Social rejection shares somatosensory representations with physical pain.
How similar are the experiences of social rejection and physical pain? Extant research suggests that a network of brain regions that support the affective but not the sensory components of physical pain underlie both experiences. Here we demonstrate that when rejection is powerfully elicited--by having people who recently experienced an unwanted break-up view a photograph of their ex-partner as they think about being rejected--areas that support the sensory components of physical pain (secondary somatosensory cortex; dorsal posterior insula) become active. We demonstrate the overlap between social rejection and physical pain in these areas by comparing both conditions in the same individuals using functional MRI. We further demonstrate the specificity of the secondary somatosensory cortex and dorsal posterior insula activity to physical pain by comparing activated locations in our study with a database of over 500 published studies. Activation in these regions was highly diagnostic of physical pain, with positive predictive values up to 88%. These results give new meaning to the idea that rejection "hurts." They demonstrate that rejection and physical pain are similar not only in that they are both distressing--they share a common somatosensory representation as well.


Developing a core outcome set for fistulising perianal Crohn's disease.
Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores. A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study. The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care.


Maleimide-based acyclic enediyne for efficient DNA-cleavage and tumor cell suppression.
A pH-sensitive acyclic enediyne (1) was synthesized for efficient DNA-cleavage and tumor cell suppression. Unlike other acyclic enediynes, this novel enediyne transforms into a highly reactive enediyne (2) in an acidic environment only, which undergoes Bergman cyclization spontaneously at ambient temperature. An EPR study on the enediyne 2 confirmed the generation of free radicals through Bergman cyclization. The activated enediyne induced DNA-cleavage and exhibited cytotoxicity towards various tumor cells under the action of diradicals arising from spontaneous Bergman cyclization at physiological temperature. These findings suggest a novel strategy of anticancer drug design, where the activation of the silent compound takes place under the acidic environment inside the tumor cells.


High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy.
Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.


Sex- and lineage-specific inheritance of depression-like behavior in the rat.
The Wistar-Kyoto (WKY) rat exhibits physiological and behavioral similarities to endophenotypes of human depression. In the forced swim test (FST), a well-characterized antidepressant-reversible test for behavioral despair in rodents, WKYs express characteristics of behavioral despair; increased immobility, and decreased climbing. To map genetic loci linked to behavior in the FST, we conducted a quantitative trait loci (QTL) analysis of the segregating F2 generation of a WKY x Fisher 344 (F344) reciprocal intercross. Using linear-model-based genome scans to include covariate (sex or lineage)-by-QTL interaction effects, four significant QTL influencing climbing behavior were identified. In addition, we identified three, seven, and two suggestive QTL for climbing, immobility, and swimming, respectively. One of these loci was pleiotropic, affecting both immobility and climbing. As found in human linkage studies, several of these QTL showed sex- and/or lineage-dependent effects. A simultaneous search strategy identified three epistatic locus pairs for climbing. Multiple regression analysis was employed to characterize the joint contributions of these QTL and to clarify the sex- and lineage-dependent effects. As expected for complex traits, FST behavior is influenced by multiple QTL of small effect, each contributing 5%-10%, accounting for a total 10%-30% of the phenotypic variance. A number of loci mapped in this study share overlapping candidate regions with previously identified emotionality QTL in mice as well as with susceptibility loci recognized by linkage or genome scan analyses for major depression or bipolar disorder in humans. The presence of these loci across species suggests that these QTL may represent universal genetic factors contributing to mood disorders.


Genes and longevity: lessons from studies of centenarians.
In population studies of aging, the data on genetic markers are often collected for individuals from different age groups. The idea of such studies is to identify "longevity" or "frailty" genes by comparing the frequencies of genotypes in the oldest and in the younger groups of individuals. In this paper we discuss a new approach to the analysis of such data. This approach, based on the maximum likelihood method, combines data on genetic markers with survival information obtained from standard demographic life tables. This method allows us to evaluate survival characteristics for individuals carrying respective candidate genes. It can also be used in the estimation of the effects of allele-area and allele-allele interaction, either in the presence or absence of hidden heterogeneity. We apply this method to the analysis of Italian data on genetic markers for five autosomal loci and mitochondrial genomes. Then we discuss basic assumptions used in this analysis and directions of further research.


Discovering Event Structure in Continuous Narrative Perception and Memory.
During realistic, continuous perception, humans automatically segment experiences into discrete events. Using a novel model of cortical event dynamics, we investigate how cortical structures generate event representations during narrative perception and how these events are stored to and retrieved from memory. Our data-driven approach allows us to detect event boundaries as shifts between stable patterns of brain activity without relying on stimulus annotations and reveals a nested hierarchy from short events in sensory regions to long events in high-order areas (including angular gyrus and posterior medial cortex), which represent abstract, multimodal situation models. High-order event boundaries are coupled to increases in hippocampal activity, which predict pattern reinstatement during later free recall. These areas also show evidence of anticipatory reinstatement as subjects listen to a familiar narrative. Based on these results, we propose that brain activity is naturally structured into nested events, which form the basis of long-term memory representations.


Occupational justice-bridging theory and practice.
The evolving theory of occupational justice links the concept to social justice and to concerns for a justice of difference: a justice that recognizes occupational rights to inclusive participation in everyday occupations for all persons in society, regardless of age, ability, gender, social class, or other differences. The purpose of this descriptive paper is to inspire and empower health professionals to build a theoretical bridge to practice with an occupational justice lens. Using illustrations from a study of leisure and the use of everyday technology in the lives of very old people in Northern Sweden, the authors argue that an occupational justice lens may inspire and empower health professionals to engage in critical dialogue on occupational justice; use global thinking about occupation, health, justice, and the environment; and combine population and individualized approaches. The authors propose that taking these initiatives to bridge theory and practice will energize health professionals to enable inclusive participation in everyday occupations in diverse contexts.


Psychometric testing of the Skull Base Inventory health-related quality of life questionnaire in a multi-institutional study of patients undergoing open and endoscopic surgery.
The skull base inventory (SBI) was developed to better assess health-related quality of life (HR-QOL) in patients with anterior and central skull base neoplasms treated by endoscopic and open approaches. The primary objective of this study was to prospectively assess the psychometric properties of the SBI. This study is part of a multi-center study of patients undergoing endoscopic and open procedures completed between 2012 and 2018. Participants were eligible if they were over 18 years of age; had benign or malignant anterior, antero-lateral, or central skull base tumors; and required either an open or endoscopic skull base surgical approach. In order to assess the psychometric properties of the SBI, patients completed the instrument at six time points (preoperative, 2 weeks, 3 months, 6 months, 12 months postoperative). Patients also completed the Anterior Skull Base (ASB) questionnaire and the Sinonasal Outcome Test (SNOT-22) to allow comparison to the SBI. One hundred and eighty-seven patients were included across five centers, with 121 having an endoscopic procedure. Internal consistency (Cronbach's alpha = 0.95) and test-retest at 12 months and 12 months plus 2 weeks (intraclass correlation > 0.90) were excellent. Concurrent validity was demonstrated by very strong correlation between total SBI scores and ASB scores (r = 0.810 to 0.869, p < 0.001) and moderate correlation between nasal domain SBI scores and SNOT-22 scores (r = - 0.616 to - 0.738, p < 0.001). Convergent validity was demonstrated by moderate correlation between change in SBI scores and global QOL change (rs = 0.4942, p < 0.001). The minimally important clinical difference (global HR-QOL change of "a little better" or "a little worse") was 6.0. The SBI questionnaire is reliable and valid for patients treated by both endoscopic and open approaches and can be used for assessment of HR-QOL in these settings.


Planning for the control of pandemic influenza A (H1N1) in Los Angeles County and the United States.
Mathematical and computer models can provide guidance to public health officials by projecting the course of an epidemic and evaluating control measures. The authors built upon an existing collaboration between an academic research group and the Los Angeles County, California, Department of Public Health to plan for and respond to the first and subsequent years of pandemic influenza A (H1N1) circulation. The use of models allowed the authors to 1) project the timing and magnitude of the epidemic in Los Angeles County and the continental United States; 2) predict the effect of the influenza mass vaccination campaign that began in October 2009 on the spread of pandemic H1N1 in Los Angeles County and the continental United States; and 3) predict that a third wave of pandemic influenza in the winter or spring of 2010 was unlikely to occur. The close collaboration between modelers and public health officials during pandemic H1N1 spread in the fall of 2009 helped Los Angeles County officials develop a measured and appropriate response to the unfolding pandemic and establish reasonable goals for mitigation of pandemic H1N1.


