Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.


Formation and characterization of non-growth states in Clostridium thermocellum: spores and L-forms.
Clostridium thermocellum is an anaerobic thermophilic bacterium that exhibits high levels of cellulose solublization and produces ethanol as an end product of its metabolism. Using cellulosic biomass as a feedstock for fuel production is an attractive prospect, however, growth arrest can negatively impact ethanol production by fermentative microorganisms such as C. thermocellum. Understanding conditions that lead to non-growth states in C. thermocellum can positively influence process design and culturing conditions in order to optimize ethanol production in an industrial setting. We report here that Clostridium thermocellum ATCC 27405 enters non-growth states in response to specific growth conditions. Non-growth states include the formation of spores and a L-form-like state in which the cells cease to grow or produce the normal end products of metabolism. Unlike other sporulating organisms, we did not observe sporulation of C. thermocellum in low carbon or nitrogen environments. However, sporulation did occur in response to transfers between soluble and insoluble substrates, resulting in approximately 7% mature spores. Exposure to oxygen caused a similar sporulation response. Starvation conditions during continuous culture did not result in spore formation, but caused the majority of cells to transition to a L-form state. Both spores and L-forms were determined to be viable. Spores exhibited enhanced survival in response to high temperature and prolonged storage compared to L-forms and vegetative cells. However, L-forms exhibited faster recovery compared to both spores and stationary phase cells when cultured in rich media. Both spores and L-forms cease to produce ethanol, but provide other advantages for C. thermocellum including enhanced survival for spores and faster recovery for L-forms. Understanding the conditions that give rise to these two different non-growth states, and the implications that each has for enabling or enhancing C. thermocellum survival may promote the efficient cultivation of this organism and aid in its development as an industrial microorganism.


Revisiting the understanding of "transactional sex" in sub-Saharan Africa: A review and synthesis of the literature.
In sub-Saharan Africa, young women ages 15-24 have more than twice the risk of acquiring HIV as their male counterparts. A growing body of epidemiological evidence suggests that the practice of "transactional sex" may contribute to this disparity. Over the last 15 years, the social sciences have contributed significantly to understanding the meaning of and motivations for this practice. The findings from these studies are rich, but varied, rendering lessons difficult to navigate for intervention and further research. We therefore contribute a historically-grounded, comprehensive literature review on the nature and motivations for women's participation in transactional sex in sub-Saharan Africa. Drawing from over 300 studies (through 2014), we distill three prominent paradigms observed in the literature that we review toward presenting a unified conceptualization of the practice. "Sex for basic needs," the first paradigm, positions women as victims in transactional sexual relationships, with implications for interventions that protect girls from exploitation. In contrast, the "sex for improved social status" paradigm positions women as sexual agents who engage in transactional sex toward attaining a middle-class status and lifestyle. Finally, a third paradigm, "sex and material expressions of love," draws attention to the connections between love and money, and the central role of men as providers in relationships. We find important commonalities in the structural factors that shape the three paradigms of transactional sex including gender inequality and processes of economic change. We suggest that there are three continua stretching across these paradigms: deprivation, agency, and instrumentality. This review proposes a definition of transactional sex and discusses implications for research and interventions aiming to reduce young women's risk of HIV through such relationships. We consider the consequences of drawing from too narrow an understanding of the practice, and highlight the benefits of a broader conceptualization.


123I-labeled HIV-1 tat peptide radioimmunoconjugates are imported into the nucleus of human breast cancer cells and functionally interact in vitro and in vivo with the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1).
To evaluate the internalization and nuclear translocation of (123)I-tat-peptide radioimmunoconjugates in MDA-MB-468 breast cancer cells and their ability to interact with the cyclin-dependent kinase inhibitor, p21(WAF-1/Cip-1). Peptides [GRKKRRQRRRPPQGYGC] harboring the nuclear-localizing sequence from HIV tat domain were conjugated to anti-p21(WAF-1/Cip-1) antibodies. Immunoreactivity was assessed by Western blot using lysate from MDA-MB-468 cells exposed to EGF to induce p21(WAF-1/Cip-1). Internalization and nuclear translocation were measured. The ability of tat-anti-p21(WAF-1/Cip-1) to block G(1)-S phase arrest in MDA-MB-468 cells caused by EGF-induced p21(WAF-1/Cip-1) was evaluated. Tumor and normal tissue uptake were determined at 48 h p.i. in athymic mice implanted s.c. with MDA-MB-468 xenografts injected intratumorally with EGF. There was 13.4+/-0.2% of radioactivity internalized by MDA-MB-468 cells incubated with (123)I-tat-anti-p21(WAF-1/Cip-1) and 34.6+/-3.1% imported into the nucleus. Tat-anti-p21(WAF-1/Cip-1)(8 muM) decreased the proportion of EGF-treated cells in G(1) phase from 81.9+/-0.7% to 46.1+/-0.7% (p<0.001), almost restoring the G(1) phase fraction to that of unexposed cells (25.8+/-0.2%). Non-specific tat-mouse IgG did not block EGF-induced G(1)-S phase arrest. Tumor uptake of radioactivity was higher in mice injected with EGF to induce p21(WAF-1/Cip-1) than in mice not receiving EGF (3.1+/-0.4% versus 1.8+/-0.2% ID/g; p=0.04). Western blot analysis of tumors revealed a threefold increase in the p21(WAF-1/Cip-1)/beta-actin ratio. We conclude that intracellular and nuclear epitopes in cancer cells can be functionally targeted with tat-radioimmunoconjugates to exploit many more epitopes for imaging and radiotherapeutic applications than have previously been accessible.


Study protocol: delayed intervention randomised controlled trial within the Medical Research Council (MRC) Framework to assess the effectiveness of a new palliative care service.
Palliative care has been proposed to help meet the needs of patients who suffer progressive non-cancer conditions but there have been few evaluations of service development initiatives. We report here a novel protocol for the evaluation of a new palliative care service in this context. Using the MRC Framework for the Evaluation of Complex Interventions we modelled a new palliative care and neurology service for patients severely affected by Multiple Sclerosis (MS). We conducted qualitative interviews with patients, families and staff, plus a literature review to model and pilot the service. Then we designed a delayed intervention randomised controlled trial to test its effectiveness as part of phase II of the MRC framework. Inclusion criteria for the trial were patients identified by referring clinicians as having unresolved symptoms or psychological concerns. Referrers were advised to use a score of greater than 8 on the Expanded Disability Scale was a benchmark. Consenting patients newly referred to the new service were randomised to either receive the palliative care service immediately (fast-track) or after a 12-week wait (standard best practice). Face to face interviews were conducted at baseline (before intervention), and at 4-6, 10-12 (before intervention for the standard-practice group), 16-18 and 22-24 weeks with patients and their carers using standard questionnaires to assess symptoms, palliative care outcomes, function, service use and open comments. Ethics committee approval was granted separately for the qualitative phase and then for the trial. We publish the protocol trial here, to allow methods to be reviewed in advance of publication of the results. The MRC Framework for the Evaluation of Complex Interventions was helpful in both the design of the service, methods for evaluation in convincing staff and the ethics committee to accept the trial. The research will provide valuable information on the effects of palliative care among non-cancer patients and a method to evaluate palliative care in this context.


Trends in the Utilization of Ankle Replacements: Data From Worldwide National Joint Registries.
Over the past decade, there has been a growth in the use of ankle replacements. Data from national joint registries have shown between-country differences in the utilization of ankle replacement. The reasons for these differences are, however, not well understood. Our aims were to describe and compare the annual incidence of primary ankle replacement between countries and, to examine potential reasons for variation over time. We used aggregate data and summary statistics on ankle replacements for the period 1993 to 2019 from national joint replacement registries in Australia, Finland, New Zealand, Norway, Sweden and the United Kingdom. From the annual recorded counts of procedures, demographic data were extracted on age, sex distribution, and indication(s) for primary ankle replacement. Registry-level summary results were also obtained on data completeness, counts of hospitals/units, and health care providers performing ankle replacements annually and data collection processes (mandatory vs voluntary). Annual ankle replacement incidence for all diagnoses and, by indication categories (osteoarthritis [OA] and rheumatoid arthritis [RA]), were calculated per 100 000 residential population aged ≥18 years. For the period with data from all 6 countries (2010-2015), New Zealand had the largest annual incidence (mean ± SD) of 3.3 ± 0.2 ankle replacement procedures per 100 000 population whereas Finland had the lowest incidence (0.92 replacements). There were no common temporal trends in the utilization of ankle replacements. Over the years studied, OA was the predominant diagnosis in the United Kingdom, Australia, and New Zealand, whereas RA was the most common indication in Scandinavia. In these 6 countries, we found marked differences in the utilization of ankle replacements. Registry-related factors including data completeness and the number of hospitals/surgeons performing ankle replacements are likely to contribute to the observed between-country differences and need to be carefully considered when interpreting comparisons for this less common site for joint replacement surgery. Level III, retrospective study.


