Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders.
The detection and identification of retroviral transcripts in brain samples, cerebrospinal fluid, and plasma of individuals with recent-onset schizophrenia and schizoaffective disorders suggest that activation or upregulation of distinct human endogenous retroviruses (HERVs) may play a role in the etiopathogenesis of neuropsychiatric diseases. To test this hypothesis, we performed a comprehensive microarray-based analysis of HERV transcriptional activity in human brains. We investigated 50 representative members of 20 HERV families in a total of 215 brain samples derived from individuals with schizophrenia or bipolar disorders and matched controls. A characteristic brain-specific retroviral activity profile was found that consists of members of the class I families HERV-E, HERV-F, and ERV9 and members of HERV-K taxa. In addition to these constitutively expressed HERVs, a number of differentially active HERV elements were identified in all brain samples independent of the disease pattern that may reflect differences in the genetic background of the tested individuals. Only a subgroup of the HML-2 family (HERV-K10) was significantly overrepresented in both bipolar-disorder- and schizophrenia-associated samples compared to healthy brains, suggesting a potential association with disease. Real-time PCR analysis of HERV env transcripts with coding capacity potentially involved in neuroinflammatory conditions revealed that env expression of HERV-W, HERV-FRD, and HML-2 remains unaffected regardless of the clinical picture. Our data suggest that HERV transcription in brains is weakly correlated with schizophrenia and related diseases but may be influenced by the individual genetic background, brain-infiltrating immune cells, or medical treatment.


Drowning in a sea of advice: pediatricians and American Academy of Pediatrics policy statements.
The proliferation of policy statements from the American Academy of Pediatrics presents pediatricians with an increasing amount of health advice to deliver, yet no quantitative estimates of pediatric health advice expectations exist in the literature. The objective of this study was to quantify and characterize verbal health advice that pediatricians are expected to deliver to patients/guardians. The authors read and coded the 344 American Academy of Pediatrics policy statements that are contained in the American Academy of Pediatrics' Pediatric Clinical Practice Guidelines and Policies, Third Edition, and identified 57 policies that contained health advice directives that are broadly relevant to pediatric practice. We extracted the individual advice text to a database in which we also coded its date of issue, its theme, and whether (1) it was duplicated in another policy, (2) a screening question was required to identify a target population for the advice, (3) handouts or other aids to delivering the advice were referenced in the policy itself, or (4) the text of the statement referred to evidence of the effectiveness of office-based delivery of the advice. These 57 policies were found to contain 192 discrete health advice directives that pediatricians are expected to deliver to patients/guardians. Seven (4%) of these directives originated before 1993, and 185 (96%) were created from 1993 to 2002. After removal of the 30 (16%) duplicates, safety advice composed 67%, media use composed 12%, substance abuse composed 5%, environmental health hazards composed 4%, development/emotional health composed 4%, sexuality and pregnancy composed 3%, nutrition composed 2%, and miscellaneous composed 3%. In 41% of the directives, a screening question was required to identify the target population for the advice. Aids to delivering advice were referenced in 20% of the policies. In no policy statements did the text refer to evidence that office-based counseling was an effective method to achieve the desired health or behavioral outcome. We examined the American Academy of Pediatrics policy statements and found 162 different verbal health advice directives on which pediatricians should counsel parents and patients throughout childhood. The expectation that delivery of all of this advice can be achieved is unrealistic. Moreover, none of the reviewed statements were found to include an evidence-based discussion of the efficacy of the suggested advice. In light of these findings, we suggest that committees should consider both the feasibility and the evidence of efficacy of office-based health advice when generating future policy statements.


Pilot study on verification of effectiveness on operability of assistance system for robotic tele-surgery using simulation.
Tele-surgery enables medical care even in remote regions, and has been accomplished in clinical cases by means of dedicated communication lines. To make tele-surgery a more widespread method of providing medical care, a surgical environment needs to be made available using public lines of communication, such as the Internet. Moreover, a support system during surgery is required, as the use of surgical tools is performed in an environment subject to delay. In our research, we focus on the operability of specific tasks conducted by surgeons during a medical procedure, with the aim of clarifying, by means of a simulation, the optimum environment for robotic tele-surgery. In the study, we set up experimental systems using our proposed simulation system. In addition, we investigate the mental workloads on subjects and verify the effect of visual-assistance information as a pilot study. The operability of the task of gripping soft tissue was evaluated using a subjective workload assessment tool, the NASA Task Load Index. Results show that the tasks were completed, but the workload did not improve to less than 300ms and 400ms in the simulated environment. Verifying the effect of the support system was an important task under a more-than 200ms delay using this experiment, and future studies will evaluate the operability of the system under varying conditions of comfort. In addition, an intra-operative assistance system will be constructed using a simulation.


Viscous compressible hydrodynamics at planes, spheres and cylinders with finite surface slip.
We consider the linearized time-dependent Navier-Stokes equation including finite compressibility and viscosity. We first constitute the Green's function, from which we derive the flow profiles and response functions for a plane, a sphere and a cylinder for arbitrary surface slip length. For high driving frequency the flow pattern is dominated by the diffusion of vorticity and compression, for low frequency compression propagates in the form of sound waves which are exponentially damped at a screening length larger than the sound wave length. The crossover between the diffusive and propagative compression regimes occurs at the fluid's intrinsic frequency omega approximately c2rho0/eta, with c the speed of sound, rho0 the fluid density and eta the viscosity. In the propagative regime the hydrodynamic response function of spheres and cylinders exhibits a high-frequency resonance when the particle size is of the order of the sound wave length. A distinct low-frequency resonance occurs at the boundary between the propagative and diffusive regimes. Those resonant features should be detectable experimentally by tracking the diffusion of particles, as well as by measuring the fluctuation spectrum or the response spectrum of trapped particles. Since the response function depends sensitively on the slip length, in principle the slip length can be deduced from an experimentally measured response function.


Successful treatment of three patients with organizing pneumonia associated with rheumatoid arthritis using clarithromycin and prednisolone.
Macrolides have anti-inflammatory effects and have been used to treat diffuse panbronchiolitis, bronchiectasis, and cystic fibrosis. Lately, several cases of cryptogenic organizing pneumonia (COP) and radiotherapy-related organizing pneumonia (OP) that were successfully treated with macrolides considering their anti-inflammatory effects were reported. We report three cases of OP associated with rheumatoid arthritis (RA) successfully treated with clarithromycin (CAM) and prednisolone (PSL). Case 1: A 70-year-old woman suffering from RA was admitted with cough and severe dyspnea. She was diagnosed with OP associated with RA on the basis of computed tomography (CT) findings and transbronchial lung biopsy results. She was successfully treated with PSL and cyclosporine A. At the exacerbation of OP, she was successfully treated with CAM and PSL. Case 2: A 74-year-old man suffering from COP visited our department with arthralgia and articular swellings. He was diagnosed with RA, which was thought to be associated with OP. He was successfully treated with CAM and PSL. Case 3: A 54-year-old man suffering from RA presented with an exacerbation of arthralgia and articular swellings and cough. He was diagnosed with OP associated with RA on the basis of CT findings. He was successfully treated with CAM and PSL. The present cases suggest that CAM and PSL treatment may be effective in some cases of OP associated with RA.


Variations in data collection can influence outcome measures of BMI measuring programmes.
The World Health Organization (WHO) promotes the surveillance of obesity prevalence through standardized and harmonized surveillance systems. However, variations in data collection between countries, or between coordinating regions in countries can affect outcome measures. Multilevel analysis of 2007/08 National Child Measurement Programme (NCMP) data estimating the relationship between BMI z-score and data collection variations within coordinating regions whilst adjusting for individual-level and school-level variables. The 2007/08 NCMP collected height and weight measurements for 478,381 Reception year pupils (4-5-year-olds) and 496,297 year 6 pupils (10-11-year-olds) from 17,279 primary schools in 152 data collection coordinating regions in England. Data collection variables accounted for 29.7% of the regional variation in BMI z-score for Reception year pupils but only 5.3% for the older Year 6 pupils. Digit preference in the rounding of weight measurements had the greatest impact of all the data collection variables, explaining 26.4% of the regional variation in BMI z-score for Reception year pupils and 4.0% for Year 6 pupils. Although variations in data collection may have a small effect on individual measurements their impact can be magnified when scaled up to regional or national figures. All measurement programmes must regularly identify and minimize variations in data collection to improve accuracy of outcome measures. These factors include those identified within this study: participation and opt out rates, the time in the year the measurements are taken and the recording of measurements to the correct decimal place.


Update on fibroblast growth factor 23 in chronic kidney disease.
Chronic kidney disease (CKD) is a public health epidemic that affects millions of people worldwide. Presence of CKD predisposes individuals to high risks of end-stage renal disease (ESRD), cardiovascular disease, and premature death. Disordered phosphate homeostasis with elevated circulating levels of fibroblast growth factor 23 (FGF23) is an early and pervasive complication of CKD. CKD is likely the most common cause of chronically elevated FGF23 levels, and the clinical condition in which levels are most markedly elevated. Although increases in FGF23 levels help maintain serum phosphate in the normal range in CKD, prospective studies in populations of pre-dialysis CKD, incident and prevalent ESRD, and kidney transplant recipients demonstrate that elevated FGF23 levels are independently associated with progression of CKD and development of cardiovascular events and mortality. It was originally thought that these observations were driven by elevated FGF23 levels acting as a highly sensitive biomarker of toxicity due to phosphate. However, FGF23 itself has now been shown to mediate 'off-target,' direct, end-organ toxicity in the heart, which suggests that elevated FGF23 levels may be a novel mechanism of adverse outcomes in CKD. This report reviews recent advances in FGF23 biology relevant to CKD, the classical effects of FGF23 on mineral homeostasis, and the studies that established FGF23 excess as a biomarker and novel mechanism of cardiovascular disease. The report concludes with a critical review of the effects of different therapeutic strategies targeting FGF23 reduction and how these might be leveraged in a future randomized trial aimed at improving outcomes in CKD.


Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation.
Steroids are synthesized in adrenal glands and gonads under the control of pituitary peptides. These peptides bind to cell surface receptors to activate the cyclic AMP (cAMP) signaling pathway leading to an increase of steroidogenic gene expression. Exactly how cAMP activates steroidogenic gene expression is not clear, except for the knowledge that transcription factor SF-1 plays a key role. Investigating the factors participating in SF-1 action, we found that c-Jun and homeodomain-interacting protein kinase 3 (HIPK3) were required for basal and cAMP-stimulated expression of one major steroidogenic gene, CYP11A1. HIPK3 enhanced SF-1 activity, and c-Jun was required for the functional interaction of HIPK3 with SF-1. Furthermore, after cAMP stimulation, both c-Jun and Jun N-terminal kinase (JNK) were phosphorylated through HIPK3. These phosphorylations were important for SF-1 activity and CYP11A1 expression. Thus, we have defined HIPK3-mediated JNK activity and c-Jun phosphorylation as important events that increase SF-1 activity for CYP11A1 transcription in response to cAMP. This finding has linked three common factors, HIPK3, JNK, and c-Jun, to the cAMP signaling pathway leading to increased steroidogenic gene expression.


Estimating Upper-Limb Impairment Level in Stroke Survivors Using Wearable Inertial Sensors and a Minimally-Burdensome Motor Task.
Upper-limb paresis is the most common motor impairment post stroke. Current solutions to automate the assessment of upper-limb impairment impose a number of critical burdens on patients and their caregivers that preclude frequent assessment. In this work, we propose an approach to estimate upper-limb impairment in stroke survivors using two wearable inertial sensors, on the wrist and the sternum, and a minimally-burdensome motor task. Twenty-three stroke survivors with no, mild, or moderate upper-limb impairment performed two repetitions of one-to-two minute-long continuous, random (i.e., patternless), voluntary upper-limb movements spanning the entire range of motion. The three-dimensional time-series of upper-limb movements were segmented into a series of one-dimensional submovements by employing a unique movement decomposition technique. An unsupervised clustering algorithm and a supervised regression model were used to estimate Fugl-Meyer Assessment (FMA) scores based on features extracted from these submovements. Our regression model estimated FMA scores with a normalized root mean square error of 18.2% ( r2=0.70 ) and needed as little as one minute of movement data to yield reasonable estimation performance. These results support the possibility of frequently monitoring stroke survivors' rehabilitation outcomes, ultimately enabling the development of individually-tailored rehabilitation programs.


Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization.
Analysis of perfusion-based bioreactors for organ engineering and a detailed evaluation of physical and biochemical parameters that measure dynamic changes within maturing cell-laden scaffolds are critical components of ex vivo tissue development that remain understudied topics in the tissue and organ engineering literature. Intricately designed bioreactors that house developing tissue are critical to properly recapitulate the in vivo environment, deliver nutrients within perfused media, and monitor physiological parameters of tissue development. Herein, we provide an in-depth description and analysis of two dual-purpose perfusion bioreactors that improve upon current bioreactor designs and enable comparative analyses of ex vivo scaffold recellularization strategies and cell growth performance during long-term maintenance culture of engineered kidney or liver tissues. Both bioreactors are effective at maximizing cell seeding of small-animal organ scaffolds and maintaining cell survival in extended culture. We further demonstrate noninvasive monitoring capabilities for tracking dynamic changes within scaffolds as the native cellular component is removed during decellularization and model human cells are introduced into the scaffold during recellularization and proliferate in maintenance culture. We found that hydrodynamic pressure drop (ΔP) across the retained scaffold vasculature is a noninvasive measurement of scaffold integrity. We further show that ΔP, and thus resistance to fluid flow through the scaffold, decreases with cell loss during decellularization and correspondingly increases to near normal values for whole organs following recellularization of the kidney or liver scaffolds. Perfused media may be further sampled in real time to measure soluble biomarkers (e.g., resazurin, albumin, or kidney injury molecule-1) that indicate degree of cellular metabolic activity, synthetic function, or engraftment into the scaffold. Cell growth within bioreactors is validated for primary and immortalized cells, and the design of each bioreactor is scalable to accommodate any three-dimensional scaffold (e.g., synthetic or naturally derived matrix) that contains conduits for nutrient perfusion to deliver media to growing cells and monitor noninvasive parameters during scaffold repopulation, broadening the applicability of these bioreactor systems.


The agreement between self-reported cervical smear abnormalities and screening programme records.
The Million Women Study is a cohort study of women aged 50-64 years in England and Scotland. As a component of the follow-up questionnaire, participants were asked to indicate if they had an abnormal cervical smear in the previous five years. This study compared self-reported cervical abnormalities with screening records obtained from the National Health Service Cervical Screening Programme. For 1944 randomly selected Million Women Study participants in Oxfordshire, screening records were assessed over a six-year period prior to the date of self-reporting. The six-year period was chosen to allow for errors in the recall of timing of abnormal smears. A total of 68 women (3.5%) had a record of at least one equivocal or abnormal smear within the last six years, whereas 49 women (2.5%) self-reported an abnormality. There was a strong trend for an increased probability of self-reporting a history of an abnormal smear as the severity of the recorded abnormality increased (P <0.001). For women with an NHS record of borderline dyskaryosis, mild dyskaryosis, or moderate dyskaryosis/severe dyskaryosis/invasive cancer, the proportions reporting an abnormality were 40%, 58% and 77%, respectively. For women with negative and inadequate smears, the proportion self-reporting an abnormality were 0.6% and 0.7%, respectively. These results indicate that among women whose screening programme records show an abnormal smear, the proportion self-reporting an abnormality increases with the severity of the recorded lesion. Almost all women with a record of negative or inadequate smear(s) correctly interpret the result and do not self-report an abnormality.


RADIOGRAPHIC HIP OSTEOARTHRITIS IS PREVALENT, AND IS RELATED TO CAM DEFORMITY 12-24 MONTHS POST-HIP ARTHROSCOPY.
The prevalence of radiographic hip osteoarthritis (OA), and its relationship with outcomes after hip arthroscopy is unclear. The aims of this study were to: (i) describe the prevalence of OA and cam deformity 12-24 months post hip arthroscopy; (ii) to determine the association between radiographic OA and cam deformity, surgical and clinical findings and symptoms; and (iii) describe the differences between legs for radiological and clinical findings. Cross sectional study. Seventy patients, mean age 36.7(range 18-59) years, 12-24 months post-arthroscopy. Outcomes were collected prospectively via clinical and radiographic examination. (i)Prevalence of OA and cam deformity measured on and anteroposterior pelvic radiographs; (ii)Hip disability and Osteoarthritis Outcome Score (HOOS) and International Hip Outcome Tool (iHOT-33) patient-reported outcomes (PROs); (iii)hip internal and external rotation range of motion (ROM). Associations between OA and surgical findings, PROs and clinical findings were determined using generalized estimated equations, between operated and non-operated sides. The prevalence of OA was 37%. The likelihood of OA 12-24 months after surgery was positively associated with alpha angle size 12-24 months post-hip arthroscopy surgery (p=0.010). There were no differences between operated and non-operated legs in radiographic or clinical findings. Radiographic OA is prevalent in a population which has undergone hip arthroscopy. Increased OA severity is associated with a higher alpha angle 12-24 months post-surgery. Cross-sectional study Level IV.


When Sharing Is a Bad Idea: The Effects of Online Social Network Engagement and Sharing Passwords with Friends on Cyberbullying Involvement.
Every day, children and adolescents communicate online via social networking sites (SNSs). They also report sharing passwords with peers and friends, a potentially risky behavior in regard to cyber safety. This longitudinal study tested the hypotheses that social network engagement in multiple settings would predict more cyberbullying involvement over time, and that youth who reported sharing passwords would also experience an increase in cyberbullying involvement. Data were collected at two time points one year apart from 1,272 third through eighth grade students. In line with the first study hypothesis, participating in more online SNSs was associated with increased cyberbullying involvement over time, as well as sharing passwords over time. Cyberbullying involvement at T1 predicted decreases in sharing passwords over time, suggesting that youth become aware of the dangers of sharing passwords as a result of their experience. Sharing passwords at T1 was unrelated to cyberbullying involvement at T2. Although it seems that youth may be learning from their previous mistakes, due to the widespread use of social media and normality of sharing passwords among young people, it is important to continue to educate youth about cyber safety and risky online behavior.


Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.
Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH. This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity. APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.


