Role of urokinase receptor in tumor progression and development.
Elevated level of urokinase receptor (uPAR) is detected in various aggressive cancer types and is closely associated with poor prognosis of cancers. Binding of uPA to uPAR triggers the conversion of plasminogen to plasmin and the subsequent activation of metalloproteinases. These events confer tumor cells with the capability to degrade the components of the surrounding extracellular matrix, thus contributing to tumor cell invasion and metastasis. uPA-uPAR interaction also elicits signals that stimulate cell proliferation/survival and the expression of tumor-promoting genes, thus assisting tumor development. In addition to its interaction with uPA, uPAR also interacts with vitronectin and this interaction promotes cancer metastasis by activating Rac and stimulating cell migration. Although underlying mechanisms are yet to be fully elucidated, uPAR has been shown to facilitate epithelial-mesenchymal transition (EMT) and induce cancer stem cell-like properties in breast cancer cells. The fact that uPAR lacks intracellular domain suggests that its signaling must be mediated through its co-receptors. Indeed, uPAR interacts with diverse transmembrane proteins including integrins, ENDO180, G protein-coupled receptors and growth factor receptors in cancer cells and these interactions are proven to be critical for the role of uPAR in tumorigenesis. Inhibitory peptide that prevents uPA-uPAR interaction has shown the promise to prolong patients' survival in the early stage of clinical trial. The importance of uPAR's co-receptor in uPAR's tumor-promoting effects implicate that anti-cancer therapeutic agents may also be developed by disrupting the interactions between uPAR and its functional partners.


May the force be with you: why resistance training is essential for subjects with type 2 diabetes mellitus without complications.
Physical activity, together with diet and pharmacological therapy, represents one of the three cornerstones in type 2 diabetes mellitus treatment and care. The therapeutic appeal of regular physical activity stems from: (i) its non-pharmacological nature; (ii) its beneficial effects on the metabolic risk factors associated with diabetes complications; (iii) its low costs. Evidence accumulated in the last years suggests that aerobic training-endurance training-constitutes a safe modality of intervention, achievable, and effective in diabetes treatment, whenever it is not limited by comorbidities. Aerobic training exerts insulin-mimetic effects and has been shown to lower mortality risk too. Anaerobic, intense physical activity, such as that of strength or power sports disciplines, is not univocally recognized as safe and simple to realize, however, it is important in stimulating energy and glucose metabolism. According to recent evidence, high-intensity training may be prescribed even in the face of cardiovascular diseases, peripheral vascular disease, or osteoarthritis. Some studies have shown resistance training to be more efficient than aerobic exercise in improving glycemic control. This review explores the most up-to-date indications emerging from literature in support of the beneficial effects of strength stimulation and resistance training in patients with type 2 diabetes without complications.


Wild chrysanthemum extract prevents UVB radiation-induced acute cell death and photoaging.
Wild chrysanthemum (Chrysanthemum indicum L.) is traditionally used in folk medicine as an anti-inflammatory agent. It is also used in the southwest plateau region of China to prevent ultraviolet-induced skin damage. However, the role and mechanism by which wild chrysanthemum prevents UV-induced skin damage and photoaging have never been investigated in vitro. In the present study, we found that aqueous extracts from wild chrysanthemum strongly reduced high-dose UVB-induced acute cell death of human immortalized keratinocytic HaCat cells. Wild chrysanthemum extract was also demonstrated to reduce low-dose UVB-induced expression of the photoaging-related matrix metalloproteinases MMP-2 and MMP-9. The ROS level elevated by UVB irradiation was strongly attenuated by wild chrysanthemum extract. Further study revealed that wild chrysanthemum extract reduced UVB-triggered ERK1/2 and p38 MAPK phosphorylation and their protective role, which is partially dependent on inhibiting p38 activation. These results suggest that wild chrysanthemum extract can protect the skin from UVB-induced acute skin damage and photoaging by reducing the intracellular reactive oxygen species (ROS) level and inhibiting p38 MAPK phosphorylation. The present study confirmed the protective role of wild chrysanthemum against UV-induced skin disorders in vitro and indicated the possible mechanism. Further study to identify the active components in wild chrysanthemum extract would be useful for developing new drugs for preventing and treating skin diseases, including skin cancer and photoaging, induced by UV irradiation.


Differential functional reorganization of ventral and dorsal visual pathways following childhood hemispherectomy.
Hemispherectomy is a surgical procedure in which an entire hemisphere of a patient's brain is resected or functionally disconnected to manage seizures in individuals with drug-resistant epilepsy. Despite the extensive loss of both ventral and dorsal visual pathways in one hemisphere, pediatric patients who have undergone hemispherectomy show a remarkably high degree of perceptual function across many domains. In the current study, we sought to understand the extent to which functions of the ventral and dorsal visual pathways reorganize to the contralateral hemisphere following childhood hemispherectomy. To this end, we collected fMRI data from an equal number of left and right hemispherectomy patients who completed tasks that typically elicit lateralized responses from the ventral or the dorsal pathway, namely, word (left ventral), face (right ventral), tool (left dorsal), and global form (right dorsal) perception. Overall, there was greater evidence of functional reorganization in the ventral pathway than in the dorsal pathway. Importantly, because ventral and dorsal reorganization was tested within the very same patients, these results cannot be explained by idiosyncratic factors such as disease etiology, age at the time of surgery, or age at testing. These findings suggest that because the dorsal pathway may mature earlier, it may have a shorter developmental window of plasticity than the ventral pathway and, hence, be less malleable after perturbation.


The Chinese hamster as a model for the study of diabetes mellitus.
Selection for and against diabetes and subsequent inbreeding of Chinese hamsters started in 1963. Currently there are six inbred sublines that have greater than 85% incidence of glycosuria and two control inbred nondiabetic sublines that are essentially free of glycosuria. At birth, hamsters from inbred sublines are considered prediabetic. There is phenotypic variation between diabetic sublines. Onset time, incidence of ketonuria, blood glucose, plasma insulin, glucagon and glycohydrolase levels vary from subline to subline, but pancreatic insulin and glucagon levels are consistently low and high, respectively, in all diabetic sublines compared with nondiabetics. Experimental breeding data suggest a minimum of two homozygous recessive genes for diabetes. It is not known if the inbred lines are similar diabetic genotypes, but the probability is high that modifier background genes vary from subline to subline. Chinese hamsters have diabetes ranging from mild to severe. Animals weighing 25 g can excrete up to 75 ml of urine containing 3 g of glucose per day. Fasting blood glucose as high as 500 mg/dl and 10 mumol/ml of beta-hydroxybutyrate have been reported. Gluconeogenesis is elevated, and some glycolytic enzymes are decreased in severe diabetes. Low levels of renal acid glycohydrolase enzymes may contribute to glomerular capillary loop basement membrane thickening in diabetic hamsters. Caloric restriction per se or reduction of dietary fat prevented onset of hyperglycemia and hyperinsulinemia in prediabetics. Morphologic changes have been observed in pancreatic islets, kidney, nerve, blood vessels, eyes, brain, and genito-urinary systems of diabetic Chinese hamsters. Pathogenesis of diabetes in this animal appears to be related to an increased demand for insulin. Initially there is a positive response to this demand by beta cells, but exhaustion occurs. This is followed by a decrease in beta-cell mass and relative or absolute insulin deficiency.


Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2.
The p57KIP2 protein is a cell cycle inhibitor and tumor suppressor encoded by a strongly paternally imprinted gene. We explored the utility of p57KIP2 as a diagnostic marker in hydatidiform mole, a disease likely the result of abnormal dosage and consequent misexpression of imprinted genes. Using a monoclonal antibody on paraffin-embedded, formalin-fixed tissue sections, the authors evaluated p57KIP2 expression in normal placenta and in 149 gestations including 59 complete hydatidiform moles, 39 PHMs, and 51 spontaneous losses with hydropic changes. p57KIP2 was strongly expressed in cytotrophoblast and villous mesenchyme in normal placenta, all cases of partial hydatidiform moles (39 of 39) and all spontaneous losses with hydropic changes (51 of 51). In contrast, p57KIP2 expression in cytotrophoblast and villous mesenchyme was absent or markedly decreased in 58 of 59 complete hydatidiform moles. In all gestations p57KIP2 was strongly expressed in decidua and in intervillous trophoblast islands, which served as internal positive controls for p57KIP2 immunostaining. p57KIP2 immunohistochemistry can reliably identify most cases of complete hydatidiform mole irrespective of gestational age and is thus a useful diagnostic adjunct, complementary to ploidy analysis, in the diagnosis of hydatidiform mole.


Aβ42/Aβ40 and Aβ42/Aβ38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study.
Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer's disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42/Aβ40 and Aβ42/Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.


Varanopid from the Carboniferous of Nova Scotia reveals evidence of parental care in amniotes.
Here we report on a fossil synapsid, Dendromaia unamakiensis gen. et sp. nov., from the Carboniferous period of Nova Scotia that displays evidence of parental care-approximately 40 million years earlier than the previous earliest record based on a varanopid from the Guadalupian (middle Permian) period of South Africa. The specimen, consisting of an adult and associated conspecific juvenile, is also identified as a varanopid suggesting parental care is more deeply rooted within this clade and evolved very close to the origin of Synapsida and Amniota in general. This specimen adds to growing evidence that parental care was more widespread among Palaeozoic synapsids than previously thought and further provides data permitting the identification of potential ontogeny-dependent traits within varanopids, the implications of which impact recent competing hypotheses of the phylogenetic affinities of the group.