Spatial and socio-demographic predictors of time-to-immunization in a rural area in Kenya: Is equity attainable?
We conducted a vaccine coverage survey in Kilifi District, Kenya in order to identify predictors of childhood immunization. We calculated travel time to vaccine clinics and examined its relationship to immunization coverage and timeliness among the 2169 enrolled children (median age: 12.5 months). 86% had vaccine cards available, >95% had received three doses of DTP-HepB-Hib and polio vaccines and 88% of measles. Travel time did not affect vaccination coverage or timeliness. The Kenyan EPI reaches nearly all children in Kilifi and delays in vaccination are few, suggesting that vaccines will have maximal impact on child morbidity and mortality.


Targeting ligand-functionalized photothermal scaffolds for cancer cell capture and in situ ablation.
Scaffolds have been explored as a useful carrier to deliver efficient photothermal conversion agents for localized photothermal therapy applications because they can confine the agents in designated regions. However, cell capture by porous structures cannot discriminate between cancer cells and normal cells. In this study, folic acid (FA) as a typical targeting ligand for cancer cells was introduced into the porous photothermal scaffolds. Poly-l-lysine was mixed with gelatin to increase the amino side groups for FA incorporation. By changing the poly-l-lysine amount, the number of free amino groups in the scaffolds could be controlled. After the reaction with activated FA, composite scaffolds incorporated with different amounts of FA were prepared. Cell culture results showed that the FA-functionalized photothermal scaffolds could efficiently capture folate-positive cervical cancer cells compared with gelatin scaffolds. The capture efficiency increased with the increase in the amount of FA in the scaffolds. Furthermore, cancer cells in the FA-functionalized photothermal scaffolds can be efficiently killed during near-infrared laser irradiation. The results indicated that the FA-functionalized photothermal scaffolds had good cancer cell capture ability and excellent cancer cell ablation efficacy, which may provide useful information for the design of multifunctional scaffolds with cancer cell capture capacity and photothermal ablation ability.


Task Learnability Modulates Surprise but Not Valence Processing for Reinforcement Learning in Probabilistic Choice Tasks.
The goal of temporal difference (TD) reinforcement learning is to maximize outcomes and improve future decision-making. It does so by utilizing a prediction error (PE), which quantifies the difference between the expected and the obtained outcome. In gambling tasks, however, decision-making cannot be improved because of the lack of learnability. On the basis of the idea that TD utilizes two independent bits of information from the PE (valence and surprise), we asked which of these aspects is affected when a task is not learnable. We contrasted behavioral data and ERPs in a learning variant and a gambling variant of a simple two-armed bandit task, in which outcome sequences were matched across tasks. Participants were explicitly informed that feedback could be used to improve performance in the learning task but not in the gambling task, and we predicted a corresponding modulation of the aspects of the PE. We used a model-based analysis of ERP data to extract the neural footprints of the valence and surprise information in the two tasks. Our results revealed that task learnability modulates reinforcement learning via the suppression of surprise processing but leaves the processing of valence unaffected. On the basis of our model and the data, we propose that task learnability can selectively suppress TD learning as well as alter behavioral adaptation based on a flexible cost-benefit arbitration.


Survival of human dental pulp cells after 4-week culture in human tooth model.
This study aimed to validate the human tooth model by investigating the growth efficiency, expression of mesenchymal stem cell (MSC) markers and differentiation ability of human dental pulp cells (hDPCs) harvested from extracted immature third molars and cultured for different periods. Moreover, the effect of exposure and capping with a hydraulic calcium-silicate cement on pulp tissue after 4-week culture in the tooth model was investigated. Primary hDPCs were collected from 18 molars from six individuals (15-19 years). One tooth of each patient was immediately cultured (control), while the other teeth were exposed to culture medium for 1, 2 or 4 weeks. After different culture periods, cells were harvested using the explant method, upon which cells were evaluated for cell-doubling time, colony-forming efficiency and expression of cell surface markers. The osteogenic, adipogenic and chondrogenic differentiation efficacy was also determined. Two teeth from three different patients (n = 6) were used for the pulp-capping assay. Three teeth were capped with ProRoot MTA (Dentsply Sirona), while three other exposed teeth remained uncapped (control). Cells were found to grow, express MSC markers and showed osteogenic, adipogenic and chondrogenic differentiation potential at all time periods. Histology of the teeth subjected to the pulp-capping assay showed the formation of mineralized tissue after 4-week exposure to ProRoot MTA (Dentsply Sirona) and normal histological features in the control teeth. This study confirmed that hDPCs of teeth cultured for up to 4 weeks in a human tooth model are viable, express MSC markers and show differentiation ability. The human tooth model can be seen as an advanced cell-culture model that makes use of the original 3D pulp-chamber structure. It can serve as a screening tool to evaluate new pulp-capping formulations in a relatively cheap and fast manner.


Cardiovascular magnetic resonance in women with cardiovascular disease: position statement from the Society for Cardiovascular Magnetic Resonance (SCMR).
This document is a position statement from the Society for Cardiovascular Magnetic Resonance (SCMR) on recommendations for clinical utilization of cardiovascular magnetic resonance (CMR) in women with cardiovascular disease. The document was prepared by the SCMR Consensus Group on CMR Imaging for Female Patients with Cardiovascular Disease and endorsed by the SCMR Publications Committee and SCMR Executive Committee. The goals of this document are to (1) guide the informed selection of cardiovascular imaging methods, (2) inform clinical decision-making, (3) educate stakeholders on the advantages of CMR in specific clinical scenarios, and (4) empower patients with clinical evidence to participate in their clinical care. The statements of clinical utility presented in the current document pertain to the following clinical scenarios: acute coronary syndrome, stable ischemic heart disease, peripartum cardiomyopathy, cancer therapy-related cardiac dysfunction, aortic syndrome and congenital heart disease in pregnancy, bicuspid aortic valve and aortopathies, systemic rheumatic diseases and collagen vascular disorders, and cardiomyopathy-causing mutations. The authors cite published evidence when available and provide expert consensus otherwise. Most of the evidence available pertains to translational studies involving subjects of both sexes. However, the authors have prioritized review of data obtained from female patients, and direct comparison of CMR between women and men. This position statement does not consider CMR accessibility or availability of local expertise, but instead highlights the optimal utilization of CMR in women with known or suspected cardiovascular disease. Finally, the ultimate goal of this position statement is to improve the health of female patients with cardiovascular disease by providing specific recommendations on the use of CMR.


An audit on public awareness of depression symptoms in Jordan.
Depression is a common mental health disorder. The aim of this study is to determine the level of public awareness regarding this illness, its symptoms, associated factors, available forms of treatment, and the attitude towards depressed people. A self administered questionnaire was filled in by approximately 5000 individuals selected from various regions of Jordan. The majority of participants thought that depression is a treatable condition that can affect patient at any age, and may be controlled by the will power. Loss of interest in things and presence of negative feelings were the most commonly recognized symptoms of depression, while, unemployment and poverty were found to be the most recognized risk factors for depression. In addition, most participants considered support from family and friends (93.6%) as well as exercise (80.4%) to be the best available forms of depression treatment. Respondents found it acceptable to work, make friends with, or marry depressed individuals. The first choice persons for seeking help by most participants were family members and friends (49.8%). Collectively, the level of awareness of depression was acceptable. However, further efforts are necessary to establish public educational programs related to depression in order to raise awareness regarding the disease.


High frequency of loss of allelic integrity at Wilms' tumor suppressor gene-1 locus in advanced breast tumors associated with aggressiveness of the tumor.
The product of Wilms' tumor suppressor gene (WT1), a nuclear transcription factor, regulates the expression of the insulin-like growth factor (IGF) and transforming growth factor (TGF) systems, both of which are implicated in breast tumorigenesis and are known to facilitate angiogenesis. In the present study, WT1 allelic integrity was examined by Loss of Heterozygosity (LOH) studies in infiltrating breast carcinoma (n=60), ductal carcinoma in situ (DCIS) (n=10) and benign breast disease (n=5) patients, to determine its possible association with tumor progression. LOH at the WT1 locus (11p13) as determined by PCR-RFLP for Hinf1 restriction site and was subsequently examined for its association with intratumoral expression of various growth factors i.e. TGF-beta1, IGF-II, IGF-1R and angiogenesis (VEGF and Intratumoral micro-vessel density) in breast carcinoma. Six of 22 (27.2%) genetically heterozygous of infiltrating breast carcinoma and 1 of 4 DCIS cases showed loss of one allele at WT1 locus. Histologically, the tumors with LOH at WT1 were Intraductal carcinoma (IDC) and were of grade II and III. There was no correlation in the appearance of LOH at WT1 locus with age, tumor stage, menopausal status, chemotherapy status and lymph node metastasis. The expression of factor IGF-II and its receptor, IGF-1R was significantly higher in carcinoma having LOH at WT1 locus. A positive correlation was observed between the TGF-beta1, VEGF expression and IMD scores in infiltrating carcinoma. The current study indicates that the high frequency of loss of allelic integrity at Wilms' tumor suppressor gene-1 locus in high-graded breast tumors is associated with aggressiveness of the tumor.