Ethics and neuropsychiatric genetics: a review of major issues.
Advances in neuropsychiatric genetics hold great hopes for improved prevention, diagnosis and treatment. However, the power of genetic testing to identify individuals at increased risk for disorders and to convey information about relatives creates a set of complex ethical issues. Public attitudes are inevitably affected by the shadow of eugenics, with its history of distorting scientific findings to serve socio-political ends. Nonetheless, the growing availability of genetic tests means that more patients will seek genetic information and physicians must manage the process of informed consent to allow meaningful decisions. Patients should be helped to understand the often-limited predictive power of current knowledge, potential psychological impact, risks of stigma and discrimination and possible implications for family members. Decisions for predictive testing of children raise additional concerns, including distortions of family dynamics and negative effects on children's self-image; testing is best deferred until adulthood unless preventive interventions exist. Pharmacogenomic testing, part of personalized medicine, may bring collateral susceptibility information for which patients should be prepared. The implications of genetic findings for families raise the question of whether physicians have duties to inform family members of implications for their health. Finally, participation in research in neuropsychiatric genetics evokes a broad range of ethical concerns, including the contentious issue of the extent to which results should be returned to individual subjects. As genetic science becomes more widely applied, the public will become more sophisticated and will be likely to demand a greater role in determining social policy on these issues.


10 GHz, 1.1 ps optical pulse generation from a regeneratively mode-locked Yb fiber laser in the 1.1 μm band.
We report a 10 GHz harmonically and regeneratively mode-locked Yb fiber laser with a phase-locked loop (PLL) technique at 1.1 μm. Stable mode locking was achieved by optimizing the average dispersion of the fiber cavity to an anomalous dispersion to operate as a soliton laser. As a result, a 1.1 ps optical pulse with a timing jitter of 140 fs was successfully generated.


Prevalence and Genetic Diversity of Avipoxvirus in House Sparrows in Spain.
Avipoxvirus (APV) is a fairly common virus affecting birds that causes morbidity and mortality in wild and captive birds. We studied the prevalence of pox-like lesions and genetic diversity of APV in house sparrows (Passer domesticus) in natural, agricultural and urban areas in southern Spain in 2013 and 2014 and in central Spain for 8 months (2012-2013). Overall, 3.2% of 2,341 house sparrows visually examined in southern Spain had cutaneous lesions consistent with avian pox. A similar prevalence (3%) was found in 338 birds from central Spain. Prevalence was higher in hatch-year birds than in adults. We did not detect any clear spatial or temporal patterns of APV distribution. Molecular analyses of poxvirus-like lesions revealed that 63% of the samples were positive. Molecular and phylogenetic analyses of 29 DNA sequences from the fpv167 gene, detected two strains belonging to the canarypox clade (subclades B1 and B2) previously found in Spain. One of them appears predominant in Iberia and North Africa and shares 70% similarity to fowlpox and canarypox virus. This APV strain has been identified in a limited number of species in the Iberian Peninsula, Morocco and Hungary. The second one has a global distribution and has been found in numerous wild bird species around the world. To our knowledge, this represents the largest study of avian poxvirus disease in the broadly distributed house sparrow and strongly supports the findings that Avipox prevalence in this species in South and central Spain is moderate and the genetic diversity low.


Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: a placebo-controlled comparison of bupivacaine and ropivacaine.
We tested the hypothesis that local anesthetics instilled at the end of laparoscopic gynecologic procedures are able to prevent postoperative pain at wake-up and during the first 24 h. A total of 180 patients were randomly assigned into three groups to receive an intraperitoneal instillation of 20 mL of either bupivacaine 0.5% (Group B), ropivacaine 0.75% (Group R) or saline (Group S) at the end of surgery. All patients received analgesia with acetaminophen and ketoprofen IV infusions. Pain was assessed by using a 0-10 graded numerical scale (NS) every 5 min in the postanesthesia care unit and IV morphine was administered if NS was >4. Assessment of pain was continued every 4 h on the ward, and subcutaneous morphine was injected if needed to keep the NS score < 4. Postoperative nausea and vomiting (PONV) was rated on a 4-point scale. The morphine consumption at wake-up and over the first 24 h was significantly lower (P < 0.05) in Group B (mean, 0.92 mg at wake-up; 3.08 mg over 24 h) and in Group R (mean, 0.25 mg at wake-up; 0.69 mg over 24 h), than in Group S (mean, 4.18 mg at wake-up; 12.93 mg over 24 h). The morphine-sparing effect of ropivacaine was significantly greater than that of bupivacaine. Both local anesthetics were effective in the prevention of PONV. We concluded that local anesthetics should be instilled in all gynecologic patients at the end of all laparoscopic procedures. Local anesthetic instillation (ropivacaine rather than bupivacaine) at the end of laparoscopy prevents postoperative pain and dramatically decreases the need for morphine. This technique, compared with placebo, is safe, improves patient comfort, shortens the stay in the postoperative care unit and decreases nursing care in the ward.


Mutations in the mitochondrial ATP synthase gamma subunit suppress a slow-growth phenotype of yme1 yeast lacking mitochondrial DNA.
In Saccharomyces cerevisiae, inactivation of the nuclear gene YME1 causes several phenotypes associated with impairment of mitochondrial function. In addition to deficiencies in mitochondrial compartment integrity and respiratory growth, yme1 mutants grow extremely slowly in the absence of mitochondrial DNA. We have identified two genetic loci that, when mutated, act as dominant suppressors of the slow-growth phenotype of yme1 strains lacking mitochondrial DNA. These mutations only suppressed the slow-growth phenotype of yme1 strains lacking mitochondrial DNA and had no effect on other phenotypes associated with yme1 mutations. One allele of one linkage group had a collateral respiratory deficient phenotype that allowed the isolation of the wild-type gene. This suppressing mutation was in ATP3, a gene that encodes the gamma subunit of the mitochondrial ATP synthase. Recovery of two of the suppressing ATP3 alleles and subsequent sequence analysis placed the suppressing mutations at strictly conserved residues near the C terminus of Atp3p. Deletion of the ATP3 genomic locus resulted in an inability to utilize nonfermentable carbon sources. atp3 deletion strains lacking mitochondrial DNA grew slowly on glucose media but were not as compromised for growth as yme1 yeast lacking mitochondrial DNA.


Benchmarks for measurement of duplicate detection methods in nucleotide databases.
Duplication of information in databases is a major data quality challenge. The presence of duplicates, implying either redundancy or inconsistency, can have a range of impacts on the quality of analyses that use the data. To provide a sound basis for research on this issue in databases of nucleotide sequences, we have developed new, large-scale validated collections of duplicates, which can be used to test the effectiveness of duplicate detection methods. Previous collections were either designed primarily to test efficiency, or contained only a limited number of duplicates of limited kinds. To date, duplicate detection methods have been evaluated on separate, inconsistent benchmarks, leading to results that cannot be compared and, due to limitations of the benchmarks, of questionable generality. In this study, we present three nucleotide sequence database benchmarks, based on information drawn from a range of resources, including information derived from mapping to two data sections within the UniProt Knowledgebase (UniProtKB), UniProtKB/Swiss-Prot and UniProtKB/TrEMBL. Each benchmark has distinct characteristics. We quantify these characteristics and argue for their complementary value in evaluation. The benchmarks collectively contain a vast number of validated biological duplicates; the largest has nearly half a billion duplicate pairs (although this is probably only a tiny fraction of the total that is present). They are also the first benchmarks targeting the primary nucleotide databases. The records include the 21 most heavily studied organisms in molecular biology research. Our quantitative analysis shows that duplicates in the different benchmarks, and in different organisms, have different characteristics. It is thus unreliable to evaluate duplicate detection methods against any single benchmark. For example, the benchmark derived from UniProtKB/Swiss-Prot mappings identifies more diverse types of duplicates, showing the importance of expert curation, but is limited to coding sequences. Overall, these benchmarks form a resource that we believe will be of great value for development and evaluation of the duplicate detection or record linkage methods that are required to help maintain these essential resources. : https://bitbucket.org/biodbqual/benchmarks.


Predictors of disease severity and outcome of hospitalized renal transplant recipients with COVID-19 infection: a systematic review of a globally representative sample.
Introduction. COVID-19 presents a special challenge to the kidney transplant population.Methods. A systematic review of articles that examined COVID-19 in kidney transplant recipients was performed. Patients' demographics, clinical, laboratory and radiological presentations, immunosuppression modification, and COVID-19 specific management were abstracted and analyzed. COVID-19 severity was classified into mild, moderate, and severe. Disease outcome was classified by whether the patient was discharged, still hospitalized, or died.Results. 44 articles reporting individual data and 13 articles reporting aggregated data on 149 and 561 kidney transplant recipients respectively with COVID-19 from Asia, Europe and America fulfilled all inclusion and exclusion criteria. Among studies reporting case specific data, 76% of cases had severe disease. Compared to patients with mild/moderate disease, patients with severe disease had higher CRP, LDH, Ferritin, D-dimer and were more likely to have bilateral lung involvement at presentation and longer time since transplantation (P < 0.05 for all). Recipients' age, gender and comorbidities did not impact disease severity. Patients with severe disease had a more aggressive CNI reduction and more antiviral medications utilization. Outcome was reported on 145 cases, of those 34 (23%) died all with severe disease. Longer duration from transplant to disease diagnosis, hypoxia and higher LDH were associated with mortality (P < 0.05). Different immunosuppression reduction strategies, high dose parenteral corticosteroids use and various antiviral combinations did not demonstrate survival advantage. Similar finding was observed for studies reporting aggregated data.Conclusion. COVID-19 in kidney transplant patients is associated with high rate of disease severity and fatality. Higher LDH and longer time since transplantation predicted both disease severity and mortality. None of the COVID-19 specific treatment correlated with, or improved disease outcome in kidney transplant recipients.


