Using rule-based machine learning for candidate disease gene prioritization and sample classification of cancer gene expression data.
Microarray data analysis has been shown to provide an effective tool for studying cancer and genetic diseases. Although classical machine learning techniques have successfully been applied to find informative genes and to predict class labels for new samples, common restrictions of microarray analysis such as small sample sizes, a large attribute space and high noise levels still limit its scientific and clinical applications. Increasing the interpretability of prediction models while retaining a high accuracy would help to exploit the information content in microarray data more effectively. For this purpose, we evaluate our rule-based evolutionary machine learning systems, BioHEL and GAssist, on three public microarray cancer datasets, obtaining simple rule-based models for sample classification. A comparison with other benchmark microarray sample classifiers based on three diverse feature selection algorithms suggests that these evolutionary learning techniques can compete with state-of-the-art methods like support vector machines. The obtained models reach accuracies above 90% in two-level external cross-validation, with the added value of facilitating interpretation by using only combinations of simple if-then-else rules. As a further benefit, a literature mining analysis reveals that prioritizations of informative genes extracted from BioHEL's classification rule sets can outperform gene rankings obtained from a conventional ensemble feature selection in terms of the pointwise mutual information between relevant disease terms and the standardized names of top-ranked genes.


The effect of interaural fluctuation rate on correlation change discrimination.
While bilateral cochlear implants (CIs) provide some binaural benefits, these benefits are limited compared to those observed in normal-hearing (NH) listeners. The large frequency-to-electrode allocation bandwidths (BWs) in CIs compared to auditory filter BWs in NH listeners increases the interaural fluctuation rate available for binaural unmasking, which may limit binaural benefits. The purpose of this work was to investigate the effect of interaural fluctuation rate on correlation change discrimination and binaural masking-level differences in NH listeners presented a CI simulation using a pulsed-sine vocoder. In experiment 1, correlation-change just-noticeable differences (JNDs) and tone-in-noise thresholds were measured for narrowband noises with different BWs and center frequencies (CFs). The results suggest that the BW, CF, and/or interaural fluctuation rate are important factors for correlation change discrimination. In experiment 2, the interaural fluctuation rate was systematically varied and dissociated from changes in BW and CF by using a pulsed-sine vocoder. Results indicated that the interaural fluctuation rate did not affect correlation change JNDs for correlated reference noises; however, slow interaural fluctuations increased correlation change JNDs for uncorrelated reference noises. In experiment 3, the BW, CF, and vocoder pulse rate were varied while interaural fluctuation rate was held constant. JNDs increased for increasing BW and decreased for increasing CF. In summary, relatively fast interaural fluctuation rates are not detrimental for detecting changes in interaural correlation. Thus, limiting factors to binaural benefits in CI listeners could be a result of other temporal and/or spectral deficiencies from electrical stimulation.


Burden of injury in childhood and adolescence in 8 European countries.
Injury is the major cause of death and suffering among children and adolescents, but awareness of the problem and political commitment for preventive actions remain unacceptably low. We have assessed variation in the burden of injuries in childhood and adolescence in eight European countries. Hospital, emergency department, and mortality databases of injury patients aged 0-24 years were analyzed for Austria, Denmark, Ireland, Latvia, Netherlands, Norway, Slovenia and the United Kingdom (England, Wales). Years lost due to premature mortality (YLL), years lived with disability (YLD), and disability adjusted life years (DALYs) were calculated. Differences in the burden of injury in childhood and adolescence are large, with a fourfold gap between the safest countries (Netherlands and UK) in western-Europe and the relatively unsafe countries (Latvia and Slovenia) in the east. Variation between countries is attributable to high variation in premature mortality (YLL varied from 14-58 per 1000 persons) and disability (YLD varied from 3-10 per 1000 persons). Highest burden is observed among males ages 15-24. If childhood and adolescence injuries are reduced to the level of current best injury prevention practices, 6 DALYs per 1000 child years can be avoided. Injuries in childhood and adolescence cause a high disability and mortality burden in Europe. In all developmental stages large inequalities between west and east are observed. Potential benefits up to almost 1 million healthy child years gained across Europe are possible, if proven ways for prevention are more widely implemented. Our children deserve action now.


The cognitive basis of classification in very young children: an analysis of object-ordering trends.
1--3 year-olds' ability to conceptually interrelate objects was studied. 8 children each at 12, 18, 24, 30, and 36 months were given 7 free classification tasks. Each task contained a scrambled array of 8 objects from 2 classes. Spontaneous manipulations were analyzed to determine (1) whether children sequentially contacted similar objects above chance level and (2) to what extent objects from 2 classes, rather than just 1, were selected. Children at each age sequentially selected similar objects above chance in some tasks. Initially such sequences were accompanied by a tendency to manipulate only 1 class of objects throughout a task, but this single-class bias declined significantly with age. Selection of only 1 class can be accounted for by perceptual salience. Selection by similarity involving 2 classes is less likely explained by salience and more likely explained by a strategy in which individual items are conceptually compared. Classification based on conceptual comparisons of the items being selected may emerge over the second and third years, even though children engage in class-consistent behavior earlier.


HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies.
Patients with HIV may have increased risk of atherosclerotic cardiovascular disease owing to multiple biological mechanisms. To evaluate the evidence for subclinical atherosclerosis among patients with HIV. Systematic review of observational studies. We searched Medline, Cochrane DSR, ACP Journal Club, DARE, CMR, HTA, NHSEED, Embase and the Cochrane Controlled Trials Register for studies published before November 2008. Eligible studies were cross-sectional, cohort, or case-control studies reporting carotid ultrasound intima-media thickness (CIMT), focal plaque incidence, or coronary artery calcium (CAC), as determined by HIV positivity or protease inhibitor (PI) exposure. Two independent reviewers abstracted data using a standardised form. The primary outcome was weighted mean difference (WMD) for CIMT comparing HIV positive versus negative patients. Other outcomes included WMD by PI exposure and the odds ratio (OR) for a focal carotid plaque or CAC. Data from six cross-sectional, seven case-control and 13 cohort studies were included, involving 5456 HIV positive and 3600 HIV negative patients. The weighted mean CIMT was 0.04 mm thicker among patients with HIV than among non-HIV patients (95% CI 0.02 to 0.06; p<0.001). HIV positivity was not associated with carotid plaque or CAC. PI exposure did not significantly affect CIMT, carotid plaque, or CAC. There was evidence of publication bias and stratified analysis and meta-regression showed outcomes were influenced by study design, age, gender and smoking. However, HIV positivity slightly increased CIMT even after sensitivity analyses. HIV infection and PI exposure are not strong independent risk factors for subclinical atherosclerosis. Confounding may contribute to overestimation of the risk associated with HIV and PI exposure.


Reduction of a diamidocarbene-supported borenium cation: isolation of a neutral boryl-substituted radical and a carbene-stabilized aminoborylene.
We have synthesized the first diamidocarbene (DAC)-supported borenium salt, [][OTf], which was found to readily undergo two sequential 1-electron reductions. The first reduction forms a thermally robust, crystalline boryl-substituted DAC-centred radical () which has been fully characterized by XRD, EPR spectroscopy, and DFT analyses. The 1-electron reduction of resulted in the formation of a DAC-supported aminoborylene, , which has been characterized computationally and by multinuclear NMR spectroscopy.


Quo Vadis HTA for Medical Devices in Central and Eastern Europe? Recommendations to Address Methodological Challenges.
Objectives: Methodological challenges in the evaluation of medical devices (MDs) may be different for early and late technology adopter countries, as well as the potential health technology assessment (HTA) solutions to tackle them. This study aims to provide guidance to Central and Eastern European (CEE) countries on how to address key challenges of HTA for MDs with special focus on the transferability of scientific evidence. Methods: As part of the COMED Horizon 2020 project, a comprehensive list of issues related to MD HTA were identified based on a targeted literature review. Health technology assessment issues which pose a greater challenge or require different solutions in late technology adopter countries were selected. Draught recommendations to address these issues were developed and discussed in a focus group. The recommendations were then validated with a wider group of experts, including HTA and reimbursement decision makers from CEE countries in May and June 2020. Results: A consolidated list of 11 recommendations were developed in 3 major areas: (1) clinical value assessment, focusing on the use of joint EU work, relying on real-world evidence, use of coverage with evidence development schemes, transferring evidence from foreign countries and addressing the challenges of learning curve and centre effect; (2) economic value assessment, covering cost calculation of complex medical devices and transferability of economic evaluations of MDs; (3) HTA processes, related to the frequent product modifications and various indications of MDs. Conclusions: Central and Eastern European countries with limited resources for conducting HTA, can benefit from HTA methods and evidence generated in early technology adopter countries. Considering the appropriate reuse of international HTA materials, late technology adopter countries can still implement HTA, even for MDs, which have a more limited evidence base compared with pharmaceuticals.


Schizophrenia and vitamin D related genes could have been subject to latitude-driven adaptation.
Many natural phenomena are directly or indirectly related to latitude. Living at different latitudes, indeed, has its consequences with being exposed to different climates, diets, light/dark cycles, etc. In humans, one of the best known examples of genetic traits following a latitudinal gradient is skin pigmentation. Nevertheless, also several diseases show latitudinal clinals such as hypertension, cancer, dismetabolic conditions, schizophrenia, Parkinson's disease and many more. We investigated, for the first time on a wide genomic scale, the latitude-driven adaptation phenomena. In particular, we selected a set of genes showing signs of latitude-dependent population differentiation. The biological characterization of these genes showed enrichment for neural-related processes. In light of this, we investigated whether genes associated to neuropsychiatric diseases were enriched by Latitude-Related Genes (LRGs). We found a strong enrichment of LRGs in the set of genes associated to schizophrenia. In an attempt to try to explain this possible link between latitude and schizophrenia, we investigated their associations with vitamin D. We found in a set of vitamin D related genes a significant enrichment of both LRGs and of genes involved in schizophrenia. Our results suggest a latitude-driven adaptation for both schizophrenia and vitamin D related genes. In addition we confirm, at a molecular level, the link between schizophrenia and vitamin D. Finally, we discuss a model in which schizophrenia is, at least partly, a maladaptive by-product of latitude dependent adaptive changes in vitamin D metabolism.