The Intracellular Domain of Amyloid Precursor Protein is a Potential Therapeutic Target in Alzheimer's Disease.
Amyloid-β (Aβ) is widely believed to cause Alzheimer's disease (AD), as it is the major constituent of the amyloid plaques observed in the brains of people with AD (the so-called amyloid hypothesis). Based on this hypothesis, therapies utilizing immune responses against Aβ have been performed and have succeeded in effectively removing amyloid plaques, but have shown no evidence of improvements in survival and/or cognitive function. Thus, it may be necessary to think about this problem from a different viewpoint. γ-Secretase was initially identified as an enzyme that cleaves amyloid precursor protein (APP) and produces Aβ. Although the primary function of γ-secretase has not been fully clarified, this enzyme is well known to play a central regulatory role in Notch signaling. After the shedding of the Notch ectodomain by metalloproteases, γ-secretase releases the intracellular domain (ICD) of Notch, which immediately translocates to the nucleus to modify the expression of certain genes. Recently, many type 1 transmembrane proteins have also been reported as substrates for γ-secretase. Interestingly, several of these substrates may share a γ-secretase-regulated signaling mechanism similar to that of Notch. Indeed, we have demonstrated that the ICD of APP (AICD) induces dynamic changes in gene expression and neuron-specific apoptosis, suggesting that APP also has a signaling mechanism that is closely linked with AD. In this review, we first summarize the evidence that γ-secretase-regulated mechanisms similar to Notch signaling may play wide-ranging roles in signaling events involving type 1 transmembrane proteins, including APP. We also focus on the possibility that APP signaling is involved in the onset and progression of AD. Based on these ideas, we hypothesize that APP signaling, especially AICD, may be an attractive therapeutic target in AD.


Astragaloside IV inhibits PMA-induced EPCR shedding through MAPKs and PKC pathway.
Astragaloside IV (AS-IV), a main active substance isolated from Astragalus membranaceus Bunge, has been shown to have multiple pharmacological effects. Endothelial cell protein C receptor (EPCR) is a marker of inflammation, and is also a major member of protein C (PC) anti-coagulation system. EPCR can be cut off from the cell surface by tumor necrosis factor-α converting enzyme (TACE), which is controlled through mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) pathways. To develop novel therapeutic drug for EPCR shedding, the effect of AS-IV was studied in phorbol-12-myristate 13-acetate (PMA)-induced human umbilical vein endothelial cells (HUVECs) and the potential molecular mechanism of AS-IV action was investigated. The results showed that AS-IV could significantly inhibit PMA-induced EPCR shedding. In further study, AS-IV suppressed the expression and activity of TACE. In addition, AS-IV could decrease the phosphorylation of MAPK such as janus kinase (JNK) and p38, and inhibit activation of PKC through the prevention of non-phosphorylation and phosphorylation of specific PKC isoforms in PMA-stimulated HUVECs. These findings indicate that AS-IV may be used as a natural medicine to treat EPCR-related systemic inflammation and cardiovascular diseases by targeting MAPK and PKC pathway.


Systems protobiology: origin of life in lipid catalytic networks.
Life is that which replicates and evolves, but there is no consensus on how life emerged. We advocate a systems protobiology view, whereby the first replicators were assemblies of spontaneously accreting, heterogeneous and mostly non-canonical amphiphiles. This view is substantiated by rigorous chemical kinetics simulations of the graded autocatalysis replication domain (GARD) model, based on the notion that the replication or reproduction of compositional information predated that of sequence information. GARD reveals the emergence of privileged non-equilibrium assemblies (composomes), which portray catalysis-based homeostatic (concentration-preserving) growth. Such a process, along with occasional assembly fission, embodies cell-like reproduction. GARD pre-RNA evolution is evidenced in the selection of different composomes within a sparse fitness landscape, in response to environmental chemical changes. These observations refute claims that GARD assemblies (or other mutually catalytic networks in the metabolism first scenario) cannot evolve. Composomes represent both a genotype and a selectable phenotype, anteceding present-day biology in which the two are mostly separated. Detailed GARD analyses show attractor-like transitions from random assemblies to self-organized composomes, with negative entropy change, thus establishing composomes as dissipative systems-hallmarks of life. We show a preliminary new version of our model, metabolic GARD (M-GARD), in which lipid covalent modifications are orchestrated by non-enzymatic lipid catalysts, themselves compositionally reproduced. M-GARD fills the gap of the lack of true metabolism in basic GARD, and is rewardingly supported by a published experimental instance of a lipid-based mutually catalytic network. Anticipating near-future far-reaching progress of molecular dynamics, M-GARD is slated to quantitatively depict elaborate protocells, with orchestrated reproduction of both lipid bilayer and lumenal content. Finally, a GARD analysis in a whole-planet context offers the potential for estimating the probability of life's emergence. The invigorated GARD scrutiny presented in this review enhances the validity of autocatalytic sets as a bona fide early evolution scenario and provides essential infrastructure for a paradigm shift towards a systems protobiology view of life's origin.


Integration of the metabolic and cardiovascular effects of exercise.
Most of the essays in this volume have adopted a reductionist approach and have focused on the biochemistry either in skeletal muscle or in the vascular wall. There is however a complex interaction between the biochemistry in the endothelium of the microvascular wall, the vascular smooth muscle and the skeletal muscle fibres involving signalling pathways in the three tissues and an intense exchange of signal molecules between them. In the present essay an integrative overview is given of this complex metabolic interaction and the impairments in it that lead to type 2 diabetes and cardiovascular disease.A reduced nitric oxide production by the (micro)vascular endothelium is identified as the key event and is reversible by regular exercise and a reduced calorie intake. The chapter also contains a description of the complex metabolic network controlled by the inducible transcription factor nuclear factor-kappaB, that is activated in more advanced stages of the chronic diseases, and either leads to repair of the microvascular wall or to irreversible damage and the severe complications of end stage cardiovascular disease and type 2 diabetes.


Structural and optical characterization of GaAs nano-crystals selectively grown on Si nano-tips by MOVPE.
We present the nanoheteroepitaxial growth of gallium arsenide (GaAs) on nano-patterned silicon (Si) (001) substrates fabricated using a CMOS technology compatible process. The selective growth of GaAs nano-crystals (NCs) was achieved at 570 °C by MOVPE. A detailed structure and defect characterization study of the grown nano-heterostructures was performed using scanning transmission electron microscopy, x-ray diffraction, micro-Raman, and micro-photoluminescence (μ-PL) spectroscopy. The results show single-crystalline, nearly relaxed GaAs NCs on top of slightly, by the SiO2-mask compressively strained Si nano-tips (NTs). Given the limited contact area, GaAs/Si nanostructures benefit from limited intermixing in contrast to planar GaAs films on Si. Even though a few growth defects (e.g. stacking faults, micro/nano-twins, etc) especially located at the GaAs/Si interface region were detected, the nanoheterostructures show intensive light emission, as investigated by μ-PL spectroscopy. Achieving well-ordered high quality GaAs NCs on Si NTs may provide opportunities for superior electronic, photonic, or photovoltaic device performances integrated on the silicon technology platform.


Social imitation of alcohol consumption and ingratiation motives in young adults.
Across 2 studies we tested the hypothesis that social ingratiation motives may be an important factor explaining social imitation of alcohol consumption. In Study 1, participants drank alcohol with a heavy versus light drinking confederate under conditions that were designed to heighten or reduce (participants believed they would not be judged) motivation for ingratiation. In Study 2 we manipulated the degree to which participants believed they had already successfully ingratiated themselves with a heavy or no (alcohol) drinking confederate. In Study 1, participants' alcohol consumption was most strongly influenced by the confederate's drinking behavior when they believed that they would later be judged by the confederate. In Study 2, participants' alcohol consumption was influenced by the confederate's drinking behavior and this effect was particularly pronounced if participants were unsure if the confederate had accepted them. The desire for social ingratiation may in part explain why people imitate the drinking behavior of those around them. (PsycINFO Database Record


I Knew I Would Be Safer. Experiences of Kenyan HIV Serodiscordant Couples Soon After Pre-Exposure Prophylaxis (PrEP) Initiation.
Pre-exposure prophylaxis (PrEP) for HIV-uninfected persons is highly efficacious for HIV prevention. Understanding how people at risk for HIV will use PrEP is important to inform PrEP scale-up and implementation. We used qualitative methods to gather insights into couples' early experiences with PrEP use within the Partners Demonstration Project, an open-label implementation study evaluating integrated delivery of PrEP and antiretroviral therapy (ART). PrEP is offered to HIV uninfected partners until the HIV-infected partner initiates and sustains ART use (i.e., PrEP as a "bridge" to ART initiation and viral suppression). From August 2013 to March 2014 we conducted 20 in-depth dyadic interviews (n = 40) with heterosexual HIV serodiscordant couples participating at the Thika, Kenya study site, exploring how couples make decisions about using PrEP for HIV prevention. We developed and applied deductive and inductive codes to identify key themes related to experiences of PrEP initiation and use of time-limited PrEP. Couples reported that PrEP offered them an additional strategy to reduce the risk of HIV transmission, meet their fertility desires, and cope with HIV serodiscordance. Remaining HIV negative at follow-up visits reinforced couples' decisions and motivated continued adherence to PrEP. In addition, confidence in their provider's advice and client-friendly services were critical to their decisions to initiate and continue use of PrEP. Strategies for wide-scale PrEP delivery for HIV serodiscordant couples in low resource settings may include building capacity of health providers to counsel on PrEP adoption while addressing couples' concerns and barriers to adoption and continued use.


