Primary undifferentiated large cell carcinoma of the lacrimal gland.
To report a unique case of primary undifferentiated large cell carcinoma (LCCA) of the lacrimal gland, a tumor not previously described in the ophthalmic literature. Single interventional case report. A patient affected by undifferentiated LCCA of the lacrimal gland. A 65-year-old white man with a 3-month history of a painful mass in the left lacrimal gland fossa underwent an incisional biopsy that revealed a "high-grade" epithelial malignancy. Systemic workup revealed enlargement of the regional lymph nodes, and subsequently the patient underwent extended exenteration with clear histologic margins and radical neck lymphadenectomy followed by adjunctive radiotherapy. Fifteen months postoperatively, the patient is alive and well without evidence of local recurrence or metastatic disease. Treatment result, evidence of local recurrences or distant metastasis, and follow-up. Histologic examination revealed a poorly circumscribed tumor composed of large cells invading orbital fat, lateral rectus muscle, and peripheral nerves. The surrounding orbital bone was infiltrated, but the surgical margins were clear. The cell population was composed of large cells (>30 μm) with eosinophilic cytoplasm and ovoid and irregular nuclei containing a prominent nucleoli and coarse chromatin. The cell borders were well defined. Mitosis figures were abundant, and Ki-67 was positive in more than 60% of the cells. The cells were arranged in cords and trabeculae or irregular sheets of discohesive cells. The immunophenotype analysis showed positivity for cytokeratin but negative cytokeratin 20 stains, which is considered a distinctive feature of LCCA. Undifferentiated LCCAs are rare tumors of the major salivary glands, especially the parotid gland. Primary undifferentiated LCCA of the lacrimal gland has never been reported in the literature. Differential diagnosis must include a primary source in another organ. Given the aggressive nature of the tumor, radical surgery followed by radiotherapy is recommended, but evidence-based indications regarding the preferred line of treatment are lacking and the prognosis remains guarded. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Eye structure, activity rhythms, and visually-driven behavior are tuned to visual niche in ants.
Insects have evolved physiological adaptations and behavioral strategies that allow them to cope with a broad spectrum of environmental challenges and contribute to their evolutionary success. Visual performance plays a key role in this success. Correlates between life style and eye organization have been reported in various insect species. Yet, if and how visual ecology translates effectively into different visual discrimination and learning capabilities has been less explored. Here we report results from optical and behavioral analyses performed in two sympatric ant species, Formica cunicularia and Camponotus aethiops. We show that the former are diurnal while the latter are cathemeral. Accordingly, F. cunicularia workers present compound eyes with higher resolution, while C. aethiops workers exhibit eyes with lower resolution but higher sensitivity. The discrimination and learning of visual stimuli differs significantly between these species in controlled dual-choice experiments: discrimination learning of small-field visual stimuli is achieved by F. cunicularia but not by C. aethiops, while both species master the discrimination of large-field visual stimuli. Our work thus provides a paradigmatic example about how timing of foraging activities and visual environment match the organization of compound eyes and visually-driven behavior. This correspondence underlines the relevance of an ecological/evolutionary framework for analyses in behavioral neuroscience.


Plant evolution: TALES of development.
TALE homeodomain proteins regulate development in many eukaryotes. Now, Lee et al. (2008) report that two TALE homeodomain proteins control zygote development of the unicellular green alga Chlamydomonas. This implicates TALE gene loss and diversification in the evolution of new diploid body plans that appeared when land plants evolved from algal ancestors over 450 million years ago.


Demographics, Clinical Characteristics, Management, and Outcomes of Acute Heart Failure Patients: Observations from the Oman Acute Heart Failure Registry.
We sought to describe the demographics, clinical characteristics, management and outcomes of patients in Oman with acute heart failure (AHF) as part of the Gulf aCute heArt failuRe rEgistry (CARE) project. Data were analyzed from 988 consecutive patients admitted with AHF to 12 hospitals in Oman between 14 February and 14 November 2012. The mean age of our patients was 63±12 years. Over half (57%) were male and 95% were Omani citizens. Fifty-seven percent of patients presented with acute decompensated chronic heart failure (ADCHF) while 43% had new-onset AHF. The primary comorbid conditions were hypertension (72%), coronary artery disease (55%), and diabetes mellitus (53%). Ischemic heart disease (IHD), hypertensive heart disease, and idiopathic cardiomyopathy were the most common etiologies of AHF in Oman. The median left ventricular ejection fraction of the cohort was 36% (27-45%) with 56% of the patients having heart failure with reduced ejection fraction (< 40%). Atrial fibrillation was seen in 15% of patients. Acute coronary syndrome (ACS) and non-compliance with medications were the most common precipitating factors. At discharge, angiotensin converting enzyme inhibitors and beta-blockers were prescribed adequately, but aldosterone antagonists were under prescribed. Within 12-months follow-up, one in two patients were rehospitalized for AHF. In-hospital mortality was 7.1%, which doubled to 15.7% at three months and reached 26.4% at one-year post discharge. Oman CARE was the first prospective multicenter registry of AHF in Oman and showed that heart failure (HF) patients present at a younger age with recurrent ADCHF and HF with reduced ejection fraction. IHD was the most common etiology of HF with a low prevalence of AHF, but a high prevalence of acute coronary syndrome and non-compliance with medications precipitating HF. A quarter of patients died at one-year follow-up even though at discharge medical therapy was nearly optimal. Our study indicates an urgent need for prevention, early diagnosis, and treatment of AHF in Oman.


Cardiac surgery using a single thoracic port-current status and future directions.
Cardiac surgery is almost universally performed through a median sternotomy, an approach which is painful, unestethical, and prone to life-threatening infections. Minimally invasive cardiac surgery has tried to avoid problems associated with full sternotomy for many years. Recently, uniportal thoracic surgery was shown to be very advantageous when compared to standard thoracotomy and classical video assisted thoracic surgery (VATS). Despite very good results in lung surgery, cardiac surgery through a single thoracic port has rarely been attempted and successfully conducted. The authors present the rational, the technique, and their experience in cardiac single thoracic port surgery (CSTPS).


Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, -1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, -1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI. Bill & Melinda Gates Foundation.


Early career choices and successful career progression in surgery in the UK: prospective cohort studies.
Changes to the structure of medical training worldwide require doctors to decide on their career specialty at an increasingly early stage after graduation. We studied trends in career choices for surgery, and the eventual career destinations, of UK graduates who declared an early preference for surgery. Postal questionnaires were sent, at regular time intervals after qualification, to all medical qualifiers from all UK medical schools in selected qualification years between 1974 and 2005. They were sent in the first year after qualification, at year three and five years after qualification, and at longer time intervals thereafter. Responses were received from 27,749 of 38,280 doctors (73%) at year one, 23,468 of 33,151 (71%) at year three, and 17,689 of 24,870 (71%) at year five. Early career preferences showed that surgery has become more popular over the past two decades. Looking forward from early career choice, 60% of respondents (64% of men, 48% of women) with a first preference for a surgical specialty at year one eventually worked in surgery (p < 0.001 for the male-female comparison). Looking backward from eventual career destinations, 90% of responders working in surgery had originally specified a first choice for a surgical specialty at year one. 'Match' rates between eventual destinations and early choices were much higher for surgery than for other specialties. Considering factors that influenced early specialty choice 'a great deal', comparing aspiring surgeons and aspiring general practitioners (GPs), a significantly higher percentage who chose surgery than general practice specified enthusiasm for the specialty (73% vs. 53%), a particular teacher or department (34% vs. 12%), inclinations before medical school (20% vs. 11%), and future financial prospects (24% vs. 13%); and a lower percentage specified that hours and working conditions had influenced their choice (21% vs. 71%). Women choosing surgery were influenced less than men by their inclinations before medical school or by their future financial prospects. Surgery is a popular specialty choice in the UK. The great majority of doctors who progressed in a surgical career made an early and definitive decision to do so.


Aptamer-based electrochemical biosensor for interferon gamma detection.
In this paper, we describe the development of an electrochemical DNA aptamer-based biosensor for detection of interferon (IFN)-γ. A DNA hairpin containing IFN-γ-binding aptamer was thiolated, conjugated with methylene blue (MB) redox tag, and immobilized on a gold electrode by self-assembly. Binding of IFN-γ caused the aptamer hairpin to unfold, pushing MB redox molecules away from the electrode and decreasing electron-transfer efficiency. The change in redox current was quantified using square wave voltammetry (SWV) and was found to be highly sensitive to IFN-γ concentration. The limit of detection for optimized biosensor was 0.06 nM with linear response extending to 10 nM. This aptasensor was specific to IFN-γ in the presence of overabundant serum proteins. Importantly, the same aptasensor could be regenerated by disrupting aptamer-IFN-γ complex in urea buffer and reused multiple times. Unlike standard sandwich immunoassays, the aptasensor described here allowed one to detect IFN-γ binding directly without the need for multiple washing steps and reagents. An electrochemical biosensor for simple and sensitive detection of IFN-γ demonstrated in this paper will have future applications in immunology, cancer research, and infectious disease monitoring.


Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm.
Studies in many model systems have shown that canonical signaling through the pathway downstream of ligands of the Wnt family can regulate multiple steps in organogenesis, including cell proliferation, differentiation, and lineage specification. In addition, misexpression of the Wnt-family member Wingless in Drosophila imaginal disc cells can lead to transdetermination of progenitors from one lineage to another. Conditional deletion of the beta-catenin component of the Wnt signaling pathway has indicated a role for Wnt signaling in mouse lung endoderm development. The full range of effects of this pathway, which includes the transcription factor Lef1, has not been explored, however. To explore this issue, we expressed a constitutively active beta-catenin-Lef1 fusion protein in transgenic embryos using a lung-endoderm-specific promoter from the surfactant protein C gene. Transgenic lungs appeared grossly normal, but internally they contained highly proliferative, cuboidal epithelium lacking fully differentiated lung cell types. Unexpectedly, microarray analysis and in situ hybridization revealed a mosaic of cells expressing marker genes characteristic of intestinal Paneth and goblet cells and other non-lung secretory cell types. In addition, there was strong ectopic expression of genes such as Cdx1 and Atoh1 that normally regulate gut development and early allocation of cells to intestinal secretory lineages. Our results show that hyperactive Wnt signaling in lung progenitors expressing a lung-specific gene can induce a dramatic switch in lineage commitment and the generation of intestinal cell types. We discuss the relevance of our findings to the poorly understood pathological condition of intestinal metaplasia in humans.


Changes in exposure to secondhand smoke among youth in Nebraska, 2002-2006.
Secondhand smoke is a major cause of morbidity and mortality. It has been associated with serious health problems in both children and adults. Efforts to reduce exposure to secondhand smoke in Nebraska have included programs to prevent tobacco use among young people and campaigns for smoke-free workplaces and homes. Despite these interventions, young people continue to be exposed to secondhand smoke at an unacceptably high rate. The objective of this study was to examine the extent to which Nebraska public middle and high school students were exposed to secondhand smoke in 2002 and 2006, to evaluate factors associated with this exposure, and to propose interventions. The Nebraska Youth Tobacco Survey was administered in 2002 and 2006 to a representative sample of students from public middle and high schools. All students who chose to participate completed an anonymous, self-administered survey that included questions on demographics, tobacco use, tobacco-related knowledge and attitudes, and exposure to secondhand smoke. Data were weighted to account for nonresponses at both student and school levels and to ensure generalizability of the estimates for public school students in Nebraska according to their grade, sex, and race/ethnicity. This study analyzed a subset of responses on secondhand smoke exposure, which was defined as being in a room or vehicle during the previous 7 days with someone who was smoking cigarettes. Secondhand smoke exposure in a room, a vehicle, or both declined significantly among all students from 2002 (69.0%) to 2006 (61.3%). In both 2002 and 2006, students were significantly more likely to be exposed to secondhand smoke in a room than in a vehicle (64.4% vs 48.2% in 2002 and 56.9% vs 40.2% in 2006). Among racial and ethnic groups, only white students experienced a significant decline in exposure from 2002 (70.0%) to 2006 (61.4%). Girls were significantly more likely to be exposed to secondhand smoke in 2006 than were boys, and only boys experienced a significant overall decline in exposure from 2002 (69.3%) to 2006 (57.7%). Smoking behaviors and attitudes continued to influence secondhand smoke exposure from 2002 to 2006, although students experienced significant declines whether they were smokers or nonsmokers, and whether they lived with a smoker or not. Those with close friends who smoked and those who did not perceive secondhand smoke as harmful, however, did not benefit. These data indicate reductions in exposure to secondhand smoke among Nebraska's middle and high school students, but exposure remains a problem, particularly in rooms. Adoption of a comprehensive statewide smoke-free policy will contribute to significantly reduced exposure to secondhand smoke among young people in public places, but other measures to address exposure in the home and private vehicles are needed or should be strengthened. These include physician counseling based on behavioral change theory to encourage cessation and home-based no-smoking rules, in addition to interventions that target minorities, who are disproportionately affected by secondhand smoke exposure. Evaluation of existing measures, such as programs to prevent tobacco use among young people and campaigns to collect pledges for smoke-free homes, will be required to determine their effectiveness in reducing exposure to secondhand smoke among youth in Nebraska.


Examining Practitioner Competencies, Organizational Support and Barriers to Engaging Fathers in Parenting Interventions.
Evidence-based parenting interventions have been developed and evaluated largely with mothers. This study examined practitioner reports of rates of father attendance, barriers to engagement, organizational support for father-inclusive practice, participation in training in father engagement, and competencies in working with fathers. It also explored predictors of practitioner competence and rates of father attendance. Practitioners (N = 210) who delivered parenting interventions completed an online survey. Participants reported high levels of confidence in engaging fathers, but only one in three had participated in training and levels of father attendance in parenting interventions were low. Logistic regressions showed that high levels of practitioner competence were predicted by participation in training. Moderate levels of father attendance (vs. low levels) were predicted by greater number of years of experience while high levels of attendance (vs. low levels) were predicted by greater experience, higher levels of competence and higher levels of organizational support. The implications of the findings to informing policy and practice for enhancing father engagement are discussed.


Nimbus-7 coastal zone color scanner: system description and initial imagery.
The Coastal Zone Color Scanner (CZCS) on Nimbus-7, launched in October 1978, is the only sensor in orbit that is specifically designed to study living marine resources. The initial imagery confirms that CZCS data can be processed to a level that reveals subtle variations in the concentration of phytoplankton pigments. This development has potential applications for the study of large-scale patchiness in phytoplankton distributions, the evolution of spring blooms, water mass boundaries, and mesoscale circulation patterns.


Falcotentorial meningiomas: clinical, neuroimaging, and surgical features in six patients.
Meningiomas arising from the falcotentorial junction are rare. As a result, their clinical presentation and surgical management are not well described. During the past 3 years, the authors have treated six patients with falcotentorial meningiomas. Most patients presented with symptoms related to raised intracranial pressure, including headaches, papilledema, and visual and gait disturbances. Magnetic resonance imaging revealed a smooth, oval, or round mass, which was typically homogeneously enhancing. Angiography was useful in evaluating arterial supply for embolization, when possible, and determining the status of venous collateral supply and sinus patency. The authors detail the surgical technique used in all six patients. Postoperatively, patients experienced transient cortical blindness, which in all cases spontaneously resolved during the course of several days to weeks. They provide a comprehensive description of the presentation and surgical management of falcotentorial meningiomas. An excellent outcome can be expected when surgery is predicated on detailed preoperative neuroimaging and knowledge of the nuances of the surgical technique.


A randomized controlled trial of continuous labor support for middle-class couples: effect on cesarean delivery rates.
Previous randomized controlled studies in several different settings demonstrated the positive effects of continuous labor support by an experienced woman (doula) for low-income women laboring without the support of family members. The objective of this randomized controlled trial was to examine the perinatal effects of doula support for nulliparous middle-income women accompanied by a male partner during labor and delivery. Nulliparous women in the third trimester of an uncomplicated pregnancy were enrolled at childbirth education classes in Cleveland, Ohio, from 1988 through 1992. Of the 686 prenatal women recruited, 420 met enrollment criteria and completed the intervention. For the 224 women randomly assigned to the experimental group, a doula arrived shortly after hospital admission and remained throughout labor and delivery. Doula support included close physical proximity, touch, and eye contact with the laboring woman, and teaching, reassurance, and encouragement of the woman and her male partner. The doula group had a significantly lower cesarean delivery rate than the control group (13.4% vs 25.0%, p = 0.002), and fewer women in the doula group received epidural analgesia (64.7% vs 76.0%, p = 0.008). Among women with induced labor, those supported by a doula had a lower rate of cesarean delivery than those in the control group (12.5% vs 58.8%, p = 0.007). On questionnaires the day after delivery, 100 percent of couples with doula support rated their experience with the doula positively. For middle-class women laboring with the support of their male partner, the continuous presence of a doula during labor significantly decreased the likelihood of cesarean delivery and reduced the need for epidural analgesia. Women and their male partners were unequivocal in their positive opinions about laboring with the support of a doula.


Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility.
Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature. Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.


Multivitamin and mineral use and breast cancer mortality in older women with invasive breast cancer in the women's health initiative.
Multivitamin use is common in the United States. It is not known whether multivitamins with minerals supplements (MVM) used by women already diagnosed with invasive breast cancer would affect their breast cancer mortality risk. To determine prospectively the effects of MVM use on breast cancer mortality in postmenopausal women diagnosed with invasive breast cancer, a prospective cohort study was conducted of 7,728 women aged 50-79 at enrollment in the women's health initiative (WHI) in 40 clinical sites across the United States diagnosed with incident invasive breast cancer during WHI and followed for a mean of 7.1 years after breast cancer diagnosis. Use of MVM supplements was assessed at WHI baseline visit and at visit closest to breast cancer diagnosis, obtained from vitamin pill bottles brought to clinic visit. Outcome was breast cancer mortality. Hazard ratios and 95 % confidence intervals (CIs) for breast cancer mortality comparing MVM users to non-users were estimated using Cox proportional hazard regression models. Analyses using propensity to take MVM were done to adjust for potential differences in characteristics of MVM users versus non-users. At baseline, 37.8 % of women reported MVM use. After mean post-diagnosis follow-up of 7.1 ± 4.1 (SD) years, there were 518 (6.7 %) deaths from breast cancer. In adjusted analyses, breast cancer mortality was 30 % lower in MVM users as compared to non-users (HR = 0.70; 95 % CI 0.55, 0.91). This association was highly robust and persisted after multiple adjustments for potential confounding variables and in propensity score matched analysis (HR = 0.76; 95 % CI 0.60-0.96). Postmenopausal women with invasive breast cancer using MVM had lower breast cancer mortality than non-users. The results suggest a possible role for daily MVM use in attenuating breast cancer mortality in women with invasive breast cancer but the findings require confirmation.