What's in Your Nomogram? Personalized Prognostication of Verbal Memory Decline after Temporal Lobe Resection in Adults With Epilepsy.
This study aims to develop and externally validate models to predict the probability of postoperative verbal memory decline in adults following temporal lobe resection (TLR) for epilepsy using easily accessible preoperative clinical predictors. Multivariable models were developed to predict delayed verbal memory outcome on 3 commonly used measures: Rey Auditory Verbal Learning Test (RAVLT), and Logical Memory (LM), and Verbal Paired Associates (VPA) subtests from Wechsler Memory Scale-Third Edition. Using Harrell's step-down procedure for variable selection, models were developed in 359 adults who underwent TLR at Cleveland Clinic and validated in 290 adults at 1 of 5 epilepsy surgery centers in the United States or Canada. Twenty-nine percent of the development cohort and 26% of the validation cohort demonstrated significant decline on at least 1 verbal memory measure. Initial models had good-to-excellent predictive accuracy (calibration (c) statistic range = .77-.80) in identifying patients with memory decline; however, models slightly underestimated decline in the validation cohort. Model coefficients were updated using data from both cohorts to improve stability. The model for RAVLT included surgery side, baseline memory score, and hippocampal resection. The models for LM and VPA included surgery side, baseline score, and education. Updated model performance was good to excellent (RAVLT c = .81, LM c = .76, VPA c = .78). Model calibration was very good, indicating no systematic over- or under-estimation of risk. Nomograms are provided in 2 easy-to-use formats to assist clinicians in estimating the probability of verbal memory decline in adults considering TLR for treatment of epilepsy.


Ectopic ureters in male dogs: review of 16 clinical cases (1999-2007).
Ureteral ectopia is a well-described cause of urinary incontinence in female dogs, but this condition has not been completely characterized in male dogs. Sixteen male dogs with ectopic ureters were evaluated between Jan 1999 and Mar 2007. Male dogs were similar to female dogs with ectopic ureters in terms of breed, presenting complaint, age of onset, and bilateral nature of the ectopia. Diagnosis was made by expert interpretation of imaging techniques such as excretory urography and contrast-enhanced computed tomography (CT). Overall, 11 of 13 dogs that had surgical correction of ectopic ureters were incontinent preoperatively. Urinary continence was restored in 82% of those dogs.


Gender-related factors in the recruitment of physicians to the rural Northwest.
This study examines differences in the factors female and male physicians considered influential in their rural practice location choice and describes the practice arrangements that successfully recruited female physicians to rural areas. This cross-sectional study was based on a mailed survey of physicians successfully recruited between 1992 and 1999 to towns of 10,000 or less in six states in the Pacific Northwest. Responses from 77 men and 37 women (response rate 61%) indicated that women were more likely than men to have been influenced in making their practice choice by issues related to spouse or personal partner, flexible scheduling, family leave, availability of childcare, and the interpersonal aspects of recruitment. Commonly reported themes reflected the respondents' desire for flexibility regarding family issues and the value they placed on honesty during recruitment. It is very important in recruitment of both men and women to highlight the positive aspects of the community and to involve and assist the physician's spouse or partner. If they want to achieve a gender-balanced physician workforce, rural communities and practices recruiting physicians should place high priority on practice scheduling, spouse-partner, and interpersonal issues in the recruitment process.


Vertical transposition of the horizontal recti (Knapp procedure) for the treatment of double elevator palsy: effectiveness and long-term stability.
Full tendon width vertical transposition (Knapp procedure) of the horizontal recti is an established treatment for double elevator palsy (DEP) but the long-term stability of the surgical results have not been well studied. We undertook a retrospective study to determine the overall effectiveness of the Knapp procedure, the postoperative stability of alignment, and the influence of prior inferior rectus muscle recession (IRc) on the magnitude of correction. Nineteen patients with DEP underwent a Knapp procedure. Eight were corrected to within 5 delta of orthophoria, six were undercorrected, and five were overcorrected by at least 5 delta after a mean follow-up of 3 years (to last visit or to further surgical intervention). The average vertical correction was 37.5 delta in patients who underwent a prior IRc compared with 21.1 delta in patients with no prior IRc (p = < 0.0017). Over and undercorrections were more likely to occur in patients with prior IRc. Postoperative drift was towards increased effect in all patients. The seven patients with long-term (> 36 months) follow-up demonstrated an increased magnitude of correction (average = 12.6 delta) over an average follow-up of 76 months. The Knapp procedure had an increasing effect over time but the amount of vertical correction did not correlate with the size of the preoperative vertical deviation and was less predictable when a prior IRc had been performed.


The Qingdao Twin Registry: a focus on chronic disease research.
With the changing patterns of morbidity and mortality in China, noncommunicable chronic diseases have become the major threats to the health of the Chinese population. The causes of chronic diseases include genetic factors and behavioral risk factors such as the use of tobacco, alcohol, and other drugs, unhealthy dietary behaviors, and lack of physical activity. Twin studies offer a unique opportunity to disentangle the genetic and environmental risk and protective factors for chronic disease. The Qingdao Twin Registry (QTR) was initiated in 1998 as part of the National Chinese Twin Registry. Over 11,000 pairs of twins and multiples of all ages have been recruited into the registry. Several studies of physical and mental health are underway. Many of the adult twins have completed health and behavioral risk factor surveys, and the adolescent twins are participating in a study of gene-environment interactions in tobacco and alcohol use. Studies of the heritability of personality factors have been conducted. In 2002, Qingdao established the Qingdao Twin Health Promotion Association, a nonprofit organization that supports health services for twins and their parents, organizes special events and health-related activities for twins, and raises funds to conduct twin health examinations. The QTR will be a useful resource for future studies of population genetics in human health and disease.


Caffeine intake is associated with a lower risk of cognitive decline: a cohort study from Portugal.
Alzheimer's disease has emerged in recent decades as a major health problem and the role of lifestyles in the modulation of risk has been increasingly recognized. Recent epidemiological studies suggest a protective effect for caffeine intake in dementia. We aimed to quantify the association between caffeine dietary intake and cognitive decline, in a cohort of adults living in Porto. A cohort of 648 subjects aged > or =65 years was recruited between 1999-2003. Follow-up evaluation (2005-2008) was carried out on 58.2% of the eligible participants and 10.9% were deceased. Caffeine exposure in the year preceding baseline evaluation was assessed with a validated food frequency questionnaire. Cognitive evaluation consisted of baseline and follow-up Mini-Mental State Examination (MMSE). Cognitive decline was defined by a decrease > or =2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95%CI) estimates adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes were computed using Poisson regression. Caffeine intake (> 62 mg/day [3rd third] vs. < 22 mg/day [1st third]) was associated with a lower risk of cognitive decline in women (RR=0.49, 95%CI 0.24-0.97), but not significantly in men (RR=0.65, 95%CI 0.27-1.54). Our study confirms the negative association between caffeine and cognitive decline in women.


Bipolar Disorder Associated microRNA, miR-1908-5p, Regulates the Expression of Genes Functioning in Neuronal Glutamatergic Synapses.
Bipolar disorder (BD), characterized by recurrent mood swings between depression and mania, is a highly heritable and devastating mental illness with poorly defined pathophysiology. Recent genome-wide molecular genetic studies have identified several protein-coding genes and microRNAs (miRNAs) significantly associated with BD. Notably, some of the proteins expressed from BD-associated genes function in neuronal synapses, suggesting that abnormalities in synaptic function could be one of the key pathogenic mechanisms of BD. In contrast, however, the role of BD-associated miRNAs in disease pathogenesis remains largely unknown, mainly because of a lack of understanding about their target mRNAs and pathways in neurons. To address this problem, in this study, we focused on a recently identified BD-associated but uncharacterized miRNA, miR-1908-5p. We identified and validated its novel target genes including DLGAP4, GRIN1, STX1A, CLSTN1 and GRM4, which all function in neuronal glutamatergic synapses. Moreover, bioinformatic analyses of human brain expression profiles revealed that the expression levels of miR-1908-5p and its synaptic target genes show an inverse-correlation in many brain regions. In our preliminary experiments, the expression of miR-1908-5p was increased after chronic treatment with valproate but not lithium in control human neural progenitor cells. In contrast, it was decreased by valproate in neural progenitor cells derived from dermal fibroblasts of a BD subject. Together, our results provide new insights into the potential role of miR-1908-5p in the pathogenesis of BD and also propose a hypothesis that neuronal synapses could be a key converging pathway of some BD-associated protein-coding genes and miRNAs.