Diminishing reciprocal fairness by disrupting the right prefrontal cortex.
Humans restrain self-interest with moral and social values. They are the only species known to exhibit reciprocal fairness, which implies the punishment of other individuals' unfair behaviors, even if it hurts the punisher's economic self-interest. Reciprocal fairness has been demonstrated in the Ultimatum Game, where players often reject their bargaining partner's unfair offers. Despite progress in recent years, however, little is known about how the human brain limits the impact of selfish motives and implements fair behavior. Here we show that disruption of the right, but not the left, dorsolateral prefrontal cortex (DLPFC) by low-frequency repetitive transcranial magnetic stimulation substantially reduces subjects' willingness to reject their partners' intentionally unfair offers, which suggests that subjects are less able to resist the economic temptation to accept these offers. Importantly, however, subjects still judge such offers as very unfair, which indicates that the right DLPFC plays a key role in the implementation of fairness-related behaviors.


Nonnutritive Sweeteners in Breast Milk.
Nonnutritive sweeteners (NNS), including saccharin, sucralose, aspartame, and acesulfame-potassium, are commonly consumed in the general population, and all except for saccharin are considered safe for use during pregnancy and lactation. Sucralose (Splenda) currently holds the majority of the NNS market share and is often combined with acesulfame-potassium in a wide variety of foods and beverages. To date, saccharin is the only NNS reported to be found in human breast milk after maternal consumption, while there is no apparent information on the other NNS. Breast milk samples were collected from 20 lactating volunteers, irrespective of their habitual NNS intake. Saccharin, sucralose, and acesulfame-potassium were present in 65% of participants' milk samples, whereas aspartame was not detected. These data indicate that NNS are frequently ingested by nursing infants, and thus prospective clinical studies are necessary to determine whether early NNS exposure via breast milk may have clinical implications.


Repeated STI and HIV testing among HIV-negative men who have sex with men attending a large STI clinic in Amsterdam: a longitudinal study.
In the Netherlands, men who have sex with men (MSM) are advised via informal guidelines to test for STI at least annually. We estimated the proportion of HIV-negative MSM testing repeatedly at 12-month or smaller intervals at a large STI clinic in the Netherlands. In addition, we explored whether repeated testing is related to risk behaviour. Longitudinal data of HIV-negative MSM visiting the Amsterdam STI clinic between 2009 and 2012 were analysed. To estimate the timing of repeated testing, Kaplan-Meier methods were used. Determinants for repeated testing (distinguishing testing at 12-month or smaller intervals and less than 12-monthly testing, with single testers as reference group) were identified using multivariate multinomial logistic regression analyses. In total, 19,479 consultations of 9174 HIV-negative MSM were identified. Of these MSM, 35% (95% CI 33% to 36%) were estimated to return to the STI clinic within 1 year following baseline consultation. Among 1767 men with at least two consultations and at least 2 years between baseline and last consultation, 43% tested repeatedly at 12-month or smaller intervals in those first 2 years. Repeated testers reported higher sexual risk behaviour (ie, only casual or both casual and steady sex partners, higher numbers of sex partners) at baseline compared with single testers. This effect tended to be slightly stronger for men testing repeatedly at 12-month or smaller intervals. The proportion of MSM testing for STI annually is low. MSM testing repeatedly had higher baseline levels of risk behaviour. Strategies to motivate MSM to test annually should be explored.


Survey on blood-sucking lice (Phthiraptera: Anoplura) of ruminants and pigs with molecular detection of Anaplasma and Rickettsia spp.
Lice may serve as biological or mechanical vectors for various infectious agents. To investigate louse infestation of ruminants and pigs, and pathogens potentially transmitted by them, anopluran lice (n=1182) were collected in Hungary, and evaluated for the presence of anaplasma, rickettsia and haemotropic mycoplasma DNA. On cattle the following species were found: Linognathus vituli (57%), Haematopinus eurysternus (38%) and Solenopotes capillatus (5%). L. vituli had a lower mean individual count/host when compared to H. eurysternus. On calves only L. vituli was observed, with a higher louse burden than on full-grown cattle. H. eurysternus and S. capillatus were more likely to occur simultaneously with another species on the same host, than L. vituli. Goats infested with Linognathus stenopsis had the overall highest prevalence (68%), while pigs harbouring Haematopinus suis showed the lowest (<1%). Anaplasma DNA was detected in 50% of pools analysed. In L. vituli Anaplasma ovis (or a closely related novel Anaplasma marginale genotype) was identified. Anaplasma-positivity of H. suis suggests that pigs may extend the reservoir and/or host spectrum of relevant species. Anaplasma-infected L. stenopsis pools show for the first time that caprine anaplasmosis is endemic in Hungary. Rickettsia spp. were demonstrated from Linognathus spp. and H. eurysternus. No haemotropic mycoplasmas were detected in any samples. In conclusion, this is the first molecularly confirmed report of bovine and ovine Anaplasma spp. in L. vituli, L. stenopsis and H. suis. The present results suggest that phthirapterosis of domestic animals deserves more attention, and lice should be evaluated among the broad range of potential vectors of arthropod-borne pathogens.


Convergent incidences of Wolbachia infection in fig wasp communities from two continents.
Wide surveys suggest that Wolbachia bacteria infect ca. 20% of all insect species, but particular taxonomic or ecological groups may display significantly higher or lower incidences. We studied 61 fig wasp species in Australia and found the highest known incidence (67%) of infection in a targeted study of this nature. A comparable study in Panama reported a similar figure (59%), confirming the exceptionally high incidence of Wolbachia in fig wasps. Importantly, these are two independent estimates of Wolbachia incidence in fig wasp communities, because no host species, or even genera, are shared between localities. The high level of infection may reflect enhanced opportunities for horizontal transmission inside fig fruits. Although incidence was similar in Panama and Australia, the actual strains involved were different and region-specific. Local strains were shared by several host species, although there was often no obvious (direct) ecological link between two hosts with the same infection.


Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma.
To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.


Modeling, simulation, and fabrication of bi-directional mode-division multiplexing for silicon-on-insulator platform.
A strip waveguide-based bi-directional mode-division multiplexer is proposed. A mathematical model has been proposed to analyze the performance, and the results are simulated. The design concept of this device to (de)multiplex three modes simultaneously has been studied previously for slab waveguides, both mathematically using the perturbative mode-coupled theory and by simulation using 2D FDTD Solutions (FDTD, finite difference time domain). As slab waveguides are not suitable for extracting fabrication parameters for most silicon-on-insulator applications, we apply the concept to a more practical device that involves strip waveguides rather than slab waveguides. The effective index method (EIM) has been used to develop the mathematical model and to get approximate forms for both the profiles and coupling coefficients. The return loss of different modes is taken into consideration to fully characterize the device performance. Simple formulas for both insertion and return losses of all multiplexing modes have been derived. In addition, full vectorial 3D FDTD simulations are performed so as to validate our mathematical model. Different design parameters have been used to get numerical results of the proposed device. Our results reveal that the EIM has enough accuracy to characterize the performance of our device compared to that of the complex full vectorial simulation. In order to validate the used model, the device has been fabricated and tested. Good insertion losses and crosstalks for all modes have been obtained.


Effects of aberrations and specimen structure in conventional, confocal and two-photon fluorescence microscopy.
Specimen-induced aberrations cause a reduction in signal levels and resolution in fluorescence microscopy. Aberrations also affect the image contrast achieved by these microscopes. We model the effects of aberrations on the fluorescence signals acquired from different specimen structures, such as point-like, linear, planar and volume structures, when imaged by conventional, confocal and two-photon microscopes. From this we derive the image contrast obtained when observing combinations of such structures. We show that the effect of aberrations on the visibility of fine features depends upon the specimen morphology and that the contrast is less significantly affected in microscopes exhibiting optical sectioning. For example, we show that point objects become indistinguishable from background fluorescence in the presence of aberrations, particularly when imaged in a conventional fluorescence microscope. This demonstrates the significant advantage of using confocal or two-photon microscopes over conventional instruments when aberrations are present.