Effect of Clotting Duration and Temperature on BDNF Measurement in Human Serum.
Brain-derived neurothrophic factor (BDNF) is a neurotrophin expressed in different tissues and cells, including neurons, endothelial cells, leukocytes, megakaryocytes and platelets. Modifications of BDNF in plasma and/or in serum are associated with neurodegenerative and psychiatric disorders, cardiovascular diseases, metabolic syndrome and with mortality risk. Indeed, changes in blood levels of BDNF may reflect those of its tissue of origin and/or promote pathological dysfunctions. The measurement of BDNF amount in plasma or in serum has been characterized with particular attention in the impact of different anti-coagulants, clotting duration, temperature (≤21 °C) and delay in blood sample centrifugation as well as in stability of storage. However, the influences of normothermic conditions (37 °C) and of clotting duration on BDNF levels in human serum have not been investigated yet. Here, we showed that time and temperature during serum preparation could be taken into consideration to assess the association and/or impact of BDNF levels in the occurrence of pathological conditions.


Abl tyrosine kinase phosphorylates nonmuscle Myosin light chain kinase to regulate endothelial barrier function.
Nonmuscle myosin light chain kinase (nmMLCK), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-Abl-mediated nmMLCK phosphorylation sites by mass spectroscopy analysis (including Y231, Y464, Y556, Y846) and examined their influence on nmMLCK function and human lung endothelial cell (EC) barrier regulation. Tyrosine phosphorylation of nmMLCK increased kinase activity, reversed nmMLCK-mediated inhibition of Arp2/3-mediated actin polymerization, and enhanced binding to the critical actin-binding phosphotyrosine protein, cortactin. EC challenge with sphingosine 1-phosphate (S1P), a potent barrier-enhancing agonist, resulted in c-Abl and phosphorylated nmMLCK recruitment into caveolin-enriched microdomains, rapid increases in Abl kinase activity, and spatial targeting of c-Abl to barrier-promoting cortical actin structures. Conversely, reduced c-Abl expression in EC (siRNA) markedly attenuated S1P-mediated cortical actin formation, reduced the EC modulus of elasticity (assessed by atomic force microscopy), reduced nmMLCK and cortactin tyrosine phosphorylation, and attenuated S1P-mediated barrier enhancement. These studies indicate an essential role for Abl kinase in vascular barrier regulation via posttranslational modification of nmMLCK and strongly support c-Abl-cortactin-nmMLCK interaction as a novel determinant of cortical actin-based cytoskeletal rearrangement critical to S1P-mediated EC barrier enhancement.


Conduct disorder among adolescent alcohol and drug abusers.
Delinquent behavior is prevalent among adolescents who abuse alcohol and other drugs. The present study examined the extent to which conduct disorder type behavior predates substance use involvement among 166 adolescents in treatment for alcohol and other drug abuse, and the prognostic significance of conduct disorder behaviors for the clinical course of teens during the first 2 years following treatment. This was prospective longitudinal study of 166 alcohol and other drug abusing adolescents, 67 girls and 99 boys, averaging 15.9 years of age. Consecutive admissions were recruited from two adolescent inpatient alcohol and drug treatment facilities. Subjects were interviewed during treatment and again at 6 months and 1 and 2 years posttreatment. Whereas the vast majority (95%) of teens entering alcohol and drug abuse treatment programs displayed a history of conduct disorder type behavior, only 47% met DSM-III-R criteria when behaviors directly or indirectly related to alcohol and drug involvement were excluded. Boys displayed a greater number of conduct disorder behaviors than girls, but the relative incidence of these behaviors was comparable across sexes. A history of conduct disorder independent of alcohol and drug involvement was related to both greater posttreatment alcohol involvement and a later diagnosis of antisocial personality disorder. This study shows that a significant portion of the delinquent behaviors found in adolescents treated for alcohol and drug abuse is secondary to involvement with alcohol and other drugs. A primary diagnosis of conduct disorder was found to be associated with poorer clinical course in the first 2 years following treatment.


From singing to speaking: facilitating recovery from nonfluent aphasia.
It has been reported for more than 100 years that patients with severe nonfluent aphasia are better at singing lyrics than they are at speaking the same words. This observation led to the development of melodic intonation therapy (MIT). However, the efficacy of this therapy has yet to be substantiated in a randomized controlled trial. Furthermore, its underlying neural mechanisms remain unclear. The two unique components of MIT are the intonation of words and simple phrases using a melodic contour that follows the prosody of speech and the rhythmic tapping of the left hand that accompanies the production of each syllable and serves as a catalyst for fluency. Research has shown that both components are capable of engaging fronto-temporal regions in the right hemisphere, thereby making MIT particularly well suited for patients with large left hemisphere lesions who also suffer from nonfluent aphasia. Recovery from aphasia can happen in two ways: either through the recruitment of perilesional brain regions in the affected hemisphere, with variable recruitment of right-hemispheric regions if the lesion is small, or through the recruitment of homologous language and speech-motor regions in the unaffected hemisphere if the lesion of the affected hemisphere is extensive. Treatment-associated neural changes in patients undergoing MIT indicate that the unique engagement of right-hemispheric structures (e.g., the superior temporal lobe, primary sensorimotor, premotor and inferior frontal gyrus regions) and changes in the connections across these brain regions may be responsible for its therapeutic effect.


Midlife Cognitive Ability, Education, and Tooth Loss in Older Danes.
To examine the possible influence of cognitive ability and education at age 50 or 60 on number of teeth at age 70. Community-dwelling population in Copenhagen, Denmark. Men and women born in 1914 (N = 302). Cognitive ability was assessed using the Wechsler Adult Intelligence Scale at age 50 or 60. A global cognitive ability measure was used as a continuous measure and according to tertile. Information on education was gathered using a questionnaire at age 50 or 60. A clinical oral examination took place at age 70, and oral health was measured according to number of teeth (<6 vs ≥6). Baseline covariates were smoking, alcohol, sex, and income. Logistic regression analyses revealed that greater cognitive ability and educational attainment had a protective effect against risk of tooth loss. The associations were significant and persisted after adjusting for confounders and a two-way interaction between cognitive ability and education. Higher education level and cognitive ability measured at age 50 or 60 were associated with having more teeth at age 70. Whether these findings are due to the interaction of these factors with oral health, related socioeconomic factors, or other factors remains to be studied.


Parental decision-making in congenital heart disease.
To explore whether prenatal diagnosis of congenital heart disease is associated with lower levels of parental distress and greater satisfaction with decisions about cardiothoracic surgery when compared to postnatal diagnosis. A combined quantitative-qualitative design was used. Participants included the parents of 31 neonates (30 mothers and 22 fathers) admitted to the cardiac intensive care unit between 1 November 2001 and 1 May 2002 for repair of congenital cardiac malformations. Participants completed self-report measures of anxiety, optimism, and life events pre-operatively, and semi-structured qualitative interviews assessing satisfaction with decision-making within 1 week of the operation. At the time of surgery, mothers of neonates receiving the diagnosis prenatally did not differ from mothers of neonates receiving the diagnosis postnatally on measures of anxiety, optimism, and life events. Fathers of neonates receiving the diagnosis prenatally, however, reported more optimism, lower state and trait anxiety, and fewer negative life events than fathers of neonates receiving the diagnosis postnatally. When we analyzed the interviews, we found that, regardless of the timing of the diagnosis, parents felt as though they made a genuine choice for their baby to have surgery. In this pilot study, fathers who learned prenatally that their child had a congenital cardiac malformation were less distressed than those who discovered this fact only postnatally. From the parental perspective, nonetheless, distress and urgency do not impair their ability to make decisions about neonatal cardiac surgery.


Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines.
We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.


Patient, physician, encounter, and billing characteristics predict the accuracy of syndromic surveillance case definitions.
Syndromic surveillance systems are plagued by high false-positive rates. In chronic disease monitoring, investigators have identified several factors that predict the accuracy of case definitions based on diagnoses in administrative data, and some have even incorporated these predictors into novel case detection methods, resulting in a significant improvement in case definition accuracy. Based on findings from these studies, we sought to identify physician, patient, encounter, and billing characteristics associated with the positive predictive value (PPV) of case definitions for 5 syndromes (fever, gastrointestinal, neurological, rash, and respiratory (including influenza-like illness)). The study sample comprised 4,330 syndrome-positive visits from the claims of 1,098 randomly-selected physicians working in Quebec, Canada in 2005-2007. For each visit, physician-facilitated chart review was used to assess whether the same syndrome was present in the medical chart (gold standard). We used multivariate logistic regression analyses to estimate the association between claim-chart agreement about the presence of a syndrome and physician, patient, encounter, and billing characteristics. The likelihood of the medical chart agreeing with the physician claim about the presence of a syndrome was higher when the treating physician had billed many visits for the same syndrome recently (ORper 10 visit, 1.05; 95% CI, 1.01-1.08), had a lower workload (ORper 10 claims, 0.93; 95% CI, 0.90-0.97), and when the patient was younger (ORper 5 years of age, 0.96; 95% CI, 0.94-0.97), and less socially deprived (ORmost versus least deprived, 0.76; 95% CI, 0.60-0.95). Many physician, patient, encounter, and billing characteristics associated with the PPV of surveillance case definition are accessible to public health, and could be used to reduce false-positive alerts by surveillance systems, either by focusing on the data most likely to be accurate, or by adjusting the observed data for known biases in diagnosis reporting and performing surveillance using the adjusted values.