Bcl-2/E1B 19 kDa-interacting protein 3-like protein (Bnip3L) interacts with bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability.
We have previously reported on cloning of the human gene encoding Bcl-2/adenovirus E1B 19 kDa-interacting protein 3-like protein (Bnip3L) and its growth inhibitory effect on cancer cells. Here we show that Bnip3L contains a motif similar to the BH3 domain which is conserved in Bcl-2 family proteins as well as containing a membrane-anchoring domain, and that Bnip3L interacts with Bcl-2 and Bcl-xL. Immunofluorescence microscopy revealed that Bnip3L was localized in the mitochondria, when in the presence of the membrane-anchoring domain. Transient expression of Bnip3L induced apoptosis of Rat-1 and HeLa cells and mutational analysis revealed that the BH3 domain and the membrane-anchoring domain were required for Bnip3L to induce cell death. Addition of recombinant Bnip3L to isolated mitochondria induced membrane potential loss and cytochrome c release both of which have been suggested to be prerequisite for apoptotic cell death. These results suggest that Bnip3L is one of the BH3-containing pro-apoptotic proteins and that it targets the mitochondria when inducing apoptosis.


The Economic Cost of Physical Inactivity and Excess Weight in American Adults.
Physical inactivity and excess weight in American adults have reached epidemic levels. This article describes how cost data from previously conducted analyses in several states were used to quantify the costs of physical inactivity and excess weight among American adults. Medical and workers' compensation cost data on selected medical conditions were obtained from various health plans and state agencies in seven states. Productivity loss norms were obtained from published studies. The estimated financial burden which includes direct medical care, workers' compensation, and productivity loss costs among the seven states is $93.32 billion for physical inactivity and $94.33 billion for excess weight. The estimated nationwide cost of these risk factors is approximately $507 billion with projected costs exceeding $708 billion in 2008. Projected cost-savings of $31 billion per year could be realized with a 5% drop in these risk factors. The cost of physical inactivity and excess weight among American adults is significant. More research on best-of-class interventions to curtail the high prevalence of these risk factors is needed.


Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia.
Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients. To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were accepted. Contact was made with trial authors and industry. Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted independently by two review authors. Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.


Alpha-synuclein immunoreactive Lewy bodies and Lewy neurites in Parkinson's disease are detectable by an advanced silver-staining technique.
Immunostaining with anti-alpha-synuclein is used to detect Lewy bodies and Lewy neurites in cases of Parkinson's disease and related disorders. To prove that the result of a modern silver method is equivalent to that achieved with immunoreactions for alpha-synuclein, individual sections were successively processed using both methods. The silver-stained sections showed all of the immunoreactive Lewy bodies, and thin Lewy neurites were detected equally well by both techniques. The present study, therefore, points to the capabilities of a modern silver-staining method which is less time consuming and less expensive than immunocytochemical techniques.


Selection of Protein Kinase Inhibitors Based on Tumor Tissue Kinase Activity Profiles in Patients with Refractory Solid Malignancies: An Interventional Molecular Profiling Study.
Clinically applicable tools are needed for treatment selection and repurposing of available protein kinase inhibitors (PKIs) in patients with advanced solid tumors refractory to standard treatment.Using a tyrosine kinase peptide substrate microarray, observed inhibitory activity in vitro could not sufficiently predict clinical benefit of treatment with the selected PKI. This exploratory molecular profiling study determined the feasibility and benefit of the selection of protein kinase inhibitors (PKIs) based on kinase activity profiling in patients with refractory solid malignancies. Adult patients with biopsy-accessible refractory solid tumors were eligible. Per patient, the inhibitory potency of sunitinib, dasatinib, erlotinib, sorafenib, everolimus, and lapatinib was determined in tumor lysates from fresh biopsies using a tyrosine kinase peptide substrate microarray. The most active PKI in this in vitro assay was selected for treatment. Thirteen patients were enrolled in the feasibility part and underwent tumor biopsy. Of 12 patients in whom kinase activity profiling was performed, 11 started treatment with a selected PKI: dasatinib in 8, sunitinib in 2, and erlotinib in 1 patient(s). Eight patients were evaluable for response. One patient had stable disease (SD) >4 months on sunitinib; one patient had SD at 6 weeks but progressive disease (PD) at 12 weeks. The remaining patients had PD after 6 weeks of treatment. Kinase inhibition profiles of multiple PKIs can be reliably determined using fresh tumor biopsies from patients with refractory solid tumors. However, the current in vitro microarray selection approach insufficiently predicted clinical benefit of PKI treatment in these patients.


Intracellular fate of Mycobacterium avium: use of dual-label spectrofluorometry to investigate the influence of bacterial viability and opsonization on phagosomal pH and phagosome-lysosome interaction.
Mycobacterium avium is a facultative intracellular pathogen that can survive and replicate within macrophages. We tested the hypotheses that survival mechanisms may include alteration of phagosomal pH or inhibition of phagosome-lysosome fusion. M. avium was surface labeled with N-hydroxysuccinimidyl esters of carboxyfluorescein (CF) and rhodamine (Rho) to enable measurement of the pH of individual M. avium-containing phagosomes and the interactions of bacterium-containing phagosomes with labeled secondary lysosomes. CF fluorescence is pH sensitive, whereas Rho is pH insensitive; pH can be calculated from their fluorescence ratios. Surface labeling of M. avium did not affect viability in broth cultures or within J774, a murine macrophage-like cell line. By fluorescence spectroscopy, live M. avium was exposed to an environmental pH of approximately 5.7 at 6 h after phagocytosis, whereas similarly labeled Salmonella typhimurium, zymosan A, or heat-killed M. avium encountered an environmental pH of < 5.0. Video fluorescence and laser scanning confocal microscopy gave consistent pH results and demonstrated the heterogeneity of intracellular fate early in infection. pH became more homogeneous 6 h after infection. M. avium cells were coated with immunoglobulin G (IgG) or opsonized to investigate whether phagocytosis by the corresponding receptors would alter intracellular fate. Opsonized, unopsonized, and IgG-coated M. avium cells entered compartments of similar pH. Finally, the spatial distribution of intracellular bacteria and secondary lysosomes was compared. Only 18% of live fluorescent M. avium cells colocalized with fluorescent lysosomes, while 98% of heat-killed bacteria colocalized. Thus, both inhibition of phagosome-lysosome fusion and alteration of phagosomal pH may contribute to the intracellular survival of M. avium.


Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon's Syndrome of Unknown Cause.
The association that exists between livedo reticularis (LR) and stroke is known as Sneddon's syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.


Genome-wide analysis of the zebrafish ETS family identifies three genes required for hemangioblast differentiation or angiogenesis.
ETS domain transcription factors have been linked to hematopoiesis, vasculogenesis, and angiogenesis. However, their biological functions and the mechanisms of action, remain incompletely understood. Here, we have performed a systematic analysis of zebrafish ETS domain genes and identified 31 in the genome. Detailed gene expression profiling revealed that 12 of them are expressed in blood and endothelial precursors during embryonic development. Combined with a phylogenetic tree assay, this suggests that some of the coexpressed genes may have redundant or additive functions in these cells. Loss-of-function analysis of 3 of them, erg, fli1, and etsrp, demonstrated that erg and fli1 act cooperatively and are required for angiogenesis possibly via direct regulation of an endothelial cell junction molecule, VE-cadherin, whereas etsrp is essential for primitive myeloid/endothelial progenitors (hemangioblasts) in zebrafish. Taken together, these results provide a global view of the ETS genes in the zebrafish genome during embryogenesis and provide new insights on the functions and biology of erg, fli1, and etsrp, which could be applicable to higher vertebrates, including mice and humans.


Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: analysis from the North American Prodrome Longitudinal Study.
Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n=8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n=154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular.


Evaporation of liquid droplets of nano- and micro-meter size as a function of molecular mass and intermolecular interactions: experiments and molecular dynamics simulations.
Transport of heat to the surface of a liquid is a limiting step in the evaporation of liquids into an inert gas. Molecular dynamics (MD) simulations of a two component Lennard-Jones (LJ) fluid revealed two modes of energy transport from a vapour to an interface of an evaporating droplet of liquid. Heat is transported according to the equation of temperature diffusion, far from the droplet of radius R. The heat flux, in this region, is proportional to temperature gradient and heat conductivity in the vapour. However at some distance from the interface, Aλ, (where λ is the mean free path in the gas), the temperature has a discontinuity and heat is transported ballistically i.e. by direct individual collisions of gas molecules with the interface. This ballistic transport reduces the heat flux (and consequently the mass flux) by the factor R/(R + Aλ) in comparison to the flux obtained from temperature diffusion. Thus it slows down the evaporation of droplets of sizes R ∼ Aλ and smaller (practically for sizes from 103 nm down to 1 nm). We analyzed parameter A as a function of interactions between molecules and their masses. The rescaled parameter, A(kBTb/ε11)1/2, is a linear function of the ratio of the molecular mass of the liquid molecules to the molecular mass of the gas molecules, m1/m2 (for a series of chemically similar compounds). Here ε11 is the interaction parameter between molecules in the liquid (proportional to the enthalpy of evaporation) and Tb is the temperature of the gas in the bulk. We tested the predictions of MD simulations in experiments performed on droplets of ethylene glycol, diethylene glycol, triethylene glycol and tetraethylene glycol. They were suspended in an electrodynamic trap and evaporated into dry nitrogen gas. A changes from ∼1 (for ethylene glycol) to approximately 10 (for tetraethylene glycol) and has the same dependence on molecular parameters as obtained for the LJ fluid in MD simulations. The value of x = A(kBTb/ε11)1/2 is of the order of 1 (for water x = 1.8, glycerol x = 1, ethylene glycol x = 0.4, tetraethylene glycol x = 2.1 evaporating into dry nitrogen at room temperature and for Lennard-Jones fluids x = 2 for m1/m2 = 1 and low temperature).