The Reinforcement Sensitivity Theory of Personality Questionnaire (RST-PQ): Development and validation.
We report the development and validation of a questionnaire measure of the revised reinforcement sensitivity theory (rRST) of personality. Starting with qualitative responses to defensive and approach scenarios modeled on typical rodent ethoexperimental situations, exploratory and confirmatory factor analyses (CFAs) revealed a robust 6-factor structure: 2 unitary defensive factors, fight-flight-freeze system (FFFS; related to fear) and the behavioral inhibition system (BIS; related to anxiety); and 4 behavioral approach system (BAS) factors (Reward Interest, Goal-Drive Persistence, Reward Reactivity, and Impulsivity). Theoretically motivated thematic facets were employed to sample the breadth of defensive space, comprising FFFS (Flight, Freeze, and Active Avoidance) and BIS (Motor Planning Interruption, Worry, Obsessive Thoughts, and Behavioral Disengagement). Based on theoretical considerations, and statistically confirmed, a separate scale for Defensive Fight was developed. Validation evidence for the 6-factor structure came from convergent and discriminant validity shown by correlations with existing personality scales. We offer the Reinforcement Sensitivity Theory of Personality Questionnaire to facilitate future research specifically on rRST and, more broadly, on approach-avoidance theories of personality. (PsycINFO Database Record


Illusory self-identification with an avatar reduces arousal responses to painful stimuli.
Looking at one's own body has been shown to induce analgesia. In the present work we investigated whether illusory self-identification with an avatar, as induced experimentally through visuo-tactile stimulation, modulates the response to painful stimuli. In 30 healthy volunteers, a robotic device was used to stroke the participants' back, while they viewed either the body of an avatar, a non-body object (control object), or a body avatar with scrambled body parts (control body). All were visually stimulated in either congruent or incongruent fashion with the participant's body. We collected physiological responses (skin conductance response: SCR) to painful stimuli delivered to the participant's hand and responses to a questionnaire inquiring about self-identification with the avatar. We expected reduced physiological responses to pain during the observation of a body avatar only during synchronous visuo-tactile stroking and no reduction for the control object and the control body. Results showed a reduced SCR to painful stimuli when participants observed the normal body avatar being stroked synchronously that was also associated with largest self-identification ratings recordable already during the pain anticipation. Moreover, a negative correlation between self-identification and SCR was observed, suggesting that a greater degree of self-identification with the avatar was associated with larger decreases in SCR. These results suggest that during states of illusory self-identification with the avatar, the vision of an alien body (anatomically compatible for the vision and congruently stroked for the touch) is effective in modulating physiological responses to painful stimuli.


The effects of children on divorce and re-marriage: a multivariate analysis of life table probabilities.
Summary Using proportional hazards models and multiple decrement life tables to analyse data from the 1973 National Survey of Family Growth, this study tests the hypotheses that, net of the effects of such factors as age at separation or divorce, the probabilities of divorce after separation and of re-marriage after divorce would be lower for women with larger numbers of children or younger children, and that these transitions would take longer than for women with fewer or older children or women who were childless; and that there would be an interaction between number of children and age of youngest child. Results included: (1) the probability that mothers of two or more children would divorce after separation was significantly lower than for childless women, or those with only one child; (2) among whites, mothers of three or more children were at a significant disadvantage regarding their chances of re-marriage, whereas the probability that a black mother of three or more children would re-marry was no smaller than that of a woman with fewer or no children; (3) among whites, the presence of a youngest child aged between two and five years at separation decreased the probability of divorce after separation; (4) there was no interaction effect between number and age of children; and (5) in each category of family size and age of youngest child, the probability that a black woman would divorce after separation or re-marry after divorce was lower than for white women. The results have important implications for the study of divorce and re-marriage, and for understanding of problems of single-parent families.


Endothelial keratoplasty versus penetrating keratoplasty for Fuchs endothelial dystrophy.
Fuchs endothelial dystrophy (FED) is a condition in which there is premature degeneration of corneal endothelial cells. When the number of endothelial cells is reduced to a significant degree, fluid begins to accumulate within the cornea. As a result, the cornea loses its transparency and the individual suffers a reduction in vision. The only successful surgical treatment for this condition is replacement of part or all of the cornea with healthy tissue from a donor. The established procedure, penetrating keratoplasty (PKP), has been used for many years and its safety and efficacy are well known. Endothelial keratoplasty (EK) techniques are relatively new surgical procedures and their safety and efficacy relative to PKP are uncertain. The objective of this review was to compare the benefits and complications related to two surgical methods (EK and PKP) of replacing the diseased endothelial layer of the cornea with a healthy layer in people with FED. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2014, Issue 1), MEDLINE (January 1950 to January 2014), EMBASE (January 1980 to January 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 27 January 2014. We included all randomised controlled trials (RCTs) comparing EK versus PKP for people (of any age and gender) who had been clinically diagnosed with FED. Two authors independently screened the search results, assessed trial quality and extracted data using the standard methodological procedures expected by The Cochrane Collaboration. We included three RCTs that enrolled a total of 139 eyes of 136 participants and analysed 123 (88%) eyes. Two RCTs randomised eyes into either the endothelial keratoplasty (EK) group or penetrating keratoplasty (PKP) group and one RCT randomised eyes into either the femtosecond laser-assisted endothelial keratoplasty (FLEK) group or PKP group. The RCTs comparing EK with PKP did not show any significant differences between procedures with respect to best corrected visual acuity (BCVA) at two years (mean difference (MD) 0.14 logMAR; 95% confidence interval (CI) -0.08 to 0.36; P = 0.23) or at one year (MD 0.09 logMAR; 95% CI -0.05 to 0.23; P = 0.22), whereas the trial comparing FLEK with PKP showed significantly better BCVA after PKP (MD 0.20 logMAR; 95% CI 0.10 to 0.30; P = 0.0001). Only one RCT reported on irregular astigmatism (higher-order aberration), which was less with EK than PKP (MD -1.20 µm; 95% CI -1.53 to -0.87; P < 0.001). Only one RCT reported on endothelial cell counts (lower after FLEK than PKP: MD -969 cells/mm²; 95% CI -1161 to -777; P < 0.001), primary graft failure (higher after FLEK than PKP: RR 7.76; 95% CI 0.41 to 145.22; P = 0.10), and graft rejection (more after FLEK than PKP: RR 1.11; 95% CI 0.07 to 17.12; P = 0.94). Only one RCT reported that 27.8% of participants had graft dislocation, 2.8% had epithelial ingrowth and postoperative pupillary block, and 13.9% had intraocular pressure (IOP)-related problems in the FLEK group compared with the PKP group, in whom 10% had suture-related problems, 5% had wound dehiscence and 10% had suture revision to correct astigmatism. Overall, the adverse events in the FLEK group appeared to be more frequent than in the PKP group. No trials reported information about quality of life or economic data. The overall methodological quality of the three trials was not satisfactory as most did not perform allocation concealment or masking of participants and outcome assessors, and all trials had a small sample size. The rapid growth of endothelial keratoplasty as the treatment of choice for FED is based upon the belief that visual recovery is more rapid, surgically induced astigmatism (regular and irregular) is less and rates of transplant rejection are lower with EK. This change in practice also assumes that the rates of long term transplant survival are equal for the two procedures. The practical differences between the surgical procedures mean that visual recovery is inherently more rapid following EK, but this review found no strong evidence from RCTs of any difference in the final visual outcome between EK and PKP for people with FED. This review also found that higher order aberrations are fewer following EK but endothelial cell loss is greater following EK. The RCTs that we included employed different EK techniques, which may have a bearing on these findings. EK procedures have evolved over the years and can be performed using different techniques, for example deep lamellar endothelial keratoplasty, Descemets stripping endothelial keratoplasty (DSEK), Descemets stripping automated endothelial keratoplasty (DSAEK), femtosecond laser-assisted endothelial keratoplasty and Descemet membrane endothelial keratoplasty (DMEK). More RCTs are needed to compare PKP with commonly performed EK procedures such as DSEK, DSAEK and DMEK in order to determine the answers to two key questions, whether there is any difference in the final visual outcome between these techniques and whether there are differences in the rates of graft survival in the long term?


ZFP36-mediated mRNA decay regulates metabolism.
Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation-many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.


Pediatric Behçet's disease - clinical aspects and current concepts.
Behçet's Disease was first described by a Turkish dermatologist, Hulusi Behçet, in 1937 as a triple symptom complex; aphthous stomatitis, genital ulcers, and uveitis. Today, in light of current trials and experiments, we know that the disease may have a wider involvement with a multisystemic recurrent course, causing significant morbidity and mortality. However, there are still unanswered questions, particularly about Pediatric Behçet's Disease. Although several immunological and genetic associations have been demonstrated, the real etiologic mechanism of the disease is unclear. The diagnosis is difficult due to its rarity in childhood, the lack of validation of the diagnostic criteria obtained from adult studies, and the inadequacy of large case-controlled studies. Also, the management is challenging and controversial due to the various geographic distribution of clinical spectrum. New therapeutic options under development in light of pathogenetic hypothesis seem to be promising.


Alcohol Use and Frailty Risk among Older Adults over 12 Years: The Health and Retirement Study.
The primary goal was to examine the relationship between alcohol use and frailty, a variable characterizing late-life decline, in a national, longitudinal survey of older adults living in the United States. The sample drawn from the Health and Retirement Study included 9,499 stroke-free participants over age 65 in 2000. The sample was 59.1% female, and had a mean age of 74.25 years (SD = 6.99). Follow-up data was from 2004, 2008, and 2012. Frailty was defined phenotypically using the Paulson-Lichtenberg Frailty Index (PLFI). Alcohol use was measured via self-report. Control variables included age, race, education, socio-economic status (SES), depressive symptomatology, medical burden score, body mass index (BMI), and partner status. With abstinent participants as the reference group, logistic regressions were conducted to determine prevalent frailty at 2000, and Cox's proportional hazard models were utilized to determine time to incident frailty over a 12-year period. Results revealed that age, depressive symptomatology, and medical burden score were significant positive correlates of prevalent and incident frailty (p < .05) for both males and females. Logistic regressions revealed that consumption of 1-7 alcoholic drinks per week was associated with reduced prevalent frailty (OR = .49, p < .001) for females. Survival analysis results reveal that compared with nondrinkers, males and females who reportedly consumed 1-7 drinks per week had a decreased probability of incident frailty (HR = .78-081, p < .05). Findings suggest that moderate alcohol use confers reduced frailty risk for both older men and women. Future research should examine the mechanism(s) relating alcohol consumption and frailty. Findings support extant literature suggesting some healthcare benefits may be associated with moderate drinking.