Seasonal response of grasslands to climate change on the Tibetan Plateau.
Monitoring vegetation dynamics and their responses to climate change has been the subject of considerable research. This paper aims to detect change trends in grassland activity on the Tibetan Plateau between 1982 and 2006 and relate these to changes in climate. Grassland activity was analyzed by evaluating remotely sensed Normalized Difference Vegetation Index (NDVI) data collected at 15-day intervals between 1982 and 2006. The timings of vegetation stages (start of green-up, beginning of the growing season, plant maturity, start of senescence and end of the growing season) were assessed using the NDVI ratio method. Mean NDVI values were determined for major vegetation stages (green-up, fast growth, maturity and senescence). All vegetation variables were linked with datasets of monthly temperature and precipitation, and correlations between variables were established using Partial Least Squares regression. Most parts of the Tibetan Plateau showed significantly increasing temperatures, as well as clear advances in late season phenological stages by several weeks. Rainfall trends and significant long-term changes in early season phenology occurred on small parts of the plateau. Vegetation activity increased significantly for all vegetation stages. Most of these changes were related to increasing temperatures during the growing season and in some cases during the previous winter. Precipitation effects appeared less pronounced. Warming thus appears to have shortened the growing season, while increasing vegetation activity. Shortening of the growing season despite a longer thermally favorable period implies that vegetation on the Tibetan Plateau is unable to exploit additional thermal resources availed by climate change. Ecosystem composition may no longer be well attuned to the local temperature regime, which has changed rapidly over the past three decades. This apparent lag of the vegetation assemblage behind changes in climate should be taken into account when projecting the impacts of climate change on ecosystem processes.


A highly parallel method for synthesizing DNA repeats enables the discovery of 'smart' protein polymers.
Robust high-throughput synthesis methods are needed to expand the repertoire of repetitive protein-polymers for different applications. To address this need, we developed a new method, overlap extension rolling circle amplification (OERCA), for the highly parallel synthesis of genes encoding repetitive protein-polymers. OERCA involves a single PCR-type reaction for the rolling circle amplification of a circular DNA template and simultaneous overlap extension by thermal cycling. We characterized the variables that control OERCA and demonstrated its superiority over existing methods, its robustness, high-throughput and versatility by synthesizing variants of elastin-like polypeptides (ELPs) and protease-responsive polymers of glucagon-like peptide-1 analogues. Despite the GC-rich, highly repetitive sequences of ELPs, we synthesized remarkably large genes without recursive ligation. OERCA also enabled us to discover 'smart' biopolymers that exhibit fully reversible thermally responsive behaviour. This powerful strategy generates libraries of repetitive genes over a wide and tunable range of molecular weights in a 'one-pot' parallel format.


Incidence of genome structure, DNA asymmetry, and cell physiology on T-DNA integration in chromosomes of the phytopathogenic fungus Leptosphaeria maculans.
The ever-increasing generation of sequence data is accompanied by unsatisfactory functional annotation, and complex genomes, such as those of plants and filamentous fungi, show a large number of genes with no predicted or known function. For functional annotation of unknown or hypothetical genes, the production of collections of mutants using Agrobacterium tumefaciens-mediated transformation (ATMT) associated with genotyping and phenotyping has gained wide acceptance. ATMT is also widely used to identify pathogenicity determinants in pathogenic fungi. A systematic analysis of T-DNA borders was performed in an ATMT-mutagenized collection of the phytopathogenic fungus Leptosphaeria maculans to evaluate the features of T-DNA integration in its particular transposable element-rich compartmentalized genome. A total of 318 T-DNA tags were recovered and analyzed for biases in chromosome and genic compartments, existence of CG/AT skews at the insertion site, and occurrence of microhomologies between the T-DNA left border (LB) and the target sequence. Functional annotation of targeted genes was done using the Gene Ontology annotation. The T-DNA integration mainly targeted gene-rich, transcriptionally active regions, and it favored biological processes consistent with the physiological status of a germinating spore. T-DNA integration was strongly biased toward regulatory regions, and mainly promoters. Consistent with the T-DNA intranuclear-targeting model, the density of T-DNA insertion correlated with CG skew near the transcription initiation site. The existence of microhomologies between promoter sequences and the T-DNA LB flanking sequence was also consistent with T-DNA integration to host DNA mediated by homologous recombination based on the microhomology-mediated end-joining pathway.


Excitatory amino acid receptors expressed in Xenopus oocytes: agonist pharmacology.
The properties of excitatory amino acid (EAA) receptors transplanted into Xenopus oocytes were investigated by voltage clamp 48 hr to 5 days after oocytes had been injected with mRNA isolated from rat brain. The application of EAA agonists to mRNA-injected cells, but not to uninjected or water-injected cells, produced several different inward currents, two of which are characteristic of neuronal EAA receptors. Currents with properties expected from activation of N-methyl-D-aspartate (NMDA) receptors were evoked by L-glutamate (EC50 = 2.3 microM), D-aspartate (10 microM), L-aspartate (13 microM), NMDA (31 microM), and ibotenate (35 microM). Inward currents activated by these agonists were blocked by Mg2+ in a voltage-dependent manner and antagonized by 10-50 microM D-2-amino-5-phosphonovaleric acid (D-APV). The D-APV block was not voltage dependent. A second type of inward current was produced by kainate, domoate, (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and L-glutamate. This smooth inward current was insensitive to Mg2+ and D-APV. L-Glutamate and domoate were equipotent for activating this current (EC50 = 14 microM) whereas kainate was less potent (98 microM). The kainate potency was somewhat voltage dependent, inasmuch as the EC50 was 33% lower when measured at +38 mV than when measured at -60 mV in the same cells. Quisqualate (50 microM) and AMPA (50 microM) drastically reduced the kainate current, suggesting these agonists also interact with this receptor. Some mRNA preparations encoded only receptors for the kainate response, which argues for distinct NMDA and non-NMDA receptors. A third type of inward current was produced by quisqualate. This current, consisting of oscillating and smooth components, was carried by chloride and not evoked by AMPA, suggesting it is not likely caused by activation of the conventional neuronal quisqualate receptor. The utility of the oocyte preparation for quantitative pharmacological studies of EAA receptors is discussed.


Experimental autoimmune myasthenia gravis in B10.BV8S2 transgenic mice: preferential usage of TCRAV1 gene by lymphocytes responding to acetylcholine receptor.
Multiple TCRBV genes have been implicated in experimental autoimmune myasthenia gravis (EAMG) pathogenesis in susceptible H-2(b) strains of mice. We studied the contribution of specific TCRBV and AV genes in EAMG pathogenesis using B10.BV8S2 transgenic mice (H-2[b]). The TCR transgenic mice predominantly have TCRBV8S2 transgene, but can use any of the endogenous AV gene repertoire. The transgenic mice were immunized with acetylcholine receptor (AChR) in CFA and evaluated for EAMG pathogenesis. Although the lymphocyte responses to AChR in B10.BV8S2 transgenic and nontransgenic TCR wild-type mice were equivalent, a marked reduction in lymphocyte response to the dominant AChR alpha chain peptide 146-162 was observed in the TCR transgenic mice. After boosting with AChR in CFA, anti-AChR Abs were detected in the serum, and 14 of 42 (33%) of the TCR transgenic mice developed clinical EAMG. Furthermore, EAMG in TCR transgenic mice was prevented by treatment with mAb to TCRBV8, which depleted BV8-expressing T cells. Cloning and sequencing of TCRAV genes from AChR-reactive T cells from B10.BV8S2 transgenic mice revealed a pattern of restricted TCRAV gene usage. The majority (60%) of the clones sequenced showed a sequence identical with that of the TCRAV1S8 gene. In the normal spleen cells of TCR transgenic mice, AV gene usage was more random. Thus, despite the presence of a complete endogenous TCRAV repertoire in B10.BV8S2 transgenic mice, T cells responding to AChR preferentially used a single endogenous TCRAV gene, thus implicating the involvement of the TCRAV1S8 gene in EAMG pathogenesis.


Effects of cations on ceramide-activated protein phosphatase 2A.
Characterization of ceramide-effector(s), which includes protein phosphatase 2A (PP2A) is an important prelude to understanding the molecular basis of sphingolipid-mediated biological effects such as cell growth, differentiation and apoptosis. Recently, the existence of a metal-dependent form of PP2A has been reported (Cai et al., 1995). In this study, we investigated the effects of metal ions and chelators on ceramide-activated PP2A (CAPP). Our study demonstrates that at 0.5 mM concentration, Mg2+ appears to have no significant effect on either basal or ceramide-stimulated phosphatase activities, whereas Ca2+ stimulated the basal phosphatase activity, but was inhibitory towards CAPP. Moreover, the divalent cations Cr2+, Mn2+, Fe2+, Ni2+, Cu2+ and Zn2+ were tested and all were found to be inhibitory towards both CAPP and basal phosphatase activities. By contrast, Cs+ and Li+ had almost no effect on CAPP, although both stimulated basal phosphatase activity. The effects of EDTA and EGTA were tested and it was observed that EDTA decreased CAPP activity in a dose-dependent fashion, but had no effect upon basal phosphatase activity. These results suggest that CAPP is a metal-dependent protein, but, because Ca2+ inhibitied CAPP and EGTA was much less potent than EDTA in inhibiting CAPP, Ca2+ is unlikely to be its metal cofactor.