Fake spawns and floating particles: a rebuttal of Karkarey et al. "Alternative reproductive tactics and inverse size-assortment in a high-density fish spawning aggregation".
Courtship and spawning behaviors of coral reef fishes are very complex, and sufficient sampling effort and proper methods are required to draw informed conclusions on their mating systems that are grounded in contemporary theories of mate choice and sexual selection. We reviewed the recent study by Karkarey et al. (BMC Ecol 17:10, 2017) on the spawning behavior of Squaretail coralgrouper (Plectropomus areolatus) from India and found no evidence to support their findings of alternative reproductive tactics, unique school-spawning involving a single male with multiple females, or inverse size-assortment. The study lacks scientific credibility due to a lack of rigor in the methodology used, misinterpretation of observed behaviors, misinterpretation of the literature, and insufficient data. Their approach led the authors to produce spurious results and profound, invalid conclusions that violate the most basic assumptions of mate choice and sexual selection theory as applied to mating systems in marine fishes.


Multifocal retroperitoneal sarcoma.
Introduction. Retroperitoneal sarcomas comprise a small proportion of all soft tissue sarcomas, and multiple factors influence their clinical behavior. Histopathological type and grade as well as complete surgical resection especially on the first operative attempt are well recognized as the main prognostic factors. Multifocality is another prognostic factor, which compromises therapy and finally makes prognosis worse due to multiple adverse implications. Case Presentation. A rare case of a 65-year-old male patient suffering from a multifocal retroperitoneal liposarcoma successfully treated in our hospital is presented herein. Discussion. Also, general considerations for these tumors are discussed, and especially multifocality is underlined as an ominous sign of retroperitoneal sarcomas behavior. Despite multifocality, once again complete surgical excision remains the mainstay of treatment of these patients, as long as further systemic and local therapies do not provide durable results.


Association of 25-hydroxyvitamin D deficiency with NT-pro BNP levels in patients with acute myocardial infarction: a cross-sectional analysis.
Nutritional vitamin D deficiency is an emerging risk factor for acute myocardial infarction (AMI) and heart failure. The association of 25-hydroxyvitamin D levels with N-terminal pro B-type natriuretic peptide (NT-proBNP), a robust prognostic marker for post-AMI mortality and heart failure, is unknown and could illuminate a potential pathway for adverse outcomes among post-AMI patients with 25-hydroxyvitamin D deficiency. In a cross-sectional analysis, we studied 238 AMI patients from 21 U.S. centers to test the association of nutritional vitamin D (25-hydroxyvitamin D [25(OH)D]) deficiency with NT-proBNP levels. Levels of 25(OH)D levels were categorized as normal (≥30 ng/mL), insufficient (>20 - <30 ng/mL), deficient (>10 - ≤20 ng/mL), or severely deficient (≤10 ng/mL). Low 25(OH)D levels were found in 95.7% of AMI patients. No significant trends for higher mean baseline log NT-proBNP levels in severely deficient (6.9 ± 1.3 pg/mL), deficient (6.9 ± 1.2 pg/mL), and insufficient (6.9 ± 0.9 pg/ml) groups were observed as compared with patients having normal (6.1 ± 1.7 pg/mL) levels, P = 0.17. Findings were similar in the subset of patients who had follow-up NT-proBNP levels drawn at one month. In multivariate regression modeling, after adjusting for multiple covariates, 25(OH)D was not associated with NT-proBNP. Potential associations between nutritional vitamin D deficiency and prognosis in the setting of AMI are unlikely to be mediated through NT-proBNP pathways. Future studies should examine other mechanisms, such as inflammation and vascular calcification, by which 25(OH)D deficiency could mediate adverse outcomes post-AMI.


Nutritional practices in very low birth weight infants: a national survey.
Significant efforts have been made to improve the nutritional support of very preterm infants. Large surveys may help to know the nutritional practices for preterm infants in neonatal units and identify if they are in line with the current guidelines. A multicentre nationwide web-based survey on clinical feeding practices in very low birth weight (VLBW) infants was conducted in tertiary neonatal hospitals that admit infants with a birth weight < 1,500 g and/or a gestational age of < 32 weeks. The questionnaire was completed by 53 units (response rate, 59%). Over 90% of the units surveyed start amino-acid administration immediately after birth and more than half use novel intravenous fish oil-based lipid emulsions. Enteral nutrition is started within 24 hours of birth in 65% of units and 86% of these are medium-sized or large. Feeding volumes are increased at a rate of 10-30 ml/kg/day in > 90% of units. Monitoring of serum phosphorus was measured more frequently than albumin (p = 0.009) or triglycerides (p = 0.037), but only 28% of centres regularly measure pre-albumin as a nutritional biomarker. Human milk fortification and iron supplementation, starting at four weeks of age, are almost universal. However, only 30% of units administer 800 IU/day of vitamin D. Nearly 50% of the units discharge infants on preterm formula. Most Spanish neonatology units use early amino-acid supplementation and over half use novel fish oil-based lipid emulsions. Post-discharge nutrition practices and vitamin administration vary greatly.


Preparation and Biocompatible Surface Modification of Redox Altered Cerium Oxide Nanoparticle Promising for Nanobiology and Medicine.
The biocompatible surface modification of metal oxide nanoparticles via surface functionalization technique has been used as an important tool in nanotechnology and medicine. In this report, we have prepared aqueous dispersible, trivalent metal ion (samarium)-doped cerium oxide nanoparticles (SmCNPs) as model redox altered CNPs of biological relevance. SmCNP surface modified with hydrophilic biocompatible (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl) triethoxysilane (MEEETES) were prepared using ammonia-induced ethylene glycol-assisted precipitation method and were characterized using a variety of complementary characterization techniques. The chemical interaction of functional moieties with the surface of doped nanoparticle was studied using powerful 13C cross polarization magic angle sample spinning nuclear magnetic resonance spectroscopy. The results demonstrated the production of the extremely small size MEEETES surface modified doped nanoparticles with significant reduction in aggregation compared to their unmodified state. Moreover, the functional moieties had strong chemical interaction with the surface of the doped nanoparticles. The biocompatible surface modification using MEEETES should also be extended to several other transition metal ion doped and co-doped CNPs for the production of aqueous dispersible redox altered CNPs that are promising for nanobiology and medicine.


Developing the High-Risk Drinking Scorecard Model in Korea.
This study aimed to develop a high-risk drinking scorecard using cross-sectional data from the 2014 Korea Community Health Survey. Data were collected from records for 149,592 subjects who had participated in the Korea Community Health Survey conducted from 2014. The scorecard model was developed using data mining, a scorecard and points to double the odds approach for weighted multiple logistic regression. This study found that there were many major influencing factors for high-risk drinkers which included gender, age, educational level, occupation, whether they received health check-ups, depressive symptoms, over-moderate physical activity, mental stress, smoking status, obese status, and regular breakfast. Men in their thirties to fifties had a high risk of being a drinker and the risks in office workers and sales workers were high. Those individuals who were current smokers had a higher risk of drinking. In the scorecard results, the highest score range was observed for gender, age, educational level, and smoking status, suggesting that these were the most important risk factors. A credit risk scorecard system can be applied to quantify the scoring method, not only to help the medical service provider to understand the meaning, but also to help the general public to understand the danger of high-risk drinking more easily.


Inducible T cell antigen 4-1BB. Analysis of expression and function.
4-1BB is an inducible receptor-like protein expressed in both cytolytic and Th cells. Optimal induction of 4-1BB mRNA in T cells required both PMA and ionomycin stimulation, indicating that protein kinase C activation and increases in intracellular Ca2+ were required for its expression. 4-1BB was categorized as an early activation gene since the protein synthesis inhibitor, cycloheximide, blocked the induction of 4-1BB mRNA. A rat mAb, 53A2, was generated against recombinant soluble 4-1BB and was used to characterize this molecule. 4-1BB is a 30-kDa glycoprotein and appears to exist as both a monomer and a 55-kDa dimer on the cell surface of a T cell clone. The 4-1BB protein may be post-translationally modified since its predicted backbone is 25 kDa. FACS analysis indicated that 4-1BB was inducible and expressed on the cell surface of activated splenic T cells and thymocytes. Cross-linking of 4-1BB on anti-CD3-stimulated T cells with 53A2 resulted in a dramatic enhancement of T cell proliferation. This suggests that 4-1BB may function as an accessory signaling molecule during T cell activation.