ApoE mimetic ameliorates motor deficit and tissue damage in rat spinal cord injury.
Apolipoprotein E (apoE), a plasma protein responsible for transporting lipid and cholesterol, modulates responses of the central nervous system to injury. Small peptides derived from the receptor-binding region of apoE can simulate some important bioactivities of apoE holoprotein and offer neuroprotection against brain injury. We tested whether COG1410, an apoE-mimetic peptide, provides protection in a rat model of spinal cord injury (SCI). Traumatic injury was created at T8 by a cortical impact device. Injured rats were randomized to four treatment groups: vehicle, 0.15, 0.3, or 0.6 mg/kg COG1410; sham surgery rats received vehicle. Basso, Beattie, Bresnahan neurological score was evaluated prior to injury and at 1, 3, 7, and 14 days after injury. Histological changes were evaluated at 14 days. All injured rats lost body weight during the first week following injury. Body weight recovery was significantly improved in rats treated with COG1410. Mechanical impact resulted in severe motor deficit, and most animals had a BBB score of 0-1 at 24 hours postinjury. COG1410-treated rats showed significantly improved functional recovery and ameliorated motor deficit at 14 days postinjury. Histological analysis showed that COG1410 groups had a significantly reduced lesion size at the site of injury, a larger preserved luxol fast blue-stained area, and more visible neurons in the surrounding area of injury. Microglial activation was also significantly suppressed. These findings indicate that this apoE mimetic effectively improved neurological and histological outcome following SCI in rats, and the effect was associated with inhibition of microglial activation.


Unexplained deaths in Connecticut, 2002-2003: failure to consider category a bioterrorism agents in differential diagnoses.
Recognition of bioterrorism-related infections by hospital and emergency department clinicians may be the first line of defense in a bioterrorist attack. We identified unexplained infectious deaths consistent with the clinical presentation of anthrax, tularemia, smallpox, and botulism using Connecticut death certificates and hospital chart information. Minimum work-up criteria were established to assess the completeness of diagnostic testing. Of 4558 unexplained infectious deaths, 133 were consistent with anthrax (2.9%) and 6 (0.13%) with tularemia. None were consistent with smallpox or botulism. No deaths had anthrax or tularemia listed in the differential diagnosis or had disease-specific serology performed. Minimum work-up criteria were met for only 53% of cases. Except for anthrax, few unexplained deaths in Connecticut could possibly be the result of the bioterrorism agents studied. In 47% of deaths from illnesses that could be anthrax, the diagnosis would likely have been missed. As of 2004, Connecticut physicians were not well prepared to intentionally or incidentally diagnose initial cases of anthrax or tularemia. More effective clinician education and surveillance strategies are needed to minimize the potential to miss initial cases in a bioterrorism attack.


Defined Culture Conditions Accelerate Small-molecule-assisted Neural Induction for the Production of Neural Progenitors from Human-induced Pluripotent Stem Cells.
The use of defined conditions for derivation, maintenance, and differentiation of human-induced pluripotent stem cells (hiPSCs) provides a superior experimental platform to discover culture responses to differentiation cues and elucidate the basic requirements for cell differentiation and fate restriction. Adoption of defined systems for reprogramming, undifferentiated growth, and differentiation of hiPSCs was found to significantly influence early stage differentiation signaling requirements and temporal kinetics for the production of primitive neuroectoderm. The bone morphogenic protein receptor agonist LDN-193189 was found to be necessary and sufficient for neural induction in a monolayer system with landmark antigens paired box 6 and sex-determining region Y-box 1 appearing within 72 h. Preliminary evidence suggests this neuroepithelium was further differentiated to generate ventral spinal neural progenitors that produced electrophysiologically active neurons in vitro, maintaining viability posttransplantation in an immunocompromised host. Our findings support current developments in the field, demonstrating that adoption of defined reagents for the culture and manipulation of pluripotent stem cells is advantages in terms of simplification and acceleration of differentiation protocols, which will be critical for future clinical translation.


Interplay of rotational, relaxational, and shear dynamics in solid ⁴He.
Using a high-sensitivity torsional oscillator (TO) technique, we mapped the rotational and relaxational dynamics of solid helium-4 ((4)He) throughout the parameter range of the proposed supersolidity. We found evidence that the same microscopic excitations controlling the torsional oscillator motions are generated independently by thermal and mechanical stimulation. Moreover, a measure for the relaxation times of these excitations diverges smoothly without any indication for a critical temperature or critical velocity of a supersolid transition. Finally, we demonstrated that the combined temperature-velocity dependence of the TO response is indistinguishable from the combined temperature-strain dependence of the solid's shear modulus. This implies that the rotational responses of solid (4)He attributed to supersolidity are associated with generation of the same microscopic excitations as those produced by direct shear strain.


Quantitation of cis-diamminedichloroplatinum II (cisplatin)-DNA-intrastrand adducts in testicular and ovarian cancer patients receiving cisplatin chemotherapy.
The antitumor activity of cis-diamminedichloroplatinum II (cisplatin) is believed to be related to its covalent interaction with DNA where a major DNA binding product is an intrastrand N7-bidentate adduct on adjacent deoxyguanosines. A novel immunoassay was used to quantitate this adduct in buffy coat DNA from testicular and ovarian cancer patients undergoing cisplatin therapy. 44 out of 120 samples taken from 45 cisplatin patients had detectable cisplatin-DNA adducts. No adducts were detected in 18 samples of DNA taken from normal controls, patients on other chemotherapy, or patients before treatment. The quantity of measurable adducts increased as a function of cumulative dose of cisplatin. This was observed both during repeated daily infusion of the drug and over long-term, repeated 21-28 d cycles of administration. These results suggested that adduct removal is slow even though the tissue has a relatively rapid turnover. Patients receiving cisplatin for the first time on 56-d cycles, and those given high doses of cisplatin as a "salvage" regimen, did not accumulate adducts as rapidly as patients on first time chemotherapy on 21- or 28-d cycles. Disease response data, evaluated for 33 cisplatin-treated patients, showed a positive correlation between the formation of DNA adducts and response to drug therapy. However, more data will be required to confirm this relationship. These data show that specific immunological probes can readily be applied to quantitate DNA adducts in patients undergoing cancer chemotherapy.


Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.
To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism.


Ketamine effects on memory reconsolidation favor a learning model of delusions.
Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.


Interactions of the DNA polymerase X from African Swine Fever Virus with the ssDNA. Properties of the total DNA-binding site and the strong DNA-binding subsite.
Interactions of the polymerase X from the African Swine Fever Virus with the ssDNA have been studied, using quantitative fluorescence titration and fluorescence resonance energy transfer techniques. The primary DNA-binding subsite of the enzyme, independent of the DNA conformation, is located on the C-terminal domain. Association of the bound DNA with the catalytic N-terminal domain finalizes the engagement of the total DNA-binding site of the enzyme and induces a large topological change in the structure of the bound ssDNA. The free energy of binding includes a conformational transition of the protein. Large positive enthalpy changes accompanying the ASFV pol X-ssDNA association indicate that conformational changes of the complex are induced by the engagement of the N-terminal domain. The enthalpy changes are offset by large entropy changes accompanying the DNA binding to the C-terminal domain and the total DNA-binding site, predominantly resulting from the release of water molecules.


Heart rate variability, prefrontal neural function, and cognitive performance: the neurovisceral integration perspective on self-regulation, adaptation, and health.
In the present paper, we describe a model of neurovisceral integration in which a set of neural structures involved in cognitive, affective, and autonomic regulation are related to heart rate variability (HRV) and cognitive performance. We detail the pathways involved in the neural regulation of the cardiovascular system and provide pharmacological and neuroimaging data in support of the neural structures linking the central nervous system to HRV in humans. We review a number of studies from our group showing that individual differences in HRV are related to performance on tasks associated with executive function and prefrontal cortical activity. These studies include comparisons of executive- and nonexecutive-function tasks in healthy participants, in both threatening and nonthreatening conditions. In addition, we show that manipulating resting HRV levels is associated with changes in performance on executive-function tasks. We also examine the relationship between HRV and cognitive performance in ecologically valid situations using a police shooting simulation and a naval navigation simulation. Finally, we review our studies in anxiety patients, as well as studies examining psychopathy. These findings in total suggest an important relationship among cognitive performance, HRV, and prefrontal neural function that has important implications for both physical and mental health. Future studies are needed to determine exactly which executive functions are associated with individual differences in HRV in a wider range of situations and populations.


Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis.
Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.


Clinical parameters for predicting radiation-induced liver disease after intrahepatic reirradiation for hepatocellular carcinoma.
Few data are available on the tolerance of reirradiation in patients with hepatocellular carcinoma (HCC). This study determined the clinical parameters contributing to the development of radiation-induced liver disease (RILD). We included 36 patients with HCC who received 2 courses of radiotherapy (RT) to the liver. Using α/β = 15 for tumor and α/β =8 for normal liver tissue for biologically equivalent doses in 2 Gy fractions, mean cumulative to the hepatic tumor and normal liver were 87.7 Gy15 and 31.1 Gy8, respectively. Hepatic toxicities were classified according to the Common Terminology Criteria for Adverse Events, Version 4.0. Clinical data, including liver function test results, radiological study findings, and RT parameters before and after both courses of RT were retrieved for analysis. Using multivariate analysis, logistic regression was used to identify the predictors of RILD, and Cox regression was performed to explore the prognostic factors for overall survival (OS). Thirteen patients (36 %) developed RILD after reirradiation. Nine of them died because of progressive liver failure without evidence of tumor progression and were categorized to have lethal RILD. A pretreatment Child-Turcotte-Pugh (CTP) score ≥6 was the only predictor of RILD [odds ratio (OR): 15.83, p = 0.001] and lethal RILD [OR: 72.56, p = 0.005]. In addition, a CTP score ≥6 and the presence of portal vein tumor thrombosis before reirradiation were 2 prognostic factors for OS. Despite a limited sample size, residual liver function using a preirradiation CTP score ≥6 is a clinical parameter associated with an increased risk of RILD in patients requiring hepatic reirradiation.


Cost-effectiveness of spinal manipulative therapy, supervised exercise, and home exercise for older adults with chronic neck pain.
Chronic neck pain is a prevalent and disabling condition among older adults. Despite the large burden of neck pain, little is known regarding the cost-effectiveness of commonly used treatments. This study aimed to estimate the cost-effectiveness of home exercise and advice (HEA), spinal manipulative therapy (SMT) plus HEA, and supervised rehabilitative exercise (SRE) plus HEA. Cost-effectiveness analysis conducted alongside a randomized clinical trial (RCT) was performed. A total of 241 older adults (≥65 years) with chronic mechanical neck pain comprised the patient sample. The outcome measures were direct and indirect costs, neck pain, neck disability, SF-6D-derived quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) over a 1-year time horizon. This work was supported by grants from the National Center for Complementary and Integrative Health (#F32AT007507), National Institute of Arthritis and Musculoskeletal and Skin Diseases (#P60AR062799), and Health Resources and Services Administration (#R18HP01425). The RCT is registered at ClinicalTrials.gov (#NCT00269308). A societal perspective was adopted for the primary analysis. A healthcare perspective was adopted as a sensitivity analysis. Cost-effectivenesswas a secondary aim of the RCT which was not powered for differences in costs or QALYs. Differences in costs and clinical outcomes were estimated using generalized estimating equations and linear mixed models, respectively. Cost-effectiveness acceptability curves were calculated to assess the uncertainty surrounding cost-effectiveness estimates. Total costs for SMT+HEA were 5% lower than HEA (mean difference: -$111; 95% confidence interval [CI] -$1,354 to $899) and 47% lower than SRE+HEA (mean difference: -$1,932; 95% CI -$2,796 to -$1,097). SMT+HEA also resulted in a greater reduction of neck pain over the year relative to HEA (0.57; 95% CI 0.23 to 0.92) and SRE+HEA (0.41; 95% CI 0.05 to 0.76). Differences in disability and QALYs favored SMT+HEA. The probability that adding SMT to HEA is cost-effective at willingness to pay thresholds of $50,000 to $200,000 per QALY gained ranges from 0.75 to 0.81. If adopting a health-care perspective, costs for SMT+HEA were 66% higher than HEA (mean difference: $515; 95% CI $225 to $1,094), resulting in an ICER of $55,975 per QALY gained. On average, SMT+HEA resulted in better clinical outcomes and lower total societal costs relative to SRE+HEA and HEA alone, with a 0.75 to 0.81 probability of cost-effectiveness for willingness to pay thresholds of $50,000 to $200,000 per QALY.


Antibacterial mono- and sesquiterpene esters of benzoic acids from Iranian propolis.
Propolis (bee glue) has been used as a remedy since ancient times. Propolis from unexplored regions attracts the attention of scientists in the search for new bioactive molecules. From Iranian propolis from the Isfahan province, five individual components were isolated: the prenylated coumarin suberosin 1, and four terpene esters: tschimgin (bornyl p-hydroxybenzoate) 2, tschimganin (bornyl vanillate) 3, ferutinin (ferutinol p-hydroxybenzoate) 4, and tefernin (ferutinol vanillate) 5. All of them were found for the first time in propolis. Compounds 2 - 5 demonstrated activity against Staphylococcus aureus. The results of the present study are consistent with the idea that propolis from unexplored regions is a promising source of biologically active compounds.


The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis.
While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in Smcr8 mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components-phenotypes that we subsequently observed in C9orf72 loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis-processes of potential importance to ALS.


Cancer stem cells in glioma: challenges and opportunities.
The discovery of cancer stem cells in glioma has created a paradigm shift in our understanding of this deadly disease. Glioma stem cells exhibit sustained self-renewal and potent tumorigenic potential and differ from their more differentiated progeny in response to current therapies. Recurrent disease is likely derived from glioma stem cells or progeny reprogrammed to gain stem cell-like phenotypes, indicating that the stem cell phenotype is a crucial therapeutic target. While debate over cancer stem cell and clonal evolution models persists, important knowledge has been gained over the past decade from glioma stem cells investigation and clinical impact is expected.


A rational model for assessing and evaluating complex interventions in health care.
Understanding how new clinical techniques, technologies and other complex interventions become normalized in practice is important to researchers, clinicians, health service managers and policy-makers. This paper presents a model of the normalization of complex interventions. Between 1995 and 2005 multiple qualitative studies were undertaken. These examined: professional-patient relationships; changing patterns of care; the development, evaluation and implementation of telemedicine and related informatics systems; and the production and utilization of evidence for practice. Data from these studies were subjected to (i) formative re-analysis, leading to sets of analytic propositions; and to (ii) a summative analysis that aimed to build a robust conceptual model of the normalization of complex interventions in health care. A normalization process model that enables analysis of the conditions necessary to support the introduction of complex interventions is presented. The model is defined by four constructs: interactional workability; relational integration; skill set workability and contextual integration. This model can be used to understand the normalization potential of new techniques and technologies in healthcare settings The normalization process model has face validity in (i) assessing the potential for complex interventions to become routinely embedded in everyday clinical work, and (ii) evaluating the factors that promote or inhibit their success and failure in practice.


A therapy impact questionnaire for quality-of-life assessment in advanced cancer research.
The first part of the validation procedure used for a Therapy Impact Questionnaire (TIQ) on quality-of-life assessment in advanced cancer patients is described. The TIQ is composed of 36 items which assess both disease and therapy impact according to four dimensions that operationally define quality of life: physical symptoms (24 items), functional status (3 items), concomitant emotional and cognitive factors (6 items) and social interaction (2 items). A global judgement expressed as "have you been feeling ill" further completes the TIQ. Patients answered each question using a 4-point verbal Likert scale: not at all, slight, a lot and very much. The TIQ was given to 1,000 consecutive patients who were no longer responsive to cancer treatment and presented symptoms due to disease progression. The compliance rate was quite high (87%). Results of confirmatory factor analysis were consistent with the operational dimensions identified during questionnaire construction. In particular, the dichotomized answers to 3 functional status items could be used as a Guttman scale. In a sub-sample of 50 patients, the reproducibility of functional status items was assessed using a 7-item parallel form. The intraclass correlation coefficient obtained indicated a reasonably high reproducibility. On the basis of the analyses conducted, the TIQ appears to be a reliable and concise instrument for studies aimed to assess the effectiveness of therapies in advanced cancer patients.


Successful living donor liver transplantation for classical maple syrup urine disease.
MSUD is an autosomal recessive condition characterized by a deficiency in the enzyme, BCKDH, which catalyzes the breakdown of BCAAs. If left untreated, MSUD can result in mental retardation, central nervous system disorders, and even death. Most patients with MSUD are treated with a restricted protein diet and milk from which BCAAs have been removed. LT has been shown effective in patients with MSUD. This report describes the case of a 15-month-old boy who received a liver graft from his mother. Transplantation was successful, and the patient was then able to ingest a normal diet. Despite episodes of acute rejection, chylous ascites, and high fever (40 °C), he has shown no evidence of MSUD recurrence. These findings indicate that patients with MSUD can be successfully treated by LDLT, even when the donor is a heterozygous carrier of a mutated BCKDH gene.


Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. Bid-/- mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, BidM148T, associates with MI predisposition. Furthermore, Bid but not BidM148T associates with Mcl-1Matrix, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.