VIP21, a 21-kD membrane protein is an integral component of trans-Golgi-network-derived transport vesicles.
In simple epithelial cells, apical and basolateral proteins are sorted into separate vesicular carriers before delivery to the appropriate plasma membrane domains. To dissect the putative sorting machinery, we have solubilized Golgi-derived transport vesicles with the detergent CHAPS and shown that an apical marker, influenza haemagglutinin (HA), formed a large complex together with several integral membrane proteins. Remarkably, a similar set of CHAPS-insoluble proteins was found after solubilization of a total cellular membrane fraction. This allowed the cloning of a cDNA encoding one protein of this complex, VIP21 (Vesicular Integral-membrane Protein of 21 kD). The transiently expressed protein appeared on the Golgi-apparatus, the plasma membrane and vesicular structures. We propose that VIP21 is a component of the molecular machinery of vesicular transport.


Outcomes in Head and Neck Resections That Require Multiple-Flap Reconstructions: A Systematic Review.
Complex head and neck cancer defects that require multiflap reconstructions are technically feasible, but the morbidity and patient outcomes of such large-scale head and neck operations have yet to be systematically reviewed. To systematically review existing literature to characterize the outcomes of large-scale head and neck resections that require multiple-flap reconstructions (defined as defects that require >1 flap [free, pedicled, or combinations thereof]). Two authors independently searched PubMed, Embase, and the Cochrane Review databases for English-only texts published on any date. Included studies examined patients who underwent complex head and neck surgical resections that required multiple simultaneous flaps for reconstruction. Included studies reported results on at least one of the following outcomes: functional and aesthetic, patient survival, or cost (estimated by operating room time, length of stay, and/or complications). Methodological Index for Non-Randomized Studies (MINORS) criteria for bias and modified Oxford Centre for Evidence-Based Medicine recommendations were used to assess study quality. Twenty-four studies published from November 1, 1992, through September 1, 2016, met the final inclusion criteria, with a total of 487 patients (370 male [79.4%]; mean [SD] weighted age, 55.1 [4.1] years). Sixty-two of 250 patients (24.8%) were partially or fully dependent on feeding tubes at follow-up. Twenty-two of 75 patients (29.3%) had poor postoperative oral competence, causing moderate to severe drooling. Nineteen of 108 patients (17.6%) had unintelligible speech. Nine of 64 patients (14.1%) were unsatisfied with their aesthetic outcome. The mean (SD) reported survival was 2.36 (1.39) years. The mean (SD) length of stay was 24.5 (12.2) days in 219 patients. Eighty-eight minor complications (eg, partial flap necrosis, donor site complications) and 185 major complications (eg, surgical reexplorations, flap loss, or cardiopulmonary complications) were reported in 380 patients. Mean (SD) MINORS scores were 16.0 (3.2) for comparison studies and 11.4 (1.8) for noncomparison studies. Because of limited patient life expectancies, modest functional and aesthetic outcomes, and significant associated costs, surgeons should weigh the curative potential and palliative benefits for individual patients with a comprehensive view of the overall outcomes of extensive head and neck resections and reconstructions. Realistic expectations should be emphasized during preoperative discussions with patients.


Fast electron transfer through a single molecule natively structured redox protein.
The electron transfer properties of proteins are normally measured as molecularly averaged ensembles. Through these and related measurements, proteins are widely regarded as macroscopically insulating materials. Using scanning tunnelling microscopy (STM), we present new measurements of the conductance through single-molecules of the electron transfer protein cytochrome b(562) in its native conformation, under pseudo-physiological conditions. This is achieved by thiol (SH) linker pairs at opposite ends of the molecule through protein engineering, resulting in defined covalent contact between a gold surface and a platinum-iridium STM tip. Two different orientations of the linkers were examined: a long-axis configuration (SH-LA) and a short-axis configuration (SH-SA). In each case, the molecular conductance could be 'gated' through electrochemical control of the heme redox state. Reproducible and remarkably high conductance was observed in this relatively complex electron transfer system, with single-molecule conductance values peaking around 18 nS and 12 nS for the SH-SA and SH-LA cytochrome b(562) molecules near zero electrochemical overpotential. This strongly points to the important role of the heme co-factor bound to the natively structured protein. We suggest that the two-step model of protein electron transfer in the STM geometry requires a multi-electron transfer to explain such a high conductance. The model also yields a low value for the reorganisation energy, implying that solvent reorganisation is largely absent.


Oxygen regulation of tumor perfusion by S-nitrosohemoglobin reveals a pressor activity of nitric oxide.
In erythrocytes, S-nitrosohemoglobin (SNO-Hb) arises from S-nitrosylation of oxygenated hemoglobin (Hb). It has been shown that SNO-Hb behaves as a nitric oxide (NO) donor at low oxygen tensions. This property, in combination with oxygen transport capacity, suggests that SNO-Hb may have unique potential to reoxygenate hypoxic tissues. The present study was designed to test the idea that the allosteric properties of SNO-Hb could be manipulated to enhance oxygen delivery in a hypoxic tumor. Using Laser Doppler flowmetry, we showed that SNO-Hb infusion to animals breathing 21% O2 reduced tumor perfusion without affecting blood pressure and heart rate. Raising the pO2 (100% O2) slowed the release of NO bioactivity from SNO-Hb (ie, prolonged the plasma half-life of the SNO in Hb), preserved tumor perfusion, and raised the blood pressure. In contrast, native Hb reduced both tumor perfusion and heart rate independently of the oxygen concentration of the inhaled gas, and did not elicit hypertensive effects. Window chamber (to image tumor arteriolar reactivity in vivo) and hemodynamic measurements indicated that the preservation of tissue perfusion by micromolar concentrations of SNO-Hb is a composite effect created by reduced peripheral vascular resistance and direct inhibition of the baroreceptor reflex, leading to increased blood pressure. Overall, these results indicate that the properties of SNO-Hb are attributable to allosteric control of NO release by oxygen in central as well as peripheral issues.


Platelet 5-hydroxytryptamine is decreased in a preliminary group of depressed patients receiving the 5-hydroxytryptamine re-uptake inhibiting drug fluoxetine.
1. In view of the importance of 5-hydroxytryptamine in coronary thrombosis, we wanted to know whether a potentially protective decrease in platelet 5-hydroxytryptamine could be achieved by treatment with an inhibitor of 5-hydroxytryptamine uptake, fluoxetine. 2. We studied 15 patients treated for psychiatric indications with fluoxetine, and compared the findings with those obtained with blood from 18 patients treated with amitriptyline and 13 controls previously treated for affective disorders. 3. Platelet-rich plasma 5-hydroxytryptamine levels were significantly decreased in the fluoxetine group (P < 0.005) but not in the amitriptyline group compared with the control group. 4. Collagen-induced aggregation in whole blood anticoagulated with hirudin was measured by sequential single platelet counting. The contribution of 5-hydroxytryptamine was assessed from the effect of adding the 5-hydroxytryptamine specific antagonist ICI 170809. This contribution was significantly decreased in the fluoxetine group but not in the amitriptyline group compared with the control group. 5. It is concluded that platelet 5-hydroxytryptamine is indeed decreased by fluoxetine, and we would predict a protective effect of fluoxetine against coronary thrombosis.


Beyond volume: A surface-based approach to bilingualism-induced grey matter changes.
Bilingualism is a sustained experience associated with structural changes in cortical grey matter (GM) morphology. Apart from a few studies, a dominant method used to assess bilingualism-induced GM changes has been the voxel-based morphometry (VBM) analysis. While VBM is sensitive to GM volume/density differences in general, it cannot be used to identify whether the observed difference is due to relative changes in, e.g., cortical thickness, area or folding, as it uses a single combined measure of them all. Here, we used surface-based analysis (SBA) approach to investigate whether early acquisition of a second language (L2) affects the cortical GM morphology relative to late L2 acquisition. More specifically, our aim was to test a hypothesis that early acquisition of two languages induces GM changes that are predominantly surface area-driven, while late acquisition is supposedly characterised with primarily thickness-driven changes. To this end, several surface-based measures were concurrently compared between the groups. In line with the hypothesis, the results revealed that early bilingual experience is associated with significantly extended cortical surface area over the left pars opercularis and the right superior temporal gyrus. Contrary to our expectations, however, we found no evidence supporting the postulated association between late L2 acquisition and increased cortical thickness. Nevertheless, our study highlights the importance of including cortical surface measures when investigating bilingualism-related GM modulations.


Diphtheria-tetanus-pertussis vaccine administered simultaneously with measles vaccine is associated with increased morbidity and poor growth in girls. A randomised trial from Guinea-Bissau.
Combined vaccination with diphtheria-tetanus-pertussis (DTP) and measles vaccine (MV) has been associated with increased mortality in observational studies. Among children missing MV and a dose of DTP and oral polio vaccine (OPV), we conducted a randomised trial of providing MV+DTP+OPV simultaneously, as currently recommended, or MV+OPV only, and examined the effect on morbidity and growth. We hypothesised that the MV+OPV group would experience less morbidity and grow better. Due to previous observations of sex differences in the non-specific effects of vaccinations, we analysed all data stratified by sex. At the Bandim Health Project in Guinea-Bissau, 568 children who were due to receive MV and who were missing either DTP3 or DTP booster were enrolled in the study. A subgroup of 332 children was followed intensively to register adverse events and infections in the first month after vaccination. A subgroup of 276 children was followed every third month for a year to monitor growth. All children were followed for one year for infectious diseases, consultations, and hospitalisations. As expected, adverse events were more common in the MV+DTP+OPV group; diarrhoea and use of medication were increased among girls but not among boys (both p=0.02, test of interaction between DTP and sex). Febrile disease with vesicular rash, as well as consultations and hospitalisations tended to be more common in the MV+DTP+OPV group than in the MV+OPV group; the hazard ratio (HR) for febrile disease with vesicular rash was 1.86 (1.00; 3.47). The strongest tendencies for more febrile diseases and hospitalisations in the MV+DTP+OPV group were found in girls. Overall, growth did not differ by randomisation group. However, results differed by sex. Girls in the MV+DTP+OPV group had a consistent pattern of worse z-scores for weight, height, and mid-upper-arm-circumference (MUAC) than girls in the MV+OPV group. The effect was opposite for boys, with boys in the MV+OPV group faring worse than those in the MV+DTP+OPV group, the interaction test for sex and DTP being significant for weight at 6 and 9 months, for MUAC at 12 months and for weight-for-height at 3 and 9 months after randomisation. This is the first randomised trial of the non-specific effects of DTP and supports that these effects may be sex-differential and of clinical and anthropometric importance. Combined vaccination with DTP+MV+OPV may be detrimental for girls.