Air pollution and daily mortality in seven major cities of Korea, 1991-1997.
The relationship between ambient air pollution and daily mortality in seven major cities of Korea for the period 1991-1997 was examined. These cities account for half of the Korean population (about 22 million). The observed concentrations of sulfur dioxide (SO(2), mean=23.3 ppb), ozone (O(3), mean=23.7 ppb), and total suspended particulates (TSP, mean=77.9 microg/m(3)) during the study period were at levels below Korea's current ambient air quality standards. Generalized additive models were applied to allow for the highly flexible fitting of seasonal and long-term time trends in air pollution as well as nonlinear associations with weather variables, such as air temperature and relative humidity. In city-specific analyses, an increase of 50 ppb of SO(2) corresponded to 1-12% more deaths, given constant weather conditions. The risk of all-cause mortality was estimated to increase by 0.5-4%, with an increase in the 2-day moving average of TSP levels equal to 100 microg/m(3). In multipollutant models with pooled data, we found that the estimated risk of death by SO(2) was notably unaffected by adding the other two pollutants (TSP and O(3)) to the model and was statistically significant in various regression models. The rate ratio (RR) for SO(2) remained elevated, indicating an excess mortality of 3% 50 ppb (RR=1.03; 95% CI, 1.01-1.05). TSP's effect on mortality maintained its significance with O(3), but not with SO(2). This implies that there may be collinearity problems where TSP and SO(2) are included in the same model or that TSP may function less than SO(2) as a surrogate for fine particles in the ambient air of Korea. In conclusion, increased mortality was associated with air pollution at SO(2) levels below the current recommendation for air quality. Further research is needed to clarify the relationship between SO(2) and fine particles in Korea.


Metabolic Obesity Phenotypes and Risk of Breast Cancer in Postmenopausal Women.
Background: Obesity and the metabolic syndrome (MetS) have both been linked to increased risk of postmenopausal breast cancer; however, their relative contributions are poorly understood.Methods: We examined the association of metabolic phenotypes of obesity defined by presence of the MetS (yes and no) and body mass index (BMI; normal, overweight, obese) with risk of postmenopausal breast cancer in a prospective analysis of a cohort of postmenopausal women (n ∼ 21,000) with baseline measurements of blood glucose, triglycerides, HDL-cholesterol, blood pressure, waist circumference, and BMI. Women were classified into 6 metabolic obesity phenotypes according to their BMI (18.5-<25.0, 25.0-<30.0, ≥30.0 kg/m2) and presence of the MetS (≥3 of the following: waist circumference ≥88 cm, triglycerides ≥150 mg/dL, HDL-C <50 mg/dL, glucose ≥100 mg/dL, and systolic/diastolic blood pressure ≥130/85 mmHg or treatment for hypertension). HRs for incident breast cancer and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models.Results: Over 15 years of follow-up, 1,176 cases of invasive breast cancer were diagnosed. Obesity, regardless of metabolic health, was associated with increased risk of breast cancer. Being obese and metabolically unhealthy was associated with the highest risk: HR, 1.62; 95% CI, 1.33-1.96. These associations were stronger in women who had never used hormone therapy.Conclusions: Our findings suggest that both obesity and metabolic dysregulation are associated with breast cancer risk.Impact: Beyond BMI, metabolic health should be considered a clinically relevant and modifiable risk factor for breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1730-5. ©2017 AACR.


Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia.
Multiple sclerosis (MS) is an inflammatory CNS demyelinating disease in which remyelination largely fails. Transmembrane TNF (tmTNF) and TNF receptor 2 are important for remyelination in experimental MS models, but it is unknown whether soluble TNF (solTNF), a major proinflammatory factor, is involved in regeneration processes. Here, we investigated the specific contribution of solTNF to demyelination and remyelination in the cuprizone model. Treatment with XPro1595, a selective inhibitor of solTNF that crosses the intact blood-brain barrier (BBB), in cuprizone-fed mice did not prevent toxin-induced oligodendrocyte loss and demyelination, but it permitted profound early remyelination due to improved phagocytosis of myelin debris by CNS macrophages and prevented disease-associated decline in motor performance. The beneficial effects of XPro1595 were absent in TNF-deficient mice and replicated in tmTNF-knockin mice, showing that tmTNF is sufficient for the maintenance of myelin and neuroprotection. These findings demonstrate that solTNF inhibits remyelination and repair in a cuprizone demyelination model and suggest that local production of solTNF in the CNS might be one reason why remyelination fails in MS. These findings also suggest that disinhibition of remyelination by selective inhibitors of solTNF that cross the BBB might represent a promising approach for treatment in progressive MS.


Genetic dissociation of two behaviors associated with nicotine addiction: beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome.
Nicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption. To examine if these two processes rely on beta2-containing nicotinic receptors--beta2*nAChRs--we analyzed the behavior of mice lacking these receptors in the two situations. First, we showed that, in contrast to wild-type (WT) mice, beta2-knockout (beta2-/-) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, beta2-/- mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that beta2-/- mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the beta2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption. Taken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.


Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications.
Methicillin resistance in staphylococci is determined by mec, composed of 50 kb or more of DNA found only in methicillin-resistant strains. mec contains mecA, the gene for penicillin-binding protein 2a (PBP 2a); mecI and mecR1, regulatory genes controlling mecA expression; and numerous other elements and resistance determinants. A distinctive feature of methicillin resistance is its heterogeneous expression. Borderline resistance, a low-level type of resistance to methicillin exhibited by strains lacking mecA, is associated with modifications in native PBPs, beta-lactamase hyperproduction, or possibly a methicillinase. The resistance phenotype is influenced by numerous factors, including mec and beta-lactamase (bla) regulatory elements, fem factors, and yet to be identified chromosomal loci. The heterogeneous nature of methicillin resistance confounds susceptibility testing. Methodologies based on the detection of mecA are the most accurate. Vancomycin is the drug of choice for treatment of infection caused by methicillin-resistant strains. PBP 2a confers cross-resistance to most currently available beta-lactam antibiotics. Investigational agents that bind PBP 2a at low concentrations appear promising but have not been tested in humans. Alternatives to vancomycin are few due to the multiple drug resistances typical of methicillin-resistant staphylococci.


"Old dogs" and new skills: how clinician characteristics relate to motivational interviewing skills before, during, and after training.
The relationships between the occupational, educational, and verbal-cognitive characteristics of health care professionals and their motivational interviewing (MI) skills before, during, and after training were investigated. Fifty-eight community-based addiction clinicians (M = 42.1 years, SD = 10.0; 66% Female) were assessed prior to enrolling in a 2-day MI training workshop and being randomized to one of three post-workshop supervision programs: live supervision via tele-conferencing (TCS), standard tape-based supervision (Tape), or workshop training alone. Audiotaped sessions with clients were rated for MI skillfulness with the Motivational Interviewing Treatment Integrity (MITI) coding system v 2.0 at pre-workshop and 1, 8, and 20 weeks post-workshop. Correlation coefficients and generalized linear models were used to test the relationships between clinician characteristics and MI skill at each assessment point. Baseline MI skill levels were the most robust predictors of pre- and post-supervision performances. Clinician characteristics were associated with MI Spirit and reflective listening skill throughout training and moderated the effect of post-workshop supervision method on MI skill. TCS, which provided immediate feedback during practice sessions, was most effective for increasing MI Spirit and reflective listening among clinicians with no graduate degree and stronger vocabulary performances. Tape supervision was more effective for increasing these skills among clinicians with a graduate degree. Further, TCS and Tape were most likely to enhance MI Spirit among clinicians with low average to average verbal and abstract reasoning performances. Clinician attributes influence the effectiveness of methods used to promote the acquisition of evidence-based practices among community-based practitioners.


Keeping up with the neighbours--measuring the bystander response.
Ionising radiation can induce responses within non-exposed neighbouring (bystander) cells, which potentially have important implications on the estimates of risk at environmentally relevant doses. Using human skin fibroblasts (AG1522), a range of methods were used to investigate the nature of the signal(s) arising from the exposed cells. The signal(s) can be transmitted by direct cell-cell communication (investigated by using partial dish irradiations) or by medium-borne factors (a co-culture system where two monolayers share the same medium but only one monolayer is exposed to ionising radiation). CDKN1A was found to be up-regulated in both directly exposed and non-exposed cells. The data suggest that direct cell-cell communication dominates for these confluent cells, with medium-borne factors also contributing.