A refined surgical treatment modality for bromhidrosis: double w incision approach with tumescent technique.
Axillary bromhidrosis has a strong negative effect on one's social life. A high success rate and few complications are criteria for an ideal treatment method. To evaluate a new surgical treatment modality for bromhidrosis: Double W incision with full-exposure excision under tumescent anesthesia. Twenty patients with bromhidrosis were treated. Patients were placed in a supine position with their treated arms abducted to 110 degrees . After injection of 60 mL of tumescent solution into each axilla, two small W incisions were made at the superior and inferior axillary poles of the hair-bearing area. The whole hair-bearing skin was undermined at the level of the superficial fat to obtain adequate skin eversion. The flaps were everted to offer full exposure of the apocrine glands, and meticulous excision of each gland was performed. Finally, the incisions were re-approximated, and bulky compressive dressings were applied to the area for 72 hours. Of the 40 axillae (20 patients), 32 (80.0%) showed excellent results, and eight (20.0%) had good results. Malodor was significantly decreased. There were no serious complications. This technique can produce excellent results with a lower complication rate than most other surgical modalities and can be performed without costly equipment.


Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus.
In 2014, Western Africa experienced an unanticipated explosion of Ebola virus infections. What distinguishes fatal from non-fatal outcomes remains largely unknown, yet is key to optimising personalised treatment strategies. We used transcriptome data for peripheral blood taken from infected and convalescent recovering patients to identify early stage host factors that are associated with acute illness and those that differentiate patient survival from fatality. The data demonstrate that individuals who succumbed to the disease show stronger upregulation of interferon signalling and acute phase responses compared to survivors during the acute phase of infection. Particularly notable is the strong upregulation of albumin and fibrinogen genes, which suggest significant liver pathology. Cell subtype prediction using messenger RNA expression patterns indicated that NK-cell populations increase in patients who survive infection. By selecting genes whose expression properties discriminated between fatal cases and survivors, we identify a small panel of responding genes that act as strong predictors of patient outcome, independent of viral load. Transcriptomic analysis of the host response to pathogen infection using blood samples taken during an outbreak situation can provide multiple levels of information on both disease state and mechanisms of pathogenesis. Host biomarkers were identified that provide high predictive value under conditions where other predictors, such as viral load, are poor prognostic indicators. The data suggested that rapid analysis of the host response to infection in an outbreak situation can provide valuable information to guide an understanding of disease outcome and mechanisms of disease.


Implications of fluorodeoxyglucose uptake in low-intermediate grade metastatic neuroendocrine tumors from peptide receptor radionuclide therapy outcome viewpoint: A semi-quantitative standardized uptake value-based analysis.
Dual tracer positron emission tomography (PET) imaging approach (with 68Ga-DOTATATE PET-computed tomography (CT) for somatostatin receptor and 18-fluorodeoxyglucose (18FDG) PET-CT for glucose transporter receptor) plays a vital role in baseline differentiation, treatment decision-making, and prognostic assessment of neuroendocrine tumors (NETs). The aims of this study were to observe and compare the clinical behavior of low-/intermediate-grade NETs depending on their baseline FDG metabolism (calculated through pre-peptide receptor radionuclide therapy [PRRT] FDG standardized uptake value [SUV]) and to determine its prognostic importance in predicting extent of therapeutic response (post-PRRT) in terms of symptomatic, biochemical, and scan parameters along with the long-term impact on progression-free survival (PFS) and overall survival (OS). Fifty-nine patients with low (≤2%) and intermediate (3-20% Mib-1/Ki-67 index) grade metastatic NET were selected for this retrospective analysis and divided into three groups: Group 1 consisted of patients having low-grade FDG uptake at baseline, predefined as SUVmax< 5 (n = 13); Group 2 consisted of those having intermediate-grade FDG uptake at baseline, SUVmax5-10 (n = 34), and Group 3 consisted of patients having high-grade FDG uptake at baseline, defined as SUVmax>10 (n = 12). The trend of FDG avidity was studied from the baseline till the time of analysis and the overall outcomes were compared in terms of symptomatic response (Karnofsky and ECOG performance score), biochemical response, scan response (anatomical and metabolic, RECIST 1.1 and PERCIST 1.0), PFS and OS. Patients in Groups 1 and 2 showed highest proportion of symptomatic complete response, biochemical partial response, and stable disease on scan. These patients also demonstrated better PFS and OS and lowest hazard ratio compared to patients in the Group 3. An important finding was a substantial fraction of the complete metabolic responders (CMRs) across the groups, achieved CMR within first 2 cycles of PRRT (85% of Group 1, 51% of Group 2, and 47% of Group 3). In conclusion, most of the patients of low-/intermediate-grade NET having low-to-moderate baseline tumor FDG metabolism (SUVmax≤10) showed favorable symptomatic response with good biochemical and anatomical disease control and were associated with prolonged PFS and OS, compared to that of those having high-grade baseline tumor FDG metabolism (SUVmax>10).


Crystal structures of ferrous and CO-, CN(-)-, and NO-bound forms of rat heme oxygenase-1 (HO-1) in complex with heme: structural implications for discrimination between CO and O2 in HO-1.
Heme oxygenase (HO) catalyzes heme degradation by utilizing O(2) and reducing equivalents to produce biliverdin IX alpha, iron, and CO. To avoid product inhibition, the heme[bond]HO complex (heme[bond]HO) is structured to markedly increase its affinity for O(2) while suppressing its affinity for CO. We determined the crystal structures of rat ferrous heme[bond]HO and heme[bond]HO bound to CO, CN(-), and NO at 2.3, 1.8, 2.0, and 1.7 A resolution, respectively. The heme pocket of ferrous heme-HO has the same conformation as that of the previously determined ferric form, but no ligand is visible on the distal side of the ferrous heme. Fe[bond]CO and Fe[bond]CN(-) are tilted, whereas the Fe[bond]NO is bent. The structure of heme[bond]HO bound to NO is identical to that bound to N(3)(-), which is also bent as in the case of O(2). Notably, in the CO- and CN(-)-bound forms, the heme and its ligands shift toward the alpha-meso carbon, and the distal F-helix shifts in the opposite direction. These shifts allow CO or CN(-) to bind in a tilted fashion without a collision between the distal ligand and Gly139 O and cause disruption of one salt bridge between the heme and basic residue. The structural identity of the ferrous and ferric states of heme[bond]HO indicates that these shifts are not produced on reduction of heme iron. Neither such conformational changes nor a heme shift occurs on NO or N(3)(-) binding. Heme[bond]HO therefore recognizes CO and O(2) by their binding geometries. The marked reduction in the ratio of affinities of CO to O(2) for heme[bond]HO achieved by an increase in O(2) affinity [Migita, C. T., Matera, K. M., Ikeda-Saito, M., Olson, J. S., Fujii, H., Yoshimura, T., Zhou, H., and Yoshida, T. (1998) J. Biol. Chem. 273, 945-949] is explained by hydrogen bonding and polar interactions that are favorable for O(2) binding, as well as by characteristic structural changes in the CO-bound form.


Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias.
Two ets family members, namely erg and Fli-1 are fused with two EWS family members namely EWS and TLS/FUS as a result of chromosome translocation in human solid tumors and leukemias. EWS-erg and EWS-Fli-1, which are involved in greater than 95% of Ewing family of tumors, were shown to function as transcriptional activators. TLS/FUS-erg, which is involved in human myeloid leukemias also functions as a transcriptional activator. Expression of these fusion proteins (EWS-erg and EWS-Fli-1) are shown to be essential for maintaining the oncogenic and tumorigenic properties of tumor cells. Cancer is thought to be caused not only by uncontrolled cell proliferation but also by deregulation of programmed cell death. Therefore, we have studied the role of normal (Fli-1 and erg) and aberrant fusion proteins (EWS-erg, EWS-Fli-1 and TLS/FUS-erg) in apoptosis. We have found that expression of normal (Fli-1 and erg) and aberrant fusion proteins inhibit the apoptosis of NIH3T3 cells induced by either serum deprivation or by treatment with calcium ionophore. We have also observed similar suppression of apoptosis in Ewing's sarcoma cells expressing EWS-Fli-1 and EWS-erg proteins suggesting that these fusion proteins may be responsible for the decreased ability of these tumor cells to undergo apoptosis. Inhibition of the expression of these aberrant fusion proteins by antisense RNA technique resulted in increased susceptibility to apoptosis leading to the death of tumor cells. Therefore, our results suggest that one can use therapeutic agents which can down regulate the expression of fusion proteins in combination with chemotherapeutic agents as an effective treatment for these human solid tumors and leukemias.


Biofilm formation by Porphyromonas gingivalis and Streptococcus gordonii.
Confocal scanning laser microscopy (CSLM) was used to visualize and quantify biofilm formation by the oral bacteria Streptococcus gordonii and Porphyromonas gingivalis. A saliva-coated glass coverslip under continuous bacterial challenge and conditions of low shear force was used to investigate attachment to the salivary pellicle and also the effect of cell-cell interactions on the extent of colonization and biofilm development. S. gordonii bound to the salivary pellicle and outcompeted P. gingivalis for attachment sites. Both P. gingivalis and S. gordonii failed to establish substantial biofilm formation independently. However, biofilm formation did occur subsequent to initial adherence of P. gingivalis to S. gordonii cells deposited on the salivary pellicle. The commensal species S. gordonii may, therefore, provide an attachment substrate for colonization and biofilm accretion by the potential pathogen, P. gingivalis.