The reality of Neandertal symbolic behavior at the Grotte du Renne, Arcy-sur-Cure, France.
The question of whether symbolically mediated behavior is exclusive to modern humans or shared with anatomically archaic populations such as the Neandertals is hotly debated. At the Grotte du Renne, Arcy-sur-Cure, France, the Châtelperronian levels contain Neandertal remains and large numbers of personal ornaments, decorated bone tools and colorants, but it has been suggested that this association reflects intrusion of the symbolic artifacts from the overlying Protoaurignacian and/or of the Neandertal remains from the underlying Mousterian. We tested these hypotheses against the horizontal and vertical distributions of the various categories of diagnostic finds and statistically assessed the probability that the Châtelperronian levels are of mixed composition. Our results reject that the associations result from large or small scale, localized or generalized post-depositional displacement, and they imply that incomplete sample decontamination is the parsimonious explanation for the stratigraphic anomalies seen in the radiocarbon dating of the sequence. The symbolic artifacts in the Châtelperronian of the Grotte du Renne are indeed Neandertal material culture.


Effect of rosmarinic acid on sertoli cells apoptosis and serum antioxidant levels in rats after exposure to electromagnetic fields.
Rosmarinic acid belongs to the group of polyphenols; it has antioxidant, anti-inflammatory and antimicrobial activities and help to prevent cell damage caused by free radicals. The objective was to study the effect of Rosmarinic acid on sertolli cells apoptosis and serum antioxidant levels in rats after they were exposed to electromagnetic fields. Male Wistar rats (n=40) were allocated into three groups: control group (n=10) that received 5 cc normal saline (0.9% NaCl) daily by gavage method, Rosmarinic acid group that received 5mg/rat (gavage) (n=10), electromagnetic fields (EMF) group that had exposure with 50 hz (n=20) which was subdivided to two groups of 10; EMF group and treatment group. Treatment group received 5mg/rat (gavage) Rosmarinic acid daily for 6 weeks, respectively. However, the control group just received an equal volume of distilled water daily (gavage). On the 42nd day of research, 5 cc blood was collected to measure testosterone hormones, total antioxidant capacity (TAC), levels from whole group's analysis. Level of malondialdehyde (MDA) levels and sertoli cells apoptosis significantly decreased in the group that received 5mg/rat of Rosmarinic acid (P<0.05) in comparison with experimental groups. Level of testosterone, total antioxidant capacity (TAC), significantly increased in groups that received Rosmarinic acid (P<0.05). Since in our study 5mg/rat of Rosmarinic acid showed significantly preventive effect on cell damages especial sertoli cells apoptosis that caused with EMF, it seems that using Rosmarinic acid as food additive can be effective for supporting people living under EMF environmental pollution.


A portable pneumatic driving unit for a left ventricular assist device.
The authors developed a portable air driving unit for an artificial heart. As the portable energy source of the driver, a commercially available Ni-Cd battery was used. A linear compressor was selected as a portable size compressor. To reduce the number of parts to be assembled, a new type of pneumatic system was employed. In this system, the pressure level was regulated by varying the output flow rate of the compressor instead of using a pressure regulator and large air reservoirs. A one-board microcomputer and pressure sensors were used to control the pressure level. The total weight of the unit is 9.5 Kg. After assembling the components into the portable unit, a blood pump was connected to examine the output characteristics of the system. It was confirmed that the unit could drive the blood pump continuously for more than 2 hours under the following conditions: output flow rate of the blood pump = 5 L/min and output pressure = 100 mmHg.


Relationship between superelectrophilicity and the electrophilicity index of isolated species.
We report a relationship between the superelectrophilicity of a series of dications and the electrophilicity index of isolated species. The enhanced electrophilicity is described by global and local reactivity indexes. Alkyloxonium and carboxonium dications and diprotonated carboxylic acids have been used as simple benchmark systems to discuss this relationship on a qualitative and quantitative basis. The theoretical scale of electrophilicity roughly reproduces the experimental superelectrophilicity hierarchy established on the basis of the (17)O and (13)C NMR chemical shifts in alkyloxonium and carboxonium ions and diprotonated carboxylic acids.


A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans.
It was recently shown that the genetic distinction between self-identified Ashkenazi Jewish and non-Jewish individuals is a prominent component of genome-wide patterns of genetic variation in European Americans. No study however has yet assessed how accurately self-identified (Ashkenazi) Jewish ancestry can be inferred from genomic information, nor whether the degree of Jewish ancestry can be inferred among individuals with fewer than four Jewish grandparents. Using a principal components analysis, we found that the individuals with full Jewish ancestry formed a clearly distinct cluster from those individuals with no Jewish ancestry. Using the position on the first principal component axis, every single individual with self-reported full Jewish ancestry had a higher score than any individual with no Jewish ancestry. Here we show that within Americans of European ancestry there is a perfect genetic corollary of Jewish ancestry which, in principle, would permit near perfect genetic inference of Ashkenazi Jewish ancestry. In fact, even subjects with a single Jewish grandparent can be statistically distinguished from those without Jewish ancestry. We also found that subjects with Jewish ancestry were slightly more heterozygous than the subjects with no Jewish ancestry, suggesting that the genetic distinction between Jews and non-Jews may be more attributable to a Near-Eastern origin for Jewish populations than to population bottlenecks.


The effects of race on diagnosis and disposition from a psychiatric emergency service.
Previous studies have reported that racial differences exist in patterns of clinical psychiatric diagnoses as well as the distribution of mental health services resources. The psychiatric emergency service serves as an entry point into the mental health system, so it plays a potentially important role in addressing racial disparities in diagnosis and disposition. To address this disparity, the authors studied two specific questions: (1) are there racial differences in diagnosis and (2) are there racial differences in disposition of patients visiting a psychiatric emergency service? Demographic and clinical data were obtained by retrospective chart review of 490 patients randomly selected from 9500 visits to a large psychiatric emergency service during a 1-year period. All clinical information had been recorded by the primary treaters who had no knowledge of this study. Black patients were significantly more likely to be diagnosed with schizophrenia and substance abuse than similar white patients, although less likely to be diagnosed with a personality disorder. Black patients were significantly more likely to be hospitalized, particularly at a public hospital, although there were no significant differences in insurance coverage or measures of suicidal or homicidal ideation. Despite the availability of DSM-III-R criteria, black patients continue to be disproportionately diagnosed with schizophrenia. In this sample, this diagnosis may have been given in lieu of a personality disorder or affective illness diagnosis. Black patients are also more likely to be hospitalized. These observations suggest that further research is needed to clarify the effects of race on the decision-making process in diagnosis and disposition from the psychiatric emergency service.


Avoiding harm and supporting autonomy are under-prioritised in cancer-screening policies and practices.
The ethical principles of avoiding harm and supporting autonomy are relevant to cancer-screening policy. We argue that more attention needs to be given to implementing them. Cancer screening may deliver excessive harms due to low-value or outdated screening programs and from poorly communicated screening options that leave people with heavy burdens of decision-making. Autonomy is inadequately supported due to limited opportunities for people to understand downsides of screening and because of institutional and societal pressures in favour of screening. Members of screening policy committees may have differing ideas about the goals of screening or have conflicts of interest that prevent them from addressing policy questions in a neutral way. We recommend the following: 1. Committees should be required to discern and discuss the values of individual members and the wider public; 2. Committee membership and voting procedures should be more carefully constructed to reduce the likelihood that committee members' interests are placed above public interests; 3. Committees should explain their policy decisions with reference to values as well as evidence, so that values considered in decision-making can be interrogated and challenged if necessary. These changes would increase the likelihood that cancer-screening policy decisions are in keeping with public views about what is important.


Comprehensive analysis of 22 XPC polymorphisms and bladder cancer risk.
Two major risk factors for bladder cancer are smoking and occupational exposure to chemicals. The XPC protein is crucial in the recognition and initiation of the nucleotide excision repair pathway which repairs the DNA adducts formed by carcinogens found in cigarette smoke and chemicals. Polymorphisms in the XPC gene have been shown to influence an individual's DNA repair capacity, and hence, increase that individual's susceptibility to cancer. We undertook a case-control study of 547 bladder cancer cases and 579 cancer-free controls to investigate the association between 22 XPC polymorphisms and bladder cancer susceptibility, and investigated gene-environment interactions. We showed that the nonsynonymous polymorphism Ala(499)Val was in strong linkage disequilibrium with two polymorphisms in the 3'-untranslated region (Ex15-184 and Ex15-177) with Lewontin's D' >or= 0.99 and r2 >or= 0.82. Individuals homozygous for the minor allele of Ala(499)Val, Ex15-184, or Ex15-177 had an increased risk of bladder cancer compared with those homozygous for the common allele [adjusted odds ratio (95% confidence interval), 1.65 (1.05-2.59), 1.82 (1.12-2.97), and 1.82 (1.12-2.96), respectively]. The associations were somewhat stronger for smokers and those occupationally exposed to chemicals, although tests for gene-environment interactions were not significant.