Interbirth intervals in wild baboons: Environmental predictors and hormonal correlates.
Interbirth intervals (IBIs) are a key metric of female reproductive success; understanding how they are regulated by environmental, social, and demographic factors can provide insight into sources of variance in female fitness. Using 36 years of reproductive data on 490 IBIs for 160 wild female baboons, we identified sources of variance in the duration of IBIs and of their component phases: postpartum amenorrhea (PPA), sexual cycling, and pregnancy. We also examined how body fat and fecal hormone concentrations varied during female IBIs. We found that IBIs tended to be shorter (reproduction was accelerated) when female traits and environmental variables promoted energy acquisition, but with different specific effects for different component phases of the IBI. We also found that females lost a substantial amount of body fat during PPA, indicating that PPA imposes accumulating energetic costs as it progresses. Prior to cycle resumption females began to regain body fat; body fat was stable across the cycling phase and increased throughout most of pregnancy. However, body fat scores per se were not associated with the duration of any of the component phases. Finally, we found that fecal glucocorticoid concentrations decreased as PPA progressed, suggesting a decline in energetic stress over this phase. Fecal progestogen and estrogen concentrations changed over time during sexual cycling; the direction of these changes depended on the phase of the sexual cycle (luteal versus early or late follicular phases). Our study lends insight into the energetic constraints on female primate reproduction, revealing how female environments, changes in body fat, and steroid hormone concentrations relate to IBI duration and to reproductive readiness.


The way things move: looking under the hood of molecular motor proteins.
The microtubule-based kinesin motors and actin-based myosin motors generate motions associated with intracellular trafficking, cell division, and muscle contraction. Early studies suggested that these molecular motors work by very different mechanisms. Recently, however, it has become clear that kinesin and myosin share a common core structure and convert energy from adenosine triphosphate into protein motion using a similar conformational change strategy. Many different types of mechanical amplifiers have evolved that operate in conjunction with the conserved core. This modular design has given rise to a remarkable diversity of kinesin and myosin motors whose motile properties are optimized for performing distinct biological functions.


Nanoscale structure of microvoids in a-Si:H: a first-principles study.
In this paper, we have studied the shape, size, and number density of atomic microvoids in hydrogenated amorphous silicon (a-Si:H). By jointly employing experimental infrared data and ab initio simulations, we propose a simple and effective hydrogenation scheme, which is capable of producing large atomistic models of a-Si:H for studying microvoids. Our results suggest that hydrogen atoms in the networks are distributed in sparse (or isolated) and clustered environments. For a-Si:H models with 9-14 at.% hydrogen, we find approximately 3-4 at.% of total hydrogen atoms are distributed in the isolated phase. The density of the clustered phase is found to be between 6-12 at.%, which appears to depend on the amount of hydrogen in the network. The calculation of radii of gyration of atomic microvoids shows that the diameter of the microvoids is distributed from 6 Å to 12 Å. A few hydrogen molecules have also been observed to form inside the microvoids in our study, the concentration of which is about 1 at.% relative to silicon atoms. A comparison of our results with those from small-angle x-ray scattering (SAXS), infrared (IR) absorption, nuclear magnetic resonance (NMR) and calorimetric studies are presented.


Comparative x-ray densitometry of bones from ovariectomized rats.
Comparative analysis of dual energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) with phantoms and rat bones showed that both are necessary to adequately quantitate ovariectomy induced bone changes, in vivo. Precision and accuracy analysis of a Hologic QDR 1000/W and a Stratec 960 QCT showed that the latter is a highly precise, modestly accurate device that is more suited to the analysis of small bones. Specifically, smaller error was achieved by threshold optimization for the QCT in the analysis of phantoms 1.04-9.6 mm in diameter, with precision comparable to or better than DXA. Additionally, the QCT measured significant differences between groups in proximal tibiae when DXA could not; and measured a larger difference between sham and ovariectomized controls which was suitable for analysis of the dose dependent effects of a pharmacological test compound, raloxifene. This may reflect the ability of the QCT to measure volumetric mineral density (VMD, mg/cc), compared to two dimensional analyses by DXA. However, QCT was not able to analyze vertebrae in vivo, a site of considerable clinical interest. Therefore, DXA is useful to analyze the axial skeleton in vivo, while the appendicular skeleton is better analyzed in vivo by QCT. By both techniques, a similar dose response was observed for raloxifene, with ED50 = 0.3 mg/kg for both axial and appendicular skeleton. Comparative analysis of rat L1-4 by the Hologic QDR 1000/W and Lunar DPXL showed 12-14% higher BMD and BMC values for the Hologic, which is the opposite relationship between these instruments to that observed clinically for this site.


Peyer's Patches in the Terminal Ileum in Ulcerative Colitis: Magnifying Endoscopic Findings.
Peyer's patches (PPs), a major component of the gut-associated lymphoid tissue, serve as important antigen entry sites in mucosal immunity. PPs may play a role in the extension of ulcerative colitis (UC) into the terminal ileum. We sought to clarify the magnified endoscopic findings of the PPs in the terminal ileum of UC patients. Eighteen UC patients underwent magnifying chromoendoscopy before initial treatment to evaluate the follicle-associated epithelium (FAE) on the PPs domes and the surrounding villi. In 8 UC patients, as in healthy controls, the PPs' domes were slightly elevated, covered with the regular FAE lining, and surrounded by dense and bulky villi; however, in 10 UC patients, the PPs' domes were irregular, and the surrounding villi were sparse and atrophic. These abnormal findings within the PPs were associated with minimal mucosal lesions but not with backwash ileitis; both electron microscopy and magnifying endoscopy confirmed that these lesions were reversible following remission with prednisolone-mesalazine therapy. Similar to Crohn's disease patients, UC patients commonly had abnormalities in the FAE on PPs' domes and the surrounding villi on magnifying endoscopy.


Structural Analysis of an Epitope Candidate of Triosephosphate Isomerase in Opisthorchis viverrini.
Opisthorchis viverrini, a parasitic trematode, was recategorized as a group 1 biological carcinogen because it causes opisthorchiasis, which may result in cholangiocarcinoma. A new strategy for controlling opisthorchiasis is needed because of issues such as drug resistance and reinfection. Triosephosphate isomerase (TIM), a key enzyme in energy metabolism, is regarded as a potential drug target and vaccine candidate against various pathogens. Here, we determined the crystal structures of wild-type and 3 variants of TIMs from O. viverrini (OvTIM) at high resolution. The unique tripeptide of parasite trematodes, the SAD motif, was located on the surface of OvTIM and contributed to forming a 310-helix of the following loop in a sequence-independent manner. Through thermal stability and structural analyses of OvTIM variants, we found that the SAD motif induced local structural alterations of the surface and was involved in the overall stability of OvTIM in a complementary manner with another parasite-specific residue, N115. Comparison of the surface characteristics between OvTIM and Homo sapiens TIM (HsTIM) and structure-based epitope prediction suggested that the SAD motif functions as an epitope.


Issues of informed consent for non-specialists conducting colorectal cancer screenings.
The United States is currently facing a physician shortage crisis including a lack of specialist providers. Due to this shortage of specialists, some primary care providers offer colorectal cancer screenings in communities with few gastroenterologists, especially in under-resourced areas such as rural regions of the United States. However, discrepancies in training and procedural outcomes raise concerns regarding informed consent for patients. Because osteopathic physicians play a critical role in addressing the physician shortage in these under-resourced communities, this commentary may be especially useful because they are likely to encounter these ethical complexities in their day-to-day practice.


Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers.
Pre-clinical studies suggest that the neurokinin-1 (NK1) receptor may modulate the response to opioids, with NK(1) inactivation leading to decreased opioid reinforcement, tolerance and withdrawal. Aprepitant is a selective NK1 antagonist currently marketed for clinical use as an anti-emetic. This 6-week in-patient study used a randomized, double-blind, double-dummy, within-subject, crossover design. Subjects (n = 8; 6 male/2 female) were healthy, adult volunteers who provided subjective and objective evidence of current prescription opioid abuse (without physical dependence) and underwent careful medical and psychiatric screening. Fifteen experimental conditions, consisting of one aprepitant dose (0, 40 and 200 mg, p.o. given as a 2-hour pre-treatment) in combination with one oxycodone dose [placebo, oral (20 and 40 mg/70 kg) and intranasal (15 and 30 mg/70 kg)], were examined. Sessions were conducted at least 48-hour apart and multi-dimensional measures were collected repeatedly throughout the 6-hour session duration. Oxycodone, by both routes of administration, produced significant dose-related effects on the predicted measures (e.g. subjective measures of abuse liability, respiratory depression and miosis). Pre-treatment with aprepitant (200 mg) significantly enhanced ratings of oxycodone subjective effects related to euphoria and liking and doubled the street value estimates for the highest test doses of oxycodone by both routes. Some objective measures (respiratory function, observer-rated opioid agonist effects) were similarly enhanced by pre-treatment with the highest dose of aprepitant. All dose combinations were safely tolerated. These findings are discussed in the context of the potential utility of NK1 antagonists in the treatment of opioid use disorders.