Effects of human pharmaceuticals on cytotoxicity, EROD activity and ROS production in fish hepatocytes.
Pharmaceuticals are found in the aquatic environment but their potential effects on non-target species like fish remain unknown. This in vitro study is a first approach in the toxicity assessment of human drugs on fish. Nine pharmaceuticals were tested on two fish hepatocyte models: primary cultures of rainbow trout hepatocytes (PRTH) and PLHC-1 fish cell line. Cell viability, interaction with cytochrome P450 1A (CYP1A) enzyme and oxidative stress were assessed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrasodium bromide tetrazolium (MTT), 7-ethoxyresorufin-o-deethylase (EROD) and dichlorofluorescein (DCFH-DA) assays, respectively. The tested drugs were clofibrate (CF), fenofibrate (FF), carbamazepine (CBZ), fluoxetine (FX), diclofenac (DiCF), propranolol (POH), sulfamethoxazole (SFX), amoxicillin (AMX) and gadolinium chloride (GdCl(3)). All substances were cytotoxic, except AMX at concentration up to 500 microM. The calculated MTT EC(50) values ranged from 2 microM (CF) to 651 microM (CBZ) in PLHC-1, and from 53 microM (FF) to 962 microM (GdCl(3)) in PRTH. CF, FF, and FX were the most cytotoxic drugs and induced oxidative stress before being cytotoxic. Compared to hepatocytes from human and dog, fish hepatocytes seemed to be more susceptible to the peroxisome proliferators (PPs) CF and FF. In PLHC-1 cells none of the tested drugs induced the EROD activity whereas POH appeared as a weak EROD inducer in PRTH. Moreover, in PRTH, SFX, DiCF, CBZ and to a lesser extend, FF and CF inhibited the basal EROD activity at clearly sublethal concentrations which may be of concern at the biological and chemical levels in a multipollution context.


Application of Laser Irradiation for Restorative Treatments.
Nowadays, lasers are widely used in many fields of medicine. Also, they can be applied at many branches of dental practice such as diagnosis, preventive procedures, restorative treatments, and endodontic therapies. Procedures like caries removal, re-mineralization, and vital pulp therapy are the most noticeable effects of laser irradiation which has gained much attention among clinicians. With controlled and appropriate wavelength, they can help stimulating dentinogenesis, controlling pulpal hemorrhage, sterilization, healing of collagenic proteins, formation of a fibrous matrix, and inducing hard tissue barrier. Nevertheless, there are many controversies in literatures regarding their effects on the quality of bonded restorations. It hampered a wide application of lasers in some aspects of restorative dentistry and requirements to identify the best way to use this technology. The aim of this mini review is to explain special characteristics of laser therapy and to introduce the possible applications of laser devices for dental purposes.


Griffithsin and Carrageenan Combination To Target Herpes Simplex Virus 2 and Human Papillomavirus.
Extensive preclinical evaluation of griffithsin (GRFT) has identified this lectin to be a promising broad-spectrum microbicide. We set out to explore the antiviral properties of a GRFT and carrageenan (CG) combination product against herpes simplex virus 2 (HSV-2) and human papillomavirus (HPV) as well as determine the mechanism of action (MOA) of GRFT against both viruses. We performed the experiments in different cell lines, using time-of-addition and temperature dependence experiments to differentiate inhibition of viral attachment from entry and viral receptor internalization. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins, and immunoprecipitation and immunohistochemistry were used to identify the specific glycoprotein involved. We determined the antiviral activity of GRFT against HSV-2 to be a 50% effective concentration (EC50) of 230 nM and provide the first evidence that GRFT has moderate anti-HPV activity (EC50 = 0.429 to 1.39 μM). GRFT blocks the entry of HSV-2 and HPV into target cells but not the adsorption of HSV-2 and HPV onto target cells. The results of the SPR, immunoprecipitation, and immunohistochemistry analyses of HSV-2 combined suggest that GRFT may block viral entry by binding to HSV-2 glycoprotein D. Cell-based assays suggest anti-HPV activity through α6 integrin internalization. The GRFT-CG combination product but not GRFT or CG alone reduced HSV-2 vaginal infection in mice when given an hour before challenge (P = 0.0352). While GRFT significantly protected mice against vaginal HPV infection when dosed during and after HPV16 pseudovirus challenge (P < 0.026), greater CG-mediated protection was afforded by the GRFT-CG combination for up to 8 h (P < 0.0022). These findings support the development of the GRFT-CG combination as a broad-spectrum microbicide.


Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair.
Accumulation of 8-oxo-7,8-dihydroguanine (8-oxoG) in the DNA results in genetic instability and mutagenesis, and is believed to contribute to carcinogenesis, aging processes and various aging-related diseases. 8-OxoG is removed from the DNA via DNA base excision repair (BER), initiated by 8-oxoguanine DNA glycosylase-1 (OGG1). Our recent studies have shown that OGG1 binds its repair product 8-oxoG base with high affinity at a site independent from its DNA lesion-recognizing catalytic site and the OGG1•8-oxoG complex physically interacts with canonical Ras family members. Furthermore, exogenously added 8-oxoG base enters the cells and activates Ras GTPases; however, a link has not yet been established between cell signaling and DNA BER, which is the endogenous source of the 8-oxoG base. In this study, we utilized KG-1 cells expressing a temperature-sensitive mutant OGG1, siRNA ablation of gene expression, and a variety of molecular biological assays to define a link between OGG1-BER and cellular signaling. The results show that due to activation of OGG1-BER, 8-oxoG base is released from the genome in sufficient quantities for activation of Ras GTPase and resulting in phosphorylation of the downstream Ras targets Raf1, MEK1,2 and ERK1,2. These results demonstrate a previously unrecognized mechanism for cellular responses to OGG1-initiated DNA BER.


Facile preparation of polysaccharide-based sponges and their potential application in wound dressing.
Wound exudate adsorption and blood clotting are of critical importance for promoting wound healing in diabetic patients. In this study, cellulose-chitosan hybrid sponges were prepared by a facile pathway with controllable structure and morphology. Aimed at wound dressing, the physical properties, cytocompatibility, and hemocompatibility of the cellulose-chitosan hybrid sponges were evaluated. The results indicated that the hybrid sponges were non-toxic and outperformed silicon in promoting blood coagulation. The sponges could also effectively adsorb abundant wound exudate due to their highly porous structure. Moreover, the maximal shape recovery of these chemically crosslinked sponges from a 50% compression strain was up to 95% of their original thickness, without obviously compromising their macro/microstructure and mechanical properties after 10 cycles. The superior blood coagulation, adsorption performance, and shape recovery properties of the sponges make them ideal for use in making wound dressings for diabetic patients.


Methionine aminopeptidase 2 is required for HSC initiation and proliferation.
In a chemical screening, we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models. Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue, and pronephric duct. metap2 was inhibited by morpholino and fumagillin treatment, resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization. It also disrupted intersegmental vessels in Tg(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34(+) cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice. metap2 knock-down in zebrafish and inhibition by fumagillin in zebrafish and human CB CD34(+) cells inhibited Calmodulin Kinase II activity and induced ERK phosphorylation. This study demonstrated a hitherto-undescribed role of MetAP2 in definitive hematopoiesis and a possible link to noncanonical Wnt and ERK signaling.


Social identification of toxic diets by Norway rats (Rattus norvegicus).
In the present experiment, a naive rat (an observer) interacted with two conspecifics (demonstrators) that had recently eaten a diet unfamiliar to the observer, ate two unfamiliar foods in succession, one of which was the food its demonstrators had eaten, suffered toxicosis, and finally, was offered a simultaneous choice between the two diets it had eaten prior to toxicosis induction. During the choice test, observers exhibited an aversion to that diet their respective demonstrators had not eaten. This result indicates that exposure of a rat to conspecifics that have eaten a diet can act, as does actual ingestion of a diet, to reduce that diet's subsequent associability with toxicosis. I discuss this finding as suggesting that interaction with conspecifics may provide an alternative to individual trial and error learning in identification of toxic foods by rats that ingest a number of novel foods in succession before becoming ill.


ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization : a report of the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology. Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography.
The American College of Cardiology Foundation (ACCF), Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, and the American Association for Thoracic Surgery, along with key specialty and subspecialty societies, conducted an appropriateness review of common clinical scenarios in which coronary revascularization is frequently considered. The clinical scenarios were developed to mimic common situations encountered in everyday practice and included information on symptom status, extent of medical therapy, risk level as assessed by noninvasive testing, and coronary anatomy. Approximately 180 clinical scenarios were developed by a writing committee and scored by a separate technical panel on a scale of 1 to 9. Scores of 7 to 9 indicate that revascularization was considered appropriate and likely to improve health outcomes or survival. Scores of 1 to 3 indicate revascularization was considered inappropriate and unlikely to improve health outcomes or survival. The mid range (4 to 6) indicates a clinical scenario for which the likelihood that coronary revascularization would improve health outcomes or survival was considered uncertain. For the majority of the clinical scenarios, the panel only considered the appropriateness of revascularization irrespective of whether this was accomplished by percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In a select subgroup of clinical scenarios in which revascularization is generally considered appropriate, the appropriateness of PCI and CABG individually as the primary mode of revascularization was considered. In general, the use of coronary revascularization for patients with acute coronary syndromes and combinations of significant symptoms and/or ischemia was viewed favorably. In contrast, revascularization of asymptomatic patients or patients with low-risk findings on noninvasive testing and minimal medical therapy were viewed less favorably. It is anticipated that these results will have an impact on physician decision making and patient education regarding expected benefits from revascularization and will help guide future research.