Attention deficit hyperactivity symptoms and internet addiction.
The objective of this study was to evaluate the relationship between attention deficit-hyperactivity/impulsivity symptoms and Internet addiction. In total, 535 elementary school students (264 boys, 271 girls; mean age, 11.0 +/- 1.0 years) were recruited. The presence or severity of Internet addiction was assessed by the Young's Internet Addiction test. Parents and teachers of the children completed the DuPaul's attention deficit hyperactivity disorder (ADHD) rating scale (ARS; Korean version, K-ARS) and Child Behavior Checklists. Children with the highest and lowest quartiles in K-ARS scores were defined to be in ADHD and non-ADHD groups, respectively. Five children (0.9%) met criteria for a definite Internet addiction and 75 children (14.0%) met criteria for a probable Internet addiction. K-ARS scores had significant positive correlations with Young's Internet Addiction test scores. The Internet addiction group had higher total scores of K-ARS and ADHD-related subcategories in the Child Behavior Checklists than the non-addiction group. The ADHD group had higher Internet addiction scores compared with the non-ADHD group. Therefore, significant associations have been found between the level of ADHD symptoms and the severity of Internet addiction in children. In addition, current findings suggest that the presence of ADHD symptoms, both in inattention and hyperactivity-impulsivity domains, may be one of the important risk factors for Internet addiction.


Mechanisms Underlying Motivational Dysfunction in Schizophrenia.
Negative symptoms are a debilitating feature of schizophrenia which are often resistant to pharmacological intervention. The mechanisms underlying them remain poorly understood, and diagnostic methods rely on phenotyping through validated questionnaires. Deeper endo-phenotyping is likely to be necessary in order to improve current understanding. In the last decade, valuable behavioural insights have been gained through the use of effort-based decision making (EBDM) tasks. These have highlighted impairments in reward-related processing in schizophrenia, particularly associated with negative symptom severity. Neuroimaging investigations have related these changes to dysfunction within specific brain networks including the ventral striatum (VS) and frontal brain regions. Here, we review the behavioural and neural evidence associated with negative symptoms, shedding light on potential underlying mechanisms and future therapeutic possibilities. Findings in the literature suggest that schizophrenia is characterised by impaired reward based learning and action selection, despite preserved hedonic responses. Associations between amotivation and reward-processing deficits have not always been clear, and may be mediated by factors including cognitive dysfunction or dysfunctional or self-defeatist beliefs. Successful endo-phenotyping of negative symptoms as a function of objective behavioural and neural measurements is crucial in advancing our understanding of this complex syndrome. Additionally, transdiagnostic research-leveraging findings from other brain disorders, including neurological ones-can shed valuable light on the possible common origins of motivation disorders across diseases and has important implications for future treatment development.


Geographically-weighted regression of knowledge and behaviour determinants to anti-malarial recommending and dispensing practice among medicine retailers in western Kenya: capacitating targeted interventions.
Most patients with malaria seek treatment first in retail drug shops. Myriad studies have examined retailer behaviours and characteristics to understand the determinants to these behaviours. Geospatial methods are helpful in discovering if geographic location plays a role in the relationship between determinants and outcomes. This study aimed to discover if spatial autocorrelation exists in the relationship between determinants and retailer behaviours, and to provide specific geographic locations and target behaviours for tailoring future interventions. Retailer behaviours and characteristics captured from a survey deployed to medicine retailers in the Webuye Demographic and Health Surveillance Site were analysed using geographic weighted regression to create prediction models for three separate outcomes: recommending the first-line anti-malarial therapy to adults, recommending the first-line anti-malarial therapy to children, and selling that therapy more than other anti-malarials. The estimated regression coefficients for each determinant, as well as the pseudo R2 values for each final model, were then mapped to assess spatial variability and local areas of best model fit. The relationships explored were found to be non-stationary, indicating that spatial heterogeneity exist in the data. The association between having a pharmacy-related health training and recommending the first-line anti-malarial treatment to adults was strongest around the peri-urban centre: comparing those with training in pharmacy to those without training (OR = 5.75, p = 0.021). The association between knowing the first-line anti-malarial and recommending it to children was strongest in the north of the study area compared to those who did not know the MOH-recommended anti-malarial (OR = 2.34, p = 0.070). This is also the area with the strongest association between attending a malaria workshop and selling the MOH-recommended anti-malarial more than other anti-malarials, compared to retailers who did not attend a workshop (OR = 2.38, p = 0.055). Evidence suggests that spatial heterogeneity exists in these data, indicating that the relationship between determinants and behaviours varies across space. This is valuable information for intervention design, allowing efforts to focus on those factors that have the strongest relationship with their targeted behaviour within that geographic space, increasing programme efficiency and cost-effectiveness.


Visualizing and quantifying Fusarium oxysporum in the plant host.
Host-specific forms of Fusarium oxysporum infect the roots of numerous plant species. I present a novel application of familiar methodology to visualize and quantify F. oxysporum in roots. Infection in the roots of Arabidopsis thaliana, tomato, and cotton was detected with colorimetric reagents that are substrates for Fusarium spp.-derived arabinofuranosidase and N-acetyl-glucosaminidase activities and without the need for genetic modification of either plant host or fungal pathogen. Similar patterns of blue precipitation were produced by treatment with 5-bromo-4-chloro-3-indoxyl-α-l-arabinofuranoside and 5-bromo-4-chloro-3-indoxyl-2-acetamido-2-deoxy-β-d-glucopyranoside, and these patterns were consistent with prior histological descriptions of F. oxysporum in roots. Infection was quantified in roots of wild-type and mutant Arabidopsis using 4-nitrophenyl-α-l-arabinofuranoside. In keeping with an expectation that disease severity above ground is correlated with F. oxysporum infection below ground, elevated levels of arabinofuranosidase activity were measured in the roots of susceptible agb1 and rfo1 while a reduced level was detected in the resistant eir1. In contrast, disease severity and F. oxysporum infection were uncoupled in tir3. The distribution of staining patterns in roots suggests that AGB1 and RFO1 restrict colonization of the vascular cylinder by F. oxysporum whereas EIR1 promotes colonization of root apices.


Extreme Lagrangian acceleration in confined turbulent flow.
A Lagrangian study of two-dimensional turbulence for two different geometries, a periodic and a confined circular geometry, is presented to investigate the influence of solid boundaries on the Lagrangian dynamics. It is found that the Lagrangian acceleration is even more intermittent in the confined domain than in the periodic domain. The flatness of the Lagrangian acceleration as a function of the radius shows that the influence of the wall on the Lagrangian dynamics becomes negligible in the center of the domain, and it also reveals that the wall is responsible for the increased intermittency. The transition in the Lagrangian statistics between this region, not directly influenced by the walls, and a critical radius which defines a Lagrangian boundary layer is shown to be very sharp with a sudden increase of the acceleration flatness from about 5 to about 20.


Feline foamy virus genome and replication strategy.
Crucial aspects of the foamy virus (FV) replication strategy have so far only been investigated for the prototypic FV (PFV) isolate, which is supposed to be derived from nonhuman primates. To study whether the unusual features of this replication pathway also apply to more-distantly related FVs, we constructed feline FV (FFV) infectious molecular clones and vectors. It is shown by quantitative RNA and DNA PCR analysis that FFV virions contain more RNA than DNA. Full-length linear DNA was found in extracellular FFV by Southern blot analysis. Similar to PFV, azidothymidine inhibition experiments and the transfection of nucleic acids extracted from extracellular FFV indicated that DNA is the functional relevant FFV genome. Unlike PFV, no evidence was found indicating that FFV recycles its DNA into the nucleus.


Safety and efficacy of influenza vaccination in a prospective longitudinal study of 31 children with juvenile idiopathic arthritis.
Influenza vaccination in children with rheumatic diseases is often recommended, but not frequently performed. Our aim was to assess the safety and efficacy of annual influenza vaccination in a longitudinal follow-up study of an unselected group of children with juvenile idiopathic arthritis (JIA). Thirty-one children with stable JIA (10 boys, 21 girls, mean age 11.0 years) receiving various therapies and 14 children in a control group (10 boys, 4 girls, mean age 11.9 years) were vaccinated with the annual influenza vaccine Begrivac® 2008/2009. The children in both groups were followed for adverse events and infections 6 months after vaccination. Autoantibodies production and antibody titers against three vaccine viruses were determined in serial samples taken before, 1 and 6 months after vaccination. Eleven (35%) children with JIA and 5 (36%) children in the control group reported short-term adverse events. A JIA flare was observed one month after vaccination in 4 (13%) patients, and in the following five months in 7 (23%) patients. The response to vaccination after one month was significant in the control and study groups as a whole, but not in a subgroup of 4 children receiving anti-TNF-α therapy. After six months, no significant differences in the protective titers against vaccine viruses among the patient and control groups were observed. Changes in the mean values of autoantibodies after vaccination were found only for IgG aCL in the JIA group. No long-term adverse events were reported after influenza vaccination in JIA and control group. Thirty-five percent of children with JIA experienced flare of the disease after vaccination. Protective antibodies against at least 2 vaccine viruses 6 months after vaccination were detected in all patients.


Adenosine therapy: a new approach to chronic heart failure.
Both the prevention and attenuation of chronic heart failure (CHF) are important issues for cardiologists. There are three different strategies to prevent patients from deleterious sequels. The first strategy is to remove the causes of CHF if possible; the second is to attenuate the events that may lead to CHF, such as myocardial ischaemia and reperfusion injury, cardiomyopathy and myocarditis, cardiac hypertrophy and ventricular remodelling; the third is to prevent or attenuate the progression of CHF. Adenosine has a number of actions which merit it as a possible cardioprotective and therapeutic agent for CHF. Firstly, adenosine induces collateral circulation via inducing growth factors and triggering ischaemic preconditioning, both of which induce ischaemic tolerance in advance. Adenosine is also known to reduce the release of noradrenaline, production of endothelin and attenuate the activation of renin-angiotensin system all of which are believed to cause cardiac hypertrophy and remodelling. Secondly, exogenous adenosine is known to reduce the severity of ischaemia and reperfusion injury. Thirdly, adenosine is reported to counteract neurohumoral factors, i.e., cytokine systems, known to be related to the pathophysiology of CHF. Recently, we revealed that adenosine metabolism is changed in patients with CHF and increases in adenosine levels may aid to reduce the severity of CHF. Thus, there are many potential mechanisms for cardioprotection attributable to adenosine and we postulate the use of adenosine therapy will be beneficial in patients with CHF.