Enhanced placental cholesterol efflux by fetal HDL in Smith-Lemli-Opitz syndrome.
Previous studies from this laboratory have shown that maternal-derived cholesterol can be effluxed from trophoblasts to fetal HDL and plasma. We had the opportunity to study for the first time the ability of HDL and plasma from a fetus with the Smith-Lemli-Opitz syndrome (SLOS) to efflux cholesterol from trophoblasts. It was unclear whether cholesterol could be effluxed to fetuses with SLOS since lipoprotein levels are often very low. To answer this question, cord blood was collected from the placentas of an SLOS fetus and unaffected fetuses just after delivery. Plasma cholesterol concentrations were very low in the affected fetus; cholesterol, 7-dehydrocholesterol, and 8-dehydocholesterol concentrations were 14.1, 4.5, and 5.2 mg/dl, respectively. The HDL from the fetal SLOS effluxed approximately 50% more cholesterol from a trophoblast cell line, were smaller in size, and had a lower cholesterol to phospholipid ratio as compared to HDL from unaffected fetuses or adults. Plasma from the SLOS fetus effluxed cholesterol to a similar percentage as unaffected fetal plasma or adult plasma, possibly due to fewer HDL particles as demonstrated in previous SLOS patients. These novel data demonstrate that the cholesterol-deficient SLOS fetus is able to obtain cholesterol from trophoblasts at a time when cholesterol is playing a critical role in development, and has implications for design of treatments for cholesterol deficiency syndromes as well as understanding of prenatal cholesterol transport in humans.


A very rare case of trisomy 4q32.3-4q35.2 and trisomy 21q11.2-21q22.11 in a patient with recombinant chromosomes 4 and 21.
We report the case of a patient with a clinical phenotype consistent with Down Syndrome (DS) who has a novel karyotypic abnormality. Karyotypic analyses were performed to investigate the cause of two spontaneous abortions. A balanced translocation between chromosomes 4 and 21 was identified, along with an additional abnormal chromosome 21. We performed high-resolution banding, comparative genomic hybridization (CGH), and FISH studies in both the patient and her mother to define the abnormality and determine its origin. CGH revealed a gain in copy number on the long arm of chromosome 4, spanning at least 24.4 Mb, and a gain in copy number on the long arm of chromosome 21, spanning at least 16.2 Mb. FISH analysis using a chromosome 21 centromere probe and chromosome 4 long arm telomere (4pter) probe confirmed the origin of the marker chromosome. It has been confirmed by the State Key Laboratory of Medical Genetics of China that this is the first reported instance of the karyotype 47,XX,t(4;21)(q31.3;q11.2),+der(21)t(4;21)mat reported in the world.


Protoporphyrin IX fluorescence contrast in invasive glioblastomas is linearly correlated with Gd enhanced magnetic resonance image contrast but has higher diagnostic accuracy.
The sensitivity and specificity of in vivo magnetic resonance (MR) imaging is compared with production of protoporphyrin IX (PpIX), determined ex vivo, in a diffusely infiltrating glioma. A human glioma transfected with green fluorescent protein, displaying diffuse, infiltrative growth, was implanted intracranially in athymic nude mice. Image contrast from corresponding regions of interest (ROIs) in in vivo MR and ex vivo fluorescence images was quantified. It was found that all tumor groups had statistically significant PpIX fluorescence contrast and that PpIX contrast demonstrated the best predictive power for tumor presence. Contrast from gadolinium enhanced T1-weighted (T1W+Gd) and absolute T2 images positively predicted the presence of a tumor, confirmed by the GFP positive (GFP+) and hematoxylin and eosin positive (H&E+) ROIs. However, only the absolute T2 images had predictive power from controls in ROIs that were GFP+ but H&E negative. Additionally, PpIX fluorescence and T1W+Gd image contrast were linearly correlated in both the GFP+ (r = 0.79, p<1×10(-8)) and H&E+ (r = 0.74, p<0.003) ROIs. The trace diffusion images did not have predictive power or significance from controls. This study indicates that gadolinium contrast enhanced MR images can predict the presence of diffuse tumors, but PpIX fluorescence is a better predictor regardless of tumor vascularity.


A cohort study of women with a Fontan circulation undergoing preconception counselling.
To describe outcomes for women with a Fontan circulation attending preconception counselling (PCC). Exploring (1) impact of counselling on decision to become pregnant; (2) pregnancy rates in those opting for pregnancy and (3) short-term and long-term outcome of those who succeeded in becoming pregnant. Retrospective review of women aged 16-45 years with a Fontan circulation from 1994 to 2014. 58 women were offered PCC, 3 declined and 55 received PCC. Following PCC, 15 opted against conception, 16 decided to delay pregnancy, 19 attempted pregnancy and 5 were lost to follow-up. Of the 19 women, 14 succeeded, becoming pregnant a total of 43 times (median 1, range 1-9). Of these, 6 miscarried all pregnancies. 8 carried 14 pregnancies to viability. Baseline hypoxaemia and cardiac disease in pregnancy (CARPREG) score was similar in those opting for and against pregnancy, but CARPREG score was better in those delaying conception. Women exclusively miscarrying or unable to conceive were more likely to have baseline hypoxaemia and greater CARPREG score. Cardiac complications included arrhythmia requiring treatment (n = 4) and one thromboembolism. Obstetric complications were greater in women with a Fontan circulation, 10 preterm births (< 37 weeks) and 8 small for gestational age babies (< 10th centile). There was one neonatal death. At follow-up, there was no deterioration in clinical status as determined by echo. Most women accept PCC and decided to pursue pregnancy; in some cases, this was despite being advised of a poor prognosis. Pregnancy outcome was related to baseline hypoxia and CARPREG scores.


Collagen-Poly(N-isopropylacrylamide) Hydrogels with Tunable Properties.
There is a lack of hydrogel materials whose properties can be tuned at the point of use. Biological hydrogels, such as collagen, gelate at physiological temperatures; however, they are not always ideal as scaffolds because of their low mechanical strength. Their mechanics can be improved through cross-linking and chemical modification, but these methods still require further synthesis. We have demonstrated that by combining collagen with a thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM), the mechanical properties can be improved while maintaining cytocompatibility. Furthermore, different concentrations of this polymer led to a range of hydrogels with shear moduli ranging from 10(5) Pa down to less than 10(2) Pa, similar to the soft tissues in the body. In addition to variable mechanical properties, the hydrogel blends have a range of micron-scale structures and porosities, which caused adipose-derived stromal cells (ADSCs) to adopt different morphologies when encapsulated within and may therefore be able to direct cell fate.


Calcium/strontium chloride impregnated zeolite A and X granules as optimized ammonia sorbents.
Calcium chloride (CaCl2) impregnated zeolite A and strontium chloride (SrCl2) impregnated zeolite A and X composite granules were evaluated as ammonia sorbents for automotive selective catalytic reduction systems. The SrCl2-impregnated zeolite A granules showed a 14% increase in ammonia uptake capacity (8.39 mmol g-1) compared to zeolite A granules (7.38 mmol g-1). Furthermore, composite granules showed 243% faster kinetics of ammonia sorption (0.24 mmol g-1 min-1) compared to SrCl2 (0.07 mmol g-1 min-1) in the first 20 min. The composite CaCl2/SrCl2 impregnated zeolite A granules combined the advantages of the zeolites and CaCl2/SrCl2, where the rapid physisorption from zeolites can reduce the ammonia loading and release time, and chemisorption from the CaCl2/SrCl2 offers abundant ammonia capacity. Moreover, by optimizing the content of SrCl2 loading, the composite granules maintained the granular form with a crushing load of 17 N per granule after ammonia sorption-desorption cycles. Such structurally stable composite sorbents offer an opportunity for fast ammonia loading/release in automotive selective catalytic reduction systems.


Use of sugammadex in patients with neuromuscular disorders: a systematic review of case reports.
Sugammadex is a modified gamma-cyclodextrin that acts by selectively encapsulating free amino-steroidal neuromuscular relaxants. Several case reports have been published on the use of sugammadex in patients with neuromuscular disorders that include neuromuscular junction diseases, myopathies, neuropathies, and motor neurone disorders. The primary aim of this review is to systematically review the evidence on the use of sugammadex in patients with this heterogeneous group of diseases and provide recommendations for clinical practice. A systematic electronic search of Medline, Embase and CINAHL databases was done until June 2019, to identify case reports describing the use of sugammadex in adult surgical patients with neuromuscular disorders. Of the 578 records identified through database searches, 43 articles were finally included for the systematic review. Of these, 17 reports were on patients with myopathy, 15 reports on myasthenia gravis, 9 reports on motor neuron diseases and 2 reports on neuropathies. Majority of the articles reviewed report successful use of sugammadex to reverse steroidal muscle relaxants, especially rocuronium, in patients with neuromuscular diseases. However, with sugammadex, unpredictability in response and uncertainty regarding optimum dose still remain issues. Quantitative neuromuscular monitoring to ensure complete reversal and adequate postoperative monitoring is strongly recommended in these patients, despite the use of sugammadex.


Hemolin: an insect-immune protein belonging to the immunoglobulin superfamily.
Insects have an efficient defense system against infections. Their antibacterial immune proteins have been well characterized. However, the molecular mechanisms by which insects recognize foreignness are not yet known. Data are presented showing that hemolin (previously named P4), a bacteria-inducible hemolymph protein of the giant silk moth Hyalophora cecropia, belongs to the immunoglobulin superfamily. Functional analyses indicate that hemolin is one of the first hemolymph components to bind to the bacterial surface, taking part in a protein complex formation that is likely to initiate the immune response.