Bcl-2 gene family expression in the brain of rat offspring after gestational and lactational dioxin exposure.
Recent epidemiological studies have shown that dioxin, a persistent organic pollutant, is related to cognitive and behavioral abnormalities in the offspring of exposed cohort. In order to investigate the possible impact of dioxin in survival gene expression during brain development, we established an animal model of gestational and lactational dioxin-exposed rat offspring. The expressions of dioxin-responsive gene cytochrome P450 1A1 (CYP1A1), apoptotic gene Bax, and anti-apoptotic genes Bcl-2 and Bcl-xL were examined in rat liver and brains using Western blot analysis and RT-PCR. The results showed that treatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (2 microg/kg body weight through oral delivery) at gestation day 15 resulted in an increase of Bcl-xL in offspring male liver and cerebral cortex, but a decrease in female offspring. In contrast, the expression of Bcl-xL in the cerebellum was decreased in male, but increased in female. Bcl-2, another anti-apoptotic gene, was also downregulated in P0 female liver, cerebral cortex, but was not observed in male. In the 4-month-old offspring, however, the Bcl-2 protein levels in the liver and cerebellum of both male and female pups were higher in the TCDD group as compared with the control group. However, the Bcl-2 level in the cerebral cortex of TCDD-treated groups was higher than the control group only in female but not male offspring at 4 months old. The expression of Bax showed no significant changes upon TCDD exposure at P0 stage, but was significantly reduced in the 4-month-old male cortex. These results indicate that early exposure of dioxin could affect the development of certain brain regions with gender difference, in terms of its differential effect on expressions of Bcl-xL, Bcl-2, and Bax.


Heavy metal contamination of prenatal vitamins.
Prenatal vitamins are often consumed daily during gestation and postnatally for up to 18-24 months with the belief that supplementation achieves better outcomes. Detrimental effects of gestational exposure to adverse chemical agents are gathering increasing attention. This study was designed to assess toxic element contamination in prenatal supplements. Twenty-six commonly used prenatal vitamin brands including one prescription brand were collected from Canadian health-food outlets and pharmacies, and tested for toxic element contamination. Results were compared to established endpoints. All samples contained Lead with average amounts being (0.535 μgm), 20/51 samples exceeded established standards for lead toxicity (0.50 μgm/day), with one sample yielding 4. μgm/day. Three samples registered inorganic arsenic levels above acceptable limits. Cadmium levels did not exceed current standards. Toxic elements such as Aluminum, Nickel, Titanium and Thallium were detected in all samples. Cumulative intake of prenatal supplement over many months may constitute a significant source of toxic element exposure to the mother and offspring. With several samples exceeding known standards for gestational toxic element exposure, guidelines for routine monitoring and reporting are required. In keeping with recommendations from the International Federation of Obstetrics and Gynecology, industry regulation would be welcomed to protect expectant mothers and their vulnerable offspring.


Relationship between leukocyte count and patient risk for excessive blood loss after cardiac surgery.
To evaluate the relationship between leukocyte counts and risk for excessive blood loss after cardiac surgery when including numerous demographic, operative, and laboratory factors in the comparison. A prospective, clinical evaluation. A point-of-care laboratory and the cardiac surgical unit of a university-affiliated tertiary center. Patient-related and hematologic variables were measured, using blood specimens obtained from 89 hospitalized patients who underwent cardiac surgery involving cardiopulmonary bypass. None. Demographic, operative, and transfusion-related data were recorded for each patient. Routinely obtained measurements of laboratory-based prothrombin time, partial thromboplastin time, complete blood count, and bleeding time were recorded. Hemoglobin concentration, platelet count, and red and white blood cell counts were measured with an on-site instrument before initiation (pre-cardiopulmonary bypass) and before discontinuation (end-cardiopulmonary bypass) of cardiopulmonary bypass. Hematocrit was calculated using recorded variables, and white blood cell percent change values were calculated using white blood cell counts from both periods, using the following formula: [(end-cardiopulmonary bypass - pre-cardiopulmonary bypass)/pre-cardiopulmonary bypass] x 100. When we excluded four patients who had a surgical source of post-cardiopulmonary bypass bleeding, significant (p < .0001) relationships were observed between white blood cell count (r2 = .46) and white blood cell percent change values (r2 = .71) and cumulative mediastinal chest tube drainage in the first 4 postoperative hours in 85 patients. Bayes theorem was used to evaluate the predictive ability of hematologic measurements in identifying patients with excessive bleeding (n = 24), defined as >1000 mL of cumulative chest tube drainage in the first 24 postoperative hours, when compared with patients without excessive bleeding (n = 61). Demographic and operative variables were similar between these patients except that patients with excessive bleeding required more red blood cell, platelet, and plasma transfusions during the postoperative interval. Significantly (p < .0001) greater white blood cell percent change values were obtained in the excessive bleeding cohort (119 +/- 93 percent change) when compared with patients without excessive bleeding (28 +/- 36 percent change). On-site measurements of white blood cell count, as an index of the inflammatory response to extracorporeal circulation, may be useful in identifying patients at increased risk for excessive bleeding. Further studies are needed to examine whether white blood cell counts during multiple cardiopulmonary bypass periods may identify patients with an exaggerated inflammatory response to extracorporeal circulation. By using this information, physicians may be able to intervene with anti-inflammatory medications and blood preservation techniques.


The StcE protease contributes to intimate adherence of enterohemorrhagic Escherichia coli O157:H7 to host cells.
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a diarrheal pathogen that causes attaching and effacing (A/E) lesions on intestinal epithelial cells. Strains of the O157 serogroup carry the large virulence plasmid pO157, which encodes the etp type II secretion system that secretes the genetically linked zinc metalloprotease StcE. The Ler regulator controls expression of many genes involved in A/E lesion formation, as well as StcE, suggesting StcE may be important at a similar time during colonization. Our laboratory has previously demonstrated that StcE cleaves C1-esterase inhibitor, a regulator of multiple inflammation pathways. Here we report two new substrates for StcE, mucin 7 and glycoprotein 340, and that purified StcE reduces the viscosity of human saliva. We tested the hypothesis that StcE contributes to intimate adherence of EHEC to host cells by cleavage of glycoproteins from the cell surface. The fluorescent actin stain (FAS) test was used to observe the intimate adherence represented by fluorescently stained bacteria colocalized with regions of bundled actin formed on HEp-2 cells. An E. coli O157:H7 strain with a stcE gene deletion was not affected in its ability to generally adhere to HEp-2 cells, but it did score threefold lower on the FAS test than wild-type or complemented strains. Addition of exogenous recombinant StcE increased intimate adherence of the mutant to wild-type levels. Thus, StcE may help block host clearance of E. coli O157:H7 by destruction of some classes of glycoproteins, and it contributes to intimate adherence of E. coli O157:H7 to the HEp-2 cell surface.


Ex Vivo Assessment of Various Histological Differentiation in Human Carotid Plaque with Near-infrared Spectroscopy Using Multiple Wavelengths.
We previously reported that near-infrared hyperspectral imaging enabled the localization of atherosclerotic plaques from outside the vessels, but not the optical characteristics of each histological component. Therefore, the near-infrared spectrum of each component was collected from the sliced section of the human carotid plaque obtained with endarterectomy and the optical characteristics were confirmed in several wavelengths. Based on this information, we assessed the diagnostic accuracy for ex vivo chemogram in each plaque component created with near-infrared spectroscopy (NIRS), using multiple wavelengths. The chemogram projected on the actual image of plaque was created based on light intensity and transmittance change at three wavelengths. The wavelengths that were mainly were 1440, 1620, 1730, and 1930 nm. We evaluated the accuracy of histological diagnosis in chemogram compared with pathological findings, analyzing interobserver agreement with κ-statistics. The chemograms that we created depicted the components of fibrous tissue, smooth muscle, lipid tissue, intraplaque hemorrhage, and calcification. Diagnostic odds ratio in each component was as follows: 259.6 in fibrous tissue, 144 in smooth muscle, 1123.5 in lipid tissue, 29.3 in intraplaque hemorrhage, and 136.3 in calcification. The κ-statistics revealed that four components, excluding intraplaque hemorrhage, had substantial or almost perfect agreement. Thus, this study demonstrated the feasibility of using chemogram focused on specific component during the histological assessment of atherosclerotic plaques, highlighting its potential diagnostic ability. Chemograms of various target components can be created by combining multiple wavelengths. This technology may prove to be useful in improving the histological assessment of plaque using NIRS.


Subsistence strategies in traditional societies distinguish gut microbiomes.
Recent studies suggest that gut microbiomes of urban-industrialized societies are different from those of traditional peoples. Here we examine the relationship between lifeways and gut microbiota through taxonomic and functional potential characterization of faecal samples from hunter-gatherer and traditional agriculturalist communities in Peru and an urban-industrialized community from the US. We find that in addition to taxonomic and metabolic differences between urban and traditional lifestyles, hunter-gatherers form a distinct sub-group among traditional peoples. As observed in previous studies, we find that Treponema are characteristic of traditional gut microbiomes. Moreover, through genome reconstruction (2.2-2.5 MB, coverage depth × 26-513) and functional potential characterization, we discover these Treponema are diverse, fall outside of pathogenic clades and are similar to Treponema succinifaciens, a known carbohydrate metabolizer in swine. Gut Treponema are found in non-human primates and all traditional peoples studied to date, suggesting they are symbionts lost in urban-industrialized societies.


Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis.
Sporadic and familiar amyotrophic lateral sclerosis (ALS) cases presented lower cholinergic activity than in healthy individuals in their still preserved spinal motoneurons (MNs) suggesting that cholinergic reduction might occur before MN death. To unravel how and when cholinergic function is compromised, we have analyzed the spatiotemporal expression of choline acetyltransferase (ChAT) from early presymptomatic stages of the SOD1(G93A) ALS mouse model by confocal immunohistochemistry. The analysis showed an early reduction in ChAT content in soma and presynaptic boutons apposed onto MNs (to 76%) as well as in cholinergic interneurons in the lumbar spinal cord of the 30-day-old SOD1(G93A) mice. Cholinergic synaptic stripping occurred simultaneously to the presence of abundant surrounding major histocompatibility complex II (MHC-II)-positive microglia and the accumulation of nuclear Tdp-43 and the appearance of mild oxidative stress within MNs. Besides, there was a loss of neuronal MHC-I expression, which is necessary for balanced synaptic stripping after axotomy. These events occurred before the selective raise of markers of denervation such as ATF3. By the same time, alterations in postsynaptic cholinergic-related structures were also revealed with a loss of the presence of sigma-1 receptor, a Ca2+ buffering chaperone in the postsynaptic cisternae. By 2 months of age, ChAT seemed to accumulate in the soma of MNs, and thus efferences toward Renshaw interneurons were drastically diminished. In conclusion, cholinergic dysfunction in the local circuitry of the spinal cord may be one of the earliest events in ALS etiopathogenesis.


Major depressive disorder in adolescence: the role of subthreshold symptoms.
To examine the longitudinal association between individual subthreshold symptoms and onset of major depressive disorder (MDD) in adolescence. Data for analysis come from the Oregon Adolescent Depression Project, a prospective epidemiological study of psychological disorders among adolescents, ages 14 to 18 years, from the general community. A total of 1,709 adolescents completed the initial diagnostic assessments between 1987 and 1989 (T1) and approximately 1 year later (T2), 1,507 adolescents returned for readministration of assessments (88% response). After controlling for history of depression and gender, seven of the nine DSM-III-R symptoms of depression predicted MDD incidence when tested in separate models. Endorsement of each symptom at T1 increased the likelihood of MDD incidence between T1 and T2. A summary model that included the seven DSM-III-R symptoms as predictors was significant, with sad mood contributing unique variance to the prediction of MDD onset (odds ratio = 2.01). These findings suggest that much of the variance is shared among symptom predictors and the co-occurrence of symptoms is what constitutes the greatest risk. Moreover, the presence of sad mood contributes additional unique variance to prediction and supports the centrality of depressed mood to MDD.


Understanding between care providers and patients with stroke and aphasia: a phenomenological hermeneutic inquiry.
Understanding between care providers and patients with stroke and aphasia: a phenomenological hermeneutic inquiry The present study illuminates the understanding in communication between formal care providers and patients with stroke and aphasia. Five care providers and three such patients participated in the study. Video recordings were made during conversations about pictures (n = 15), and the care providers were also interviewed (n = 15) after the video-recorded conversations. A phenomenological hermeneutic method of interpretation of the interview text was used. The findings showed that a range of conditions for 'understanding and being understood' in the communication on the part of the care providers exists. These different conditions are: lacking both knowledge and understanding; having knowledge but not necessarily accompanied by understanding; and being in understanding. Within the condition 'being in understanding', the care providers create a feeling of at-homeness in a relaxed atmosphere and thus have the opportunity to be in 'understanding and being understood' together with the patient. The condition 'being in understanding' appears in connection with the care providers' creating of a 'calm liturgy of caring' by mediating humility and calm vitality affects to the patients, and further, when needed, being present on the level of mystery, i.e. caring communion.


Specific recognition of the collagen triple helix by chaperone HSP47. II. The HSP47-binding structural motif in collagens and related proteins.
The endoplasmic reticulum-resident chaperone heat-shock protein 47 (HSP47) plays an essential role in procollagen biosynthesis. The function of HSP47 relies on its specific interaction with correctly folded triple-helical regions comprised of Gly-Xaa-Yaa repeats, and Arg residues at Yaa positions have been shown to be important for this interaction. The amino acid at the Yaa position (Yaa(-3)) in the N-terminal-adjoining triplet containing the critical Arg (defined as Arg(0)) was also suggested to be directly recognized by HSP47 (Koide, T., Asada, S., Takahara, Y., Nishikawa, Y., Nagata, K., and Kitagawa, K. (2006) J. Biol. Chem. 281, 3432-3438). Based on this finding, we examined the relationship between the structure of Yaa(-3) and HSP47 binding using synthetic collagenous peptides. The results obtained indicated that the structure of Yaa(-3) determined the binding affinity for HSP47. Maximal binding was observed when Yaa(-3) was Thr. Moreover, the required relative spatial arrangement of these key residues in the triple helix was analyzed by taking advantage of heterotrimeric collagen-model peptides, each of which contains one Thr(-3) and one Arg(0). The results revealed that HSP47 recognizes the Yaa(-3) and Arg(0) residues only when they are on the same peptide strand. Taken together, the data obtained led us to define the HSP47-binding structural epitope in the collagen triple helix and also define the HSP47-binding motif in the primary structure. A motif search against human protein database predicted candidate clients for this molecular chaperone. The search result indicated that not all collagen family proteins require the chaperoning by HSP47.


Proteomic blood profiling in mild, severe and critical COVID-19 patients.
The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.


The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis.
The authors sought to map gray matter changes in first-episode schizophrenia and to compare these with the changes in chronic schizophrenia. They postulated that the data would show a progression of changes from hippocampal deficits in first-episode schizophrenia to include volume reductions in the amygdala and cortical gray matter in chronic schizophrenia. A systematic search was conducted for voxel-based structural MRI studies of patients with first-episode schizophrenia and chronic schizophrenia in relation to comparison groups. Meta-analyses of the coordinates of gray matter differences were carried out using anatomical likelihood estimation. Maps of gray matter changes were constructed, and subtraction meta-analysis was used to compare them. A total of 27 articles were identified for inclusion in the meta-analyses. A marked correspondence was observed in regions affected by both first-episode schizophrenia and chronic schizophrenia, including gray matter decreases in the thalamus, the left uncus/amygdala region, the insula bilaterally, and the anterior cingulate. In the comparison of first-episode schizophrenia and chronic schizophrenia, decreases in gray matter volume were detected in first-episode schizophrenia but not in chronic schizophrenia in the caudate head bilaterally; decreases were more widespread in cortical regions in chronic schizophrenia. Anatomical changes in first-episode schizophrenia broadly coincide with a basal ganglia-thalamocortical circuit. These changes include bilateral reductions in caudate head gray matter, which are absent in chronic schizophrenia. Comparing first-episode schizophrenia and chronic schizophrenia, the authors did not find evidence for the temporolimbic progression of pathology from hippocampus to amygdala, but there was evidence for progression of cortical changes.


Evidence supporting endoscopic sinus surgery in the management of adult chronic rhinosinusitis: a systematic review.
Evidence-based medicine calls for a critical evaluation of the scientific evidence for treatments of disease. This report synthesizes the available evidence on the use of endoscopic sinus surgery (ESS) in the management of adult chronic rhinosinusitis (CRS) examining the clinical question: "In adults with CRS who have failed medical management, does ESS improve symptoms and/or quality of life (QOL)?" The American Rhinologic Society and the American Academy of Otolaryngology-Head and Neck Surgery convened a steering committee composed of the authors. Primary research articles evaluated for this report were identified using appropriate search terms and a Medline search. Two authors independently reviewed each article. Articles were assigned an evidence level based on accepted guidelines (level 1 = randomized trials; level 2 = prospective cohort studies with comparison group; level 3 = case-control studies; level 4 = retrospective case series; level 5 = expert opinion). We identified 886 abstracts to review, retrieved 75 articles for full review, and included 45 articles in our report. The vast majority of articles represented level 4 evidence (n = 42) and two articles represented level 5 evidence. One article was identified that qualified for level 2 evidence. All of these articles generally supported the finding that ESS improves symptoms and/or QOL in adult patients with CRS. There is substantial level 4 evidence with supporting level 2 evidence that ESS is effective in improving symptoms and/or QOL in adult patients with CRS. Future research efforts should focus on prospective studies that include appropriate comparison groups in their design.


De novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (eNOS) palmitoylation.
Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the multifunctional enzyme fatty-acid synthase (FAS), maintains endothelial function by targeting endothelial nitric-oxide synthase (eNOS) to the plasma membrane. In mice with endothelial inactivation of FAS (FASTie mice), eNOS membrane content and activity were decreased. eNOS and FAS were physically associated; eNOS palmitoylation was decreased in FAS-deficient cells, and incorporation of labeled carbon into eNOS-associated palmitate was FAS-dependent. FASTie mice manifested a proinflammatory state reflected as increases in vascular permeability, endothelial inflammatory markers, leukocyte migration, and susceptibility to LPS-induced death that was reversed with an NO donor. FAS-deficient endothelial cells showed deficient migratory capacity, and angiogenesis was decreased in FASTie mice subjected to hindlimb ischemia. Insulin induced FAS in endothelial cells freshly isolated from humans, and eNOS palmitoylation was decreased in mice with insulin-deficient or insulin-resistant diabetes. Thus, disrupting eNOS bioavailability through impaired lipogenesis identifies a novel mechanism coordinating nutritional status and tissue repair that may contribute to diabetic vascular disease.