Long-term results of surgery for lithium-associated hyperparathyroidism.
Lithium therapy for affective bipolar disease is frequently associated with hyperparathyroidism (HPT), but the results of surgical treatment are virtually unknown. The aim of this retrospective review was to analyse the long-term outcome after surgery for lithium-induced HPT in a large series of patients. Seventy-one patients on chronic lithium therapy who underwent surgery in three university and three district hospitals in Sweden were followed for a median of 6.3 years. Histopathology, complications of surgery and normocalcaemia at 6 months after surgery and last follow-up were analysed. The primary histopathological diagnoses were adenoma (45 per cent), double adenomas (3 per cent) and hyperplasia (52 per cent). No permanent paresis of the recurrent laryngeal nerve was recorded but 13 per cent of the patients suffered from permanent hypoparathyroidism. At follow-up, the rate of persistent and recurrent HPT was 42 per cent regardless of the histopathological diagnosis. The results of conventional surgery for lithium-associated HPT are poor. The surgical approach should be adjusted for the multiglandular disease that is usually the cause of HPT in patients on chronic lithium therapy.


Xenopus Ssbp2 is required for embryonic pronephros morphogenesis and terminal differentiation.
The nephron, functional unit of the vertebrate kidney, is specialized in metabolic wastes excretion and body fluids osmoregulation. Given the high evolutionary conservation of gene expression and segmentation patterning between mammalian and amphibian nephrons, the Xenopus laevis pronephric kidney offers a simplified model for studying nephrogenesis. The Lhx1 transcription factor plays several roles during embryogenesis, regulating target genes expression by forming multiprotein complexes with LIM binding protein 1 (Ldb1). However, few Lhx1-Ldb1 cofactors have been identified for kidney organogenesis. By tandem-affinity purification from kidney-induced Xenopus animal caps, we identified s ingle- s tranded DNA b inding p rotein 2 (Ssbp2) interacts with the Ldb1-Lhx1 complex. Ssbp2 is expressed in the Xenopus pronephros, and knockdown prevents normal morphogenesis and differentiation of the glomus and the convoluted renal tubules. We demonstrate a role for a member of the Ssbp family in kidney organogenesis and provide evidence of a fundamental function for the Ldb1-Lhx1-Ssbp transcriptional complexes in embryonic development.


Emancipated Foster Youth and Intimate Partner Violence: An Exploration of Risk and Protective Factors.
Due to their high rates of parental maltreatment and violence exposure, youth in the foster care system are considered particularly vulnerable to experiencing intimate partner violence (IPV) in adolescence and young adulthood. Those who have emancipated from foster care may be at a heightened risk, as they are significantly more likely to struggle in a variety of critical domains (i.e., mental health, substance use, and delinquency). This longitudinal study is the first to explore the impact of demographic, individual, family, and foster care system factors on IPV involvement for foster care alumni at age 23/24. Analyses were conducted on three waves of quantitative data from the Midwest Evaluation of the Adult Functioning of Former Foster Youth (the Midwest Study). We find that approximately 21% of the young adults in our sample were involved in some type of IPV at age 23/24, with bidirectional violence the most commonly reported form. Males were more likely than females to report IPV victimization, whereas females were more likely than males to report IPV perpetration and bidirectional violence. Young adults who reported parental IPV prior to foster care entry were more likely to be involved in bidirectionally violent partnerships than nonviolent partnerships in young adulthood, as were young adults who reported neglect by a foster caregiver and those who reported greater placement instability while in the foster care system. Anxiety at baseline increased the odds of IPV perpetration at age 23/24, and posttraumatic stress disorder (PTSD) at baseline decreased the odds of IPV perpetration at age 23/24. Understanding the characteristics and experiences that place these young adults at risk for IPV will allow for more effective and targeted prevention efforts.


Adeno-associated virus encoding green fluorescent protein as a label for retinal pigment epithelium.
To determine whether transduction with adeno-associated virus encoding green fluorescent protein (AAV-GFP) is useful for labeling transplanted retinal pigment epithelial cells (RPE). Transduction was performed by infection of confluent or subconfluent cultured feline RPE or by subretinal injection. Cells transduced in vitro were analyzed to determine label stability over time and label conservation with cell division. RPE transduced in vivo were harvested at 5 weeks for transplantation or immunohistochemical detection. Two cats received subretinal injections of harvested cells and were killed at 3 or 7 days. In vitro transduction of confluent RPE resulted in stable GFP fluorescence for at least 3 months. There was a marked decline in fluorescence after cell division. Nonconfluent transduced cells conserved label after cell division but showed a marked decline in the number of cells, due to cell death. In vivo transduction resulted in a high level of labeling, allowing labeled cells to be harvested and transplanted. Transplanted cells were detected immunohistochemically. Photoreceptor labeling was detected over areas containing a high density of transplanted, labeled RPE derived from cells transduced in vivo. Possible light toxicity to transduced RPE was observed. AAV-GFP-labeling of confluent cultured RPE and RPE in situ can be used to identify transplanted RPE, with some reservations. Cell division may cause dilution of the label, and release of cell contents into the subretinal space may cause label transfer to photoreceptors. Exposure to light of transduced cells should be limited.


ST2 and mortality in non-ST-segment elevation acute coronary syndrome.
ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non-ST-elevation acute coronary syndrome (NSTE-ACS) has not been established. We measured ST2 at randomization and after 24, 48, and 72 hours in 403 NSTE-ACS patients from the GUSTO IV study, and studied its kinetics and its associations to clinical baseline factors and 1-year mortality. Median ST2 levels decreased from 28.4 U/mL at randomization to 21.8 U/mL at 72 hours (P < .001). Peak levels were noted 6 to 17 hours after symptom onset. Randomization ST2 levels were independently associated to N-terminal pro-B-type natriuretic peptide but otherwise exhibited only weak relations to cardiovascular risk factors and comorbidities, and biomarkers of myocardial necrosis or inflammation. ST2 was related to 1-year mortality independently of clinical risk indicators (odds ratio 2.3 [95% CI 1.1-4.6], P = .03) but lost its predictive value after additional adjustment for prognostic biomarkers, in particular N-terminal pro-B-type natriuretic peptide. ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality. Our data indicate that ST2 represents an interesting novel pathophysiologic pathway in the setting of ischemia-related myocardial dysfunction. However, future prospective evaluations in larger populations are needed before the clinical utility of ST2 can be determined.


Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: the genetics of hypertension associated treatment study.
Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the Genetics of Hypertension Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine whether it modifies clinical outcome response to blood pressure-lowering drugs. The effect of the MMP3 5A/6A polymorphism on stroke rates was examined by using multivariate-adjusted Cox regression models, including a test for interactions between genotype and antihypertensive drug class. Compared with participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard ratio=1.32; 95% CI, 1.08 to 1.61; P=0.007) and 5A/6A individuals taking lisinopril had lower stroke rates (hazard ratio(interaction)=0.74; 95% CI, 0.53 to 1.04; P(interaction)=0.08), whereas 5A/5A individuals taking lisinopril had the lowest stroke rate (hazard ratio(interaction)=0.51; 95% CI, 0.31 to 0.85; P(interaction)=0.009). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin vs chlorthalidone. The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared with patients treated with chlorthalidone, whereas a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00563901.


Nuclear PTEN Localization Contributes to DNA Damage Response in Endometrial Adenocarcinoma and Could Have a Diagnostic Benefit for Therapeutic Management of the Disease.
Endometrial adenocarcinoma (EndoCA) is the most common gynecologic cancer type in the United States, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiotherapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway. Nuclear functions for PTEN have been proposed as well, but whether those affect EndoCA development, progression, or outcomes is not well understood. Using immunohistochemistry, nuclear PTEN expression was observed in approximately half of EndoCA patient tumors, independent of grade and cytoplasmic PTEN expression. Higher levels of the DNA damage response (DDR) marker, γH2AX, were observed by immunohistochemistry and immunofluorescence in human EndoCA tumor sections that were PTEN-negative, in murine EndoCA tissues that were genetically modified to be PTEN-null, and in Ishikawa EndoCA cells, which do not express endogenous PTEN. Overexpression of exogenous PTEN-WT or PTEN-NLS, a modified PTEN with an added nuclear localization signal, significantly improved both DDR and G2-M transition in Ishikawa cells treated with a DNA-damaging agent. Whereas PARP inhibition with Olaparib was not as effective in Ishikawa cells expressing native or PTEN-NLS, inhibition with Talazoparib was not affected by PTEN overexpression. These results suggest that nuclear PTEN subcellular localization in human EndoCA could be diagnostic when considering DDR therapeutic intervention. Mol Cancer Ther; 17(9); 1995-2003. ©2018 AACR.