An integrative data mining approach to identifying adverse outcome pathway signatures.
The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or population. Computational approaches to explore and determine these connections can accelerate the assembly of AOPs. By leveraging the wealth of publicly available data covering chemical effects on biological systems, computationally-predicted AOPs (cpAOPs) were assembled via data mining of high-throughput screening (HTS) in vitro data, in vivo data and other disease phenotype information. Frequent Itemset Mining (FIM) was used to find associations between the gene targets of ToxCast HTS assays and disease data from Comparative Toxicogenomics Database (CTD) by using the chemicals as the common aggregators between datasets. The method was also used to map gene expression data to disease data from CTD. A cpAOP network was defined by considering genes and diseases as nodes and FIM associations as edges. This network contained 18,283 gene to disease associations for the ToxCast data and 110,253 for CTD gene expression. Two case studies show the value of the cpAOP network by extracting subnetworks focused either on fatty liver disease or the Aryl Hydrocarbon Receptor (AHR). The subnetwork surrounding fatty liver disease included many genes known to play a role in this disease. When querying the cpAOP network with the AHR gene, an interesting subnetwork including glaucoma was identified. While substantial literature exists to support the potential for AHR ligands to elicit glaucoma, it was not explicitly captured in the public annotation information in CTD. The subnetwork from this analysis suggests a cpAOP that includes changes in CYP1B1 expression, which has been previously established in the literature as a primary cause of glaucoma. These case studies highlight the value in integrating multiple data sources when defining cpAOPs for HTS data.


How to prevent and address safeguarding concerns in global health research programmes: practice, process and positionality in marginalised spaces.
Safeguarding is rapidly rising up the international development agenda, yet literature on safeguarding in related research is limited. This paper shares processes and practice relating to safeguarding within an international research consortium (the ARISE hub, known as ARISE). ARISE aims to enhance accountability and improve the health and well-being of marginalised people living and working in informal urban spaces in low-income and middle-income countries (Bangladesh, India, Kenya and Sierra Leone). Our manuscript is divided into three key sections. We start by discussing the importance of safeguarding in global health research and consider how thinking about vulnerability as a relational concept (shaped by unequal power relations and structural violence) can help locate fluid and context specific safeguarding risks within broader social systems. We then discuss the different steps undertaken in ARISE to develop a shared approach to safeguarding: sharing institutional guidelines and practice; facilitating a participatory process to agree a working definition of safeguarding and joint understandings of vulnerabilities, risks and mitigation strategies and share experiences; developing action plans for safeguarding. This is followed by reflection on our key learnings including how safeguarding, ethics and health and safety concerns overlap; the challenges of referral and support for safeguarding concerns within frequently underserved informal urban spaces; and the importance of reflective practice and critical thinking about power, judgement and positionality and the ownership of the global narrative surrounding safeguarding. We finish by situating our learning within debates on decolonising science and argue for the importance of an iterative, ongoing learning journey that is critical, reflective and inclusive of vulnerable people.


Dissociation and childhood trauma in psychologically disturbed adolescents.
To test the hypothesis that dissociation in adolescence is positively correlated with stress or abuse experienced earlier, the authors assessed dissociation in a heterogeneous group of disturbed adolescents and examined the relationship between the degree of dissociation and the degree of reported childhood stress, abuse, or trauma. The subjects were 47 adolescents, 13-17 years old, who were institutionalized for periods of 1-13 weeks in a private mental hospital; 35 were girls and 12 were boys. Participants completed the Dissociative Experiences Scale and a child abuse and trauma questionnaire. The hospital records of 40 of the 47 adolescents were also available. Scores on the Dissociative Experiences Scale correlated significantly with self-reported physical abuse or punishment, sexual abuse, psychological abuse, neglect, and negative home atmosphere but not with abuse ratings made from hospital records. Together with the authors' previous work showing a relation between childhood stress and later dissociation in normal college students, these findings support the view that dissociation represents a reaction to early negative experience and places multiple personality disorder at the extreme end of a continuum of dissociative sequelae of childhood trauma. Researchers should continue to try to identify psychiatric patients with prominent dissociative characteristics or symptoms and attempt to correlate this phenomenology with negative earlier experiences.


Dual function of MyD88 in RAS signaling and inflammation, leading to mouse and human cell transformation.
Accumulating evidence points to inflammation as a promoter of carcinogenesis. MyD88 is an adaptor molecule in TLR and IL-1R signaling that was recently implicated in tumorigenesis through proinflammatory mechanisms. Here we have shown that MyD88 is also required in a cell-autonomous fashion for RAS-mediated carcinogenesis in mice in vivo and for MAPK activation and transformation in vitro. Mechanistically, MyD88 bound to the key MAPK, Erk, and prevented its inactivation by its phosphatase, MKP3, thereby amplifying the activation of the canonical RAS pathway. The relevance of this mechanism to human neoplasia was suggested by the finding that MyD88 was overexpressed and interacted with activated Erk in primary human cancer tissues. Collectively, these results show that in addition to its role in inflammation, MyD88 plays what we believe to be a crucial direct role in RAS signaling, cell-cycle control, and cell transformation.


Volatiles from soil-borne fungi affect directional growth of roots.
Volatiles play major roles in mediating ecological interactions between soil (micro)organisms and plants. It is well-established that microbial volatiles can increase root biomass and lateral root formation. To date, however, it is unknown whether microbial volatiles can affect directional root growth. Here, we present a novel method to study belowground volatile-mediated interactions. As proof-of-concept, we designed a root Y-tube olfactometer, and tested the effects of volatiles from four different soil-borne fungi on directional growth of Brassica rapa roots in soil. Subsequently, we compared the fungal volatile organic compounds (VOCs) previously profiled with Gas Chromatography-Mass Spectrometry (GC-MS). Using our newly designed setup, we show that directional root growth in soil is differentially affected by fungal volatiles. Roots grew more frequently toward volatiles from the root pathogen Rhizoctonia solani, whereas volatiles from the other three saprophytic fungi did not impact directional root growth. GC-MS profiling showed that six VOCs were exclusively emitted by R. solani. These findings verify that this novel method is suitable to unravel the intriguing chemical cross-talk between roots and soil-borne fungi and its impact on root growth.


Net clinical benefit of anticoagulant treatments in elderly patients with nonvalvular atrial fibrillation: Experience from the real world.
Oral anticoagulation (OAC) is effective in stroke prevention in elderly patients with nonvalvular atrial fibrillation (AF), but older patients are also at higher risk of bleeding. We aimed to examine whether OAC has net clinical benefit (NCB) in elderly patients with AF. This is a retrospective cohort study of patients with AF, aged 75 years and older, who were diagnosed from January 1, 2013, through December 31, 2015. Incidences of stroke and intracranial hemorrhage (ICH) were estimated as the number of events per 100 person-years. The NCBs were estimated with respect to time in therapeutic range (TTR) (<60% or ≥60%) and treatment type (warfarin and low or high dose of direct oral anticoagulants [DOACs]). We included 11,760 patients, of whom 4982 (42.4%) were treated with OACs: 2042 (17.4%) with warfarin and 2940 (25.0%) with DOACs. Among patients treated with warfarin, those who achieved TTR ≥ 60% had a lower incidence of stroke (2.54 per 100 person-years vs 5.21 per 100 person-years; P = .01) but without a statistically significant lower incidence of ICH (0.68 per 100 person-years vs 1.10 per 100 person-years; P = .45) and a higher NCB (9.78 vs 6.52) than did those with TTR < 60%. Among patients treated with DOACs, patients treated with the high dose had a statistically significant similar incidence of stroke (8.40 per 100 person-years vs 9.81 per 100 person-years; P = .67), a statistically significant lower incidence of ICH (0.33 per 100 person-years vs 1.20 per 100 person-years; P = .02), and a higher NCB (4.42 vs 1.78) than did patients treated with the low dose. A large proportion of elderly patients are not treated with OACs. We found that the NCB of OAC in the elderly is positive, with the highest benefit in elderly patients treated with warfarin who achieved TTR ≥ 60% or high dose of DOACs.


Long-distance interdisciplinarity leads to higher scientific impact.
Scholarly collaborations across disparate scientific disciplines are challenging. Collaborators are likely to have their offices in another building, attend different conferences, and publish in other venues; they might speak a different scientific language and value an alien scientific culture. This paper presents a detailed analysis of success and failure of interdisciplinary papers--as manifested in the citations they receive. For 9.2 million interdisciplinary research papers published between 2000 and 2012 we show that the majority (69.9%) of co-cited interdisciplinary pairs are "win-win" relationships, i.e., papers that cite them have higher citation impact and there are as few as 3.3% "lose-lose" relationships. Papers citing references from subdisciplines positioned far apart (in the conceptual space of the UCSD map of science) attract the highest relative citation counts. The findings support the assumption that interdisciplinary research is more successful and leads to results greater than the sum of its disciplinary parts.


Association between birth order and emergency room visits and acute hospital admissions following pediatric vaccination: a self-controlled study.
We investigated the association between a child's birth order and emergency room (ER) visits and hospital admissions following 2-,4-,6- and 12-month pediatric vaccinations. We included all children born in Ontario between April 1(st), 2006 and March 31(st), 2009 who received a qualifying vaccination. We identified vaccinations, ER visits and admissions using health administrative data housed at the Institute for Clinical Evaluative Sciences. We used the self-controlled case series design to compare the relative incidence (RI) of events among 1(st)-born and later-born children using relative incidence ratios (RIR). For the 2-month vaccination, the RIR for 1(st)-borns versus later-born children was 1.37 (95% CI: 1.19-1.57), which translates to 112 additional events/100,000 vaccinated. For the 4-month vaccination, the RIR for 1(st)-borns vs. later-borns was 1.70 (95% CI: 1.45-1.99), representing 157 additional events/100,000 vaccinated. At 6 months, the RIR for 1(st) vs. later-borns was 1.27 (95% CI: 1.09-1.48), or 77 excess events/100,000 vaccinated. At the 12-month vaccination, the RIR was 1.11 (95% CI: 1.02-1.21), or 249 excess events/100,000 vaccinated. Birth order is associated with increased incidence of ER visits and hospitalizations following vaccination in infancy. 1(st)-born children had significantly higher relative incidence of events compared to later-born children.