Low systolic blood pressure and self perceived wellbeing in middle aged men.
To examine the relation between systolic blood pressure and self perceived wellbeing in 50 year old men. Cross sectional population study of data derived from questionnaires and physical examination as a part of a cardiovascular risk factor survey. City of Gothenburg, Sweden. 776 men from a random population sample of 1016 men aged 50. Self perceived wellbeing according to the Gothenburg quality of life questionnaire, which is an assessment of social, physical, and mental wellbeing in 15 different areas. Low systolic blood pressure was significantly (p < 0.05) related to impaired social wellbeing in four areas: work, home and family, financial situation, and housing. Of the items dealing with physical wellbeing, health, memory, and appetite were significantly related to blood pressure. As regards mental wellbeing, energy and self confidence were significantly related to systolic blood pressure. Diastolic blood pressure was significantly related to housing, memory, energy, patience, and self confidence. In multiple regression analyses that controlled for smoking, stress, physical activity, social activity, and emotional support, poor social, physical, and mental wellbeing were all significantly related to low systolic blood pressure independently of other factors. Low diastolic blood pressure was independently associated with poor physical and mental, but not social, wellbeing. Low systolic blood pressure was associated with poor perception of wellbeing in several areas. The cause is unclear.


Association between social climate for smoking and youth smoking behaviors in Taiwan: an ecological study.
Social acceptance of smoking is associated with smoking prevalence. Higher smoking rates and ETS exposure might be considered as important indicators for pro-tobacco social norms or social climate. Among studies indicating the association between youth smoking and adult smoking behaviors, most were from individual-level study designs. An ecological study was conducted to determine the role of social climate, i.e., adult smoking behaviors and exposure to environmental tobacco smoke (ETS), on youth smoking behaviors. Data on the smoking behavior and ETS of 16,688 Taiwanese adults were collected in 2004 by telephone administration of the Taiwan Adult Smoking Survey. Similar data on 22,339 junior high school students were collected in 2004 by school-based administration of the Taiwan Youth Tobacco Survey. City/county-level data were analyzed across 25 counties by descriptive statistics, Pearson's correlation, and hierarchical multiple regression. In both adult and youth populations, overall or gender-specific smoking prevalence and ETS varied widely across counties/cities. The current youth smoking rate within counties was significantly positively correlated with the current adult smoking prevalence as well as home ETS exposure in adults or youth. For male youth, a 1% increase in the rate of home ETS exposure reported by youth increased the current male youth smoking rate by 0.20% after controlling the female youth smoking rate and home ETS exposure reported by adults (p=0.0197). For female youth, male youth smoking prevalence was the only variable that contributed significantly (Beta=0.46, p<0.001). Community health nurses should develop tobacco-control interventions that are tailored to support smoke-free environments by decreasing the social acceptability of smoking.


Antioxidant Properties of Whole Body Periodic Acceleration (pGz).
The recognition that oxidative stress is a major component of several chronic diseases has engendered numerous trials of antioxidant therapies with minimal or no direct benefits. Nanomolar quantities of nitric oxide released into the circulation by pharmacologic stimulation of eNOS have antioxidant properties but physiologic stimulation as through increased pulsatile shear stress of the endothelium has not been assessed. The present study utilized a non-invasive technology, periodic acceleration (pGz) that increases pulsatile shear stress such that upregulation of cardiac eNOS occurs, We assessed its efficacy in normal mice and mouse models with high levels of oxidative stress, e.g. Diabetes type 1 and mdx (Duchene Muscular Dystrophy). pGz increased protein expression and upregulated eNOS in hearts. Application of pGz was associated with significantly increased expression of endogenous antioxidants (Glutathioneperoxidase-1(GPX-1), Catalase (CAT), Superoxide, Superoxide Dismutase 1(SOD1). This led to an increase of total cardiac antioxidant capacity along with an increase in the antioxidant response element transcription factor Nrf2 translocation to the nucleus. pGz decreased reactive oxygen species in both mice models of oxidative stress. Thus, pGz is a novel non-pharmacologic method to harness endogenous antioxidant capacity.


Optimizing nutrition of the preterm infant.
The goal of nutrition of the preterm infant is to meet the growth rate of the healthy fetus of the same gestational age and to produce the same body composition of the healthy fetus in terms of organ growth, tissue components, and cell number and structure. Nutritional quantity and quality are fundamental for normal growth and development of preterm infants, including neurodevelopmental outcomes. Failure to provide the necessary amounts of all of the essential nutrients has produced not only growth failure, but also increased morbidity and less than optimal neurodevelopment. Growth velocities during the NICU hospitalization period for preterm infants exert a significant effect on neurodevelopmental and anthropometric outcomes. Despite the obvious need for optimal nutrition, growth failure is almost universal among preterm infants. There is every reason, therefore, to optimize nutrition of the preterm infant, in terms of total energy and protein, but also in terms of individual components such as amino acids, specific carbohydrates and lipids, and even oxygen. This review presents scientific rationale for nutrient requirements and practical guidelines and approaches to intravenous and enteral feeding for preterm infants. Intravenous feeding, including amino acids, should be started right after birth at rates that are appropriate for the gestational age of the infant. Enteral feeding should be started as soon as possible after birth, using mother's colostrum and milk as first choices. Enteral feeding should begin with trophic amounts and advanced as rapidly as tolerated, decreasing IV nutrition accordingly, while maintaining nutrient intakes at recommended rates. Feeding protocols are valuable for improving nutrition and related outcomes. Further research is needed to determine the optimal nutrition and rate of growth in preterm infants that will achieve optimal neurocognitive benefits while minimizing the longer-term risk of chronic diseases.


The tumour antigen PRAME is a subunit of a Cul2 ubiquitin ligase and associates with active NFY promoters.
The human tumour antigen PRAME (preferentially expressed antigen of melanoma) is frequently overexpressed in tumours. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumourigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. PRAME can be recruited to DNA in vitro, and genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at transcriptionally active promoters that are also bound by NFY and at enhancers. Our results are consistent with a role for the PRAME ubiquitin ligase complex in NFY-mediated transcriptional regulation.


Comparison of the gross tumor volume in end-expiration/end-inspiration (2 Phase) and summated all phase volume captured in four-dimensional computed tomography in carcinoma lung patients.
The aim of this study was to compare the delineation and treatment planning of 2 Phase based (end-expiration and end-inspiration) internal gross tumor volume (IGTV) with 10-phase based (four-dimensional [4D]) IGTV. Patients with lung tumors at different sites were selected for the study. The location of the tumor in Groups A, B, C were at the upper lobe (attached to the chest wall), middle lobe, and lower lobe, respectively. We contoured the GTV on each of the 10 respiratory phases of the 4D computed tomography (4DCT) data set. The combination of these GTVs produced the IGTV "All Phases." GTV was also generated on the extreme respiratory phases. The combination of these two GTVs produced IGTV "2 Phases." Treatment planning was done, and dose to organs at risks (OARs) were compared in both cases. The average volume of IGTV "2 Phases" and IGTV "All Phases" for Group A were nearly same. However, for Group B and Group C, IGTV "2 Phases" were smaller than the IGTV "All Phases." Lung-GTV doses were less in "exp-insp" phases than in "4DCT" for Groups B, C, whereas it was same for "expiration-inspiration" and "4DCT" in Patient A. Patients with tumor upper lobe tumor have no difference in tumor coverage and OARs sparing in the 2 Phase and all phases but middle lobe and lower lobe have a greater excursion during respiration and hence greater all phases IGTV.


In depth comparison of an individual's DNA and its lymphoblastoid cell line using whole genome sequencing.
A detailed analysis of whole genomes can be now achieved with next generation sequencing. Epstein Barr Virus (EBV) transformation is a widely used strategy in clinical research to obtain an unlimited source of a subject's DNA. Although the mechanism of transformation and immortalization by EBV is relatively well known at the transcriptional and proteomic level, the genetic consequences of EBV transformation are less well understood. A detailed analysis of the genetic alterations introduced by EBV transformation is highly relevant, as it will inform on the usefulness and limitations of this approach. We used whole genome sequencing to assess the genomic signature of a low-passage lymphoblastoid cell line (LCL). Specifically, we sequenced the full genome (40X) of an individual using DNA purified from fresh whole blood as well as DNA from his LCL. A total of 217.33 Gb of sequence were generated from the cell line and 238.95 Gb from the normal genomic DNA. We determined with high confidence that 99.2% of the genomes were identical, with no reproducible changes in structural variation (chromosomal rearrangements and copy number variations) or insertion/deletion polymorphisms (indels). Our results suggest that, at this level of resolution, the LCL is genetically indistinguishable from its genomic counterpart and therefore their use in clinical research is not likely to introduce a significant bias.


Cooperation and Shared Beliefs about Trust in the Assurance Game.
Determinants of cooperation include ingroup vs. outgroup membership, and individual traits, such as prosociality and trust. We investigated whether these factors can be overridden by beliefs about people's trust. We manipulated the information players received about each other's level of general trust, "high" or "low". These levels were either measured (Experiment 1) or just arbitrarily assigned labels (Experiment 2). Players' choices whether to cooperate or defect in a stag hunt (or an assurance game)--where it is mutually beneficial to cooperate, but costly if the partner should fail to do so--were strongly predicted by what they were told about the other player's trust label, as well as by what they were told that the other player was told about their own label. Our findings demonstrate the importance for cooperation in a risky coordination game of both first- and second-order beliefs about how much people trust each other. This supports the idea that institutions can influence cooperation simply by influencing beliefs.