Identification of copper (Cu) stress-responsive grapevine microRNAs and their target genes by high-throughput sequencing.
MicroRNAs (miRNAs) are a class of single-stranded non-coding small RNAs (sRNAs) that are 20-24 nucleotides (nt) in length. Extensive studies have indicated that miRNAs play important roles in plant growth, development and stress responses. With more copper (Cu) and copper containing compounds used as bactericides and fungicides in plants, Cu stress has become one of the serious environmental problems that affect plant growth and development. In order to uncover the hidden response mechanisms of Cu stress, two small RNA libraries were constructed from Cu-treated and water-treated (Control) leaves of 'Summer Black' grapevine. Following high-throughput sequencing and filtering, a total of 158 known and 98 putative novel miRNAs were identified in the two libraries. Among these, 100 known and 47 novel miRNAs were identified as differentially expressed under Cu stress. Subsequently, the expression patterns of nine Cu-responsive miRNAs were validated by quantitative real-time PCR (qRT-PCR). There existed some consistency in expression levels of Cu-responsive miRNAs between high throughput sequencing and qRT-PCR assays. The targets prediction of miRNAs indicates that miRNA may regulate some transcription factors, including AP2, SBP, NAC, MYB and ARF during Cu stress. The target genes for two known and two novel miRNAs showed specific cleavage sites at the 10th and/or 11th nucleotide from the 5'-end of the miRNA corresponding to their miRNA complementary sequences. The findings will lay the foundation for exploring the role of the regulation of miRNAs in response to Cu stress and provide valuable gene information for breeding some Cu-tolerant grapevine cultivars.


What to expect when you're expecting a hepatopancreatobiliary surgeon: self-reported experiences of HPB surgeons from different training pathways.
Hepatopancreatobiliary (HPB) surgery fellowship training has multiple paths. Prospective trainees and employers must understand the differences between training pathways. This study examines self-reported fellowship experiences and current scope of practice across three pathways. An online survey was disseminated to 654 surgeons. These included active Americas Hepato-Pancreato-Biliary Association (AHPBA) members and recent graduates of HPB, transplant-HPB and HPB-heavy surgical oncology fellowships. A total of 416 (64%) surgeons responded. Most respondents were male (89%) and most were practising in an academic setting (83%). 290 (70%) respondents underwent formal fellowship training. Although fellowship experiences varied, current practice was largely similar. Minimally invasive surgery (MIS) and ultrasound were the most commonly identified areas of training deficiencies and were, respectively, cited as such by 47% and 34% of HPB-, 49% and 50% of transplant-, and 52% and 25% of surgical oncology-trained respondents. Non-HPB cases performed in current practice included gastrointestinal (GI) and general surgery cases (56% and 49%, respectively) for HPB-trained respondents, transplant and general surgery cases (87% and 21%, respectively) for transplant-trained respondents, and GI surgery and non-HPB surgical oncology cases (70% and 28%, respectively) for surgical oncology-trained respondents. Fellowship training in HPB surgery varies by training pathway. Training in MIS and ultrasound is deficient in each pathway. The ultimate scope of non-transplant HPB practice appears similar across training pathways. Thus, training pathway choice is best guided by the training experience desired and non-HPB components of anticipated practice.


A clinical anatomic study of internal mammary perforators as recipient vessels for breast reconstruction.
Partially resecting ribs of the recipient site to facilitate easy anastomosis of the internal mammary vessels to free flaps during breast reconstruction can cause chest wall pain or deformities. To avoid this, the intercostal perforating branches of the internal mammary vessels can be used for anastomosis. The purpose of this study was to investigate the location and size of the internal mammary perforator vessels based on clinical intraoperative findings and to determine their reliability as recipient vessels for breast reconstruction with microsurgical free tissue transfer. Twelve patients were preoperatively screened for the presence of internal mammary perforators using Doppler tracing. After modified radical mastectomy was performed by a general surgeon, the location and size of the internal mammary perforator vessels were microscopically investigated. The external diameter was examined using a vessel-measuring gauge from a mechanical coupling device, and the distance from the mid-sternal line to the perforator was also measured. The largest arterial perforator averaged 1.5 mm, and the largest venous perforator averaged 2.2 mm. Perforators emerging from the second intercostal space had the largest average external diameter; the second intercostal space also had the largest number of perforators arising from it. The average distance from the mid-sternal line to the perforator was 20.2 mm. Internal mammary perforators presented consistent and reliable anatomy in this study. Based on these results, the internal mammary perforators appear to have a suitable diameter for microvascular anastomosis and should be considered as an alternative recipient vessel to the internal mammary vessel.


In from the cold: prospects for conversion of the defense industrial base.
At the end of the Cold War, the manufacturing operations involved in making military equipment and commercial goods are commonly believed to intersect hardly at all. Our analyses of 1991 survey data from a large sample of establishments in the machining-intensive durable goods sector show that there are few technical and competitive conditions separating the defense and commercial industrial spheres. Commercial-military integration of production is now the normal practice among the majority of defense contractors in this sector. Moreover, we find little difference between defense and commercial producers in the competitive conditions they face or in the diversity of their customers. However, defense contractors have an advantage over their strictly commercial counterparts because of their greater use of productivity-enhancing technologies.


Prediction of Number of Cases of 2019 Novel Coronavirus (COVID-19) Using Social Media Search Index.
Predicting the number of new suspected or confirmed cases of novel coronavirus disease 2019 (COVID-19) is crucial in the prevention and control of the COVID-19 outbreak. Social media search indexes (SMSI) for dry cough, fever, chest distress, coronavirus, and pneumonia were collected from 31 December 2019 to 9 February 2020. The new suspected cases of COVID-19 data were collected from 20 January 2020 to 9 February 2020. We used the lagged series of SMSI to predict new suspected COVID-19 case numbers during this period. To avoid overfitting, five methods, namely subset selection, forward selection, lasso regression, ridge regression, and elastic net, were used to estimate coefficients. We selected the optimal method to predict new suspected COVID-19 case numbers from 20 January 2020 to 9 February 2020. We further validated the optimal method for new confirmed cases of COVID-19 from 31 December 2019 to 17 February 2020. The new suspected COVID-19 case numbers correlated significantly with the lagged series of SMSI. SMSI could be detected 6-9 days earlier than new suspected cases of COVID-19. The optimal method was the subset selection method, which had the lowest estimation error and a moderate number of predictors. The subset selection method also significantly correlated with the new confirmed COVID-19 cases after validation. SMSI findings on lag day 10 were significantly correlated with new confirmed COVID-19 cases. SMSI could be a significant predictor of the number of COVID-19 infections. SMSI could be an effective early predictor, which would enable governments' health departments to locate potential and high-risk outbreak areas.


Widowhood, family size, and post-reproductive mortality: a comparative analysis of three populations in nineteenth-century Europe.
Researchers from a number of disciplines have offered competing theories about the effects oJ childbearing on parents 'postreproductive longevity. The "disposable soma theory" argues that investments in somatic maintenance increase longevity but reduce childbearing. "Maternal depletion" models suggest that the rigors of childrearing increase mortality in later years. Other researchers consider continued childbearing a sign of healthy aging and a predictor of future longevity. Empirical studies have produced inconsistent and contradictory results. Our focus is on the experience of widowhood, which has been ignored in previous studies. We hypothesize that the death of a spouse is a stressful event with long-term consequences for health, especially for women with small children. Data are drawn from historical sources in Sweden, Belgium, and the Netherlands from 1766 to 1980. Postreproductive mortality was highest among young widows with larger families in all three samples. Age at last birth had little or no effect. We conclude that raising children under adverse circumstances can have long-lasting, harmful effects on a mother's health.


Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice.
The second messenger cAMP plays a critical role in regulating immune responses. Although well known for its immunosuppressive effect, cAMP is also required for the development of optimal immune responses. Thus, the regulation of this second messenger needs to be finely tuned and well balanced in a context dependent manner. To further understand the role of cAMP synthesis in the functions of the immune system, we focus on a specific adenylyl cyclase (AC) isoform, AC VII (AC7), which is highly expressed in the immune system. We show that mice deficient of AC7 are hypersensitive to LPS-induced endotoxic shock. Macrophages from AC7-deficient mice produce more of the proinflammatory cytokine, TNF-alpha, in response to LPS. The inability to generate intracellular cAMP response to serum factors, such as lysophosphatidic acid, is a potential cause for this phenotype. Thus, AC7 functions to control the extent of immune responses toward bacterial infection. However, it is also required for the optimal functions of B and T cells during adaptive immune responses. AC7 is the major isoform that regulates cAMP synthesis in both B and T cells. AC7-deficient mice display compromised Ab responses toward both T cell-independent and T cell-dependent Ags. The generation of memory T cells is also reduced. These results are the first to ascribe specific functions to an AC isoform in the immune system and emphasize the importance of cAMP synthesis by this isoform in shaping the immune responses.