Opinion formation on adaptive networks with intensive average degree.
We study the evolution of binary opinions on a simple adaptive network of N nodes. At each time step, a randomly selected node updates its state ("opinion") according to the majority opinion of the nodes that it is linked to; subsequently, all links are reassigned with probability p̃ (q̃) if they connect nodes with equal (opposite) opinions. In contrast to earlier work, we ensure that the average connectivity ("degree") of each node is independent of the system size ("intensive"), by choosing p̃ and q̃ to be of O(1/N). Using simulations and analytic arguments, we determine the final steady states and the relaxation into these states for different system sizes. We find two absorbing states, characterized by perfect consensus, and one metastable state, characterized by a population split evenly between the two opinions. The relaxation time of this state grows exponentially with the number of nodes, N. A second metastable state, found in the earlier studies, is no longer observed.


A cytosolic factor that inhibits KATP channels expressed in Xenopus oocytes by impairing Mg-nucleotide activation by SUR1.
ATP-sensitive K(+) (K(ATP)) channels couple cell metabolism to cell electrical activity. Wild-type (Kir6.2/SUR1) K(ATP) channels heterologously expressed in Xenopus oocytes give rise to very small inward currents in cell-attached patches. A large increase in the current is observed on patch excision into zero ATP solution. This is presumably due to loss of intracellular ATP leading to unblock of K(ATP) channels. In contrast, channels containing Kir6.2 mutations associated with reduced ATP-sensitivity display non-zero cell-attached currents. Unexpectedly, these cell-attached currents are significantly smaller (by approximately 40%) than those observed when excised patches are exposed to physiological ATP concentrations (1-10 mm). Cramming the patch back into the oocyte cytoplasm restores mutant K(ATP) current amplitude to that measured in the cell-attached mode. This implies that the magnitude of the cell-attached current is regulated not only by intracellular ATP but also by another cytoplasmic factor/s. This factor seems to require the nucleotide-binding domains of SUR1 to be effective. Thus a mutant Kir6.2 (Kir6.2DeltaC-I296L) expressed in the absence of SUR1 exhibited currents of similar magnitude in cell-attached patches as in inside-out patches exposed to 10 mm MgATP. Similar results were found when Kir6.2-I296L was coexpressed with an SUR1 mutant that is insensitive to MgADP or MgATP activation. This suggests the oocyte contains a cytoplasmic factor that reduces nucleotide binding/hydrolysis at the NBDs of SUR1. In conclusion, our results reveal a novel regulatory mechanism for the K(ATP) channel. This was not evident for wild-type channels because of their high sensitivity to block by ATP.


Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance.
Copper is an essential transition metal ion for the function of key metabolic enzymes, but its uncontrolled redox reactivity is source of reactive oxygen species. Therefore a network of transporters strictly controls the trafficking of copper in living systems. Deficit, excess, or aberrant coordination of copper are conditions that may be detrimental, especially for neuronal cells, which are particularly sensitive to oxidative stress. Indeed, the genetic disturbances of copper homeostasis, Menkes' and Wilson's diseases, are associated with neurodegeneration. Furthermore, copper interacts with the proteins that are the hallmarks of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion diseases, and familial amyotrophic lateral sclerosis. In all cases, copper-mediated oxidative stress is linked to mitochondrial dysfunction, which is a common feature of neurodegeneration. In particular we recently demonstrated that in copper deficiency, mitochondrial function is impaired due to decreased activity of cytochrome c oxidase, leading to production of reactive oxygen species, which in turn triggers mitochondria-mediated apoptotic neurodegeneration.


Selection of PD1/PD-L1 X-Aptamers.
Specific, chemically modified aptamers (X-Aptamers) were identified against two immune checkpoint proteins, recombinant Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1). Selections were performed using a bead-based X-Aptamer (XA) library containing several different amino acid functional groups attached to dU at the 5-position. The binding affinities and specificities of the selected XA-PD1 and XA-PDL1 were validated by hPD-1 and hPD-L1 expression cells, as well as by binding to human pancreatic ductal adenocarcinoma tissue. The selected PD1 and PDL1 XAs can mimic antibody functions in in vitro assays.


Gallium, germanium, indium, and iridium in lunar samples.
Neutron activation analyses of gallium, germanium, indium, and iridium in eight lunar samples and in meteorites and rocks (including four calciulnrich achondrites and five terrestrial basalts) with similar bulk compositions are reported. Lunar gallium concentrations are remarkably constant at about 5 parts per million, three times higher and four times lower than those in eucritic (calcium-rich) achondrites and terrestrial basalts, respectively. Lunar germanium concentrations range from </= 0.04 to 0.4 part per million. Basaltic achondrites have similar germanium concentrations, whereas those in terrestrial basalts are uniformly higher at about 1.4 parts per million. Concentrations of indium in Ilunar samples range from 3 to 60 parts per billion, whereas those in terrestrial basalts are 80 to 100 parts per billion, and those in basaltic achondrites 0.4 to 3 parts per billion. Lunar iridium concentrations appear to be in the 0.1 to 10 parts per billion range. The Tranquillitatis samples are distinctly different from calcium-rich achondrites and terrestrial basalts.


Light charged-particle production in 96 MeV neutron-induced reactions on carbon and oxygen.
In recent years, an increasing number of applications involving fast neutrons have been developed or are under consideration, e.g. radiation treatment of cancer, neutron dosimetry at commercial aircraft altitudes, soft-error effects in computer memories, accelerator-driven transmutation of nuclear waste and energy production and determination of the response of neutron detectors. Data on light-ion production in light nuclei such as carbon, nitrogen and oxygen are particularly important in calculations of dose distributions in human tissue for radiation therapy at neutron beams, and for dosimetry of high-energy neutrons produced by high-energy cosmic radiation interacting with nuclei (nitrogen and oxygen) in the atmosphere. When studying neutron dose effects, it is especially important to consider carbon and oxygen, since they are, by weight, the most abundant elements in human tissue. Preliminary experimental double-differential cross sections of inclusive light-ion (p, d, t, (3)He and alpha) production in carbon induced by 96-MeV neutrons have been presented. Energy spectra were measured at eight laboratory angles: 20, 40, 60, 80, 100, 120, 140 and 160 degrees. Measurements were performed at The Svedberg Laboratory (TSL), Uppsala, using the dedicated MEDLEY experimental setup. The authors have earlier reported experimental double-differential cross sections of inclusive light-ion production in oxygen. In this paper, the deduced kerma coefficients for oxygen has been presented and compared with reaction model calculations.


Flow-based Generative Models for Learning Manifold to Manifold Mappings.
Many measurements or observations in computer vision and machine learning manifest as non-Euclidean data. While recent proposals (like spherical CNN) have extended a number of deep neural network architectures to manifold-valued data, and this has often provided strong improvements in performance, the literature on generative models for manifold data is quite sparse. Partly due to this gap, there are also no modality transfer/translation models for manifold-valued data whereas numerous such methods based on generative models are available for natural images. This paper addresses this gap, motivated by a need in brain imaging - in doing so, we expand the operating range of certain generative models (as well as generative models for modality transfer) from natural images to images with manifold-valued measurements. Our main result is the design of a two-stream version of GLOW (flow-based invertible generative models) that can synthesize information of a field of one type of manifold-valued measurements given another. On the theoretical side, we introduce three kinds of invertible layers for manifold-valued data, which are not only analogous to their functionality in flow-based generative models (e.g., GLOW) but also preserve the key benefits (determinants of the Jacobian are easy to calculate). For experiments, on a large dataset from the Human Connectome Project (HCP), we show promising results where we can reliably and accurately reconstruct brain images of a field of orientation distribution functions (ODF) from diffusion tensor images (DTI), where the latter has a 5 × faster acquisition time but at the expense of worse angular resolution.


Importance of tachycardia cycle length for differentiating typical atrial flutter from scar-related in adult congenital heart disease.
Radiofrequency catheter ablation (RFCA) for intraatrial reentrant tachycardia (IART) in congenital heart disease (CHD) remains difficult. Thirty-four consecutive adult patients (age, 37.6 ± 12.8 years; male, 21) with previously repaired CHD and IART underwent an electrophysiological study and RFCA. CHD included atrial septal defect (ASD, n = 14), tetralogy of Fallot (n = 11), ventricular septal defect (n = 4), pulmonary atresia (n = 2), atrioventricular septal defect (n = 1), transposition of the great arteries (n = 1), and double-outlet right ventricle (n = 1). Duration of CHD repair to IART onset was 19.1 ± 8.5 years. Thirty and four patients had single- and double-loop reentrant tachycardia, respectively. Among the total of 38 IARTs, which were mapped, 22 (57.9%) and 13 (34.2%) IARTs were cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) and scar-related AFL, respectively. Typical AFL electrocardiography findings including definite sawtooth appearance in inferior leads and positive F wave in lead V1 were observed in only 12 of 21 patients (57.1%) with CTI-dependent AFL. CTI-dependent AFL had a significantly longer tachycardia cycle length (TCL) than scar-related AFL (267.6 ± 34.4 ms and 235.9 ± 37.0 ms, respectively; P = 0.031). TCL > 250 ms had 79% sensitivity as the cutoff value for differentiating CTI-dependent from scar-related AFL. The acute success rates of RFCA in CTI-dependent and scar-related AFLs were 85.7% and 90.0%, respectively. The recurrence rates in CTI-dependent and scar-related AFLs were 11.1% and 11.1%, respectively, during a follow-up of 21.2 ± 28.3 months. CTI-dependent AFL was the most common IART in adult patients with repaired CHD and was easily manageable by RFCA. TCL might help to differentiate CTI-dependent AFL from other IARTs.


