is a focus of imprinted gene action.
Imprinted genes are subject to germline epigenetic modification resulting in parental-specific allelic silencing. Although genomic imprinting is thought to be important for maternal behaviour, this idea is based on serendipitous findings from a small number of imprinted genes. Here, we undertook an unbiased systems biology approach, taking advantage of the recent delineation of specific neuronal populations responsible for controlling parental care, to test whether imprinted genes significantly converge to regulate parenting behaviour. Using single-cell RNA sequencing datasets, we identified a specific enrichment of imprinted gene expression in a recognised "parenting hub", the galanin-expressing neurons of the preoptic area. We tested the validity of linking enriched expression in these neurons to function by focusing on MAGE family member L2 (Magel2), an imprinted gene not previously linked to parenting behaviour. We confirmed expression of Magel2 in the preoptic area galanin expressing neurons. We then examined the parenting behaviour of Magel2-null(+/p) mice. Magel2-null mothers, fathers and virgin females demonstrated deficits in pup retrieval, nest building and pup-directed motivation, identifying a central role for this gene in parenting. Finally, we show that Magel2-null mothers and fathers have a significant reduction in POA galanin expressing cells, which in turn contributes to a reduced c-Fos response in the POA upon exposure to pups. Our findings identify a novel imprinted gene that impacts parenting behaviour and, moreover, demonstrates the utility of using single-cell RNA sequencing data to predict gene function from expression and in doing so here, have identified a purposeful role for genomic imprinting in mediating parental behaviour.


Waterpipe use and cognitive susceptibility to cigarette smoking among never-cigarette smoking Jordanian youth: analysis of the 2009 Global Youth Tobacco Survey.
Susceptibility to cigarette smoking, defined as lack of a firm decision to not initiate smoking, predicts youth smoking initiation and experimentation and is a first step in the transition to regular smoking. This study investigated whether waterpipe (WP) smoking, an increasingly prevalent form of tobacco use among Arab adolescents, was associated with increased susceptibility to cigarette smoking. A secondary analysis of the 2009 Jordan Global Youth Tobacco Survey was conducted to assess the association between WP use and cigarette susceptibility, after adjusting for important confounders. A total of 1,476 youth aged 13-15 years old who had never smoked cigarettes were identified and represented 166,593 never-cigarette smoking Jordanian youth. We found 40% of boys and 29% of girls were susceptible to cigarette smoking, and both boys (adjusted odds ratio [AOR] = 1.49, 95% confidence interval [CI] = 1.41-1.54) and girls (AOR = 1.95, 95% CI = 1.83-2.04) who had ever smoked WP were more susceptible to cigarette smoking than those who never smoked WP. This is the first study to report that WP use may increase youth's susceptibility to initiate cigarette smoking.


Initial data release and announcement of the 10,000 Fish Genomes Project (Fish10K).
With more than 30,000 species, fish-including bony, jawless, and cartilaginous fish-are the largest vertebrate group, and include some of the earliest vertebrates. Despite their critical roles in many ecosystems and human society, fish genomics lags behind work on birds and mammals. This severely limits our understanding of evolution and hinders progress on the conservation and sustainable utilization of fish. Here, we announce the Fish10K project, a portion of the Earth BioGenome Project aiming to sequence 10,000 representative fish genomes in a systematic fashion within 10 years, and we officially welcome collaborators to join this effort. As a step towards this goal, we herein describe a feasible workflow for the procurement and storage of biospecimens, as well as sequencing and assembly strategies. To illustrate, we present the genomes of 10 fish species from a cohort of 93 species chosen for technology development.


Words of power: personal empowerment and healing.
This paper examines instances of ritual use of words in a diverse selection of alternative healing groups in a modern society. These words are distinguished by their users' belief that they are endowed with a power, an effectiveness, separate from and in addition to their literal meaning. Three specific features of ritual language contribute to its effectiveness: (1) its function as an objectification of power, (2) its transformative functions--especially its metaphoric and metonymic usages, and (3) its performative aspects. This paper argues that one of the key factors in healing illness is mobilizing resources of power, especially enhancing the ill person's sense of personal empowerment. Ritual language use in alternative healing is one of the foremost elements in this empowerment, because it both represents and objectifies power. Within a belief system in which they are significant, words of power indeed have the power to effect healing.


Is suicide assessment harmful to participants? Findings from a randomized controlled trial.
There is considerable debate on whether suicide assessment carries an iatrogenic risk for participants/patients. A double-blind randomized controlled trial (registration: R000022314) tested the emotional impact of suicide assessment on participants (n = 259) randomly assigned to experimental (n = 122) or control conditions (n = 137). The experimental condition included the Suicidal Affect-Behavior-Cognition Scale and intensive death-related questions, the control condition a quality of life scale. Both included measures of depression, social support and loneliness. Affective states were assessed immediately before and after testing, and research biases minimized. Post-test debriefing interviews collected qualitative reactions. Experimental participants ranged from nonsuicidal to highly suicidal. Between-groups ANCOVAs and repeated measures ANOVAs showed no differences by study condition, and no pre-post-test affect changes for either condition or suicidal participants (P > 0.10), supporting the null hypothesis of no iatrogenic effects. However, depressive participants in both conditions showed significant decreases in positive affect (P < 0.05). Smallest real difference (SRD) scores approximated clinically meaningful differences and showed 20% of participants had a significant positive survey reaction, 24% a negative reaction, with the rest neutral. Linear regressions revealed depressive symptoms and perceived family support, but not suicidality or other factors, predicted negative affect changes, which was supported by qualitative findings. Social desirability bias was also found in qualitative survey responses. No evidence of iatrogenic effects of suicide assessment were found. Recommendations are made to counter possible negative assessment effects on depressive participants/patients, and nurses and other caregivers are encouraged to talk to patients about suicidal symptoms.


At low pH, influenza virus matrix protein M1 undergoes a conformational change prior to dissociating from the membrane.
The M1 matrix protein of influenza A virus, which plays multiple roles in virion assembly and infection, underlies the viral envelope. However, previous studies have given differing accounts of the number of layers in the M1-envelope complex and their thicknesses and compositions. To resolve this issue, we performed cryo-electron microscopy and cryo-electron tomography on the self-same specimens. At neutral pH, there were two kinds of complexes, corresponding to a lipid bilayer with embedded glycoproteins, with and without a closely associated, 4-nm-thick sheet of M1 protein. The reported discrepancies arose from differences in imaging conditions, i.e., in defocus and in whole-particle projections versus thin tomographic slices. Exposure of virions to low pH (as in the endosome) promotes membrane fusion, and previous work has shown that the M2 ion channel causes the virion interior to acidify also. We found that after 5 min at pH 4.9, the proportion of virions lacking an M1 layer increased from 10% to 50%. In virions retaining an M1 layer under these conditions, the M1-envelope complex exhibited two states, viz, the original, neutral-pH state and one in which the M1 layer appeared thinner and/or closer to the membrane. These observations extend previous indications that acidic pH causes the M1 layer to dissociate, leaving the envelope more pliable and, consequently, fusion compatible, and they show that dissociation is preceded by a conformational change in M1.