Self-reported medical history was generally accurate among Japanese workplace population.
To assess the validity of self-reported medical history of several diseases among the Japanese population, and to clarify to what extent the self-reported year of diagnosis for chronic diseases is different from the physician's reports. Subjects were 8,947 persons who responded to questions about medical history in a self-administered questionnaire. Of them, 854 subjects reported one or more medical histories and gave permission to contact their physician. The physicians were then requested to provide information on 809 subjects. Valid responses of 714 subjects were collected. We compared the self-reported medical histories with those reported by the physician. Of 15 persons who reported myocardial infarction, 13 (87%) were confirmed. Angina pectoris was verified in eight out of the 11 (73%). The confirmation proportions of hypertension, diabetes, hyperlipidemia, and hyperuricemia were 97%, 96%, 95%, and 95%, respectively. The self-reported year of diagnosis was 1.70-2.49 years earlier than the physician-reported year for chronic diseases. Agreement between the self-reported and the physician-reported years was higher, the more recent the self-reported year was. Self-reported medical histories were generally accurate, especially for diseases with clear diagnostic criteria. However, investigators should be aware of the errors in reporting the year of diagnosis.


An efficient two-photon fluorescent probe for measuring γ-glutamyltranspeptidase activity during the oxidative stress process in tumor cells and tissues.
Oxidative stress, a disturbance in the balance between oxidant/antioxidant ratios, is associated with cancer, aging, inflammation, neurodegenerative diseases and other conditions. γ-Glutamyltranspeptidase (GGT) is a redox-related enzyme that plays a key role in mitigating the effects of oxidative stress by maintaining cellular glutathione (GSH) metabolism and homeostasis. Therefore, oxidative stress will upregulate the intracellular GGT level. To better understand the major pathophysiological resist mechanism to oxidative injury in mediating many disease states, we designed and synthesized a novel two-photon (TP) fluorescent turn-on probe, Np-Glu, for GGT detection and bioimaging. Under the optimized conditions, Np-Glu exhibited remarkable fluorescence enhancement (150-fold), good selectivity and high sensitivity (LOD is 0.033 U L-1), with a wide linear concentration range (0-50 U L-1). More importantly, the probe Np-Glu was successfully applied in one-photon and TP fluorescence imaging of GGT activity in an oxidative stress model in living cells and tissues, suggesting Np-Glu as an ideal indicator for clinical and biological samples.


In vivo assessment of a new method of pulsatile perfusion based on a centrifugal pump.
The aim of this study was to assess platelet dysfunction and damage to organs after extracorporeal circulation using a pump based on a new method that adds a pulsatile flow to the continuous flow provided by a centrifugal pump. The continuous component of the total flow (2-3 L/min) is created by a Bio-Pump centrifugal pump, while the pulsatile component is created by the pulsating of an inner membrane pneumatically controlled by an intra-aortic counterpulsation balloon console (systolic volume of 37.5 mL in an asynchronous way with a frequency of 60 bpm). Six pigs were subjected to a partial cardiopulmonary bypass lasting 180 min and were sacrificed 60 min after extracorporeal circulation was suspended. The hematological study included the measurement of hematocrit, hemoglobin, leukocytes, and platelet function. The new pump did not significantly alter either platelet count or platelet function. In contrast, hematocrit and hemoglobin were significantly reduced during extracorporeal circulation (approximately 5% P = 0.011, and 2 g/dL P = 0.01, respectively). The leukocyte count during extracorporeal circulation showed a tendency to decrease, but this was not significant. In general, the short-term use of the new pump (4 h) did not cause any serious morphological damage to the heart, lung, kidney, or liver. The results suggest that the hemodynamic performance of the new pump is similar to a conventional centrifugal pump and could therefore be appropriate for use in extracorporeal circulation.


Genetic diversity of blastocystis isolated from cattle in khorramabad, iran.
Blastocystis is a zoonotic protozoan parasite living in the digestive system of some vertebrates. This parasite has some subtypes, pathogenicity status of which has still remained controversial. The aim of this study was to determine the subtype of Blastocystis in infected cattle. This descriptive cross-sectional study was performed on 196 isolates from cattle stool samples collected from slaughterhouse in Khorramabad city, Iran, in 2012. Genomic DNA was extracted and to determine the Blastocystis subtype, seven pairs of sequence-tagged sites (STS) primers were used. Of 196 specimens, 19 (9.6%) were infected with Blastocystis. Among the 19 positive samples, the most common subtype was ST5 (47.36 %), followed by ST3 (10.53%) and ST6 (10.53%). Two (10.53%) samples had mixed infections by ST3 and ST5. The four isolates not amplified by any STS primers were probably unknown genotypes. In the present study, the highest prevalence was for ST5, which is so important for epidemiology and risk of human infection. The report related to ST3 in cattle as a subtype of human showed mutual infection between human and cattle. Another important point in this study was the ST6 report. Finally, it seems that gathering epidemiological data is needed for a better understanding of the potential animal reservoirs for human infection.


Diet Matters: Endotoxin in the Diet Impacts the Level of Allergic Sensitization in Germ-Free Mice.
Germ-free animals have been used to define the vital role of commensal bacteria on the maturation of the host immune system. However, the role of bacterial residues in diet in this setting is poorly understood. Here we investigated the effect of bacterial contamination in sterile diet on the level of allergic sensitization in germ-free mice. Sterile grain-based diets ST1 and R03 were tested for the level of bacterial contamination. ST1 contained higher amount of bacterial DNA, approximately ten times more endotoxin, and induced higher, TLR4-dependent, cytokine production in dendritic cells compared to R03. In a germ-free mouse model of sensitization to the major birch pollen allergen Bet v 1, feeding on ST1 for at least two generations was associated with decreased production of allergen-specific IgE and IgG1 antibodies in sera in comparison to R03. Furthermore, reduced levels of allergen-specific and ConA-induced cytokines IL-4, IL-5 and IL-13 accompanied by increased levels of IFN-γ were detected in splenocytes cultures of these mice. Our results show that contamination of experimental diet with bacterial residues, such as endotoxin, significantly affects the development of allergic sensitization in germ-free mice. Therefore, careful selection of sterile food is critical for the outcomes of germ-free or gnotobiotic experimental models of immune-deviated diseases.


Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50.
We recently showed that the COOH terminus of the cystic fibrosis transmembrane conductance regulator associates with the submembranous scaffolding protein EBP50 (ERM-binding phosphoprotein 50 kD; also called Na(+)/H(+) exchanger regulatory factor). Since EBP50 associates with ezrin, this interaction links the cystic fibrosis transmembrane conductance regulator (CFTR) to the cortical actin cytoskeleton. EBP50 has two PDZ domains, and CFTR binds with high affinity to the first PDZ domain. Here, we report that Yes-associated protein 65 (YAP65) binds with high affinity to the second EBP50 PDZ domain. YAP65 is concentrated at the apical membrane in airway epithelia and interacts with EBP50 in cells. The COOH terminus of YAP65 is necessary and sufficient to mediate association with EBP50. The EBP50-YAP65 interaction is involved in the compartmentalization of YAP65 at the apical membrane since mutant YAP65 proteins lacking the EBP50 interaction motif are mislocalized when expressed in airway epithelial cells. In addition, we show that the nonreceptor tyrosine kinase c-Yes is contained within EBP50 protein complexes by association with YAP65. Subapical EBP50 protein complexes, containing the nonreceptor tyrosine kinase c-Yes, may regulate apical signal transduction pathways leading to changes in ion transport, cytoskeletal organization, or gene expression in epithelial cells.


Fast method for computing pore size distributions of model materials.
Recently developed atomistic models of highly disordered nanoporous materials offer hope for a much more realistic description of the pore morphology and topology in such materials; however, a factor limiting their application has been the computationally intensive characterization of the models, particularly determination of the pore size distribution. We report a new technique for fast computation of pore size distributions of model materials from knowledge of the molecular coordinates. The pore size distribution (PSD) is defined as the statistical distribution of the radius of the largest sphere that can be fitted inside a pore at a given point. Using constrained nonlinear optimization, we calculate the maximum radii of test particles at random points inside the pore cavity. The final pore size distribution is then obtained by sampling the test particle radii using Monte Carlo integration. The computation time depends on factors such as the number of atoms, the sampling resolution, and the desired accuracy. However, even for large systems, PSDs with very high accuracy (>99.9%) are obtained in less than 24 h on a 3 GHz Pentium IV processor. The technique is validated by applying it to model structures, whose pore size distributions are already known. We then apply this method to investigate the pore structures of several mesoporous silica models such as SBA-15 and mesostructured cellular foams.


Low Body Fat Does Not Influence Recovery after Muscle-Damaging Lower-Limb Plyometrics in Young Male Team Sport Athletes.
This study assessed the influence of fat mass to fat-free mass ratio (FM:FFM) on recovery from plyometric exercise. After assessment of body composition, 20 male team sport players (age 20.7 ± 1.1 years; body mass 77.1 ± 11.5 kg) were divided into low- (n = 10; 0.11 ± 0.03) and normal- (n = 10; 0.27 ± 0.09) fat groups based on FM:FFM ratio. Thereafter, participants completed measurements of knee extensor torque at 60 and 240°∙s-1, countermovement jump flight time, plasma creatine kinase (CK) activity and perceived muscle soreness (VAS) before and at 0, 24 and 48 h after 10 × 10 maximal plyometric vertical jumps. Evidence of muscle damage was confirmed by alterations in VAS, peak torque at 60 and 240°∙s-1 and flight time at 0, 24 and 48 h after plyometric exercise (P < 0.05). CK was increased at 0 and 24 h (P < 0.05) but returned to baseline values by 48 h. No time by group effects were observed for any of the dependent variables (P > 0.05). The current findings indicate that while muscle damage was present after plyometric exercise, the magnitude was similar across the two body composition groups. Applied practitioners can allow for a similar recovery time after plyometric exercise in those with low and normal body fat.