High-dose oral methylprednisolone for the treatment of multiple sclerosis relapses: cost-minimisation analysis and patient's satisfaction.
To study the use of high-dose oral methylprednisolone compounded formulation and intravenous methylprednisolone for the treatment of multiple sclerosis relapses. To compare both routes of methylprednisolone administration related to cost and patient's satisfaction with the treatment. A retrospective cohort observational study was performed from January 2012 to December 2016. All multiple sclerosis relapses treated with high-dose oral methylprednisolone compounded formulation or intravenous methylprednisolone were studied. Patient's acceptance grade of the treatment was analysed with a survey based on the Treatment Satisfaction Questionnaire for Medication. A cost-minimisation analysis using real world data from our hospital was performed to compare the high-dose oral methylprednisolone formulation and intravenous administration. 92 patients were included (88% had recurrent remitting multiple sclerosis). Median Expanded Disability Status Scale score was 2 (IRC: 1-3.5). 162 relapses were treated: 77 with intravenous methylprednisolone and 85 with high-dose oral methylprednisolone formulation. The most frequent prescriptions were 1000 mg intravenous methylprednisolone and 1250 mg oral methylprednisolone during 4 days. Recovery from relapse was achieved in 91% of patients in the intravenous group and 93% in the oral group. The survey revealed that 79% of patients preferred the oral route because of convenience (P<0.001) and global satisfaction (P<0.04). Real world data demonstrated savings of €61 708 (91%) using the high-dose oral methylprednisolone formulation during the study period. High-dose oral methylprednisolone compounded formulation was a cost-effective alternative compared with methylprednisolone intravenous administration. Moreover, patients with multiple sclerosis preferred the oral compounded formulation for the treatment of relapses.


Profile of cognitive deficits and associations with depressive symptoms and intelligence in chronic early-onset schizophrenia patients.
Cognitive deficits in several domains have been demonstrated in early-onset schizophrenia patients but their profile and relation to depressive symptoms and intelligence need further characterization. The purpose was to characterize the profile of cognitive deficits in chronic, early-onset schizophrenia patients, assess the potential associations with depressive symptom severity, and examine whether cognitive deficits within several domains reflect intelligence impairments. This study compared attention, visual-construction, aspects of visual and verbal memory, and executive functions in chronic, early-onset schizophrenia patients (mean age = 20.7 years) (N = 18) and healthy controls (N = 38). Schizophrenia diagnoses were established at the time of the patients' first clinical presentation during childhood or adolescence and were confirmed five years later. In the chronic phase of early-onset schizophrenia, significant deficits were observed in all specific cognitive functions. The profile of cognitive deficits was jagged, and visual-construction, attention, and one aspect of verbal memory (verbal stories recall) were differentially impaired. Deficits of visual recall, visual recognition, and executive functions were accounted for by deficits in intelligence, while this was not the case for deficits of verbal recall of stories or attention. No significant associations were observed between the severity of cognitive deficits and that of depressive symptoms. Chronic, early-onset schizophrenia is characterized by a broad and jagged profile of cognitive deficits. Deficits of attention and verbal recall of stories appear not to be accounted for by deficits in intelligence, and the severity of cognitive deficits seems independent from that of depressive symptoms.


The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review and meta-analysis.
Significant uncertainty remains surrounding the diagnostic accuracy of sonographic features used to predict the malignant potential of thyroid nodules. The objective of the study was to summarize the available literature related to the accuracy of thyroid nodule ultrasound (US) in the prediction of thyroid cancer. We searched multiple databases and reference lists for cohort studies that enrolled adults with thyroid nodules with reported diagnostic measures of sonography. A total of 14 relevant US features were analyzed. We included 31 studies between 1985 and 2012 (number of nodules studied 18,288; average size 15 mm). The frequency of thyroid cancer was 20%. The most common type of cancer was papillary thyroid cancer (84%). The US nodule features with the highest diagnostic odds ratio for malignancy was being taller than wider [11.14 (95% confidence interval 6.6-18.9)]. Conversely, the US nodule features with the highest diagnostic odds ratio for benign nodules was spongiform appearance [12 (95% confidence interval 0.61-234.3)]. Heterogeneity across studies was substantial. Estimates of accuracy depended on the experience of the physician interpreting the US, the type of cancer and nodule (indeterminate), and type of reference standard. In a threshold model, spongiform appearance and cystic nodules were the only two features that, if present, could have avoided the use of fine-needle aspiration biopsy. Low- to moderate-quality evidence suggests that individual ultrasound features are not accurate predictors of thyroid cancer. Two features, cystic content and spongiform appearance, however, might predict benign nodules, but this has limited applicability to clinical practice due to their infrequent occurrence.


Characterization of a human acute phase protein found in association with rubella virus infection.
A precipitating antigen, rho, was first detected in the blood of persons with rubella and in rubella virus-infected cell culture fluids (1). Partially purified antigens from both sources were examined and shown to have similar properties, although antigen from serum sedimented more heterogeneously, with estimated coefficients from 15 to 21 S, while that from culture fluids sedimented in the 11-14 S region. In each case, antigen was located in the beta-1 zone after electrophoresis in agarose, and at a density of 1.305 g/ml after centrifugation in CsCl. Stability characteristics were typical of protein antigens. Immunofluorescent microscopy revealed that rubella virus induced the appearance of rho antigen scattered throughout the cytoplasm of infected cells. When cells containing antigen were exposed for 24 h to 5 microg/ml actinomycin D rho was no longer detectable, indicating the probable cellular origin of the antigen. Also, titers in medium of infected cultures showed a reduction after actinomycin treatment, but levels of the virus-specified antigen, iota, were relatively unaffected. Rho appears to be a protein common to man and many animals. In vitro, it was induced by rubella virus and by adenovirus. In vivo, rho titers were shown to be elevated after rubella virus infection and, to a lesser extent, after infection with certain other viruses. High titers were also demonstrated in women late in pregnancy and in patients with rheumatoid arthritis. In man and the chimpanzee, the appearance and decline of rho in the blood after rubella virus infection were temporally similar to the patterns of CRP, although rho seemed to be a more sensitive indicator of infection. The data presented indicate that rho is a newly recognized acute phase protein inducible by certain virus infections and by other unidentified stimuli present prominently in pregnancy and rheumatoid arthritis.


Light-harvesting complexes access analogue emissive states in different environments.
The light-harvesting complexes (LHCs) of plants can regulate the level of excitation in the photosynthetic membrane under fluctuating light by switching between different functional states with distinct fluorescence properties. One of the most fascinating yet obscure aspects of this regulation is how the vast conformational landscape of LHCs is modulated in different environments. Indeed, while in isolated antennae the highly fluorescent light-harvesting conformation dominates, LHC aggregates display strong fluorescence quenching, representing therefore a model system for the process of energy dissipation developed by plants to avoid photodamage in high light. This marked difference between the isolated and oligomeric conditions has led to the widespread belief that aggregation is the trigger for the photoprotective state of LHCs. Here, a detailed analysis of time-resolved fluorescence experiments performed on aggregates of CP29 - a minor LHC of plants - provides new insights into the heterogeneity of emissive states of this antenna. A comparison with the data on isolated CP29 reveals that, though aggregation can stabilize short-lived conformations to a certain extent, the massive quenching upon protein clustering is mainly achieved by energetic connectivity between complexes that maintain the same long-lived and dissipative states accessed in the isolated form. Our results also explain the typical far-red enhancement in the emission of antenna oligomers in terms of a sub-population of long-lived redshifted complexes competing with quenched complexes in the energy trapping. Finally, the role of selected chlorophylls in shaping the conformational landscape of the antenna is also addressed by studying mutants lacking specific pigments.


Analysis of Cameroon's Sectoral Policies on Physical Activity for Noncommunicable Disease Prevention.
Physical inactivity is increasing in low- and middle-income countries (LMICs), where noncommunicable diseases (NCDs), urbanisation and sedentary living are rapidly growing in tandem. Increasing active living requires the participation of multiple sectors, yet it is unclear whether physical activity (PA)-relevant sectors in LMICs are prioritising PA. We investigated to what extent sectors that influence PA explicitly integrate it in their policies in an LMIC such as Cameroon. We systematically identified policy documents relevant to PA and NCD prevention in Cameroon; and using the Walt and Gilson policy triangle we described, analysed, and interpreted the policy contexts, contents, processes, and actors. We found 17 PA and NCD policy documents spanning from 1974 to 2019 across seven ministries. Thirteen (13/17) policies targeted infrastructure improvement, and four (4/17) targeted communication for behaviour change, all aiming to enhance leisure domain PA. Only the health sector explicitly acknowledged the role of PA in NCD prevention. Notably, no policy from the transport sector mentioned PA. Our findings highlight the need for intersectoral action to integrate PA into policies in all relevant sectors. These actions will need to encompass the breadth of PA domains, including transport, while emphasising the multiple health benefits of PA for the population.


Identification of human flap endonuclease 1 (FEN1) inhibitors using a machine learning based consensus virtual screening.
Human Flap endonuclease1 (FEN1) is an enzyme that is indispensable for DNA replication and repair processes and inhibition of its Flap cleavage activity results in increased cellular sensitivity to DNA damaging agents (cisplatin, temozolomide, MMS, etc.), with the potential to improve cancer prognosis. Reports of the high expression levels of FEN1 in several cancer cells support the idea that FEN1 inhibitors may target cancer cells with minimum side effects to normal cells. In this study, we used large publicly available, high-throughput screening data of small molecule compounds targeted against FEN1. Two machine learning algorithms, Support Vector Machine (SVM) and Random Forest (RF), were utilized to generate four classification models from huge PubChem bioassay data containing probable FEN1 inhibitors and non-inhibitors. We also investigated the influence of randomly selected Zinc-database compounds as negative data on the outcome of classification modelling. The results show that the SVM model with inactive compounds was superior to RF with Matthews's correlation coefficient (MCC) of 0.67 for the test set. A Maybridge database containing approximately 53 000 compounds was screened and top ranking 5 compounds were selected for enzyme and cell-based in vitro screening. The compound JFD00950 was identified as a novel FEN1 inhibitor with in vitro inhibition of flap cleavage activity as well as cytotoxic activity against a colon cancer cell line, DLD-1.


Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation end products and oxidative stress in diabetic rats.
The reactive advanced glycation end product (AGE) precursor methylglyoxal (MGO) and MGO-derived AGEs are associated with diabetic vascular complications and also with an increase in oxidative stress. Glyoxalase-I (GLO-I) transgenic rats were used to explore whether overexpression of this MGO detoxifying enzyme reduces levels of AGEs and oxidative stress in a rat model of diabetes. Rats were made diabetic with streptozotocin, and after 12 weeks, plasma and multiple tissues were isolated for analysis of AGEs, carbonyl stress, and oxidative stress. GLO-I activity was significantly elevated in multiple tissues of all transgenic rats compared with wild-type (WT) littermates. Streptozotocin treatment resulted in a 5-fold increase in blood glucose concentrations irrespective of GLO-I overexpression. Levels of MGO, glyoxal, 3-deoxyglucosone, AGEs, and oxidative stress markers nitrotyrosine, malondialdehyde, and F2-isoprostane were elevated in the diabetic WT rats. In diabetic GLO-I rats, glyoxal and MGO composite scores were significantly decreased by 81%, and plasma AGEs and oxidative stress markers scores were significantly decreased by ∼50%. Hyperglycemia induced a decrease in protein levels of the mitochondrial oxidative phosphorylation complex in the gastrocnemius muscle, which was accompanied by an increase in the lipid peroxidation product 4-hydroxy-2-nonenal, and this was counteracted by GLO-I overexpression. This study shows for the first time in an in vivo model of diabetes that GLO-I overexpression reduces hyperglycemia-induced levels of carbonyl stress, AGEs, and oxidative stress. The reduction of oxidative stress by GLO-I overexpression directly demonstrates the link between glycation and oxidative stress.


Associative (not Hebbian) learning and the mirror neuron system.
The associative sequence learning (ASL) hypothesis suggests that sensorimotor experience plays an inductive role in the development of the mirror neuron system, and that it can play this crucial role because its effects are mediated by learning that is sensitive to both contingency and contiguity. The Hebbian hypothesis proposes that sensorimotor experience plays a facilitative role, and that its effects are mediated by learning that is sensitive only to contiguity. We tested the associative and Hebbian accounts by computational modelling of automatic imitation data indicating that MNS responsivity is reduced more by contingent and signalled than by non-contingent sensorimotor training (Cook et al. [7]). Supporting the associative account, we found that the reduction in automatic imitation could be reproduced by an existing interactive activation model of imitative compatibility when augmented with Rescorla-Wagner learning, but not with Hebbian or quasi-Hebbian learning. The work argues for an associative, but against a Hebbian, account of the effect of sensorimotor training on automatic imitation. We argue, by extension, that associative learning is potentially sufficient for MNS development.


Phenotypic variation within a clonal lineage of Phytophthora infestans infecting both tomato and potato in Nicaragua.
Late blight caused by Phytophthora infestans (Mont.) de Bary is a constraint to both potato and tomato crops in Nicaragua. The hypothesis that the Nicaraguan population of P. infestans is genotypically and phenotypically diverse and potentially subdivided based on host association was tested. A collection of isolates was analyzed using genotypic markers (microsatellites and mitochondrial DNA haplotype) and phenotypic markers (mating type, virulence, and fungicide sensitivity). The genotypic analysis revealed no polymorphism in 121 of 132 isolates of P. infestans tested. Only the Ia haplotype and the A2 mating type were detected. Most of the tested isolates were resistant to metalaxyl. The virulence testing showed variation among isolates of P. infestans. No evidence was found of population differentiation among potato and tomato isolates of P. infestans based on the genotypic and phenotypic analysis. We conclude that the Nicaraguan population of P. infestans consists of a single clonal lineage (NI-1) which belongs to the A2 mating type and the Ia mitochondrial DNA haplotype. Moreover, based on the markers used, this population of P. infestans does not resemble the population in countries from which potato seed is imported to Nicaragua or the population in neighboring countries. The data presented here indicate that the NI-1 clonal lineage is the primary pathogen on both potato and tomato, and its success on both host species is unique in a South American context.


Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age.
The first year of life is an important period for emergence of fear in humans. While animal models have revealed developmental changes in amygdala circuitry accompanying emerging fear, human neural systems involved in early fear development remain poorly understood. To increase understanding of the neural foundations of human fear, it is important to consider parallel cognitive development, which may modulate associations between typical development of early fear and subsequent risk for fear-related psychopathology. We, therefore, examined amygdala functional connectivity with rs-fcMRI in 48 neonates (M=3.65 weeks, SD=1.72), and measured fear and cognitive development at 6-months-of-age. Stronger, positive neonatal amygdala connectivity to several regions, including bilateral anterior insula and ventral striatum, was prospectively associated with higher fear at 6-months. Stronger amygdala connectivity to ventral anterior cingulate/anterior medial prefrontal cortex predicted a specific phenotype of higher fear combined with more advanced cognitive development. Overall, findings demonstrate unique profiles of neonatal amygdala functional connectivity related to emerging fear and cognitive development, which may have implications for normative and pathological fear in later years. Consideration of infant fear in the context of cognitive development will likely contribute to a more nuanced understanding of fear, its neural bases, and its implications for future mental health.


Representation of Sound Objects within Early-Stage Auditory Areas: A Repetition Effect Study Using 7T fMRI.
Environmental sounds are highly complex stimuli whose recognition depends on the interaction of top-down and bottom-up processes in the brain. Their semantic representations were shown to yield repetition suppression effects, i. e. a decrease in activity during exposure to a sound that is perceived as belonging to the same source as a preceding sound. Making use of the high spatial resolution of 7T fMRI we have investigated the representations of sound objects within early-stage auditory areas on the supratemporal plane. The primary auditory cortex was identified by means of tonotopic mapping and the non-primary areas by comparison with previous histological studies. Repeated presentations of different exemplars of the same sound source, as compared to the presentation of different sound sources, yielded significant repetition suppression effects within a subset of early-stage areas. This effect was found within the right hemisphere in primary areas A1 and R as well as two non-primary areas on the antero-medial part of the planum temporale, and within the left hemisphere in A1 and a non-primary area on the medial part of Heschl's gyrus. Thus, several, but not all early-stage auditory areas encode the meaning of environmental sounds.


Characterization of subcellular localization and stability of a splice variant of G alpha i2.
Alternative mRNA splicing of alpha(i2), a heterotrimeric G protein alpha subunit, has been shown to produce an additional protein, termed salpha(i2). In the salpha(i2) splice variant, 35 novel amino acids replace the normal C-terminal 24 amino acids of alpha(i2). Whereas alpha(i2) is found predominantly at cellular plasma membranes, salpha(i2) has been localized to intracellular Golgi membranes, and the unique 35 amino acids of salpha(i2) have been suggested to constitute a specific targeting signal. This paper proposes and examines an alternative hypothesis: disruption of the normal C-terminus of alpha(i2) produces an unstable protein that fails to localize to plasma membranes. salpha(i2) is poorly expressed upon transfection of cultured cells; however, radiolabeling indicated that alpha(i2) and salpha(i2) undergo myristoylation, a co-translational modification, equally well suggesting that protein stability rather than translation is affected. Indeed, pulse-chase analysis indicates that salpha(i2) is more rapidly degraded compared to alpha(i2). Co-expression of betagamma rescues PM localization and increases expression of salpha(i2). In addition, alpha(i2)A327S, a mutant previously shown to be unstable and defective in guanine-nucleotide binding, and alpha(i2)(1-331), in which the C-terminal 24 amino acids of alpha(i2) are deleted, show a similar pattern of subcellular localization as salpha(i2) (i.e., intracellular membranes rather than plasma membranes). Finally, salpha(i2) displays a propensity to localize to potential aggresome-like structures. Thus, instead of the novel C-terminus of salpha(i2) functioning as a specific Golgi targeting signal, the results presented here indicate that the disruption of the normal C-terminus of alpha(i2) causes mislocalization and rapid degradation of salpha(i2).


Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the early diagnosis of dementia across a variety of healthcare settings.
The Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) is a structured interview based on informant responses that is used to assess for possible dementia. IQCODE has been used for retrospective or contemporaneous assessment of cognitive decline. There is considerable interest in tests that may identify those at future risk of developing dementia. Assessing a population free of dementia for the prospective development of dementia is an approach often used in studies of dementia biomarkers. In theory, questionnaire-based assessments, such as IQCODE, could be used in a similar way, assessing for dementia that is diagnosed on a later (delayed) assessment. To determine the diagnostic accuracy of IQCODE in a population free from dementia for the delayed diagnosis of dementia (test accuracy with delayed verification study design). We searched these sources on 16 January 2016: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE Ovid SP, Embase Ovid SP, PsycINFO Ovid SP, BIOSIS Previews on Thomson Reuters Web of Science, Web of Science Core Collection (includes Conference Proceedings Citation Index) on Thomson Reuters Web of Science, CINAHL EBSCOhost, and LILACS BIREME. We also searched sources specific to diagnostic test accuracy: MEDION (Universities of Maastricht and Leuven); DARE (Database of Abstracts of Reviews of Effects, in the Cochrane Library); HTA Database (Health Technology Assessment Database, in the Cochrane Library), and ARIF (Birmingham University). We checked reference lists of included studies and reviews, used searches of included studies in PubMed to track related articles, and contacted research groups conducting work on IQCODE for dementia diagnosis to try to find additional studies. We developed a sensitive search strategy; search terms were designed to cover key concepts using several different approaches run in parallel, and included terms relating to cognitive tests, cognitive screening, and dementia. We used standardised database subject headings, such as MeSH terms (in MEDLINE) and other standardised headings (controlled vocabulary) in other databases, as appropriate. We selected studies that included a population free from dementia at baseline, who were assessed with the IQCODE and subsequently assessed for the development of dementia over time. The implication was that at the time of testing, the individual had a cognitive problem sufficient to result in an abnormal IQCODE score (defined by the study authors), but not yet meeting dementia diagnostic criteria. We screened all titles generated by the electronic database searches, and reviewed abstracts of all potentially relevant studies. Two assessors independently checked the full papers for eligibility and extracted data. We determined quality assessment (risk of bias and applicability) using the QUADAS-2 tool, and reported quality using the STARDdem tool. From 85 papers describing IQCODE, we included three papers, representing data from 626 individuals. Of this total, 22% (N = 135/626) were excluded because of prevalent dementia. There was substantial attrition; 47% (N = 295) of the study population received reference standard assessment at first follow-up (three to six months) and 28% (N = 174) received reference standard assessment at final follow-up (one to three years). Prevalence of dementia ranged from 12% to 26% at first follow-up and 16% to 35% at final follow-up.The three studies were considered to be too heterogenous to combine, so we did not perform meta-analyses to describe summary estimates of interest. Included patients were poststroke (two papers) and hip fracture (one paper). The IQCODE was used at three thresholds of positivity (higher than 3.0, higher than 3.12 and higher than 3.3) to predict those at risk of a future diagnosis of dementia. Using a cut-off of 3.0, IQCODE had a sensitivity of 0.75 (95%CI 0.51 to 0.91) and a specificity of 0.46 (95%CI 0.34 to 0.59) at one year following stroke. Using a cut-off of 3.12, the IQCODE had a sensitivity of 0.80 (95%CI 0.44 to 0.97) and specificity of 0.53 (95C%CI 0.41 to 0.65) for the clinical diagnosis of dementia at six months after hip fracture. Using a cut-off of 3.3, the IQCODE had a sensitivity of 0.84 (95%CI 0.68 to 0.94) and a specificity of 0.87 (95%CI 0.76 to 0.94) for the clinical diagnosis of dementia at one year after stroke.In generaI, the IQCODE was sensitive for identification of those who would develop dementia, but lacked specificity. Methods for both excluding prevalent dementia at baseline and assessing for the development of dementia were varied, and had the potential to introduce bias. Included studies were heterogenous, recruited from specialist settings, and had potential biases. The studies identified did not allow us to make specific recommendations on the use of the IQCODE for the future diagnosis of dementia in clinical practice. The included studies highlighted the challenges of delayed verification dementia research, with issues around prevalent dementia assessment, loss to follow-up over time, and test non-completion potentially limiting the studies. Future research should recognise these issues and have explicit protocols for dealing with them.


[Evidence on the key role of the metabotrobic glutamatergic receptors in the pathogenesis of schizophrenia: a "breakthrough" in pharmacological treatment].
The metabotropic glutamate receptors (mGluRs) are expressed pre- and post synaptically throughout the nervous system where they serve as modulators of synaptic transmission and neuronal excitability. The glutamatergic system is involved in a wide range of physiological processes in the brain, and its dysfunction plays an important role in the etiology and pathophysiology of psychiatric disorders, including schizophrenia. This paper reviews the neurodevelopmental origin and genetic susceptibility of schizophrenia relevant to NMDA receptor neurotransmission, and discusses the relationship between NMDA hypofunction and different domains of symptom in schizophrenia as well as putative treatment modality for the disorder. mGlu receptors have been hypothesizes as attractive therapeutic targets for the development of novel interventions for psychiatric disorders. Group II of mGlu receptors are of particular interest because of their unique distribution and the regulatory roles they have in neurotransmission. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.


Why direct effects of predation complicate the social brain hypothesis: And how incorporation of explicit proximate behavioral mechanisms might help.
A growing number of studies have found that large brains may help animals survive by avoiding predation. These studies provide an alternative explanation for existing correlative evidence for one of the dominant hypotheses regarding the evolution of brain size in animals, the social brain hypothesis (SBH). The SBH proposes that social complexity is a major evolutionary driver of large brains. However, if predation both directly selects for large brains and higher levels of sociality, correlations between sociality and brain size may be spurious. We argue that tests of the SBH should take direct effects of predation into account, either by explicitly including them in comparative analyses or by pin-pointing the brain-behavior-fitness pathway through which the SBH operates. Existing data and theory on social behavior can then be used to identify precise candidate mechanisms and formulate new testable predictions.


ODF maxima extraction in spherical harmonic representation via analytical search space reduction.
By revealing complex fiber structure through the orientation distribution function (ODF), q-ball imaging has recently become a popular reconstruction technique in diffusion-weighted MRI. In this paper, we propose an analytical dimension reduction approach to ODF maxima extraction. We show that by expressing the ODF, or any antipodally symmetric spherical function, in the common fourth order real and symmetric spherical harmonic basis, the maxima of the two-dimensional ODF lie on an analytically derived one-dimensional space, from which we can detect the ODF maxima. This method reduces the computational complexity of the maxima detection, without compromising the accuracy. We demonstrate the performance of our technique on both artificial and human brain data.


Multimodality treatment of locally advanced breast carcinoma.
Forty patients with 41 locally advanced breast lesions at stages IIIA and IIIB and the inflammatory stage were treated with combined-modality therapy from July 1980 to August 1985. Treatment included induction chemotherapy consisting of three cycles of fluorouracil, doxorubicin hydrochloride, and cyclophosphamide, followed by mastectomy in those patients whose lesions were operable (n = 28), and resumption of chemotherapy. Nine patients received postoperative radiation therapy. The mean follow-up was 34 months. Greater than 50% reduction in tumor size was achieved in 72% of patients after three cycles of chemotherapy. Overall, local control was achieved in 85% of patients with 59% survival and 53% disease-free survival, while 10% of patients developed local recurrences. Excluding lymphedema of the upper extremity (n = 2) and inflammatory carcinomas (n = 4), local control was achieved in 96% of patients, with 75% survival and 68% disease-free survival, while 4% of patients developed local recurrences. The rate of disease-free survival was 71% in patients with partial response to chemotherapy, contrasted with 43% in patients who did not respond or only minimally responded to chemotherapy. Actuarial five-year survival, based on life-table analysis, was calculated to be 46% for the group overall, 58% for the group excluding lymphedema of the upper extremity and inflammatory carcinoma, and 56% for the 28 patients undergoing mastectomy.


Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling.
Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo. Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s). Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a β2AR- and βarr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on βarr-dependent β2AR signaling. Conclusion: Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits.


Cancer risks in a population with prolonged low dose-rate gamma-radiation exposure in radiocontaminated buildings, 1983-2002.
To assess cancer risks in a population that received prolonged low dose-rate gamma-irradiation for about 10 years as a result of occupying buildings containing 60Co-contaminated steel in Taiwan. The cancer risks were compared with those populations with the same temporal and geographic characteristics in Taiwan by standardized incidence ratios (SIR), adjusted for age and gender. The association of cancer risks with excess cumulative exposure was further evaluated for their relative risks by the Poisson multiple regression analysis. A total of 7271 people were registered as the exposed population, with 101,560 person-years at risk. The average excess cumulative exposure was approximately 47.8 mSv (range < 1 - 2,363 mSv). A total of 141 exposed subjects with various cancers were observed, while 95 developed leukemia or solid cancers after more than 2 or 10 years initial residence in contaminated buildings respectively. The SIR were significantly higher for all leukemia except chronic lymphocytic leukemia (n = 6, SIR = 3.6, 95% confidence interval [CI] 1.2 - 7.4) in men, and marginally significant for thyroid cancers (n = 6, SIR = 2.6, 95% CI 1.0 - 5.7) in women. On the other hand, all cancers combined, all solid cancers combined were shown to exhibit significant exposure-dependent increased risks in individuals with the initial exposure before the age of 30, but not beyond this age. The results suggest that prolonged low dose-rate radiation exposure appeared to increase risks of developing certain cancers in specific subgroups of this population in Taiwan.