A Multicenter Noncomparative Clinical Study on Midface Rejuvenation Using a Nonabsorbable Polypropylene Mesh: Evaluation of Efficacy and Safety.
Facial rejuvenation can be achieved using a variety of techniques. Since minimally invasive procedures for face lifting have become popular because of their convenience and short operating time, numerous minimally invasive surgical procedures have been developed. In this study, a nonabsorbable polypropylene mesh is introduced as a new face lifting instrument, with the nasolabial fold as the main target area. In this paper, we report the efficacy and safety of a polypropylene mesh in midface rejuvenation. Thirty-three subjects with moderate-to-severe nasolabial folds were enrolled from two medical institutions for a noncomparative single-sample study. A mesh was inserted above the superficial muscular aponeurotic system layer, reaching the nasolabial folds through a temporal scalp incision. After 3 weeks, the temporal end of the mesh was pulled to provide a lifting effect. Then, the mesh was fixed to the deep temporal fascia using nonabsorbable sutures. To evaluate efficacy, we compared the scores on the Wrinkle Severity Rating Scale and a visual analog scale for patient satisfaction between the baseline and 7 weeks postoperatively. In addition, we evaluated safety based on the incidence of adverse events. The treatment was deemed effective at improving wrinkles in 23 of 28 cases, and patient satisfaction improved significantly during the study period. There were seven cases of skin or subcutaneous tissue complications, including edema and erythema, but there were no suspected serious adverse events. Face lifting using a nonabsorbable mesh can improve nasolabial folds without serious adverse effects. Thus, this technique is safe and effective for midface rejuvenation.


Hyaluronan in the bovine ocular anterior segment, with emphasis on the outflow pathways.
It has been postulated that glycosaminoglycans play a role in the regulation of outflow resistance. The purpose of these studies was to localize the distribution of hyaluronan (HA) in the anterior segments of bovine eyes to understand better the possible role of HA in the outflow pathway. Eyes from four 2-week-old calves and four 1-year-old cows were examined using a biotinylated-hyaluronan binding protein to localize HA in tissue sections of the anterior segment of bovine eyes. Various fixations and microwave irradiation were compared. The vitreous body in each section served as a positive control. Sections treated with Streptomyces hyaluronidase were used to confirm specificity. No significant difference in distribution of HA was found between various fixations and between calves and cows. HA was found in subconjunctival connective tissue and in intercellular spaces of limbal and conjunctival epithelium, but not in corneal epithelium. Staining was sometimes found on the surface of the corneal epithelium and endothelium, as well as on the conjunctival epithelium. No staining was found within the corneal stroma. There was HA in iris stroma, but not in the root of the iris or ciliary body stroma. HA was present in the anterior, nonfiltering part of the trabecular meshwork (TM) and surrounding collector channels and blood vessels in the sclera; to a lesser extent, it was present in the juxtacanalicular region of the TM. HA was detectable neither within trabecular beams nor filling the intertrabecular spaces. Strong staining was found, however, in the nerve bundles in the angle region. Staining for HA in vitreous was invariably positive, and in Streptomyces hyaluronidase-treated sections it was negative. HA was not uniformly distributed in the bovine TM. The distribution of HA in the flow pathway of the aqueous outflow system indicates that only a small fraction of the HA found in biochemical analyses of the bovine meshwork is located in the region where the flow resistance is thought to reside.


Disability pension due to musculoskeletal diagnoses: importance of work-related factors in a prospective cohort study of Finnish twins.
The aim of this study was to investigate the impact of work-related risk factors for future disability pension (DP) due to musculoskeletal diagnoses and for a subgroup of these, namely, DP due to osteoarthritis. For this prospective study of 16,028 Finnish twins born in 1911-1957 and employed at baseline, a postal questionnaire collected information in 1975 on work-related factors; follow-up data on DP was gathered through register linkages up to 2004. A series of proportional hazards (Cox) regression models were used to analyze the associations between work-related factors and the incidence of DP. During the 30-year follow-up, 1297 participants (8%) were granted DP due to musculoskeletal diagnoses, 376 of which were due to osteoarthritis. High stress of daily activities, monotonous work, physical workload (namely work including lifting and carrying or physically heavy work), several workplace changes, and unemployment displayed a strong association with DP due to musculoskeletal diagnoses that was not affected by familial factors, including genetics and shared environment. Additionally, standing work increased the risk for DP due to osteoarthritis. Uninfluenced by family background or other confounding factors, several work-related factors were identified as being strong and direct risk factors for DP due to musculoskeletal diagnoses.


Role of the N-terminal alpha-helix in biogenesis of alpha7 nicotinic receptors.
We studied the role of the alpha-helix present at the N-terminus of nicotinic acetylcholine receptor (nAChR) subunits in the expression of functional channels. Deletion of this motif in alpha7 subunits abolished expression of nAChRs at the membrane of Xenopus oocytes. The same effect was observed upon substitution by homologous motifs of other ligand-gated receptors. When residues from Gln4 to Tyr15 were individually mutated to proline, receptor expression strongly decreased or was totally abolished. Equivalent substitutions to alanine were less harmful, suggesting that proline-induced break of the alpha-helix is responsible for the low expression. Steady-state levels of wild-type and mutant subunits were similar but the formation of pentameric receptors was impaired in the latter. In addition, those mutants that reached the membrane showed a slightly increased internalization rate. Expression of alpha7 nAChRs in neuroblastoma cells confirmed that mutant subunits, although stable, were unable to reach the cell membrane. Analogous mutations in heteromeric nAChRs (alpha3beta4 and alpha4beta2) and 5-HT(3A) receptors also abolished their expression at the membrane. We conclude that the N-terminal alpha-helix of nAChRs is an important requirement for receptor assembly and, therefore, for membrane expression.


Quantitative analysis of fragrance and odorants released from fresh and decaying strawberries.
The classes and concentrations of volatile organic compounds (VOC) released from fresh and decaying strawberries were investigated and compared. In this study, a total of 147 strawberry volatiles were quantified before and after nine days of storage to explore differences in the aroma profile between fresh strawberries (storage days (SRD) of 0, 1, and 3) and those that had started to decay (SRD = 6 and 9). In terms of concentration, seven compounds dominated the aroma profile of fresh strawberries (relative composition (RC) up to 97.4% by mass, sum concentration): (1) ethyl acetate = 518 mg∙m⁻³, (2) methyl acetate = 239 mg∙m⁻³, (3) ethyl butyrate = 13.5 mg∙m⁻³, (4) methyl butyrate = 11.1 mg∙m⁻³, (5) acetaldehyde = 24.9 mg∙m⁻³, (6) acetic acid = 15.2 mg∙m⁻³, and (7) acetone = 13.9 mg∙m⁻³. In contrast, two alcohols dominated the aroma profile of decayed samples (RC up to 98.6%): (1) ethyl alcohol = 94.2 mg∙m⁻³ and (2) isobutyl alcohol = 289 mg∙m⁻³. Alternatively; if the aroma profiles are re-evaluated by summing odor activity values (ΣOAV); four ester compounds ((1) ethyl butyrate (6,160); (2) ethyl hexanoate (3,608); (3) ethyl isovalerate (1,592); and (4) ethyl 2-methylbutyrate (942)) were identified as the key constituents of fresh strawberry aroma (SRD-0). As the strawberries began to decay; isobutyl alcohol recorded the maximum OAV of 114 (relative proportion (RP) (SRD = 6) = 58.3%). However, as the decay process continued, the total OAV dropped further by 3 to 4 orders of magnitude--decreasing to 196 on SRD = 6 to 7.37 on SRD = 9. The overall results of this study confirm dramatic changes in the aroma profile of strawberries over time, especially with the onset of decay.


The Unhappy Mental Health Triad: Comorbid Severe Mental Illnesses, Personality Disorders, and Substance Use Disorders in Prison Populations.
Information on the comorbidity of mental health problems in prison populations is scarce. The aim of the present study was to assess the prevalence of comorbidities at intake to prison between three diagnostic groups: severe mental illnesses (SMIs), personality disorders (PDs), and substance use disorders (SUDs). The co-occurrence of those disorders in prison populations may require the integration of differential treatment approaches and novel treatment trials. A consecutive sample of N = 427 (229 male and 198 female) individuals committed to imprisonment in Santiago de Chile was assessed with the Mini Neuropsychiatric Interview and the Structured Clinical Interview for DSM-IV (module for borderline personality disorders) on arrival at prison. Diagnoses were a priori grouped as SMI including psychosis, bipolar disorder and major depression, PD including borderline and antisocial PD and SUD including alcohol and drug abuse or dependence. Sex stratified multivariate binary logistic regression analyses were conducted to assess sociodemographic, criminal and treatment characteristics of individuals with at least one diagnosis from each of the three diagnostic groups. The triad of SMI, PD, and SUD was present in n = 138 (32.3%; 95% IC: 28.0-36.9) study participants, n = 105 (45.9%; 95% CI: 39.4-52.4) of the men and n = 33 (16.7%; 95% CI: 12.1-22.6) of the women. Among those with the disorder triad, n = 129 (30.2%; 95% CI: 26.0-34.8) had major depression, PD and SUD; n = 54 (12.6%; 95% CI: 9.8-16.2) had psychosis, PD and SUD. The disorder triad was more common in men (OR = 4.86; 95% IC: 2.63-8.95), younger age (OR = 0.94; 95% CI: 0.91-0.97), and participants with lower educational levels (OR = 1.69; 95% CI: 1.01-2.82). The disorder triad was significantly associated with previous incarcerations (OR 2.60; 95% CI: 1.55-4.34) and histories of psychiatric hospitalizations (OR 2.82; 95% CI: 1.27-6.28). The complex triad of disorders from different diagnostic groups is common in prison populations, especially among young men. Successful treatment interventions may have the potential to break a cycle of repeat institutionalization in prisons and psychiatric institutions.


Inhibition of PP2A activity confers a TRAIL-sensitive phenotype during malignant transformation.
TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAIL-induced apoptosis. Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator.


Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass.
Pulmonary neutrophil entrapment and resultant oxidative injury is thought to be the primary mechanism of cardiopulmonary bypass (CPB) induced lung injury. Interleukin-8 (IL-8), a potent neutrophil chemoattractant induced by cytokines, including tumor necrosis factor-alpha (TNF), is found in increased concentrations in bronchial alveolar lavage fluid (BALF) in lung inflammation. Since aprotinin reduces TNF release during CPB, the effects of aprotinin on BALF IL-8 concentrations and neutrophil levels were determined after CPB in adult humans. Study patients were equally divided into a control group (n = 8, Group 1) and an aprotin-intreated group (n = 8, Group 2). In vitro neutrophil chemotaxis was done with volunteer neutrophils using three different chemoattractants: 1) N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP); 2) the supernatant of a human bronchial epithelial cell culture line, A549, after 24 h of TNF stimulation with or without aprotinin or N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK) (a potent protease inhibitor), and 3) BALF. Aprotinin treatment significantly (P < 0.05) reduced post-CPB BALF IL-8 concentrations and percentage of neutrophils. In vitro, BALF from Group 1 had significantly greater chemotactic ability when compared with Group 2. The TNF stimulated A549 cell culture supernatant had significantly (P < 0.05) greater chemotactic ability than control supernatant, while aprotinin and TLCK significantly (P < 0.05) reduced this chemotactic ability. These results demonstrate that aprotinin blunts IL-8 production and reduces neutrophil lung accumulation post-CPB.


Recessions and seniors' health, health behaviors, and healthcare use: analysis of the Medicare Current Beneficiary Survey.
A number of studies report that U.S. state mortality rates, particularly for the elderly, decline during economic downturns. Further, several prior studies use microdata to show that as state unemployment rates rise, physical health improves, unhealthy behaviors decrease, and medical care use declines. We use data on elderly mortality rates and data from the Medicare Current Beneficiary Survey from a time period that encompasses the start of the Great Recession. We find that elderly mortality is countercyclical during most of the 1994-2008 period. Further, as unemployment rates rise, seniors report worse mental health and are no more likely to engage in healthier behaviors. We find suggestive evidence that inpatient utilization increases perhaps because of an increased physician willingness to accept Medicare patients. Our findings suggest that either elderly individuals respond differently to recessions than do working age adults, or that the relationship between unemployment and health has changed.


Probing Distinctive Electron Conduction in Multilayer Rhenium Disulfide.
Charge carrier transport in multilayer van der Waals (vdW) materials, which comprise multiple conducting layers, is well described using Thomas-Fermi charge screening (λTF ) and interlayer resistance (Rint ). When both effects occur in carrier transport, a channel centroid migrates along the c-axis according to a vertical electrostatic force, causing redistribution of the conduction centroid in a multilayer system, unlike a conventional bulk material. Thus far, numerous unique properties of vdW materials are discovered, but direct evidence for distinctive charge transport behavior in 2D layered materials is not demonstrated. Herein, the distinctive electron conduction features are reported in a multilayer rhenium disulfide (ReS2 ), which provides decoupled vdW interaction between adjacent layers and much high interlayer resistivity in comparison with other transition-metal dichalcogenides materials. The existence of two plateaus in its transconductance curve clearly reveals the relocation of conduction paths with respect to the top and bottom surfaces, which is rationalized by a theoretical resistor network model by accounting of λTF and Rint coupling. The effective tunneling distance probed via low-frequency noise spectroscopy further supports the shift of electron conduction channel along the thickness of ReS2 .


In vivo imaging of structural, metabolic and functional brain changes in glaucoma.
Glaucoma, the world's leading cause of irreversible blindness, is a condition for which elevated intraocular pressure is currently the only modifiable risk factor. However, the disorder can continue to progress even at reduced intraocular pressure. This indicates additional key factors that contribute to the etiopathogenesis. There has been a growing amount of literature suggesting glaucoma as a neurodegenerative disease of the visual system. However, it remains debatable whether the observed pathophysiological conditions are causes or consequences. This review summarizes recent in vivo imaging studies that helped advance the understanding of early glaucoma involvements and disease progression in the brains of humans and experimental animal models. In particular, we focused on the non-invasive detection of early structural and functional brain changes before substantial clinical visual field loss in glaucoma patients; the eye-brain interactions across disease severity; the metabolic changes occurring in the brain's visual system in glaucoma; and, the widespread brain involvements beyond the visual pathway as well as the potential behavioral relevance. If the mechanisms of glaucomatous brain changes are reliably identified, novel neurotherapeutics that target parameters beyond intraocular pressure lowering can be the promise of the near future, which would lead to reduced prevalence of this irreversible but preventable disease.


Type 2 deiodinase and host responses of sepsis and acute lung injury.
The role of thyroid hormone metabolism in clinical outcomes of the critically ill remains unclear. Using preclinical models of acute lung injury (ALI), we assessed the gene and protein expression of type 2 deiodinase (DIO2), a key driver for synthesis of biologically active triiodothyronine, and addressed potential association of DIO2 genetic variants with ALI in a multiethnic cohort. DIO2 gene and protein expression levels in murine lung were validated by microarrays and immunoblotting. Lung injury was assessed by levels of bronchoalveolar lavage protein and leukocytes. Single-nucleotide polymorphisms were genotyped and ALI susceptibility association assessed. Significant increases in both DIO2 gene and D2 protein expression were observed in lung tissues from murine ALI models (LPS- and ventilator-induced lung injury), with expression directly increasing with the extent of lung injury. Mice with reduced levels of DIO2 expression (by silencing RNA) demonstrated reduced thyroxine levels in plasma and increased lung injury (increased bronchoalveolar lavage protein and leukocytes), suggesting a protective role for DIO2 in ALI. The G (Ala) allele of the Thr92Ala coding single-nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis-associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans. Our studies indicate that DIO2 is a novel ALI candidate gene, the nonsynonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolism is intimately linked to the integrated response to inflammatory injury in critically ill patients.


Management of local recurrences and regional failure in early stage non-small cell lung cancer after stereotactic body radiation therapy.
Stereotactic body radiation therapy (SBRT) is a very effective way to treat early stage non-small cell lung cancer (NSCLC) and small oligometastatic lung lesions with consistently high rates of local control, but both local and regional/distant recurrences still occur. The management of recurrences remains unsettled and may entail repeat SBRT, conventionally fractionated external beam RT (EF-EBRT), chemotherapy or surgery. Most patients with local recurrences [within the initial planning target volume (PTV)] can be salvaged successfully with good cancer specific survival. Nonetheless, proximity of the initial SBRT delivery to organs at risk (ribs, blood vessels, airways) may make retreatment more difficult. With attention to detail and careful patient selection, both surgery and reirradiation can be performed safely and effectively. Strategies for management of regional (nodal) recurrences may require conventional therapies tailored to the patterns of failure. The role of immunotherapy in salvage has not been elucidated as yet. We review here data on the available literature concerning salvage of SBRT lung patients.


Paeoniflorin exerts protective effect on radiation-induced hepatic fibrosis in rats via TGF-β1/Smads signaling pathway.
This study aimed to investigate the protective effects of paeoniflorin (PAE) on radiation-induced hepatic fibrosis in a rat model. Fifty healthy male Sprague-Dawley rats were randomly assigned to normal control group, hepatic fibrosis group, and PAE treatment groups. X-ray exposure was employed to establish radiation-induced hepatic fibrosis model. PAE was administered once daily, and rats were sacrificed at week 26 after irradiation. The liver histopathology was evaluated under a light microscope after HE staining and Masson staining. Meanwhile, the protein expression of transforming growth factor-beta 1 (TGF-β1), Smad3/4 and Smad7 was detected by immunohistochemistry. Radiation-induced liver damage and collagen deposition were observed in the model group as compared to normal control group, but PAE treatment significantly attenuated the liver injury and reduce collagen deposition (P<0.05 or 0.01). The hepatic hydroxyproline content and serum levels of TGF-β1, hyaluronic acid, ro-collagen type III and laminin markedly increased in model group as compared to control group (P<0.01), but they decreased dramatically after PAE treatment. The expression of TGF-β1, Smad3/4 and Smad7 in the liver increased significantly in model group as compared to control group (P<0.01), and PAE could down-regulate the expression of Smad3/4 and up-regulate Smad7 expression (P<0.05 or 0.01). The activities of serum amino-transferase and aspartate aminotransferase were significantly higher in hepatic fibrosis group than in normal control group, but PAE treatment markedly reduced them (P<0.05). PAE can inhibit the radiation induced hepatic fibrosis via regulating TGF-β1/Smads signaling pathway.


Reflectance spectral analysis for novel characterization and clinical assessment of aspirated coronary thrombi in patients with ST elevation myocardial infarction.
The visual appearance of coronary thrombi may be clinically informative in ST elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). However, subjective assessment is poorly reproducible and cannot provide an objective basis for treatment decisions or patient stratification. We have assessed the feasibility of a novel reflectance spectroscopy technique to systematically characterize coronary artery thrombi retrieved by aspiration during pPCI in patients with STEMI, and the clinical utility for predicting distal microvascular obstruction. Patients with STEMI treated with pPCI and thrombus aspiration (n = 288) were recruited from the Oxford Acute Myocardial Infarction (OxAMI) Study. Of these, 158 patients underwent cardiac magnetic resonance imaging within 48 h for assessment of microvascular obstruction (MVO). Coronary thrombi were imaged by reflectance spectroscopy across wavelengths 500-800 nm. Spectral data were analysed using function fitting and multivariate models. The coefficient 'c red' determined from the fitting procedure correlated with the visually-assessed colour of thrombi ('red' or 'white') and with MVO. When applied to a reduced data set, consisting of spectra from 20 patients with the largest MVO and from 20 propensity-score-matched patients with no MVO, three multivariate analysis methods were able to discriminate spectra of thrombi from patients without MVO and with the largest MVO. Reflectance spectral analysis of coronary thrombus provides new insights into the pathology of STEMI, with potential clinical implications for emergency patient care. Further studies are warranted for validation as a point-of-care stratification tool in predicting the degree of microvascular injury and clinical outcomes in STEMI.