MEMO associated with an ErbB2 receptor phosphopeptide reveals a new phosphotyrosine motif.
Tyrosine phosphorylations are essential in signal transduction. Recently, a new type of phosphotyrosine binding protein, MEMO (Mediator of ErbB2-driven cell motility), has been reported to bind specifically to an ErbB2-derived phosphorylated peptide encompassing Tyr-1227 (PYD). Structural and functional analyses of variants of this peptide revealed the minimum sequence required for MEMO recognition. Using a docking approach we have generated a structural model for MEMO/PYD complex and compare this new phosphotyrosine motif to SH2 and PTB phosphotyrosine motives.


Diffusivity parameters of diffusion tensor imaging and apparent diffusion coefficient as imaging markers for predicting the treatment response of patients with trigeminal neuralgia.
Trigeminal neuralgia (TN) is facial pain that is usually caused by neurovascular compression syndrome and is characterized by suddenly intense and paroxysmal pain. Radiofrequency lesioning (RFL) is one of the major treatments for TN, but the treatment response for RFL is sometimes inconsistent, and the recurrence of TN is not uncommon. This study aimed to estimate the outcome predictors of TN treated with RFL by using the parameters of diffusion tensor imaging (DTI). Fifty-one patients with TN who were treated with RFL were enrolled in the study. MRI was performed in all patients within 1 week before surgery. The visual analog scale was used to evaluate symptom severity at three time points: before, 1 week after, and 3 months after RFL. The involved cisternal segment of the trigeminal nerves was manually selected, and the histograms of each of the diffusivity metrics-including the apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD)-were measured. The differences in the means, as well as the kurtosis and skewness of each of the diffusivity metrics between the nonrecurrent and recurrent groups, were then analyzed using the Mann-Whitney U-test. There were significantly lower kurtosis values (a broader peak of the distributional curves) for both FA and ADC in the recurrent group (p = 0.0004 and 0.015, respectively), compared to the nonrecurrent group. The kurtoses of AD and RD, as well as the mean and skewness of all other diffusivity metrics, did not show significant differences between the two groups. The pretreatment diffusivity metrics of DTI and ADC may be feasible imaging biomarkers for predicting the outcome of TN after RFL. A clarification of the kurtosis value of FA and ADC is helpful for determining the prognosis of patients after RFL.


Describing variability of MSW composition data with the log-logistic distribution.
Variations in solid waste composition data are necessary as inputs to solid waste planning, yet uncertainty exists regarding which probability distributions might be generally valuable to describe the variability. Twenty-two detailed analyses of solid waste from British Columbia, Canada, were fitted to distributions using the BestFit software. Alternative distributions were ranked based on three goodness-of-fit parameters and twelve waste fractions. The log-logistic distribution was found to be the most able to fit over the wide range of composition types considered. The results were demonstrated to be insensitive to the number of waste components or to the choice of a two- or three-parameter distribution. Although other distributions were able to better match the waste composition for individual waste types, the log-logistic distribution was demonstrated to fit, overall, a wide variety of waste composition types.


Associations between high-risk alcohol consumption and sarcopenia among postmenopausal women.
Sarcopenia is an age-related process, leading to cardio-metabolic diseases and disabilities. High-risk drinking is also closely related to diabetes, hypertension, and dyslipidemia, which are modifiable risk factors for sarcopenia. In the present study, we aimed to investigate the association between alcohol-drinking patterns and sarcopenia in Korean postmenopausal women. Data from 2,373 postmenopausal women were analyzed from the 2008 to 2011 Korean National Health and Nutrition Examination Survey. We defined sarcopenia as two standard deviations below the sex-specific means of the appendicular skeletal muscle/weight (percentage) values of a young reference group. Participants were categorized into three groups according to alcohol-drinking patterns, as assessed by the Alcohol Use Disorders Identification Test questionnaire. The odds ratios and 95% confidence intervals for sarcopenia were calculated using multiple logistic regression analyses. In total, 8.2% of Korean postmenopausal women met criteria for sarcopenia. The prevalence of sarcopenia increased from low-risk to high-risk alcohol-drinking groups as follows: 7.6, 11.0, and 22.7%, respectively. Compared with the low-risk group, the odds ratio (95% confidence interval) for the high-risk group was 4.29 (1.87-9.82) after adjusting for age, body mass index, systolic blood pressure, total cholesterol, fasting blood glucose, household income, education level, daily calorie intake, current smoking and regular exercise, and household food security status CONCLUSIONS:: High-risk alcohol drinking was associated with a higher risk of sarcopenia in postmenopausal Korean women.


The Chlamydial Type III Secretion Mechanism: Revealing Cracks in a Tough Nut.
Present-day members of the Chlamydiaceae contain parasitic bacteria that have been co-evolving with their eukaryotic hosts over hundreds of millions of years. Likewise, a type III secretion system encoded within all genomes has been refined to complement the unique obligate intracellular niche colonized so successfully by Chlamydia spp. All this adaptation has occurred in the apparent absence of the horizontal gene transfer responsible for creating the wide range of diversity in other Gram-negative, type III-expressing bacteria. The result is a system that is, in many ways, uniquely chlamydial. A critical mass of information has been amassed that sheds significant light on how the chlamydial secretion system functions and contributes to an obligate intracellular lifestyle. Although the overall mechanism is certainly similar to homologous systems, an image has emerged where the chlamydial secretion system is essential for both survival and virulence. Numerous apparent differences, some subtle and some profound, differentiate chlamydial type III secretion from others. Herein, we provide a comprehensive review of the current state of knowledge regarding the Chlamydia type III secretion mechanism. We focus on the aspects that are distinctly chlamydial and comment on how this important system influences chlamydial pathogenesis. Gaining a grasp on this fascinating system has been challenging in the absence of a tractable genetic system. However, the surface of this tough nut has been scored and the future promises to be fruitful and revealing.


How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry.
Metabolic status impacts on the emotional brain to induce behavior that maintains energy balance. While hunger suppresses the fear circuitry to promote explorative food-seeking behavior, satiety or obesity may increase fear to prevent unnecessary risk-taking. Here we aimed to unravel which metabolic factors, that transfer information about the acute and the chronic metabolic status, are of primary importance to regulate fear, and to identify their sites of action within fear-related brain regions. We performed a de novo analysis of central and peripheral metabolic factors that can penetrate the blood-brain barrier using genome-wide expression data across the mouse brain from the Allen Brain Atlas (ABA). The central fear circuitry, as defined by subnuclei of the amygdala, the afferent hippocampus, the medial prefrontal cortex and the efferent periaqueductal gray, was enriched with metabolic receptors. Some of their corresponding ligands were known to modulate fear (e.g., estrogen and thyroid hormones) while others had not been associated with fear before (e.g., glucagon, ACTH). Additionally, several of these enriched metabolic receptors were coexpressed with well-described fear-modulating genes (Crh, Crhr1, or Crhr2). Co-expression analysis of monoamine markers and metabolic receptors suggested that monoaminergic nuclei have differential sensitivity to metabolic alterations. Serotonergic neurons expressed a large number of metabolic receptors (e.g., estrogen receptors, fatty acid receptors), suggesting a wide responsivity to metabolic changes. The noradrenergic system seemed to be specifically sensitive to hypocretin/orexin modulation. Taken together, we identified a number of novel metabolic factors (glucagon, ACTH) that have the potential to modulate the fear response. We additionally propose novel cerebral targets for metabolic factors (e.g., thyroid hormones) that modulate fear, but of which the sites of action are (largely) unknown.


Healing gardens and cognitive behavioral units in the management of Alzheimer's disease patients: the Nancy experience.
The French Alzheimer Plan 2008-2012 anticipates the implementation of new Units specialized in cognitive rehabilitation and psycho-behavioral therapy of Alzheimer's disease (AD) patients. Conceived for AD and other dementia patients of all ages, their objectives are to propose a cognitive rehabilitation program, to prevent or treat psycho-behavioral crises, and to provide support and educational therapy to the family and professional caregivers, in order to ease the patient's return to his or her previous way of life. Studies on green spaces and healing gardens in health-care settings have revealed objective and measurable improvements in the patient's well-being. The Plan officially stipulates for the first time the need to make healing gardens an integral part of these Units, but it does not provide specific recommendations or criteria for implementing such gardens. Although green spaces and gardens are available in many French Care Units, they are rarely specifically adapted to the needs of AD patients. In Nancy, the Art, Memory and Life garden, a specific concept guided by a neuropsychological approach, was developed and complemented by an artistic vision based on cultural invariants. The main objective of this article is to describe the various steps of the process that led to the creation of this garden: the collection of experiences and information by a pilot group, surveys of patients, visitors, and caregivers before and after establishment of the garden, and implementation of a multi-professional group project. The specifications, the organizational criteria, the therapeutic project, and the criteria for the conception of such a garden stemming from our clinical experience with the Art, Memory and Life garden in Nancy, are described herein. We also present the first assessment following the implementation of the project.