Approved IFCC recommendation on reporting results for blood glucose: International Federation of Clinical Chemistry and Laboratory Medicine Scientific Division, Working Group on Selective Electrodes and Point-of-Care Testing (IFCC-SD-WG-SEPOCT).
In current clinical practice, plasma and blood glucose are used interchangeably with a consequent risk of clinical misinterpretation. In human blood, glucose is distributed, like water, between erythrocytes and plasma. The molality of glucose (amount of glucose per unit water mass) is the same throughout the sample, but the concentration is higher in plasma, because the concentration of water and therefore glucose is higher in plasma than in erythrocytes. Different devices for the measurement of glucose may detect and report fundamentally different quantities. Different water concentrations in the calibrator, plasma, and erythrocyte fluid can explain some of the differences. Results for glucose measurements depend on the sample type and on whether the method requires sample dilution or uses biosensors in undiluted samples. If the results are mixed up or used indiscriminately, the differences may exceed the maximum allowable error for glucose determinations for diagnosing and monitoring diabetes mellitus, thus complicating patient treatment. The goal of the International Federation of Clinical Chemistry and Laboratory Medicine, Scientific Division, Working Group on Selective Electrodes and Point of Care Testing (IFCC-SD-WG-SEPOCT) is to reach a global consensus on reporting results. The document recommends reporting the concentration of glucose in plasma (in the unit mmol/L), irrespective of sample type or measurement technique. A constant factor of 1.11 is used to convert concentration in whole blood to the equivalent concentration in plasma. The conversion will provide harmonized results, facilitating the classification and care of patients and leading to fewer therapeutic misjudgments.


Gorillas in our midst: sustained inattentional blindness for dynamic events.
With each eye fixation, we experience a richly detailed visual world. Yet recent work on visual integration and change direction reveals that we are surprisingly unaware of the details of our environment from one view to the next: we often do not detect large changes to objects and scenes ('change blindness'). Furthermore, without attention, we may not even perceive objects ('inattentional blindness'). Taken together, these findings suggest that we perceive and remember only those objects and details that receive focused attention. In this paper, we briefly review and discuss evidence for these cognitive forms of 'blindness'. We then present a new study that builds on classic studies of divided visual attention to examine inattentional blindness for complex objects and events in dynamic scenes. Our results suggest that the likelihood of noticing an unexpected object depends on the similarity of that object to other objects in the display and on how difficult the priming monitoring task is. Interestingly, spatial proximity of the critical unattended object to attended locations does not appear to affect detection, suggesting that observers attend to objects and events, not spatial positions. We discuss the implications of these results for visual representations and awareness of our visual environment.


In vivo properties of an IgG3-IL-2 fusion protein. A general strategy for immune potentiation.
In this report, we describe a strategy for enhancing the immunogenicity of a wide variety of Ags by linking them to IL-2 via an IgG3-IL-2 fusion protein with high affinity for a convenient hapten Ag, dansyl (DNS; N,N-dimethyl-1-aminonaphthalene-5-sulfonyl chloride). This fusion protein, anti-DNS-IgG3-IL-2, combines the functional characteristics of its constituents and has pharmacokinetic properties that are greatly improved over those of IL-2 and a previously described IgG1-IL-2 fusion. The molecule is intact and recoverable from the blood of mice hours after i.p. injection and reaches distant organs throughout the animal. The 7-h in vivo half-life of this molecule is much longer than that of IL-2, addressing a major obstacle in the application of IL-2 to human diseases, including cancer and AIDS. Additionally, the Ab's specificity for the hapten dansyl and the convenient chemistry of dansyl provide a means to link IL-2 to virtually any molecule of interest without the complexities and uncertainties of making IL-2 fusions with each molecule individually. Using hapten-conjugated-BSA (DNS-BSA) as a model Ag we show that the Ab response elicited by anti-DNS-IgG3-IL-2-bound DNS-BSA-Sepharose injected into mice is increased over that of DNS-BSA-Sepharose or anti-DNS-IgG3-bound DNS-BSA-Sepharose. Anti-DNS-IgG3-IL-2 also increased the Ab response to soluble DNS-BSA after a booster injection. This system should be useful in testing the ability of IL-2 to potentiate the immune response to Ag and in screening a large number of potential Ags for use in vaccines. The dramatically improved pharmacokinetics should also overcome one of the major difficulties in applying IL-2 to the treatment of human disease, its short half-life.


Approximate theory of photon migration in a two-layer medium.
We recently examined properties of the surface emission profiles of particles (photons) injected into a turbid medium consisting of two layers [R. Nossal, J. Kiefer, G. H. Weiss, R. F. Bonner, H. Taitelbaum, and S. Havlin, "Photon Migration in Layered Media," Appl. Opt. 27, 3382-3391 (1988)]. The two layers differ in the coefficient that appears when internal absorption is modeled in terms of Beer's law. The model relates to the injection of laser radiation into tissue for diagnostic or therapeutic purposes. Results of our earlier work were derived from extensive computer simulations. In the present paper we discuss a simple analytical approximation to the surface intensity profile valid when the absorptivity of the upper layer is greater than that of the lower.


Reasonable disagreement and the justification of pre-emptive ethics governance in social research: a response to Hammersley.
In this response, we first tackle what we take to be the core disagreement between ourselves and Hammersley, namely the justification for our model of social research ethics governance. We then consider what follows from our defence of governance for ethics review and show how these claims attend to the specific concerns outlined by Hammersley.


Novel objective classification of reactive microglia following hypoglossal axotomy using hierarchical cluster analysis.
A total of 136 microglia were intracellularly labeled and their morphological features were evaluated by 3D morphometric measurement. According to hierarchical cluster analysis, microglia were objectively categorized into four groups termed types I-IV. The validity of this classification was confirmed by principal component analysis and linear discriminant analysis. Type I microglia were found in sham-operated mice and in mice sacrificed 28 days (D28) after axotomy. The appearance of type I cells was similar to so-called ramified microglia in a resting state. Type II microglia were mainly seen in D14 mice, which exhibited small cell bodies with thin and short processes. Interestingly, none of the already-known morphological types of microglia seemed to be comparable to type II cells. We thus named type II microglia "small ramified" cells. Types III and IV microglia were mainly seen in D3 and D7 mice and their appearances were similar to hypertrophied and bushy cells, respectively. Proliferating cell nuclear antigen (PCNA), a mitosis marker, was almost exclusively expressed in D3 mice. On the other hand, voltage-dependent potassium channels (Kv1.3/1.5), neurotoxicity-related molecules, were most highly expressed in D14 mice. Increased expression of Kv1.3/1.5 in D14 mice was suppressed by minocycline treatment. These findings indicate that type II and III microglia may be involved in neurotoxicity and mitosis, respectively. Type IV microglial cells are assumed to be in the process of losing mitotic activity and gaining neurotoxicity. Our data also suggest that type II microglia can be a potential therapeutic target against neurodegenerative diseases.


Cervical laminoplasty (Hattori's method). Procedure and follow-up results.
Posterior decompression plus posterior reconstruction (laminoplasty) is a useful surgical method for treatment of cervical compressive myelopathy. There are many laminoplasty procedures. This paper describes the Z-shaped laminoplasty developed by Hattori in 1971, and presents a clinical follow-up of the authors' experience with 130 patients. The procedure involves grinding the laminae down with an air drill and making a Z-shaped cut into the thinned laminae without excising the laminae. This technique enlarges the spinal canal. The purpose of this technique is to decompress the spinal cord and at the same time maintain clinical stability. Postoperative results were satisfactory without any major complication. Follow-up study was conducted in 78 cases with a minimal follow-up period of more than 2 years. Satisfactory clinical results were maintained for long periods postoperatively, and the enlargement of the spinal canal was well maintained as demonstrated on follow up X-ray study.


Variation in treatment associated with life expectancy in a population-based cohort of men with early-stage prostate cancer.
Men with major comorbidities are at risk for overtreatment of prostate cancer due to uncertainty regarding their life expectancy. We sought to characterize life expectancy and treatment in a population-based cohort of men with differing ages and comorbidity burdens at diagnosis. We sampled 96,032 men aged ≥66 years with early-stage prostate cancer who had Gleason scores ≤7 and were diagnosed during 1991 to 2007 from the Surveillance, Epidemiology, and End Results-Medicare database. We calculated cumulative incidence of other-cause mortality and determined treatment patterns among subgroups defined by age and Charlson comorbidity index scores. Overall, life expectancy was <10 years (10-year other-cause mortality rate, >50%) for 50,049 of 96,032 men (52%). Life expectancy differed by age and comorbidity score and was <10 years for men ages 66 to 69 years with Charlson scores ≥2, for men ages 70 to 74 years with Charlson scores ≥1, and for all men ages 75 to 79 years and ≥80 years. Among those who had a life expectancy <10 years, treatment was aggressive (surgery, radiation, or brachytherapy) for 68% of men aged 66 to 69 years, 69% of men aged 70 to 74 years, 57% of men aged 75 to 79 years, and 24% of men aged ≥80 years. Among these men, aggressive treatment was predominantly radiation therapy (50%, 53%, 63%, and 69%, respectively) and less frequently was surgery (30%, 25%, 13%, and 9%, respectively). Multivariate models revealed little variation in the probability of aggressive treatment by comorbidity status within age subgroups despite substantial differences in mortality. Men aged <80 years at diagnosis who have life expectancies <10 years often receive aggressive treatment for low-risk and intermediate-risk prostate cancer, mostly with radiation therapy.