A cross-sectional study exploring the different roles of individual and group assessment methods in assessing public health nutrition competence.
Competency in the practice of public health is essential for dietitians, yet little is known about credible and dependable assessment in this field. The present study aimed to investigate the role of individual and group assessment tasks as elements of a public health nutrition competency-based assessment system. Assessment performance data from 158 dietetics students (three group tasks and one individual task) who had completed a practical placement learning experience in a public health nutrition setting were examined using nonparametric techniques. All 158 students were deemed individually 'competent' on completion of the placement. The median mark was significantly lower for the individual compared to the group task, with a greater range of marks achieved in the individual assessment. There was a weak relationship between individual and group marks for the whole cohort (n = 158) (Spearman's rho correlation coefficient = 0.193, P = 0.015). Bland-Altman analysis showed that the mean (SD) agreement between the two assessment tasks was -5.9 (17.7) marks. Systematic bias between the two tasks was also demonstrated, indicating that students with the lowest average mark of the two assessments scored lower on the individual assessment task compared to their group task and those who had a higher average mark scored higher on the individual group assessment compared to their group task. Student performance in public health differs between individual and group assessment. Individual assessment appears to differentiate between students, yet group work is essential for the development of teamwork skills. Both should be considered in the judgement of public health nutrition competency.


Global effects of homocysteine on transcription in Escherichia coli: induction of the gene for the major cold-shock protein, CspA.
Homocysteine (Hcy) is a thiol-containing amino acid that is considered to be medically important because it is linked to the development of several life-threatening diseases in humans, including cardiovascular disease and stroke. It inhibits the growth of Escherichia coli when supplied in the growth medium. Growth inhibition is believed to arise as a result of partial starvation for isoleucine, which occurs because Hcy perturbs the biosynthesis of this amino acid. This study attempted to further elucidate the inhibitory mode of action of Hcy by examining the impact of exogenously supplied Hcy on the transcriptome. Using gene macroarrays the transcript levels corresponding to 68 genes were found to be reproducibly altered in the presence of 0.5 mM Hcy. Of these genes, the biggest functional groups affected were those involved in translation (25 genes) and in amino acid metabolism (19 genes). Genes involved in protection against oxidative stress were repressed in Hcy-treated cells and this correlated with a decrease in catalase activity. The gene showing the strongest induction by Hcy was cspA, which encodes the major cold-shock protein CspA. RT-PCR and reporter fusion experiments confirmed that cspA was induced by Hcy. Induction of cspA by Hcy was not caused by nutritional upshift, a stimulus known to induce CspA expression, nor was it dependent on the presence of a functional CspA protein. The induction of cspA by Hcy was suppressed when isoleucine was included in the growth medium. These data suggest that the induction of CspA expression in the presence of Hcy occurs because of a limitation for isoleucine. The possibility that Hcy-induced cspA expression is triggered by translational stalling that occurs when the cells are limited for isoleucine is discussed.


Comparison of fluorescent gentamicin-thallous-carbonate and KF streptococcal agars to enumerate enterococci and fecal streptococci in meats.
Two selective and differential media were compared for their abilities to enumerate enterococci and fecal streptococci in pork, beef, and poultry products. Counts obtained on KF streptococcal (KF) agar were compared with counts obtained on fluorescent gentamicin-thallous-carbonate (fGTC) agar. Reactions of 13 known enterococcal species were also observed. All 13 species of enterococci as well as Streptococcus bovis and Streptococcus equinus grew equally well on fGTC agar. KF streptococcal medium allowed growth of most species of enterococci but not S. bovis and S. equinus. Quantitative comparisons between the two media inoculated with pure cultures of known species of enterococci revealed equivalent plate counts following incubation. However, when meat samples were plated, counts on fGTC agar were consistently and significantly higher than counts on KF agar for all sample sources.


Gene-environment Interactions in the Etiology of Dental Caries.
Dental caries is a multifactorial disease that can be conceptualized as an interaction between genetic and environmental risk factors. The aim of this study is to examine the effects of AMELX, CA6, DEFB1, and TAS2R38 gene polymorphism and gene-environment interactions on caries etiology and susceptibility in adults. Genomic DNA was extracted from the buccal mucosa, and adults aged 20 to 60 y were placed into 1 of 2 groups: low caries risk (DMFT ≤ 5; n = 77) and high caries risk (DMFT ≥ 14; n = 77). The frequency of AMELX (+522), CA6 (T55M), DEFB1 (G-20A), and TAS2R38 (A49P) single-nucleotide polymorphisms was genotyped with the polymerase chain reaction-restriction fragment length polymorphism method. Environmental risk factors examined in the study included plaque amount, toothbrushing frequency, dietary intake between meals, saliva secretion rate, saliva buffer capacity, mutans streptococci counts, and lactobacilli counts. There was no difference between the caries risk groups in relation to AMELX (+522) polymorphism (χ(2) test, P > 0.05). The distribution of CA6 genotype and allele frequencies in the low caries risk group did not differ from the high caries risk group (χ(2) test, P > 0.05). Polymorphism of DEFB1 (G-20A) was positively associated, and TAS2R38 (A49P) negatively associated, with caries risk (χ(2) test, P = 0.000). There were significant differences between caries susceptibility and each environmental risk factor, except for the saliva secretion rate (Mann-Whitney U test, P = 0.000). Based on stepwise multiple linear regression analyses, dental plaque amount, lactobacilli count, age, and saliva buffer capacity, as well as DEFB1 (G-20A), TAS2R38 (A49P), and CA6 (T55M) gene polymorphism, explained a total of 87.8% of the variations in DMFT scores. It can be concluded that variation in CA6 (T55M), DEFB1 (G-20A), and TAS2R38 (A49P) may be associated with caries experience in Turkish adults with a high level of dental plaque, lactobacilli count, and age and when saliva buffer capacity is low.


Structural and functional characterization of Salmonella enterica serovar Typhimurium YcbL: an unusual Type II glyoxalase.
YcbL has been annotated as either a metallo-β-lactamase or glyoxalase II (GLX2), both members of the zinc metallohydrolase superfamily, that contains many enzymes with a diverse range of activities. Here, we report crystallographic and biochemical data for Salmonella enterica serovar Typhimurium YcbL that establishes it as GLX2, which differs in certain structural and functional properties compared with previously known examples. These features include the insertion of an α-helix after residue 87 in YcbL and truncation of the C-terminal domain, which leads to the loss of some recognition determinants for the glutathione substrate. Despite these changes, YcbL has robust GLX2 activity. A further difference is that the YcbL structure contains only a single bound metal ion rather than the dual site normally observed for GLX2s. Activity assays in the presence of various metal ions indicate an increase in activity above basal levels in the presence of manganous and ferrous ions. Thus, YcbL represents a novel member of the GLX2 family.


Expression of type 1 fimbriae (SEF 21) of Salmonella enterica serotype enteritidis in the early colonisation of the rat intestine.
The involvement of type 1 fimbriae in colonisation of the rat gastrointestinal tract in vivo was investigated with Salmonella enterica serotype Enteritidis LA5 and a mutant of LA5 denoted EAV3 unable to elaborate type 1 fimbriae (SEF 21). Rats were given a single dose of LA5 or EAV3 or a 1:1 mixture of both. LA5 was found in higher numbers in the stomach and small intestine than EAV3 at 6 h after infection with a single strain, but not after 6 days. LA5 did not out-compete EAV3 when the strains were administered together. Indeed, after 6 and 21 days, EAV3 was found in the distal small intestine and large intestine in far higher numbers than LA5. These findings suggest that SEF 21 have an important role(s) in the early stages of infection in vivo. However, SEF 21 expression may disadvantage the pathogen in the longer term as indicated by EAV3 out-competing LA5 in the gut at 21 days.


Patterns of occurrence and implications of neratinib-associated diarrhea in patients with HER2-positive breast cancer: analyses from the randomized phase III ExteNET trial.
We characterized patterns of occurrence and the impact of neratinib-associated diarrhea in the absence of protocol-directed antidiarrheal prophylaxis or a formal diarrhea management plan using data from Extended Adjuvant Treatment of Breast Cancer with Neratinib (ExteNET). ExteNET is a multicenter, double-blind, placebo-controlled, randomized phase III trial involving community-based and academic institutions in 40 countries. Women with HER2-positive early-stage breast cancer with prior standard primary therapy and trastuzumab-based (neo)adjuvant therapy were randomized to neratinib 240 mg/day or placebo for 12 months. Safety, a secondary outcome, was assessed using the National Cancer Institute Common Terminology Criteria version 3.0. Health-related quality of life by diarrhea grade was assessed using Functional Assessment of Cancer Therapy-Breast (FACT-B). Two thousand eight hundred sixteen women (1408 per group) were safety-evaluable. Grade 3 and 4 diarrhea occurred in 561 (39.8%) and 1 (0.1%) patients with neratinib versus 23 (1.6%) and 0 patients with placebo, respectively. In the neratinib group, 28.6% of patients had grade 3 events during month 1 decreasing to ≤ 6% after month 3. The median cumulative duration of grade 3/4 diarrhea with neratinib was 5 days (interquartile range, 2-9). Serious diarrheal events (n = 22, 1.6%) and diarrheal events requiring hospitalization (n = 20, 1.4%) were rare with neratinib. Changes in FACT-B total score by diarrhea grade in the neratinib group did not meet the threshold for clinically important differences. In the absence of antidiarrheal prophylaxis, neratinib-related diarrhea is short-lived and not associated with complications or long-term sequelae. This suggests that targeted preventive management with antidiarrheal prophylaxis early during neratinib treatment is appropriate. ClinicalTrials.gov NCT00878709. Registered 9 April 2009.


Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes: a science advisory from the American Heart Association.
The results of cohort studies relating sodium (Na) intake to blood pressure-related cardiovascular disease (CVD) are inconsistent. To understand whether methodological issues account for the inconsistency, we reviewed the quality of these studies. We reviewed cohort studies that examined the association between Na and CVD. We then identified methodological issues with greatest potential to alter the direction of association (reverse causality, systematic error in Na assessment), some potential to alter the direction of association (residual confounding, inadequate follow-up), and the potential to yield false null results (random error in Na assessment, insufficient power). We included 26 studies with 31 independent analyses. Of these, 13 found direct associations between Na and CVD, 8 found inverse associations, 2 found J-shaped associations, and 8 found null associations only. On average there were 3 to 4 methodological issues per study. Issues with greater potential to alter the direction of association were present in all but 1 of the 26 studies (systematic error, 22; reverse causality, 16). Issues with lesser potential to alter the direction of association were present in 18 studies, whereas those with potential to yield false null results were present in 23. Methodological issues may account for the inconsistent findings in currently available observational studies relating Na to CVD. Until well-designed cohort studies in the general population are available, it remains appropriate to base Na guidelines on the robust body of evidence linking Na with elevated blood pressure and the few existing general population trials of the effects of Na reduction on CVD.


Frequency, Morbidity, and Mortality of Bone Metastases in Advanced Hepatocellular Carcinoma.
Background: Bone metastases are common in hepatocellular carcinoma (HCC), but their incidence, morbidity, and mortality are not well defined. Methods: The Memorial Sloan Kettering Cancer Center database was queried for all patients with HCC and metastases seen from 2002 to 2014. The prevalence of bone metastasis was determined and cumulative incidence function was used to estimate the probability of developing a bone metastasis. Regression models were created to identify risk factors for osseous metastasis. The frequency of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, need for radiation therapy to bone, and/or surgical resection of bone, was determined and cumulative incidence function was used to estimate the probability of SRE development. Regression models were created to identify SRE risk factors. Correlation of clinicopathologic parameters, including bone metastases and SREs, with overall survival was analyzed using Kaplan-Meier methodology. Results: A total of 459 patients with HCC and extrahepatic metastases were identified; 151 patients (32.9%) had or developed bone metastases: 128 (27.9%) as a primary site and 23 (4.6%) as a secondary site of extrahepatic disease. Among the 331 patients without bone metastasis at presentation, the yearly incidence of bone metastasis was 6.4% (95% CI, 3.6%-9.2%). Hepatitis B virus (HBV) infection increased the chance of developing a bone metastasis (P=.02). The cumulative incidence of SREs was 50% at 6 months. Univariate analysis showed that patients with HBV-related HCC had a significantly higher incidence of SREs (P=.02). Sorafenib and bisphosphonates each protected against SREs. The presence of SREs was independently associated with a worse overall survival (hazard ratio, 2.13; 95% CI, 1.52-2.97; P<.01) in the multivariable model. Conclusions: Patients with AJCC stage IV HCC and bone metastases that are clinically evident on routine radiography or on clinical examination at presentation are apt to develop frequent, morbid, and mortal SREs, whereas those without evident bone metastasis at presentation are unlikely to develop these complications.


Robotic-assisted laparoscopic repair of ureteral injury: an evidence-based review of techniques and outcomes.
Iatrogenic ureteral injuries represent a common surgical problem encountered by practicing urologists. With the rapidly expanding applications of robotic-assisted laparoscopic surgery, ureteral reconstruction has been an important field of recent advancement. This collaborative review sought to provide an evidence-based analysis of the latest surgical techniques and outcomes for robotic-assisted repair of ureteral injury. A systematic review of the literature up to December 2017 using PubMed/Medline was performed to identify relevant articles. Those studies included in the systematic review were selected according to Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria. Additionally, expert opinions were included from study authors in order to critique outcomes and elaborate on surgical techniques. A cumulative outcome analysis was conducted analyzing comparative studies on robotic versus open ureteral repair. Thirteen case series have demonstrated the feasibility, safety, and success of robotic ureteral reconstruction. The surgical planning, timing of intervention, and various robotic reconstructive techniques need to be tailored to the specific case, depending on the location and length of the injury. Fluorescence imaging can represent a useful tool in this setting. Recently, three studies have shown the feasibility and technical success of robotic buccal mucosa grafting for ureteral repair. Soon, additional novel and experimental robotic reconstructive approaches might become available. The cumulative analysis of the three available comparative studies on robotic versus open ureteral repair showed no difference in operative time or complication rate, with a decreased blood loss and hospital length of stay favoring the robotic approach. Current evidence suggests that the robotic surgical platform facilitates complex ureteral reconstruction in a minimally invasive fashion. High success rates of ureteral repair using the robotic approach mirror those of open surgery, with the additional advantage of faster recovery. Novel techniques in development and surgical adjuncts show promise as the role of robotic surgery evolves.


The distribution of heavy-chain isoforms of myosin in airways smooth muscle from adult and neonate humans.
Changes in the expression of heavy chains of myosin during development determine the functional characteristics of striated muscles. The distribution of heavy-chain isoforms of smooth-muscle myosin was determined in the airways of adult and infant humans to see whether it might underlie the hyperreactivity of human airways. The protein bands corresponding to myosin were separated using SDS/polyacrylamide-gel electrophoresis (4% gels) and identified by immunoblotting using both monoclonal and polyclonal antibodies against smooth-muscle myosin and non-muscle myosin. The relative proportion of each heavy chain stained by Coomassie Blue was measured by densitometric scanning. Three major bands corresponding to myosin heavy-chain isoforms were found; the two slower migrating bands (MHC1 and MHC2) were smooth-muscle myosin, and the third band was non-muscle myosin. The MHC1/MHC2 ratio was 0.69:1 in adult bronchus, and in infant bronchus and trachea. This contrasted with the airway smooth muscle in pigs, which was run concurrently, where the smooth-muscle heavy-chain ratio changed with development [Mohammad & Sparrow (1988) FEBS Lett. 228, 109-112]. The non-muscle myosin heavy chain comprised 63% of the smooth-muscle myosin. In both adult and infant lungs an additional putative myosin heavy chain which migrated slightly more rapidly than non-muscle myosin heavy chain was identified using the monoclonal smooth-muscle myosin antibody BF 48. This was unique to the human species.


Hypnosis can reduce pain in hospitalized older patients: a randomized controlled study.
Chronic pain is a common and serious health problem in older patients. Treatment often includes non pharmacological approaches despite a relatively modest evidence base in this population. Hypnosis has been used in younger adults with positive results. The main objective of this study was to measure the feasibility and efficacy of hypnosis (including self hypnosis) in the management of chronic pain in older hospitalized patients. A single center randomized controlled trial using a two arm parallel group design (hypnosis versus massage). Inclusion criteria were chronic pain for more than 3 months with impact on daily life activities, intensity of > 4; adapted analgesic treatment; no cognitive impairment. Brief pain inventory was completed. Fifty-three patients were included (mean age: 80.6 ± 8.2--14 men; 26 hypnosis; 27 massage. Pain intensity decreased significantly in both groups after each session. Average pain measured by the brief pain index sustained a greater decrease in the hypnosis group compared to the massage group during the hospitalisation. This was confirmed by the measure of intensity of the pain before each session that decreased only in the hypnosis group over time (P = 0.008). Depression scores improved significantly over the time only in the hypnosis group (P = 0.049). There was no effect in either group 3 months post hospitals discharge. Hypnosis represents a safe and valuable tool in chronic pain management of hospitalized older patients. In hospital interventions did not provide long term post discharge relief. ISRCTN15615614; registered 2/1/2015.


[Incomplete and accessory pulmonary fissures studied by high resolution x-ray computed tomography].
High resolution CT examinations with 1.5 mm thick slices were performed on 30 healthy volunteers for the study of normal and accessory pulmonary fissures. In only one case were the three fissures entirely present. The major fissure is incomplete in 87% of the cases on the right side, and in 77% on the left side. When a part of a fissure is absent it is always the internal part. One or more accessory fissures were seen in 59% of the cases. The most frequent accessory fissures are in the inferior lobes (33%). A left minor fissure was seen in 10% of the cases. Some aspects of the top of the minor fissures (opacity, false cavitary lesion) which can be misinterpreted are emphasized.


Invited review: Advances in starter cultures and cultured foods.
With 2005 retail sales close to $4.8 million, cultured dairy products are driving the growth of dairy foods consumption. Starter cultures are of great industrial significance in that they play a vital role in the manufacturing, flavor, and texture development of fermented dairy foods. Furthermore, additional interest in starter bacteria has been generated because of the data accumulating on the potential health benefits of these organisms. Today, starter cultures for fermented foods are developed mainly by design rather than by the traditional screening methods and trial and error. Advances in genetics and molecular biology have provided opportunities for genomic studies of these economically significant organisms and engineering of cultures that focuses on rational improvement of the industrially useful strain. Furthermore, much research has been published on the health benefits associated with ingesting cultured dairy foods and probiotics, particularly their role in modulating immune function. The aim of this review is to describe some of the major scientific advances made in starter and non-starter lactic acid bacteria during the past 10 yr, including genomic studies on dairy starter cultures, engineering of culture attributes, advances in phage control, developments in methods to enumerate lactic acid bacteria and probiotics in dairy foods, and the potential role of cultured dairy foods in modulation of immune function.


Mutated Pathways as a Guide to Adjuvant Therapy Treatments for Breast Cancer.
Adjuvant therapy following breast cancer surgery generally consists of either a course of chemotherapy, if the cancer lacks hormone receptors, or a course of hormonal therapy, otherwise. Here, we report a correlation between adjuvant strategy and mutated pathway patterns. In particular, we find that for breast cancer patients, pathways enriched in nonsynonymous mutations in the chemotherapy group are distinct from those of the hormonal therapy group. We apply a recently developed method that identifies collaborative pathway groups for hormone and chemotherapy patients. A collaborative group of pathways is one in which each member is altered in the same-generally large-number of samples. In particular, we find the following: (i) a chemotherapy group consisting of three pathways and a hormone therapy group consisting of 20, the members of the two groups being mutually exclusive; (ii) each group is highly enriched in breast cancer drivers; and (iii) the pathway groups are correlates of subtype-based therapeutic recommendations. These results suggest that patient profiling using these pathway groups can potentially enable the development of personalized treatment plans that may be more accurate and specific than those currently available.