Peripheral fatigue is not critically regulated during maximal, intermittent, dynamic leg extensions.
Central motor drive to active muscles is believed to be reduced during numerous exercise tasks to prevent excessive peripheral fatigue development. The purpose of the present study was to use hypoxia to exacerbate physiological perturbations during a novel, intermittent exercise task and to explore the time-course and interplay between central and peripheral neuromuscular adjustments. On separate days, 14 healthy men performed four sets of 6 × 5 maximal-intensity, isokinetic leg extensions (1 repetition lasting ∼7 s) at 300°/s (15 and 100 s of passive rest between repetitions and sets, respectively) under normoxia (NM, fraction of inspired O2 0.21), moderate (MH, 0.14), and severe normobaric hypoxia (SH, 0.10). Neuromuscular assessments of the knee extensors were conducted before and immediately after each set. There was an interaction between time and condition on the mean peak torque produced during each set (P < 0.05). RMS/M-wave activity of the rectus femoris decreased across the four sets of exercise, but there was no difference between conditions (8.3 ± 5.1% all conditions compounded, P > 0.05). Potentiated twitch torque decreased post set 1 in all conditions (all P < 0.05) with greater reductions following each set in SH compared with NM but not MH (end-exercise reductions 41.3 ± 3.0% vs. 28.0 ± 3.2%, P < 0.05 and 32.1 ± 3.3%, P > 0.05). In conclusion, severe hypoxia exacerbates both peripheral fatigue development and performance decrements during maximal, intermittent, dynamic leg extensions. In contrast to observations with other exercise modes, during exercise involving a single muscle group the attenuation of central motor drive does not appear to independently regulate the development of peripheral muscle fatigue.


Seed germination of GA-insensitive sleepy1 mutants does not require RGL2 protein disappearance in Arabidopsis.
We explore the roles of gibberellin (GA) signaling genes SLEEPY1 (SLY1) and RGA-LIKE2 (RGL2) in regulation of seed germination in Arabidopsis thaliana, a plant in which the hormone GA is required for seed germination. Seed germination failure in the GA biosynthesis mutant ga1-3 is rescued by GA and by mutations in the DELLA gene RGL2, suggesting that RGL2 represses seed germination. RGL2 protein disappears before wild-type seed germination, consistent with the model that GA stimulates germination by causing the SCF(SLY1) E3 ubiquitin ligase complex to trigger ubiquitination and destruction of RGL2. Unlike ga1-3, the GA-insensitive sly1 mutants show variable seed dormancy. Seed lots with high seed dormancy after-ripened slowly, with stronger alleles requiring more time. We expected that if RGL2 negatively controls seed germination, sly1 mutant seeds that germinate well should accumulate lower RGL2 levels than those failing to germinate. Surprisingly, RGL2 accumulated at high levels even in after-ripened sly1 mutant seeds with 100% germination, suggesting that RGL2 disappearance is not a prerequisite for seed germination in the sly1 background. Without GA, several GA-induced genes show increased accumulation in sly1 seeds compared with ga1-3. It is possible that the RGL2 repressor of seed germination is inactivated by after-ripening of sly1 mutant seeds.


Distant metastasis dynamics following subsequent surgeries after primary breast cancer removal.
The aim of the research was to separate the distant metastasis (DM) enhancing effect due to breast tumour removal from that due to surgical manoeuvre by itself. DM dynamics following surgery for ipsilateral breast tumour recurrence (IBTR), contralateral breast cancer (CBC) and delayed reconstruction (REC), which was performed after the original breast cancer surgical removal, was analysed. A total of 338 patients with IBTR, 239 with CBC and 312 with REC were studied. The DM dynamics following IBTR, CBC and REC, when assessed with time origin at their surgical treatment, is similar to the analogous pattern following primary tumour removal, with a first major peak at about 18 months and a second lower one at about 5 years from surgery. The time span between primary tumour removal and the second surgery is influential on DM risk levels for IBTR and CBC patients, not for REC patients. The role of breast tumour removal is different from the role of surgery by itself. Our findings suggest that the major effect of reconstructive surgery is microscopic metastasis acceleration, while breast tumour surgical removal (either primary or IBTR or CBC) involves both tumour homeostasis interruption and microscopic metastasis growth acceleration. The removal of a breast tumour would eliminate its homeostatic restrains on metastatic foci, thus allowing metastasis development, which, in turn, would be supported by the forwarding action of the mechanisms triggered by the surgical wounding.


Perinatal depression and child development: exploring the economic consequences from a South London cohort.
Depression in mothers during pregnancy and in the postnatal period has been recognized to have wide-ranging adverse impacts on offspring. Our study examines some of the outcomes and long-term economic implications experienced by offspring who have been exposed to perinatal depression. We analysed the effects of perinatal depression on child development outcomes of children at ages 11 and 16 years from the community-based South London Child Development Study. Economic consequences were attached to those outcomes through simple decision-analytic techniques, building on evidence from studies of epidemiology, health-related quality of life, public sector costs and employment. The economic analysis takes a life-course perspective from the viewpoints of the public sector, individual and society. Additional risks that children exposed to perinatal depression develop emotional, behavioural or cognitive problems ranged from 5% to 21%. In addition, there was a high risk (24%) that children would have special educational needs. We present results in the form of cost consequences attached to adverse child outcomes. For each child exposed to perinatal depression, public sector costs exceeded £3030, costs due to reduced earnings were £1400 and health-related quality of life loss was valued at £3760. Action to prevent or treat mothers' depression during pregnancy and after birth is likely to reduce public sector costs, increase earnings and improve quality of life for children who were exposed to the condition.


Mycophenolate mofetil treatment in children and adolescents with lupus.
Safety and efficacy data are presented on the use of mycophenolate mofetil (MMF) in 26 children and adolescents with lupus. Data include therapy before and 12 months after starting MMF. 18 of 26 patients had biopsy-proved lupus nephritis. Group 1 were commenced on MMF induction and/or maintenance therapy (n=14), group 2 converted from azathioprine because of inadequate disease control (n=12). 73% of all (10 (71%) group 1 and 10 (83%) group 2) patients experienced a significant improvement in British Isles Lupus Assessment Group score (from median 9.0 to 3.0). Children with hypocomplementaemia increased their C3 significantly in both groups (0.53-1.15 for group 1 and 0.63-1.2 g/l for group 2, p=0.001), and C4 level only in group 1 (0.08-0.17, p=0.01). Renal function and albuminuria improved in those with active nephritis (p≤0.01). Significant improvements were seen in both groups in haemoglobin, erythrocyte sedimentation rate and lymphocyte counts. Prednisolone dose was weaned in both groups, p<0.05. Side-effects were seen in four patients, but none was judged to be severe enough to discontinue treatment. MMF treatment in this cohort of children with lupus seemed to be safe, well tolerated and effective.


A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures.
The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60(190), N3.43(240), Q7.49(394), and H6.52(363) as key residues involved in peptide-mediated biased agonism, with R2.60(190), N3.43(240), and Q7.49(394) predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53(364)A, N3.43(240)Q, Q7.49(394)N, and N3.43(240)Q/Q7.49(394)N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53(364) and R2.60(190) was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49(394), but not R2.60(190)/E6.53(364) was critical for calcium mobilization for all three peptides. Mutation of N3.43(240) and Q7.49(394) had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.


Current and emerging therapeutic targets of alzheimer's disease for the design of multi-target directed ligands.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and a major cause of death worldwide. The number of people suffering from this debilitating disorder is rising at an unprecedented rate, with a subsequent surge in healthcare costs. Only four drugs are clinically available for the treatment of AD symptoms, but they are not disease-modifying. Consequently, there is an urgent need for a cure. Although the cause of this debilitating condition remains poorly understood, it is believed that several factors may be involved in combination - including, health and lifestyle, environmental, and genetic factors. In recent years, a number of hallmarks of the disease have also been discovered, and it is believed that these factors may play an important role in the development of AD. Amyloid aggregation is one such factor which has been highly investigated, in addition to cholinesterase enzymes and tau aggregation. In the last decade, multi-target drugs have been increasingly investigated for their application to AD treatment. By combining two or more pharmacophores in a single compound, it is possible to synthesise a drug which can target several factors that are involved in AD development. This is a particularly attractive approach as it would avoid the use of combination therapies. As a result, it could reduce the burden on carers and families, and decrease healthcare and social care costs. Many active pharmacophores have been employed for the development of hybrid drugs, due to their abilities to inhibit the factors currently widely recognised to be involved in AD. These compounds have demonstrated promising results; however, research is still required to optimise the pharmacological profiles of the drugs, in addition to their potencies. Meanwhile, extensive research is continuously being performed into other potential targets for the treatment of AD. Based on the results obtained thus far, it is likely that multi-target compounds will continue to be increasingly studied in the future as potential treatments for AD.


HTLV-I-associated myelopathy associated with blood transfusion in the United States: epidemiologic and molecular evidence linking donor and recipient.
Six months after receiving 58 units of blood components, a 65-year-old white man from New York City, with no other risk factors for human T-lymphotropic virus type I (HTLV-I) infection, developed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Investigation of blood donors identified a 25-year-old white Hispanic woman from Florida whose platelets had been given to the patient and who was seropositive for the virus on a serum specimen obtained 2 years after the donation. She was born in Cuba and had had 2 sexual relationships with men who either had been born in or had resided in the Caribbean. Polymerase chain reaction (PCR) studies of peripheral blood mononuclear cells indicated that both donor and recipient were infected with HTLV-I. Molecular studies of a 595-nucleotide sequence in the 5' envelope region of HTLV-I indicated that the viruses from donor and recipient were identical in each of 32 positions in which published HTLV-I sequences demonstrate molecular heterogeneity; the donor and recipient viruses were also identical in 2 additional positions in which they differed from all published sequences. Transfusion-associated HAM/TSP has occurred in the United States, but additional cases should be prevented by screening blood donations for HTLV-I. Molecular studies of HTLV-I may prove useful in defining the genetic heterogeneity of HTLV-I isolates in the United States and in studying transmission of this virus.