A multicenter, randomized, triple-masked, placebo-controlled trial of the effect of ambulatory continuous femoral nerve blocks on discharge-readiness following total knee arthroplasty in patients on general orthopaedic wards.
A continuous femoral nerve block (cFNB) involves the percutaneous insertion of a catheter adjacent to the femoral nerve, followed by a local anesthetic infusion, improving analgesia following total knee arthroplasty (TKA). Portable infusion pumps allow infusion continuation following hospital discharge, raising the possibility of decreasing hospitalization duration. We therefore used a multicenter, randomized, triple-masked, placebo-controlled study design to test the primary hypothesis that a 4-day ambulatory cFNB decreases the time until each of three predefined readiness-for-discharge criteria (adequate analgesia, independence from intravenous opioids, and ambulation 30m) are met following TKA compared with an overnight inpatient-only cFNB. Preoperatively, all patients received a cFNB with perineural ropivacaine 0.2% from surgery until the following morning, at which time they were randomized to either continue perineural ropivacaine (n=39) or switch to normal saline (n=38). Patients were discharged with their cFNB and portable infusion pump as early as postoperative day 3. Patients who were given 4 days of perineural ropivacaine attained all three criteria in a median (25th-75th percentiles) of 47 (29-69)h, compared with 62 (45-79)h for those of the control group (Estimated ratio=0.80, 95% confidence interval: 0.66-1.00; p=0.028). Compared with controls, patients randomized to ropivacaine met the discharge criterion for analgesia in 20 (0-38) versus 38 (15-64)h (p=0.009), and intravenous opioid independence in 21 (0-37) versus 33 (11-50)h (p=0.061). We conclude that a 4-day ambulatory cFNB decreases the time to reach three important discharge criteria by an estimated 20% following TKA compared with an overnight cFNB, primarily by improving analgesia.


Phospholipase A2 superfamily members play divergent roles after spinal cord injury.
Spinal cord injury (SCI) results in permanent loss of motor functions. A significant aspect of the tissue damage and functional loss may be preventable as it occurs, secondary to the trauma. We show that the phospholipase A(2) (PLA(2)) superfamily plays important roles in SCI. PLA(2) enzymes hydrolyze membrane glycerophospholipids to yield a free fatty acid and lysophospholipid. Some free fatty acids (arachidonic acid) give rise to eicosanoids that promote inflammation, while some lysophospholipids (lysophosphatidylcholine) cause demyelination. We show in a mouse model of SCI that two cytosolic forms [calcium-dependent PLA(2) group IVA (cPLA(2) GIVA) and calcium-independent PLA(2) group VIA (iPLA(2) GVIA)], and a secreted form [secreted PLA(2) group IIA (sPLA(2) GIIA)] are up-regulated. Using selective inhibitors and null mice, we show that these PLA(2)s play differing roles. cPLA(2) GIVA mediates protection, whereas sPLA(2) GIIA and, to a lesser extent, iPLA(2) GVIA are detrimental. Furthermore, completely blocking all three PLA(2)s worsens outcome, while the most beneficial effects are seen by partial inhibition of all three. The partial inhibitor enhances expression of cPLA(2) and mediates its beneficial effects via the prostaglandin EP1 receptor. These findings indicate that drugs that inhibit detrimental forms of PLA(2) (sPLA(2) and iPLA2) and up-regulate the protective form (cPLA2) may be useful for the treatment of SCI.


[Consensus of the Polish Society of Endocrinology. Presurgical somatostatin analogs therapy in acromegaly].
Consensus statement of the Polish Society of Endocrinology, regarding presurgical somatostatin analogs in acromegaly has been presented. It is suggested to administer depot somatostatin analog (Octreotide LAR at the dose 20 mg and then 30 mg or equivalent doses of Lanreotide Autogel 90/120 mg every 4 weeks) in order to normalize or suppress to a maximal extent GH and IGF-1 concentrations. The period of therapy in case of microadenoma would be at least 3 months (targets: biochemical improvement, reduced risk of disease's complications, perioperative risk reduction, inhibition of tumor growth). The period of therapy in case of macroadenoma would be at least 6 months, until maximal possible reduction of GH and IGF-1 concentrations (targets: tumor shrinkage, biochemical improvement, reduced risk of disease's complications, perioperative risk reduction). Using an uniform approach in a group, as numerous as possible, of treated patients would allow objective evaluation of long-term efficacy of the treatment.


A reclaiming process for solar cell silicon wafer surfaces.
The low yield of epoxy film and Si3N4 thin-film deposition is an important factor in semiconductor production. A new design system using a set of three lamination-shaped electrodes as a machining tool and micro electro-removal as a precision reclaiming process of the Si3N4 layer and epoxy film removal from silicon wafers of solar cells surface is presented. In the current experiment, the combination of the small thickness of the anode and cathodes corresponds to a higher removal rate for the thin films. The combination of the short length of the anode and cathodes combined with enough electric power produces fast electroremoval. A combination of the small edge radius of the anode and cathodes corresponds to a higher removal rate. A higher feed rate of silicon wafers of solar cells combined with enough electric power produces fast removal. A precise engineering technology constructed a clean production approach for the removal of surface microstructure layers from silicon wafers is to develop a mass production system for recycling defective or discarded silicon wafers from solar cells that can reduce pollution and lower cost.


Deregulation of the miR-222-ABCG2 regulatory module in tongue squamous cell carcinoma contributes to chemoresistance and enhanced migratory/invasive potential.
Chemoresistance is often associated with other clinical characteristics such as enhanced migratory/invasive potential. However, the correlation and underlying molecular mechanisms remain unclear. The aim of this study was to elucidate the function of the miR-222-ABCG2 pathway in the correlation between cisplatin (DDP) resistance and enhanced cell migration/invasion in tongue squamous cell carcinoma (TSCC). Using TSCC cell lines and primary cultures from TSCC cases, we first confirmed the correlation among DDP resistance (measured by IC50 values and ABCG2/ERCC1 expression), migratory/invasive potential (assessed by migration/invasion assays) and miR-222 expression. In TSCC cells, siRNA-mediated ABCG2 knockdown led to enhanced DDP responsiveness and reduced migratory/invasive potential, whereas ABCG2 overexpression induced DDP resistance and enhanced cell migration/invasion. Luciferase assays revealed that ABCG2 is a direct target of miR-222. In addition to reducing cell migration/invasion, functional analyses in TSCC cells indicated that miR-222 can reduce expression of the ABCG2 gene and enhance DDP responsiveness. However, co-transfection with ABCG2 cDNA restored both DDP resistance and migration/invasion. Moreover, miR-222 mimics and ABCG2 siRNA inhibited tumor growth and lung metastasis in vivo. Thus, our results verified that DDP resistance is correlated with enhanced migratory/invasive potential in TSCC. ABCG2 is a direct target of miR-222,and deregulation of the miR-222-ABCG2 regulatory module in TSCC contributes to both DDP resistance and enhanced migratory/invasive potential.


Bounded-depth threshold circuits for computer-assisted CT image classification.
We present a stochastic algorithm that computes threshold circuits designed to discriminate between two classes of computed tomography (CT) images. The algorithm employs a partition of training examples into several classes according to the average grey scale value of images. For each class, a sub-circuit is computed, where the first layer of the sub-circuit is calculated by a new combination of the Perceptron algorithm with a special type of simulated annealing. The algorithm is evaluated for the case of liver tissue classification. A depth-five threshold circuit (with pre-processing: depth-seven) is calculated from 400 positive (abnormal findings) and 400 negative (normal liver tissue) examples. The examples are of size n=14,161 (119 x 119) with an 8 bit grey scale. On test sets of 100 positive and 100 negative examples (all different from the learning set) we obtain a correct classification close to 99%. The total sequential run-time to compute a depth-five circuit is about 75h up to 230h on a SUN Ultra 5/360 workstation, depending on the width of the threshold circuit at depth-three. In our computational experiments, the depth-five circuits were calculated from three simultaneous runs for depth-four circuits. The classification of a single image is performed within a few seconds.


IGF1R Derived PI3K/AKT Signaling Maintains Growth in a Subset of Human T-Cell Acute Lymphoblastic Leukemias.
Insulin-like growth factor 1 receptor (IGF1R) is a prevalent signaling pathway in human cancer that supports cell growth/survival and thus contributes to aggressive biological behavior. Much work has gone into development of IGF1R inhibitors; however, candidate agents including small molecule tyrosine kinase inhibitors and blocking antibodies have yet to fulfill their promise clinically. Understanding cellular features that define sensitivity versus resistance are important for effective patient selection and anticipation of outgrowth of a resistant clone. We previously identified an important role for IGF signaling in T-cell acute lymphoblastic leukemia (T-ALL) relying primarily upon genetically defined mouse models. We present here an assessment of IGF1R dependence in human T-ALL using a broad panel of 27 established cell lines that capture a spectrum of the genetic variation that might be encountered in clinical practice. We observed that a subset of cell lines are sensitive to IGF1R inhibition and are characterized by high levels of surface IGF1R expression and PTEN positivity. Interestingly, lentiviral expression or knock-down of PTEN in PTEN-negative/positive cell lines, respectively, had limited effects on their response to IGF1R inhibition, suggesting that PTEN contributes to, but does not define IGF dependence. Additionally, we characterize downstream PI3K/AKT signaling as dominant over RAS/RAF/MEK/ERK in mediating growth and/or survival in this context. Finally, we demonstrate that IGF and interleukin-7 (IL-7) fulfill non-overlapping roles in supporting T-ALL growth. These findings are significant in that they reveal cellular features and downstream mechanisms that may determine the response of an individual patient's tumor to IGF1R inhibitor therapy.