Oxidant/antioxidant status in men with Behçet's disease.
Behçet's disease (BD) is a chronic, progressive disorder that affects many systems of the body including the eye. The aim of this study was to assess whether the increase in oxidative stress in the affected tissues is reflected by lipid peroxidation and to check for alterations in antioxidants and antioxidant enzyme activities in patients with BD. Erythrocyte antioxidant potential (AOP), glutathione (GSH) and GSH-dependent enzymes (glutathione peroxidase (GSH-Px), glutathione reductase (GRD) and glutathione-S-transferase (GST), catalase (CAT), Cu-Zn superoxide dismutase (Cu-Zn SOD) activities, malondialdehyde (MDA) and some trace elements (zinc, Zn; copper, Cu; manganese, Mn) levels in men with BD. Erythrocyte CAT, GSH-Px activities, MDA, GSH, AOP and serum Zn values were significantly lower in patients with BD than in the control group. However, erythrocyte Cu-Zn SOD, GRD activities, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) and Cu values were significantly higher in patients with BD than in the control group, but GST activity and serum Mn values were unchanged. In conclusion, our results confirm the presence of oxidative stress in patients with BD and suggest that the severity of BD may arise from impaired antioxidant mechanisms. Therapy with antioxidants may lead to the increase in the antioxidant defense system and thus improvement in clinical symptoms.


Plasmacytoid DCs, exposed to TSLP in synergy with TLR ligands, acquire significant potential towards Th2 polarization.
Thymic stromal lymphopoietin (TSLP) has been reported to activate myeloid dendritic cells (mDCs) to induce Th2 T lymphocyte responses. Its effect on plasmacytoid dendritic cells (pDCs) with TLR ligands has not yet been studied. We investigated the effects of TSLP and TLR ligands on mDCs and pDCs subsets. Myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) were stimulated by TLR ligands (mDC with TLR1/2 LTA, TLR2 PGN, TLR3 poly I: C, TLR4 LPS, TLR5 Flagellin) (pDC with TLR9 CpG2006, CpG 2216, TLR7 loxoribine) in the presence or absence of TSLP. Supernatants from mDCs and pDCs were analyzed for cytokine production. mDCs and pDCs were collected and cultured with allogeneic naïve T cells and after 7 days of co-culture. DC-primed CD4+ T cells were washed and restimulated with PMA and ionomycin. Cytokine production in supernatants from restimulated cells - IL-4, IL-5, IL-10, IL-13, TNF-a was analyzed by Luminex. TSLP alone induced the expression of maturation markers on mDCs and increased their ability to polarize lymphocytes into the Th2 phenotype. We demonstrated that pDCs also have the capacity to become even more potent inducers of Th2 immune responses, but only after combined treatment with TSLP and TLR ligands, particularly with TLR9 ligand CpG 2006. TSLP plays a major role in Th2 polarization of immune response mediated by myeloid DCs. Here, we demonstrate that plasmacytoid DCs, exposed to TSLP together with TLR ligands, acquire significant potential towards Th2 polarization.


Rational design of DNA-actuated enzyme nanoreactors guided by single molecule analysis.
The control of enzymatic reactions using nanoscale DNA devices offers a powerful application of DNA nanotechnology uniquely derived from actuation. However, previous characterization of enzymatic reaction rates using bulk biochemical assays reported suboptimal function of DNA devices such as tweezers. To gain mechanistic insight into this deficiency and to identify design rules to improve their function, here we exploit the synergy of single molecule imaging and computational modeling to characterize the three-dimensional structures and catalytic functions of DNA tweezer-actuated nanoreactors. Our analysis revealed two important deficiencies--incomplete closure upon actuation and conformational heterogeneity. Upon rational redesign of the Holliday junctions located at their hinge and arms, we found that the DNA tweezers could be more completely and uniformly closed. A novel single molecule enzyme assay was developed to demonstrate that our design improvements yield significant, independent enhancements in the fraction of active enzyme nanoreactors and their individual substrate turnover frequencies. The sequence-level design strategies explored here may aid more broadly in improving the performance of DNA-based nanodevices including biological and chemical sensors.


An unexpectedly efficient catalytic antibody operating by ping-pong and induced fit mechanisms.
A transition state analogue was used to produce a mouse antibody that catalyzes transesterification in water. The antibody behaves as a highly efficient catalyst with a covalent intermediate and the characteristic of induced fit. While some features of the catalytic pathway were programmed when the hapten was designed and reflect favorable substrate-antibody interactions, other features are a manifestation of the chemical potential of antibody diversity. The fact that antibodies recapitulate mechanisms and pathways previously thought to be a characteristic of highly evolved enzymes suggests that once an appropriate binding cavity is achieved, reaction pathways commensurate with the intrinsic chemical potential of proteins ensue.


Factors associated with utilization of maternal serum screening for Down syndrome in mainland China: a cross-sectional study.
Knowledge of the factors that influence maternal serum screening (MSS) service utilization can be used to develop health policies to promote equitable access to MSS and further diagnostic tests. The purpose of this study was to find the factors associated with utilization of MSS as well as the current status of service utilization in mainland China. This was a hospital-based cross-sectional study with respondents interviewed with a questionnaire designed based on Andersen's behavioral model. Descriptive statistics, univariate analysis, and multilevel logistic regression analysis were used to identify the factors associated with MSS utilization, and to explore potential methods to improve screening uptake. A total of 8110 women who had given birth within the previous 7 days in one of 111 participating institutions from six provinces in mainland China were interviewed. Approximately 36% of the participants had used MSS. Women between 20 and 35 years, who resided in urban areas, were educated, were in a stable occupation, who had health knowledge, who attended maternal preparation classes, who had received eight or more prenatal checkups, who were from a region of higher social economic status, and who delivered in a tertiary healthcare institution were significantly more likely to use MSS than their counterparts. As compared with other factors, insufficient education is the single most important demographic factor for service underutilization. Efforts should not only be made to target the population that underuses MSS, but the overall organization of MSS service delivery should be assessed during policy development to make access to MSS equitable to the entire population of mainland China.


Validation of the "World Health Organization Disability Assessment Schedule, WHODAS-2" in patients with chronic diseases.
The WHODAS-2 is a disability assessment instrument based on the conceptual framework of the International Classification of Functioning, Disability, and Health (ICF). It provides a global measure of disability and 7 domain-specific scores. The aim of this study was to assess WHODAS-2 conceptual model and metric properties in a set of chronic and prevalent clinical conditions accounting for a wide scope of disability in Europe. 1,119 patients with one of 13 chronic conditions were recruited in 7 European centres. Participants were clinically evaluated and administered the WHODAS-2 and the SF-36 at baseline, 6 weeks and 3 months of follow-up. The latent structure was explored and confirmed by factor analysis (FA). Reliability was assessed in terms of internal consistency (Cronbach's alpha) and reproducibility (intra-class correlation coefficients, ICC). Construct validity was evaluated by correlating the WHODAS-2 and SF-36 domains, and comparing known groups based on the clinical-severity and work status. Effect size (ES) coefficient was used to assess responsiveness. To assess reproducibility and responsiveness, subsamples of stable (at 6 weeks) and improved (after 3 moths) patients were defined, respectively, according to changes in their clinical-severity. The satisfactory FA goodness of fit indexes confirmed a second order factor structure with 7 dimensions, and a global score for the WHODAS-2. Cronbach's alpha ranged from 0.77 (self care) to 0.98 (life activities: work or school), and the ICC was lower, but achieved the recommended standard of 0.7 for four domains. Correlations between global WHODAS-2 score and the different domains of the SF-36 ranged from -0.29 to -0.65. Most of the WHODAS-2 scores showed statistically significant differences among clinical-severity groups for all pathologies, and between working patients and those not working due to ill health (p < 0.001). Among the subsample of patients who had improved, responsiveness coefficients were small to moderate (ES = 0.3-0.7), but higher than those of the SF-36. The latent structure originally designed by WHODAS-2 developers has been confirmed for the first time, and it has shown good metric properties in clinic and rehabilitation samples. Therefore, considerable support is provided to the WHODAS-2 utilization as an international instrument to measure disability based on the ICF model.


Genetic susceptibility to malaria and other infectious diseases: from the MHC to the whole genome.
There is substantial evidence that host genetic factors play a major role in determining the outcome of infection with many pathogens. Detailed analysis of malaria has identified twelve genes that affect susceptibility in various human populations. However, less attention has been paid to other major infectious diseases where twin studies have identified an important host genetic component to susceptibility. Recent progress in the analysis of the human genome offers exciting prospects for the mapping and identification of new susceptibility and resistance genes for common infectious diseases. Screening of the whole genome in affected sibling pair studies is now feasible by employing highly informative microsatellite markers. In addition, many polymorphic candidate genes have become available for analysis in case-control studies. It is proposed that these new genetic tools offer a powerful approach to the epidemiological analysis of many infectious diseases in humans and supersede traditional genetic approaches to identifying susceptibility genes in mouse models. Progress in characterizing the role of major histocompatibility genes in susceptibility to malaria and other infectious diseases is reviewed before outlining the methodologies for and progress in identifying non-MHC susceptibility genes.


NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons.
We have previously shown that presynaptic N-methyl-D-aspartate receptors (NMDARs) can facilitate glutamate release onto principal neurons in the entorhinal cortex (EC). In the present study, we have investigated the subunit composition of these presynaptic NMDARs. We recorded miniature alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (mEPSCs), from visually identified neurons in layers II and V of the EC in vitro. In both layers, bath application of the NR2A/B subunit-selective agonist, homoquinolinic acid (HQA), resulted in a marked facilitation of mEPSC frequency. Blockade of presynaptic Ca(2+) entry through either NMDARs or voltage-gated Ca(2+) channels with Co(2+) prevented the effects of HQA, confirming that Ca(2+) entry to the terminal was required for facilitation. When the NR2B-selective antagonist, ifenprodil, was applied prior to HQA, the increase in mEPSC frequency was greatly reduced. In addition, we found that an NMDAR antagonist blocked frequency-dependent facilitation of evoked release and reduced mEPSC frequency in layer V. Thus we have demonstrated that NMDA autoreceptors in layer V of the EC bear the NR2B subunit, and that NMDARs are also present at terminals onto superficial neurons.


An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes.
Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls. Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records. Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume. The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples.