A comparison of patient characteristics and outcomes in selected European and U.S. rheumatoid arthritis registries.
Randomized controlled trials (RCTs) have demonstrated the efficacy of biologic agents in the treatment of rheumatic diseases. However, results from RCTs may not be generalizable to clinical practice because of their strict inclusion and exclusion criteria. Assessment of safety using RCT data also is limited by short duration of follow-up and relatively small sample sizes, which generally preclude analysis of longer term outcomes and rare adverse events. In rheumatology, various observational cohorts and registries have been created to complement information obtained from RCTs, some with the primary purpose of monitoring effectiveness and safety of biologic agents. Most registries are either drug based or disease based. These registries include patients with a variety of rheumatic diseases including RA. To provide a qualitative comparison of selected U.S. and European rheumatoid arthritis (RA) biologics registries and cohorts including ARTIS, BIOBADASER, BSRBR, BRASS, CLEAR, CORRONA, NDB, RABBIT, SCQM, and VARA. A careful comparison of these registries, as provided in this article, can provide a basis for understanding the many similarities and differences inherent in their design, as well as societal context and content, all of which can significantly impact their results and comparisons across registers. The increasing use of biologic agents for treatment of rheumatic diseases has raised important questions about cost, safety, and effectiveness of these agents. The unique and variable features of patient populations and registry designs in Europe and the U.S. provide valuable and complementary data on comparative effectiveness and safety of biologic agents to what can be derived from RCTs.


Strong spatial genetic structure in peripheral but not core populations of Sitka spruce [Picea sitchensis (Bong.) Carr.].
We examined spatial genetic structure within eight populations of Sitka spruce classified as core or peripheral based on ecological niche, and continuous or disjunct based on species distribution. In each population, 200 trees were spatially mapped and genotyped for eight cDNA-based sequence tagged site (STS) codominant markers. Spatial autocorrelation was assessed by estimating p(ij), the average co-ancestry coefficient, between individuals within distance intervals. The distribution of alleles and genotypes within core populations was almost random, with nonsignificant co-ancestry values among trees as close as 50 m in core populations. In contrast, the distribution of alleles and genotypes within peripheral populations revealed an aggregation of similar multilocus genotypes, with co-ancestry values greater than 0.20 among trees up to 50 m apart and significant, positive values between trees up to 500 m. The relatively high density of reproductive adults in core populations may lead to highly overlapping seed shadows that limit development of spatial genetic structure. However, in peripheral populations with a lower density of adults, the distribution of alleles and genotypes was highly structured, likely due to offspring establishment near maternal trees and subsequent biparental inbreeding, as well as more recent population establishment at the leading edge of post-Pleistocene range expansion. Conserving genetic diversity in peripheral populations may require larger reserves for in situ conservation than required in core populations. These data on spatial genetic structure can be used to provide guidance for sampling strategies for both ex situ conservation and research collections.


Self-assembling dual component nanoparticles with endosomal escape capability.
This study reports a novel nanoparticle system with simple and modular one-step assembly, which can respond intelligently to biologically relevant variations in pH. Importantly, these particles also show the ability to induce escape from the endosomal/lysosomal compartments of the cell, which is integral to the design of efficient polymeric delivery systems. The nanoparticles were formed by the nanoprecipitation of pH-responsive poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) and poly(2-(diethylamino)ethyl methacrylate)-b-poly(ethylene glycol) (PDEAEMA-b-PEG). Rhodamine B octadecyl ester perchlorate was successfully encapsulated within the hydrophobic core of the nanoparticle upon nanoprecipitation into PBS at pH 8. These particles disassembled when the pH was reduced below 6.8 at 37 °C. Cellular experiments showed the successful uptake of the nanoparticles into the endosomal/lysosomal compartments of 3T3 fibroblast cells. The ability to induce escape from the endosomes was demonstrated by the use of calcein, a membrane-impermeable fluorophore. The modular nature of these particles combined with promising endosomal escape capabilities make these dual component PDEAEMA nanoparticles useful for drug and gene delivery applications.


Pigment epithelium-derived factor expression in colorectal cancer patients.
Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis and has been proposed to be a tumor suppressor in a variety of tumors. Limited reports exist of PEDF in colorectal cancer (CRC). We noted a 55% lower plasma level (p < .001) of PEDF in the CRC patient group (1.6 μg/mL) than in of a healthy control group (3.6 μg/mL). A single nucleotide polymorphism (rs1136287, T>C) was screened. In the control group, the CC genotype showed 30% lower PEDF plasma levels compared with the TT genotype (p < .01), whereas the CRC patients failed to show any association regarding these genotypes.


A SPECTRAL GRAPH APPROACH TO DISCOVERING GENETIC ANCESTRY.
Mapping human genetic variation is fundamentally interesting in fields such as anthropology and forensic inference. At the same time, patterns of genetic diversity confound efforts to determine the genetic basis of complex disease. Due to technological advances, it is now possible to measure hundreds of thousands of genetic variants per individual across the genome. Principal component analysis (PCA) is routinely used to summarize the genetic similarity between subjects. The eigenvectors are interpreted as dimensions of ancestry. We build on this idea using a spectral graph approach. In the process we draw on connections between multidimensional scaling and spectral kernel methods. Our approach, based on a spectral embedding derived from the normalized Laplacian of a graph, can produce more meaningful delineation of ancestry than by using PCA. The method is stable to outliers and can more easily incorporate different similarity measures of genetic data than PCA. We illustrate a new algorithm for genetic clustering and association analysis on a large, genetically heterogeneous sample.


Matrix Gla protein expression in NRK-52E cells exposed to oxalate and calcium oxalate monohydrate crystals.
Matrix Gla protein (MGP), a potent calcification inhibitor in extracellular matrix, is a molecular determinant regulating vascular calcification. Here, we characterized MGP expression in cultured renal tubular epithelial cells exposed to oxalate and calcium oxalate monohydrate (COM) crystals. NRK-52E cells were cultured and exposed to medium containing oxalate or COM for 1, 3, 6, 12 and 24 h. The levels of MGP mRNA expression were quantified using real-time PCR (RT-PCR), and the levels of protein expression were characterized by Western blot. MGP was expressed rapidly and intensively following exposure to COM and was time-dependent with exposure to oxalate. Our results have given a profile of MGP expression in renal tubular epithelial cells exposed to oxalate and crystals and provided support for an association between MGP and kidney stones. Further investigations on the mechanism of the MGP in the process of crystal-cell interaction may be important in the future.


Integrating metabolic performance, thermal tolerance, and plasticity enables for more accurate predictions on species vulnerability to acute and chronic effects of global warming.
Predicting species vulnerability to global warming requires a comprehensive, mechanistic understanding of sublethal and lethal thermal tolerances. To date, however, most studies investigating species physiological responses to increasing temperature have focused on the underlying physiological traits of either acute or chronic tolerance in isolation. Here we propose an integrative, synthetic approach including the investigation of multiple physiological traits (metabolic performance and thermal tolerance), and their plasticity, to provide more accurate and balanced predictions on species and assemblage vulnerability to both acute and chronic effects of global warming. We applied this approach to more accurately elucidate relative species vulnerability to warming within an assemblage of six caridean prawns occurring in the same geographic, hence macroclimatic, region, but living in different thermal habitats. Prawns were exposed to four incubation temperatures (10, 15, 20 and 25 °C) for 7 days, their metabolic rates and upper thermal limits were measured, and plasticity was calculated according to the concept of Reaction Norms, as well as Q10 for metabolism. Compared to species occupying narrower/more stable thermal niches, species inhabiting broader/more variable thermal environments (including the invasive Palaemon macrodactylus) are likely to be less vulnerable to extreme acute thermal events as a result of their higher upper thermal limits. Nevertheless, they may be at greater risk from chronic exposure to warming due to the greater metabolic costs they incur. Indeed, a trade-off between acute and chronic tolerance was apparent in the assemblage investigated. However, the invasive species P. macrodactylus represents an exception to this pattern, showing elevated thermal limits and plasticity of these limits, as well as a high metabolic control. In general, integrating multiple proxies for species physiological acute and chronic responses to increasing temperature helps providing more accurate predictions on species vulnerability to warming.


Implications of Incorporating Plasma Lipoprotein Binding into a Physiologically-Based Pharmacokinetic Model: A Simulation Study with Amiodarone.
Although various lipophilic drugs are bound to lipoproteins, lipoprotein binding in plasma is not usually considered in current physiologically-based pharmacokinetic (PBPK) models. Amiodarone is extensively bound to serum triglyceride-rich lipoproteins. Total plasma amiodarone concentration, which is the sum of both unbound and bound concentrations, increases with increasing serum triglyceride levels. We investigated the impact of lipoprotein binding on amiodarone pharmacokinetics using PBPK modeling and simulations. An amiodarone PBPK model that incorporates plasma lipoprotein binding (LPP model) was developed based on the correlation between serum triglyceride levels and lipoprotein-bound amiodarone. The predicted unbound fraction of amiodarone in plasma and systemic clearance in the LPP and base models (with albumin binding only) were similar, but the coefficients of variation for the LPP model were greater than those for the base model and were closer to the observed data. The total plasma amiodarone concentration predicted using the LPP model increased with higher levels of plasma lipoprotein binding and serum albumin. In contrast, changes in plasma lipoprotein binding and serum albumin levels did not influence the predicted unbound plasma amiodarone concentration at steady-state. This study demonstrates that incorporating plasma lipoprotein binding into a PBPK model improves the accuracy of predicting interindividual variabilities in amiodarone clearance by more reliably predicting the interindividual variability in the plasma unbound fraction of amiodarone. Plasma lipoprotein binding should be considered in PBPK modeling and simulations for lipoprotein-associated drugs if there is available information on the relationship between plasma lipoprotein binding and hyperlipidemia.


Comparison of responses of tracheal twin spirals to bronchoactive agents.
Cumulative concentration-effect relationships of tracheal twin spirals to histamine, carbamylcholine and isoprenaline were determined by an in vitro study. A tracheal spiral was prepared by cutting a guinea pig trachea from the carina to the larynx in a spiral fashion. This tracheal spiral was then bisected longitudinally into two equal halves to produce tracheal twin spirals. The validity of using tracheal twin spirals as paired tissue was examined in this study by comparing their responses to bronchoactive agents. Concentration-effect relationships of the agents tested did not show significant differences between the twin spirals. This method is recommended to minimize animal variations.


[The sociological survey of health workers morbidity at the multidisciplinary hospital].
Some parameters of the health status of medical workers using a sociological method were studied at a large multidisciplinary hospital of Nizhny Novgorod. The results of self-registration of chronic diseases are indicative of the high level of morbidity in the study group. The differences in the level and structure of chronic pathology as compared with literature data prove the validity of using the sociological method to study the health status of medical workers.


A nonradioisotope chemiluminescent assay for evaluation of 2-deoxyglucose uptake in 3T3-L1 adipocytes. Effect of various carbonyls species on insulin action.
We have developed a rapid nonradioisotope chemiluminescent assay adapted to high-throughput screening experiments, to evaluate glucose uptake activity in cultured cells. For chemiluminescence quantification of 2-deoxyglucose, we used a luminol oxidation reaction after an enzymatic dephosphorylation of 2-deoxyglucose-6-phosphate. All reactions were performed at 37 °C by consecutive addition of reagents, and the assay is able to quantify 2DG in picomole per well. To confirm the reliability of this method, we have evaluated the dose-effect of insulin, GLUT4 inhibitors and insulin-sensitizing agent on 2DG uptake into 3T3-L1 cells. The results obtained with the assay for 2DG uptake in vitro in the absence or presence of insulin stimulation, were similar to those obtained by the previous radioisotopic and enzymatic methods. We have also used this assay to evaluate the effect of various reactive carbonyl and oxygen species on insulin-stimulated 2DG-uptake into adipocytes. All reactive carbonyl species tested decreased insulin-stimulated glucose uptake in a time- and dose-dependent manner without affecting basal glucose uptake in 3T3-L1 cells. 4-hydroxynonenal was found to be the most potent in the impairment of glucose uptake. This new enzymatic chemiluminescent assay is rapid and useful for measurement of 2DG uptake in insulin-responsive in cultured cells.


Revisiting the Continuing Bonds Theory: The Cultural Uniqueness of the Bei Dao Phenomenon in Taiwanese Widows/Widowers.
In the present study, we used the phenomenological approach to rediscover the ontological meaning of relationships with the deceased in Taiwanese widows/widowers. We first revised the original Western definitions of grief, bereavement, and mourning to fit Taiwanese culture. We used the word bei dao to indicate the mixed nature of grief and mourning in the Taiwanese bereavement process. Then we reanalyzed data from a previous study, which was conducted in 2006. In the previous qualitative research, each subject was interviewed 3 to 4 times in the mourning state over an 18-month interval that began at the point of the spouse's death. Results showed that two main themes emerged in the present analysis: (a) a blurred boundary of life and death and (b) a transformation of ethical bonds. The present study reveals the culturally unique aspects of the Taiwanese bei dao process. Limitations of the present study and future directions are discussed and reflected.


Improved influenza viral vector based Brucella abortus vaccine induces robust B and T-cell responses and protection against Brucella melitensis infection in pregnant sheep and goats.
We previously developed a potent candidate vaccine against bovine brucellosis caused by Brucella abortus using the influenza viral vector expressing Brucella Omp16 and L7/L12 proteins (Flu-BA). Our success in the Flu-BA vaccine trial in cattle and results of a pilot study in non-pregnant small ruminants prompted us in the current study to test its efficacy against B. melitensis infection in pregnant sheep and goats. In this study, we improved the Flu-BA vaccine formulation and immunization method to achieve maximum efficacy and safety. The Flu-BA vaccine formulation had two additional proteins Omp19 and SOD, and administered thrice with 20% Montanide Gel01 adjuvant, simultaneously by both subcutaneous and conjunctival routes at 21 days intervals in pregnant sheep and goats. At 42 days post-vaccination (DPV) we detected antigen-specific IgG antibodies predominantly of IgG2a isotype but also IgG1, and also detected a strong lymphocyte recall response with IFN-γ production. Importantly, our candidate vaccine prevented abortion in 66.7% and 77.8% of pregnant sheep and goats, respectively. Furthermore, complete protection (absence of live B. melitensis 16M) was observed in 55.6% and 66.7% of challenged sheep and goats, and 72.7% and 90.0% of their fetuses (lambs/yeanlings), respectively. The severity of B. melitensis 16M infection in vaccinated sheep and goats and their fetuses (index of infection and rates of Brucella colonization in tissues) was significantly lower than in control groups. None of the protection parameters after vaccination with Flu-BA vaccine were statistically inferior to protection seen with the commercial B. melitensis Rev.1 vaccine (protection against abortion and vaccination efficacy, alpha = 0.18-0.34, infection index, P = 0.37-0.77, Brucella colonization, P = 0.16 to P > 0.99). In conclusion, our improved Flu-BA vaccine formulation and delivery method were found safe and effective in protecting pregnant sheep and goats against adverse consequences of B. melitensis infection.


Proteogenomic Analysis of Epibacterium Mobile BBCC367, a Relevant Marine Bacterium Isolated From the South Pacific Ocean.
Epibacterium mobile BBCC367 is a marine bacterium that is common in coastal areas. It belongs to the Roseobacter clade, a widespread group in pelagic marine ecosystems. Species of the Roseobacter clade are regularly used as models to understand the evolution and physiological adaptability of generalist bacteria. E. mobile BBCC367 comprises two chromosomes and two plasmids. We used gel-free shotgun proteomics to assess its protein expression under 16 different conditions, including stress factors such as elevated temperature, nutrient limitation, high metal concentration, and UVB exposure. Comparison of the different conditions allowed us not only to retrieve almost 70% of the predicted proteins, but also to define three main protein assemblages: 584 essential core proteins, 2,144 facultative accessory proteins and 355 specific unique proteins. While the core proteome mainly exhibited proteins involved in essential functions to sustain life such as DNA, amino acids, carbohydrates, cofactors, vitamins and lipids metabolisms, the accessory and unique proteomes revealed a more specific adaptation with the expression of stress-related proteins, such as DNA repair proteins (accessory proteome), transcription regulators and a significant predominance of transporters (unique proteome). Our study provides insights into how E. mobile BBCC367 adapts to environmental changes and copes with diverse stresses.


Divergent phenotypes in Gaucher disease implicate the role of modifiers.
Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown. The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines. Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed. The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.


A complex intervention to enhance the involvement of general practitioners in cancer rehabilitation. Protocol for a randomised controlled trial and feasibility study of a multimodal intervention.
The effect of interventions that support rehabilitation among cancer patients has to be tested before implementation. A randomised controlled trial was conducted to test the hypothesis that a multimodal intervention may give the general practitioner (GP) an enhanced role and improve rehabilitation for cancer patients. The intervention included an interview about rehabilitation needs with a rehabilitation coordinator (RC), information from the hospital to the general practitioner about individual needs for rehabilitation and an incentive for the GP to contact the patient about rehabilitation. The objective of this first report from the study was to examine the acceptability and feasibility of the intervention. Adult patients treated for incident cancer at Vejle Hospital, Denmark were included between May 12, 2008 and February 28, 2009. All general practices in Denmark were randomised. Patients were allocated to intervention or control (usual procedures) based on the randomisation status of their GP. The feasibility of the intervention was analysed with regard to recruitment of patients, acceptability by patients and GPs and the degree to which the planned contacts between patients, RCs and GPs were implemented. The primary outcome of the randomised controlled trial (RCT) will be health-related quality of life at six months (EORTC-30). Following assessment of 1 896 cancer patients, 955 patients (50%) registered with 323 general practices were included. The interview was conducted at the hospital with 50% of the patients in the intervention group, 31% were contacted by phone. Patients valued the fact that the conversation was dedicated to needs beyond the medical treatment. The GPs were generally available for information by phone and positive towards having a central role in the cancer rehabilitation. It was feasible to conduct a RCT to evaluate a complex intervention in the healthcare system. All elements of the intervention were acceptable and feasible and may be implemented in future practice if the effect is positive.


Perception of health risks in Lao market vendors.
Wet markets are a critical part of South-East Asian culture and economy. However, their role in circulation and transmission of both endemic and emerging disease is a source of concern in a region considered a hotspot of disease emergence. In the Lao People's Democratic Republic (Lao PDR, Laos), live and dead wild animals are frequently found in wet markets, despite legislation against the bushmeat trade. This is generally considered to increase the risk of disease transmission and emergence, although whether or not wildlife vendors themselves have indeed increased incidence of zoonotic disease has rarely been assessed. In preparation for a future longitudinal study of market vendors investigating vendors' exposure to zoonotic pathogens, we conducted a pilot survey of Lao market vendors of wildlife meat, livestock meat and vegetables, to identify demographic characteristics and potential control groups within markets. We also investigated baseline risk perception for infectious diseases among market vendors and assessed the association between risk perception and risk mitigation behaviours. The surveys conducted with 177 vendors revealed similar age, sex, ethnic background and geographical origin between vendor types, but differences in professional background and work history for livestock meat vendors. The perception of disease risk was very low across all vendors, as was the reported use of personal protective equipment, and the two appeared unrelated. Personal risk discounting and assumptions about transmission routes may explain this lack of association. This information will help inform the development of future research, risk communication and risk mitigation policy, especially in the light of the COVID-19 pandemic.


Comparison of treatment responses and clinical characteristics of early-onset and late-onset obsessive-compulsive disorder.
Objective. The clinical characteristics and response to pharmacotherapy of adult patients with early-onset and late-onset obsessive-compulsive disorder (OCD) were compared in this study. Methods. A total of 50 outpatients with OCD diagnosed according to DSM-IV criteria (early-onset: 20; late-onset: 30) were included in the study. After initial clinical evaluation with The Structured Clinical Interview for DSM-IV/Clinical Version (SCID-I/CV), The Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), all patients were treated with fluvoxamine, sertraline or paroxetine for 12 weeks. Treatment response was defined as a ≥35% reduction in the Y-BOCS-total scores from baseline in a 12-week follow-up period. Results. Forty-three patients (early-onset: 16; late-onset: 27) completed the study. The early-onset group had higher frequencies of symmetry/exactness obsessions and ordering/arranging compulsions, and the late-onset group had higher mean age at assessment. Nine (56.3%) patients with early-onset and 18 (66.7%) with late-onset responded to pharmacotherapy. The difference between response rates was not statistically significant. Conclusions. Our study suggests that although there are some phenomenological differences between patients with early-onset OCD and late-onset OCD, these patients have similar responses to pharmacotherapy.


Associations Between miRNAs and Two Different Cancers: Breast and Colon.
Screening approaches using microRNAs (miRNAs) have been gaining increased attention owing to their potential applications in the diagnosis, prognosis, and monitoring of cancer, because aberrant miRNA expression plays a role in the development and advancement of malignancies. The objectives of this study were to characterize mir21, miR31, mir143, mir145, and control RNU43, which are differentially expressed in peripheral blood mononuclear cells (PBMCs) of breast and colorectal cancer patients, compared to that in controls and to establish whether this is specific to breast and colon cancer for use as tumor markers. Thirty newly diagnosed patients with breast cancer and 30 patients with colorectal cancer were enrolled together with 30 healthy controls. PBMCs were isolated from venous blood samples of individuals. Next, miRNA expression analysis was performed by a two-step method of reverse transcription and qPCR. The expression levels of miR-143 and miR-31 were significantly decreased, whereas the expression levels of miR-145 and miR-21 were significantly increased in breast cancer patients compared to those in healthy subjects. Moreover, the expression levels of miR-143, miR-145, and miR-21 were significantly increased and, in contrast, the changes in the expression levels of miR-31 were not statistically significant in colon cancer compared to those in healthy subjects. miR-21 exhibited the highest increase in both breast and colon cancers. There was a weak positive correlation between miR-145 and CA-15.3 in patients with breast cancer (r = 0.451; p = 0.012). miR-143 was positively correlated with the TNM stage in colon cancer patients (r = 0.568; p = 0.001). A biomarker panel composed of miR-21, miR-31, miR-143, and miR-145 in PBMC may provide a new diagnostic approach for the early detection of breast and colon cancer. As miR-21 expression was found to be the highest among all the miRNAs evaluated, it may represent a new tumor biomarker and a candidate therapeutic drug or gene target in colon and breast cancer.


[A reproductive function in metallurgists].
The analysis of the results of a complex investigation of a reproductive function including examination of semen and blood hormones in 100 metallurgists and 80 workers not engaged in metallurgy of ferrous metals (a control group) has shown that 44% metallurgists and 18.5% controls have pathology (p < 0.001). Metallurgists had more often agglutination, asthenozoospermia, increased semen viscosity, oligospermia, teratospermia, asthenoteratospermia, male sterility than the control group (p < 0.001). Metallurgists have a moderate and high relative risk of reproduction function pathology (RR = 1.6-2.9). Urological pathology in metallurgists can be reduced after prophylactic programs. This proves the necessity of including urological examination and ultrasonic scanning in programs of regular check-up of metallurgists.


Isolation and characterization of a portal protein-DNA complex from dsDNA bacteriophage.
A portal protein-DNA complex was isolated from bacteriophage disrupted in 70% acetic acid. This treatment dissociated most of the phage structural proteins, while the portal protein ring remained attached to the highly condensed naked DNA. In the absence of a headful of DNA, the portal ring was not protected. Purification of the portal ring-DNA complex by density gradient centrifugation showed that a dsDNA fragment of about 40 bp was protected from DNase digestion by this association, suggesting it was internalized within the 140 A long, 20-40 A in diameter T4 apical channel of the ring dodecamer. A portal ring-DNA complex could be isolated from a number of phages (T4, T7, Phi29), and the end(s) of phage T7 DNA was (were) found to be preferentially associated with the ring complex.


Pukalide, a widely distributed octocoral diterpenoid, induces vomiting in fish.
Tissue and extractable metabolites from the subtropical gorgonianLeptogorgia virgulata (Coelenterata: Anthozoa: Octocorallia: Gorgonacea) induce vomiting in a variety of fish species. To elucidate the chemical bases of this phenomenon, experiments were undertaken with purified pukalide, a cembranoid diterpene that comprises as much as 0.1-0.5% of the wet tissue weight ofL. virgulata. When incorporated into artificial foods at concentrations corresponding to the levels found inL. virgulata, pukalide induced emesis when delivered orally to killifish (Fundulus heteroclitus). The threshold dose for pukalide-induced emesis was 0.05 mg/g fish body weight. Control pellets devoid of pukalide did not induce vomiting. The emetic effect of pukalide was dose-dependent, as fish ingesting more than 0.100 mg pukalide/ g body weight exhibited a significantly higher incidence of vomiting than fish ingesting lower doses of pukalide (G=5.5,df=1,P<0.025). The elapsed time between ingestion of pukalide-containing pellets and emesis was significantly longer in fish that ingested marginally emetic doses of pukalide (Kruskal-WallisH=4.00, significant withP<0.05). Although not markedly unpalatable to fish, pukalide may function in nature as a defensive toxin by inducing emesis and learned aversion in potential octocoral predators.


Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS.
Adrenomedullin (ADM) is upregulated independently by hypoxia and LPS, two key factors in the pathogenesis of acute lung injury (ALI). This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O2) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O2). ADM expression was analyzed by in situ hybridization, Northern blot, Western blot, and RIA analyses. In the rat lung, combination of hypoxia and LPS treatments overcomes ADM induction occurring after each treatment alone. With in situ techniques, the synergistic effect of both stimuli mainly correlates with ADM expression in inflammatory cells within blood vessels and, to a lesser extent, to cells in the lung parenchyma and bronchiolar epithelial cells. In the in vitro model, hypoxia and hypoxia + LPS treatments caused a similar strong induction of ADM expression and secretion in epithelial and endothelial cell lines. In alveolar macrophages, however, LPS-induced ADM expression and secretion were further increased by the concomitant exposure to hypoxia, thus paralleling the in vivo response. In conclusion, ADM expression is highly induced in a variety of key lung cell types in this rat model of ALI by combination of hypoxia and LPS, suggesting an essential role for this mediator in this syndrome.


Non-ablative Er:YAG laser therapy effect on stress urinary incontinence related to quality of life and sexual function: A randomized controlled trial.
Stress urinary incontinence (SUI) is a common complaint in women after childbirth. It affects their quality of life and sexual satisfaction and is one of the major reasons for gynaecological surgery. There is a need for effective non-invasive treatment alternatives. The aim of this study was to evaluate the efficacy and safety of non-ablative Er:YAG laser therapy in the treatment of SUI and improvement of sexual gratification in parous women. 114 premenopausal parous women with SUI were randomized in two groups of 57 women; a laser intervention group and sham group. Both groups were treated according to the IncontiLase® clinical treatment protocol for SUI with non-ablative thermal-only Er:YAG laser, except that there was no energy output when treating the sham group. Patients were blinded to the allocation. At baseline and 3 months after treatment patients were clinically examined, answered questionnaires for SUI severity and sexual function assessment and their pelvic floor muscle (PFM) function was assessed with perineometry. Validated International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF) was used as the primary outcome measure. The Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire short form (PISQ-12) and The Female Sexual Function Index (FSFI) were used to assess the sexual function. Patients were monitored for discomfort and side-effects during treatment and follow-up period. 3 months after treatment the ICIQ-UI SF (p < 0.001), PISQ-12 (p = 0.014) and FSFI (p = 0.025) scores were significantly more improved in the laser group than in the sham control group. All perineometry variables improved in the laser group after treatment; duration and maximum pressure had statistically significantly better improvement than the sham group, whereas average pressure did not. 21% of laser treated patients were dry (ICIQ-UI SF = 0) at follow up compared to only 4% of the sham control patients. No serious adverse effects were observed or reported. The treatment was well tolerated by patients. The non-ablative Er:YAG laser therapy improves the impact of SUI symptoms on quality of life and sexual function in premenopausal parous women significantly better than placebo. It provides a promising minimally-invasive safe treatment alternative for SUI.


Late talkers: do good predictors of outcome exist?
Both small-scale and epidemiological longitudinal studies of early language delay indicate that most late talkers attain language scores in the average range by age 5, 6, or 7. However, late talker groups typically obtain significantly lower scores than groups with typical language histories on most language measures into adolescence. These findings support a dimensional account of language delay, whereby late talkers and typically developing peers differ quantitatively on a hypothetical language ability spectrum. Variation in language ability is presumed to derive from variation in skills subserving language, such as auditory perception/processing, word retrieval, verbal working memory, motor planning, phonological discrimination, and grammatical rule learning. Expressive language screening at 18-35 months can serve an important public health function by identifying children whose expressive delay is secondary to autism spectrum disorder, intellectual disability, hearing impairment, receptive language delay, or demographic risk. Finally, the review suggests that demographic risk associated with low SES may become more important as a causal factor in language delay as children get older.


Immunization method for multi-pass membrane proteins using highly metastatic cell lines.
A novel method using metastatic breast cancer cell lines was established for producing monoclonal antibodies (mAbs) against multi-span membrane proteins. Grafting of metastatic cells (MCF7-14) into the mammary gland of BALB/cJ/nu/nu mice induced splenic hypertrophy (1.6-3.0×10(8)cells/spleen [n=6]). More than half of the mAbs against MCF7-14 cells reacted with the cell membrane. Inducing production of antibodies against the extracellular domain of multi-pass membrane proteins is difficult. Because the protein structure becomes more complex as the number of transmembrane domains increases, preparing antigens for immunization in which the original structure is maintained is challenging. Using highly metastatic MDA-MB231 cells as the host cell line, we produced mAbs against a 12 transmembrane protein, solute carrier family 6 member 6 (SLC6A6), as a model antigen. When SLC6A6-overexpressing MDA-MB231 cells were grafted into nude mice, the number of splenocytes increased to 2.7-11.4×10(8)cells/spleen (n=10). Seven mAb-producing clones that not only recognized the extracellular domain of SLC6A6 but also were of the IgG subclass were obtained. Immunocytochemistry and flow cytometry analyses revealed that these mAbs recognized the native form of the extracellular domain of SLC6A6 on the cell surface. Our novel immunization method involving highly metastatic cells could be used to develop therapeutic mAbs against other multi-pass membrane proteins.


Caregivers' burden in patients with COPD.
Chronic obstructive pulmonary disease (COPD) is a very prevalent and invalidating disease. The aim of this study was to analyze the burden borne by informal caregivers of patients with COPD. We used the Survey on Disabilities, Personal Autonomy, and Dependency Situations (Encuesta sobre Discapacidad, Autonomía personal y Situaciones de Dependencia [EDAD]-2008) to obtain information on the characteristics of disabled individuals with COPD and their caregivers in Spain. Additionally, statistical multivariate analyses were performed to analyze the impact that an increase in dependence would have on the problems for which caregivers provide support, in terms of health, professional, and leisure/social dimensions. A total of 461,884 individuals with one or more disabilities and with COPD were identified, and 220,892 informal caregivers were estimated. Results showed that 35% of informal caregivers had health-related problems due to the caregiving provided; 83% had leisure/social-related problems; and among caregivers of working age, 38% recognized having profession-related problems. The probability of a problem arising was significantly associated with the degree of dependence of the patient receiving care. Caregivers of patients with great dependence showed a 39% higher probability of presenting health-related problems, 27% more professional problems, and 23% more leisure problems compared with those with nondependent patients. The results show the large impact on society in terms of the welfare of informal caregivers of patients with COPD. A higher level of dependence was associated with more severe problems in caregivers, in all dimensions.


[The signal behavior of parathyroid adenomas in MRT--the contrast ratio of the thyroid and fatty tissue].
A quantitative analysis of signal relationships using T1, proton and T2 weighted spin echo sequences was carried out using 20 parathyroid adenomas demonstrated by MRI. T1 weighted sequences from 15 adenomas were also examined following intravenous injection of Gd-DTPA. No typical signal relationship could be defined. In 4 cases the administration of contrast medium markedly increased the contrast between the adenoma and the thyroid gland. In 12 cases the tumour could be examined histologically following removal. In 2 cases there was oedema of the tumour and corresponding increased intensity of the T2 weighted sequences; in none of the other cases was there any clear correlation between the signals and the histology.


Pleomorphic xanthoastrocytoma: a brief review.
Pleomorphic xanthoastrocytoma (PXA) is a rare primary CNS tumor. Recent advances in the molecular characterization are helping to define subtypes of tumor. The discovery of BRAF mutations within a substantial percentage of PXA fosters a clearer understanding of the pathophysiology of these tumors with clear prognostic and therapeutic implications. These findings are expected to provide insight into the spectrum of clinical behavior observed in PXA, ranging from cure with surgery to diffuse dissemination throughout the neuraxis. This review details the clinical presentation including radiographic appearance of PXA. Pathology, including molecular pathology is discussed. Therapeutic management including surgical resection, radiotherapy and systemic therapies are reviewed.


A Fully Amorphous, Dynamic Cross-Linked Polymer Electrolyte for Lithium-Sulfur Batteries Operating at Subzero-Temperatures.
Solid-state lithium-sulfur batteries have shown prospects as safe, high-energy electrochemical storage technology for powering regional electrified transportation. Owing to limited ion mobility in crystalline polymer electrolytes, the battery is incapable of operating at subzero temperature. Addition of liquid plasticizer into the polymer electrolyte improves the Li-ion conductivity yet sacrifices the mechanical strength and interfacial stability with both electrodes. In this work, we showed that by introducing a spherical hyperbranched solid polymer plasticizer into a Li+-conductive linear polymer matrix, an integrated dynamic cross-linked polymer network was built to maintain fully amorphous in a wide temperature range down to subzero. A quasi-solid polymer electrolyte with a solid mass content >90% was prepared from the cross-linked polymer network, and demonstrated fast Li+ conduction at a low temperature, high mechanical strength, and stable interfacial chemistry. As a result, solid-state lithium-sulfur batteries employing the new electrolyte delivered high reversible capacity and long cycle life at 25 oC, 0 oC and -10 oC to serve energy storage at complex environmental conditions.


GnRH antagonists in ovarian stimulation for IVF.
The present review describes, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of gonadotropin-releasing hormone (GnRH) antagonists in ovarian stimulation for IVF. The single or multiple low-dose administration of GnRH antagonist during the late-follicular phase effectively prevents a premature rise in serum luteinizing hormone (LH) levels in most women. Although controversy remains, most comparative studies suggest a slight, not significant reduction in the probability of pregnancy after IVF using GnRH antagonist versus GnRH agonist co-treatment. Published meta-analyses suggest that this slight difference in pregnancy rates is not attributed to chance. Further studies applying varying treatment regimens and outcome measures are required. Data are not in favour of a need to modify the starting dose of gonadotropins. Data are not in favour of increasing gonadotropin dose at GnRH antagonist initiation. The addition of LH from the initiation of ovarian stimulation or from GnRH antagonist administration does not appear to be necessary. Replacement of human chorionic gonadotropin (HCG) by GnRH agonist for triggering final oocyte maturation is associated with a lower probability of pregnancy. The optimal timing for HCG administration needs to be explored further. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14-16 mm, although earlier GnRH antagonist administration is worth further evaluation. Luteal phase supplementation in GnRH antagonist protocols remains mandatory in IVF. Effects of GnRH antagonist co-treatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists. The role of GnRH antagonists in ovarian stimulation for IVF appears to be promising, although many questions regarding preferred dose regimens and effects on clinical outcomes remain.


Transient receptor potential ion channel TRPM2 promotes AML proliferation and survival through modulation of mitochondrial function, ROS, and autophagy.
Transient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in maintaining cell survival following oxidant injury. Here, we show that TRPM2 is highly expressed in acute myeloid leukemia (AML). The role of TRPM2 in AML was studied following depletion with CRISPR/Cas9 technology in U937 cells. In in vitro experiments and in xenografts, depletion of TRPM2 in AML inhibited leukemia proliferation, and doxorubicin sensitivity was increased. Mitochondrial function including oxygen consumption rate and ATP production was reduced, impairing cellular bioenergetics. Mitochondrial membrane potential and mitochondrial calcium uptake were significantly decreased in depleted cells. Mitochondrial reactive oxygen species (ROS) were significantly increased, and Nrf2 was decreased, reducing the antioxidant response. In TRPM2-depleted cells, ULK1, Atg7, and Atg5 protein levels were decreased, leading to autophagy inhibition. Consistently, ATF4 and CREB, two master transcription factors for autophagosome biogenesis, were reduced in TRPM2-depleted cells. In addition, Atg13 and FIP200, which are known to stabilize ULK1 protein, were decreased. Reconstitution with TRPM2 fully restored proliferation, viability, and autophagy; ATF4 and CREB fully restored proliferation and viability but only partially restored autophagy. TRPM2 expression reduced the elevated ROS found in depleted cells. These data show that TRPM2 has an important role in AML proliferation and survival through regulation of key transcription factors and target genes involved in mitochondrial function, bioenergetics, the antioxidant response, and autophagy. Targeting TRPM2 may represent a novel therapeutic approach to inhibit myeloid leukemia growth and enhance susceptibility to chemotherapeutic agents through multiple pathways.


Technique for Performing Lumbar Puncture in Microgravity Using Portable Radiography.
Visual Impairment and Intracranial Pressure Syndrome (VIIP) has caused symptomatology during and after long duration missions on the International Space Station (ISS). Only indirect measurements of intracranial pressure (ICP), such as ultrasound, have been performed on ISS. Discussion and interest has happened at NASA about performing lumbar puncture (LP) in microgravity. Only the "blind" palpation approach and the ultrasound-assisted approach have been discussed. This article, as proof of concept, discusses the possibility of portable radiography to assist lumbar punctures in microgravity. An anthropomorphic radiological phantom of an adult lumbar spine was made containing a fluid-filled space in the spinal canal with a latex membrane which simulated the dural sac and cerebrospinal fluid. A portable direct-digital radiography system with wireless transmitting image receptor and screen was used to perform image-guided lumbar puncture. Using the same equipment and technique, this procedure was then performed on a cadaver for final proof of concept. Technical success was achieved in all approaches on the first try without needle redirection. There was no difference between the cadaver model and the phantom model in terms of difficulty in reaching the fluid space or visually confirming needle location. Portable radiography via proof of concept has the potential to guide lumbar puncture while minimizing volume and mass of equipment. This could be ideal for assisting in performing lumbar puncture in microgravity, as this is the standard of care on Earth for difficult or failed "blind" lumbar punctures. Lerner DJ, Parmet AJ, Don S, Shimony JS, Goyal MS. Technique for performing lumbar puncture in microgravity using portable radiography. Aerosp Med Hum Perform. 2016; 87(8):745-747.


Adaptation and Norm Determination Study of the Boston Naming Test for Healthy Turkish Elderly.
The main purpose of this research is develop the Turkish version of the BNT long form (consist of 60 items) [BNT-60 (TR)] and to determine the normative data for Turkish healthy geriatric population. BNT is a neuropsychological test which was widely used to measure naming disorders associated with a variety of neuropathological events. This research consists of two stages. In the stage of pilot study, adaptation of test was completed and BNT-60 (TR) version was developed; and in the stage of normative study, normative data was collected and norm determination was completed. Ninety healthy and volunteer elderly were participated in pilot study and 317 were in normative study. Three screening tests called Montreal Cognitive Assessment (MOCA), Functional Activities Questionnaire (FAQ) and Geriatric Depression Scale (GDS) were administered for participant selection. BNT-60 (TR) was applied to participants who meet the inclusion criteria. According to 5 (age) x 2 (gender) x 3 (education) factorial ANOVA results, main effects of age and education level on BNT-60 (TR) total score were found statistically significant. Then according to MANOVA results, main effects of age and education level on BNT-60 (TR) sub-scores were found statistically significant. On the other hand, main effect of gender was not significant on BNT-60 (TR) scores. The age and BNT-60 (TR) total score were negatively correlated. This results consistent with other normative studies of BNT in the literature. Finally, BNT-60 (TR) is adopted for Turkish culture, determined normative data and a test which is evaluating naming ability of the older adults was put into use.


Public health approaches to gambling: a global review of legislative trends.
The public health community has called for governments to recognise the harms associated with gambling, and for gambling policies to include population-based harm prevention approaches. This Health Policy explores the translation of this call into global policy action by systematically reviewing legislation of jurisdictions that introduced major gambling legislation change (ie, restricting or extending gambling provision) between Jan 1, 2018, and Dec 31, 2021. We mapped the global availability of legal gambling and changes in its provision, and conducted critical frame analysis on a sample of 33 jurisdictions introducing major policy change to assess the extent to which the protection of health and wellbeing was embedded within legislation. More than 80% of countries worldwide now legally permit gambling. Harmful gambling was recognised as a health and wellbeing issue in most of the analysed jurisdictions, but near-exclusive focus was given to individual-level harms rather than to wider social and economic harms, or harms to others. Most of the proposed prevention measures focused on individual responsibility. Gambling policies worldwide are changing, but addressing gambling as a public health issue is not yet translating into comprehensive policy action across jurisdictions.


On the evolution of morphogenetic models: mechano-chemical interactions and an integrated view of cell differentiation, growth, pattern formation and morphogenesis.
In the 1950s, embryology was conceptualized as four relatively independent problems: cell differentiation, growth, pattern formation and morphogenesis. The mechanisms underlying the first three traditionally have been viewed as being chemical in nature, whereas those underlying morphogenesis have usually been discussed in terms of mechanics. Often, morphogenesis and its mechanical processes have been regarded as subordinate to chemical ones. However, a growing body of evidence indicates that the biomechanics of cells and tissues affect in striking ways those phenomena often thought of as mainly under the control of cell-cell signalling. This accumulation of data has led to a revival of the mechano-transduction concept in particular, and of complexity in general, causing us now to consider whether we should retain the traditional conceptualization of development. The researchers' semantic preferences for the terms 'patterning', 'pattern formation' or 'morphogenesis' can be used to describe three main 'schools of thought' which emerged in the late 1970s. In the 'molecular school', the term patterning is deeply tied to the positional information concept. In the 'chemical school', the term 'pattern formation' regularly implies reaction-diffusion models. In the 'mechanical school', the term 'morphogenesis' is more frequently used in relation to mechanical instabilities. Major differences among these three schools pertain to the concept of self-organization, and models can be classified as morphostatic or morphodynamic. Various examples illustrate the distorted picture that arises from the distinction among differentiation, growth, pattern formation and morphogenesis, based on the idea that the underlying mechanisms are respectively chemical or mechanical. Emerging quantitative approaches integrate the concepts and methods of complex sciences and emphasize the interplay between hierarchical levels of organization via mechano-chemical interactions. They draw upon recent improvements in mathematical and numerical morphogenetic models and upon considerable progress in collecting new quantitative data. This review highlights a variety of such models, which exhibit important advances, such as hybrid, stochastic and multiscale simulations.


The effects of ketamine on suicidality across various formulations and study settings.
Suicidality and self-injurious behavior afflict patients with a wide variety of psychiatric illnesses. Currently, there are few pharmacologic treatments for suicidality and self-injurious behavior and none that treat these conditions emergently. Recently, ketamine has demonstrated efficacy in treating both depression and acute suicidal ideation. An increasing usage of ketamine, of a variety of formulations, has been studied for these indications. This article reviews the evidence for use of ketamine in self-injurious behavior and suicidality. A review of the MEDLINE database for articles relating to ketamine, self-injurious behavior, suicidality, and self-harm was conducted. Additional articles were assessed via cross-reference. A total of 24 articles that included clinical trials, meta-analyses, case series, and case reports were analyzed. The majority of studies of ketamine for suicidal ideation include the intravenous route using a dose of 0.5 mg/kg over 40 minutes. These studies suggest that intravenous ketamine may be effective at reducing suicidal ideation acutely. Data on use of ketamine in the intramuscular, intranasal, and oral forms are limited and of poorer quality. Studies on these formulations contain greater variability of positive and negative results of ketamine for reducing suicidality and self-injurious behavior. The durability of the antisuicidal effects across all formulations is limited. Ketamine may be an effective option for the treatment of suicidal ideation in patients across inpatient, outpatient, or emergent settings. At this time, more research is needed on the efficacy of ketamine across all formulations being used in clinical practice.


Congenital and acquired anomalies of the caudal vertebrae in dogs: Radiographic classification and prevalence evaluation.
A prospective study to create radiographic classification of caudal vertebral anomalies in dogs was performed and the prevalence of the disorders estimated. Radiographic examination of the caudal vertebrae was performed in 595 client-owned dogs undergoing routine radiological examination of the hip joints. Anomalies of the caudal vertebrae were divided into four groups: (1) congenital anomalies with aberrant fusion of the vertebral epiphysis, like hemivertebra, block or transitional vertebra; (2) morphological anomalies like vertebra curva and dysplastic vertebral epiphysis; (3) post-traumatic changes, represented by fracture or luxation; and (4) degenerative changes, represented by spondylosis, osteophyte formation and mineralisation of intervertebral spaces. A total of 303 caudal vertebral anomalies were detected in 259 dogs (43.53% of all dogs examined). A single type of vertebral anomaly was present in 215 dogs and a combination of two pathologies was recorded in 44 dogs, which represents 83.01% and 16.99%, respectively, of the affected dogs. Congenital anomaly was present in 11.09% of the dogs examined. Sacrocaudal transitional vertebra was the most common congenital anomaly, present in 12.74% of the affected dogs. Radiographic examination of the caudal vertebrae is recommended as an essential part of any screening process to confirm the presence of congenital anomaly as a cause of kinked tail.


Priority setting and patient adaptation to disability and illness: outcomes of a qualitative study.
The study examined the question of who should make decisions for a National Health Scheme about the allocation of health resources when the health states of beneficiaries could change because of adaptation. Eight semi-structured small group discussions were conducted. Following focus group theory, interviews commenced with general questions followed by transition questions and ended with a 'focus' or 'key' question. Participants were presented with several scenarios in which patients adapted to their health states. They were then asked their views about the appropriate role of the public, patients and health professionals in making social judgements of quality of life. After discussion and debate, all groups were asked the key question: 'In light of adaptation, who should evaluate quality of life for the purpose of setting priorities in the allocation of health care?' In all groups participants presented strong arguments for and against decision making by patients, the public and health professionals. However, most groups thought a representative body which included a range of perspectives should make the relevant judgements. This is at odds with the recommendations in most national pharmaceutical guidelines. The main conclusion of the paper is that health economists and other researchers should explore the possibility of adopting a deliberative, consensus-based approach to evaluating health-related quality of life when such judgements are to be used to inform priority setting in a public system.


Hierarchical morphological segmentation for image sequence coding.
This paper deals with a hierarchical morphological segmentation algorithm for image sequence coding. Mathematical morphology is very attractive for this purpose because it efficiently deals with geometrical features such as size, shape, contrast, or connectivity that can be considered as segmentation-oriented features. The algorithm follows a top-down procedure. It first takes into account the global information and produces a coarse segmentation, that is, with a small number of regions. Then, the segmentation quality is improved by introducing regions corresponding to more local information. The algorithm, considering sequences as being functions on a 3-D space, directly segments 3-D regions. A 3-D approach is used to get a segmentation that is stable in time and to directly solve the region correspondence problem. Each segmentation stage relies on four basic steps: simplification, marker extraction, decision, and quality estimation. The simplification removes information from the sequence to make it easier to segment. Morphological filters based on partial reconstruction are proven to be very efficient for this purpose, especially in the case of sequences. The marker extraction identifies the presence of homogeneous 3-D regions. It is based on constrained flat region labeling and morphological contrast extraction. The goal of the decision is to precisely locate the contours of regions detected by the marker extraction. This decision is performed by a modified watershed algorithm. Finally, the quality estimation concentrates on the coding residue, all the information about the 3-D regions that have not been properly segmented and therefore coded. The procedure allows the introduction of the texture and contour coding schemes within the segmentation algorithm. The coding residue is transmitted to the next segmentation stage to improve the segmentation and coding quality. Finally, segmentation and coding examples are presented to show the validity and interest of the coding approach.


Intra-axial tumors of the cervicomedullary junction: surgical results and long-term outcome.
Until recently, intra-axial brainstem tumors were traditionally regarded as surgically inaccessible lesions with a uniformly poor prognosis. However, increasing data indicate that distinct subgroups of brainstem tumors exist that are amenable to surgical intervention. To address this question, we reviewed our experience in the operative management of 39 consecutive patients, in the magnetic resonance imaging (MRI) era, with intra-axial cervicomedullary tumors, in order to determine those factors associated with long-term outcome. Thirty-nine patients (26 male, 13 female) underwent surgery by a single surgeon (F.J.E.) between 1985 and 1994. Mean age of diagnosis was 14 years (range 3 months - 60 years); mean duration of preoperative symptoms was 24 weeks (range 1-168). Twenty patients presented with lower cranial nerve dysfunction and 19 presented with motor and/or sensory dysfunction. All patients were graded according to the McCormick Scale, pre- and postoperatively, and at the time of follow-up. All patients were evaluated with MRI scanning. Twenty-three patients had either previous biopsy or subtotal resection, 13 previous radiation therapy, and 6 previous chemotherapy. The mean time to follow-up was 48 months (range 7-138). Twelve patients underwent gross total resection, 7 near total resection (>90%), 15 subtotal resection (50-90%), and 5 partial resection (< 50%). Histologically, there were 15 low-grade fibrillary astrocytomas, 9 ependymomas, 7 gangliogliomas, 3 anaplastic astrocytomas, 3 juvenile pilocytic astrocytomas, and 2 mixed gliomas. Although the vast majority of tumors were low grade histologically, a higher proportion of the patients with high-grade lesions experienced tumor progression when compared to low-grade tumors (75 vs. 30%). Overall, the 5-year progression-free and total survivals were 60 and 89%, respectively. There was 1 death within the first postoperative month. Preoperative duration of symptoms greater than 15 weeks was associated with a longer progression-free survival. There was a trend for preoperative neurologic grade to predict functional neurologic outcome at follow-up. In summary, intra-axial tumors of the cervicomedullary junction are a distinct subset of brainstem tumors, predominantly of low-grade histology, with favorable long-term progression-free and total survivals following surgical resection. A long duration of preoperative symptoms may indicate an indolent clinical course and a more favorable prognosis. Our data also indicate that early surgical intervention is warranted prior to neurologic deterioration.


[The use of highly sensitive immunoblotting for detecting the phenylalanine hydroxylase antigen in human platelets].
Incubation of nitrocellulose filters containing proteins in solutions of organic alcohols (ethanol, methanol, isopropanol) enabled to increase the immunoblotting sensitivity after denaturating electrophoresis in presence of SDS. Maximal elevation of the label sensitivity (4-6-fold) was observed after incubation of these filters in 30% isopropanol within 2 hrs. The effect of sensitivity elevation appears to be caused by the antigen renaturation due to SDS washing off. The modified procedure of immunoblotting allowed to detect phenylalanine hydroxylase antigen in human thrombocytes. The antigen had electrophoretic mobility similar to that of phenylalanine hydroxylase from liver tissue; its concentration constituted less than 0.1 microgram per 1 mg of protein in thrombocytes.


[The evolution of a contusion focus after the microsurgical autotransplantation of the omentum (an experimental study)].
The purpose of treatment of head trauma cannot be limited by simple life saving, it also should be targeted at the improvement of the quality of life. Twenty dogs with graded local head trauma underwent microsurgical revascularization of the area adjacent to the contused brain with an autologous omental graft to provide functional improvement. The effectiveness of surgery was demonstrated in series of 5 experiments when the operation was performed on posttraumatic days 7-14, with the follow-up of as long as 180 days. After the procedure, no macroscopic signs of contusion could be demonstrated. Microscopically the contused area resembled a slit two times smaller than in controls. Microscopic and histochemical studies revealed both the morphologic recovery and an improvement in cellular enzyme activity. The data obtained adds some more information regarding clinical applications of microsurgical revascularization technique.


δ-expansion method for nonlinear stochastic differential equations describing wave propagation in a random medium.
We apply the δ-expansion method to nonlinear stochastic differential equations describing wave propagation in a random medium. In particular, we focus our attention on a model describing a nonlinear wave propagating in a turbulent atmosphere which has random variations in the refractive index (we take these variations to be stochastic). The method allows us to construct much more reasonable perturbation solutions with relatively few terms (compared to standard "small-parameter" perturbation methods) due to more accurate linearization used in constructing the initial approximation. We demonstrate that the method allows one to compute effective wave numbers more precisely than other methods applied to the problem in the literature. The method also picks up on the stochastic damping of the solutions quickly, holding all of the relevant data in the initial term. These properties allow for both a qualitative and a quantitative construction of physically meaningful solutions. In particular, we show that the method allows one to retain higher-order harmonics which are hard to capture with standard perturbation methods based on small parameters.


[The presence of the corpse and semiotic effectiveness in Geoffrey Chaucer and Caïn in Mctatio Abel].
This article grapples with the question of the corpse through two particular literary texts. Rather than an elucidation of the physiological principle of the human body by means of dissection, the play Mactatio Abel, written in England in the 15th century, stages the difficulty of the relation to the corpse, via an amplification of the biblical narrative of Abel's murder by Cain. As for Chaucer's work, The Book of the Duchess, it rewrites Ovid's and Machaut's texts featuring the figure of Morpheus in a way that distinguishes between an imitation of the living and its simulacrum in the sense Wolfgang Iser gives this concept. Chaucer's Morpheus, instead of promoting verisimilitude, forbids it. Indeed, he animates a corpse from within instead of simulating an apparition of the deceased. The simulacrum, rather than a mimetic copy of the real, blocks all representational illusion, in order to formulate absence. The readability of the corpse in both works is relational. Both literary texts express the corpse as being always already grounded in a relational and narratorial space.


Health and aging in elderly farmers: the AMI cohort.
The health of the agricultural population has been previously explored, particularly in relation to the farming exposures and among professionally active individuals. However, few studies specifically focused on health and aging among elders retired from agriculture. Yet, this population faces the long-term effects of occupational exposures and multiple difficulties related to living and aging in rural area (limited access to shops, services, and practitioners). However, these difficulties may be counter-balanced by advantages related to healthier lifestyle, richer social support and better living environment. The general aim of the AMI cohort was to study health and aging in elderly farmers living in rural area through a multidisciplinary approach, with a main focus on dementia. The study initially included 1 002 participants, randomly selected from the Farmer Health Insurance rolls. Selection criteria were: being 65 years and older; living in rural area in Gironde (South-Western France); being retired from agriculture after at least 20 years of activity and being affiliated to the Health Insurance under own name. The study started in 2007, with two follow-up visits over 5 years. Baseline visits were conducted at home by a neuropsychologist then by a geriatrician for all cases suspected of dementia, Parkinson's disease and depression (to confirm the diagnosis), and by a nurse for others. A large panel of data were collected through standardised questionnaires: complete neuropsychological assessment, material and social living environment, psychological transition to retirement, lifestyle (smoking, alcohol and diet), medications, disability in daily living, sensory impairments and some clinical measures (blood pressure, depression symptomatology, anxiety, visual test, anthropometry...). A blood sampling was performed with biological measurements and constitution of a biological bank, including DNA. Brain MRI were also performed on 316 of the participants. Finally, the three-year data on health-related reimbursements were extracted from the Health System database (medications, medical and paramedical consultations, biological examinations and medical devices), and the registered Long-Term Diseases (30 chronic diseases 100% covered by the Insurance System). AMI is the first French longitudinal study on health and aging set up in a population of elderly farmers living in rural area through a multidisciplinary approach.


I'm not a diagnosis: Adolescents' perspectives on user participation and shared decision-making in mental healthcare.
Adolescents have the right to be involved in decisions affecting their healthcare. More knowledge is needed to provide quality healthcare services that is both suitable for adolescents and in line with policy. Shared decision-making has the potential to combine user participation and evidence-based treatment. Research and governmental policies emphasize shared decision-making as key for high quality mental healthcare services. To explore adolescents' experiences with user participation and shared decision-making in mental healthcare inpatient units. We carried out ten in-depth interviews with adolescents (16-18 years old) in this qualitative study. The participants were admitted to four mental healthcare inpatient clinics in Norway. Transcribed interviews were subjected to qualitative content analysis. Five themes were identified, representing the adolescents' view of gaining trust, getting help, being understood, being diagnosed and labeled, being pushed, and making a customized treatment plan. Psychoeducational information, mutual trust, and a therapeutic relationship between patients and therapists were considered prerequisites for shared decision-making. For adolescents to be labeled with a diagnosis or forced into a treatment regimen that they did not initiate or control tended to elicit strong resistance. User involvement at admission, participation in the treatment plan, individualized treatment, and collaboration among healthcare professionals were emphasized. Routines for participation and involvement of adolescents prior to inpatient admission is recommended. Shared decision-making has the potential to increase adolescents' engagement and reduce the incidence of involuntary treatment and re-admission to inpatient clinics. In this study, shared decision-making is linked to empowerment and less to standardized decision tools. To be labeled and dominated by healthcare professionals can be a barrier to adolescents' participation in treatment. We suggest placing less emphasis on diagnoses and more on individualized treatment.


Campylobacter jejuni Pericarditis: A Case Report.
Campylobacter jejuni is one of the most common causes of enteritis. In rare cases, extraintestinal infection can occur, with a handful of cases of cardiac involvement, of which the pathophysiological mechanism is unclear. We report a case of pericarditis in a patient with X-linked agammaglobulinemia presenting with chronic diarrhea and chest pain who evolved to cardiac tamponade, requiring a pericardial window and a long course of broad-spectrum antibiotics. To the best of our knowledge, this is the third case of pericarditis caused by Campylobacter jejuni reported in the literature, the second in a patient with X-linked agammaglobulinemia. Despite its rarity, this case serves as a reminder of Campylobacter as a potential cause of cardiac inflammation for clinicians treating pericarditis/myocarditis, especially in patients with a history of diarrhea or immunosuppression.


[Physiology in Russia: state, problems].
The issue of the content of physiology as science, its methods, directions of modern physiology, and its place in the system of life sciences is discussed. Structure of the system of regulations, the role of endocrine system and autacoids in particular, and physiological significance of homeostasis are analyzed in detail. Problems are considered concerning the applied significance of physiology, interaction of universities and research institutions, organization ofphysiological studies in Russia. Data on members in the regional divisions of Pavlov Physiological Society are presented.


Fast-track virtual reality software to facilitate 3-dimensional reconstruction in congenital heart disease.
Two limitations of the clinical use of 3-dimensional (3D) reconstruction and virtual reality systems are the relatively high cost and the amount of experience required to use hardware and software to effectively explore medical images. We have tried to simplify the process and validate a new tool developed for this purpose with a novel software package. Five patients with right partial anomalous pulmonary venous return with adequate preoperative images acquired with magnetic resonance imaging were enrolled. Five volunteers with no previous experience in the field of 3D reconstruction were instructed to use the software after viewing a short video tutorial. Users were then asked to create a 3D model of each patient's heart using DIVA software. Their results were compared quantitatively and qualitatively with a benchmark reconstruction performed by an experienced user. All our participants recreated 3D models in a relatively short time, maintaining a good overall quality (average quality score ≥ 3 on a scale of 1-5). The overall trend of all the parameters analysed showed a statistical improvement between case 1 and case 5, as users became more and more experienced. DIVA is a simple software program that allows accurate 3D reconstruction in a relatively short time ("fast-track" virtual reality). In this study, we demonstrated the potential use of DIVA by inexperienced users, with a significant improvement in quality and time after a few cases were performed. Further studies are needed to confirm the potential application of this technology on a larger scale.


Up-regulation of cytochrome oxidase in the retina following optic nerve injury.
The purpose of this study is to investigate the cytochrome oxidase (COX) activity in the retina and optic nerve following an optic nerve injury. The optic nerve crush of one eye was carried out in Balb/c mice. A semi-quantitative RT-PCR method was then adopted to evaluate the mRNA expression of cytochrome oxidase subunit 1 (COX1) in the retina after surgery. Up-regulation of COX1 mRNA in the retina was detected by RT-PCR at 24 hr following the optic nerve injury. Total retinal mitochondrial mass measured by fluorescent intensity of MitoTracker green was not altered following the injury. COX histochemistry performed on cryostat sections showed an elevated enzyme activity of COX in the retina and in the optic nerve. In the retina, elevation of the COX activity was observed in the retinal ganglion cell layer and the overlying nerve fibre layer. The increase of COX activity began from 24 hr after injury, peaked around day 3, and maintained up to 1 week after the operation. In the optic nerve, increase of COX activity was observed in regions distal to the crush line and distributed either randomly or in a cone shape. In conclusion, both the expression of COX1 mRNA in retina and the activity of COX in inner plexiform layer and retinal ganglion cell layer were elevated following optic nerve injury without affecting total retinal mitochondrial mass. These findings suggested that one of early responses in the retina and in the optic nerve after the optic nerve injury is to scale up the energy production.


The Meaning In Life Questionnaire: psychometric properties with individuals with serious mental illness in an inpatient setting.
This study examined the psychometric properties of the Meaning in Life Questionnaire (MLQ) with individuals with serious mental illness (SMI) in an inpatient setting (N = 96). The 10-item MLQ comprises Presence (perceived meaning) and Search (motivation to discover meaning) scales. This study focused on the reliability and validity of the MLQ, reporting a range of data, including correlations and regression (predicting scores on a measure of psychopathology, the Brief Symptom Inventory). Both MLQ scales yielded reliable scores. The current sample tended to report greater Presence, whereas Search means tended to be similar to those reported in other studies. The association between Presence and the Brief Symptom Inventory was not statistically significant. As for Search, people reporting greater motivation to discover meaning tended to report greater degrees of symptoms. The Presence and Search scales correlated at r =.12, which was unexpected given that most studies note an inverse relationship. However, this finding is considered in light of an interaction effect between Presence and Search when predicting psychological distress. The current findings are supportive of the MLQ's utility with individuals with SMI. Limitations and directions for research are offered.


Non-targeted metabolomics study for discovery of hepatocellular carcinoma serum diagnostic biomarker.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant cancers worldwide. Due to the asymptomatic features of HCC at early stages, patients are often diagnosed at advanced stages and missed effective treatment. Thus, there is an urgent need to identify sensitive and specific biomarkers for HCC early diagnosis. In the present study, an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) approach was used to profile serum metabolites from HCC patients, liver cirrhosis (LC) patients, and normal controls (NC). Univariate and multivariate statistical analyses were performed to obtain the metabolomic differences of the three groups and select significantly changed metabolites that can be used as diagnostic biomarkers. In total, 757 differential metabolites were quantified among the three groups, and pathway enrichment analysis of these metabolites indicated that glycerophospholipid metabolism, pentose and glucuronate interconversions, phenylalanine, tyrosine and tryptophan biosynthesis, and linoleic acid metabolism were the most altered pathways involved in HCC development. Receiver operating characteristic (ROC) curve analysis was performed to select and evaluate the diagnostic biomarker performance. Seven metabolites were identified as potential biomarkers that can differentiate HCC from LC and NC, and LC from NC with the good diagnostic performance of area under the curve (AUC) from 0.890 to 0.990. In summary, our findings provide highly effective biomarker candidates to differentiate HCC from LC and NC, LC, and NC, which shed insight into HCC pathological mechanisms and will be helpful in better understanding and managing HCC.


Identification of poliovirus polypeptide P63 as a soluble RNA-dependent RNA polymerase.
A poliovirus-specific RNA-dependent RNA polymerase was isolated from a cytoplasmic extract of infected HeLa cells and was shown to copurify with a single virus-specific protein. The polymerase was isolated from cells labeled with [35S]-methionine and was fractionated from other soluble cytoplasmic proteins by ammonium sulfate precipitation, phosphocellulose chromatography, gel filtration on Sephacryl S-200, and chromatography on hydroxylapatite. The activity of the enzyme was measured by using either polyadenylic acid or poliovirion RNA as a template in the presence of an oligouridylic acid primer. A single virus-specific protein that had an apparent molecular weight of 63,000 (p63) was found to copurify with this activity. Host-coded proteins were present in reduced molar amounts relative to p63. Noncapsid viral protein 2 (NCVP2) and other viral proteins were clearly separated from p63 by gel filtration on Sephacryl S-200. Polymerase activity coeluted from the column precisely with p63. NCVP2 was totally inactive as an RNA polymerase and did not stimulate the polymerase activity of p63. The purified enzyme sedimented at about 4S on a glycerol gradient and thus appeared to be a monomer of p63. Two-dimensional gel electrophoresis of the polymerase protein indicated that it had an isoelectric point of about 7.5. Thus, the viral polypeptide, p63, as defined by the above physical parameters, is an RNA-dependent RNA polymerase that can copy poliovirion RNA when oligouridylic acid is used as a primer.


Subject global evaluation and subject satisfaction using injectable poly-L-lactic acid versus human collagen for the correction of nasolabial fold wrinkles.
This is a report of the secondary endpoints, Subject Global Evaluation (overall improvement) and Subject Satisfaction scores, from a study designed to examine the efficacy of injectable poly-L-lactic acid for the correction of nasolabial fold wrinkles over 25 months. A randomized, subject-blinded, parallel-group, multicenter clinical study was conducted to compare the effects of injectable poly-L-lactic acid with those of human collagen for the treatment of nasolabial fold wrinkles at 13 months following the last treatment. Injectable poly-L-lactic acid-treated subjects were followed for 25 months. From month 3 through month 13 following the last treatment, injectable poly-L-lactic acid-treated subjects (n = 116) reported significantly higher Subject Global Evaluation scores compared with human collagen-treated subjects (n = 117; p < 0.001). Overall Subject Global Evaluation scores for injectable poly-L-lactic acid-treated subjects were 99 percent at week 3, 91 percent at month 13, and 81 percent at month 25 (all times following the last treatment). In contrast, for human collagen-treated subjects, overall Subject Global Evaluation scores declined by 84 percent, from 96 percent at week 3 to 15 percent at month 13. Subject Satisfaction scores were significantly different (p < 0.01) between treatment groups beginning week 3 and continuing through month 13. Overall Subject Satisfaction scores were maintained for over 80 percent of injectable poly-l-lactic acid-treated subjects (n = 106) at month 25 after the last treatment. Treatment of nasolabial fold wrinkles with injectable poly-l-lactic acid resulted in statistically significantly higher Subject Global Evaluation and Subject Satisfaction scores compared with human collagen at 13 months. Injectable poly-l-lactic acid-treated subjects maintained improvements for up to 25 months after treatment.


Drug-induced subacute cutaneous lupus erythematosus: a paradigm for bedside-to-bench patient-oriented translational clinical investigation.
At least 71 patients have been reported in which their otherwise typical subacute cutaneous lupus erythematosus (SCLE) skin lesions were felt to have been temporally associated with the systemic administration of a drug. The mean age of this cohort of drug-induced SCLE (DI-SCLE) patients was 59 years of age which is somewhat older than the mean age of previously reported idiopathic SCLE patient cohorts. Patients had been taking the suspected triggering drug for weeks to years before the onset of SCLE skin lesions. In addition, it was not unusual for 2-3 months to be required for resolution of the SCLE skin lesions following discontinuation of the triggering drug. A relatively large number of drugs representing different pharmacological classes have been implicated in the induction of SCLE. The drug classes that were more frequently encountered were those used for the treatment of cardiovascular disease, especially hypertension. Calcium channel blockers were especially common in this regard. Elderly individuals being treated for hypertension are often taking multiple classes of drugs that have been implicated in triggering SCLE (thiazide diuretics, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, beta-blockers). An approach to the management of DI-SCLE is presented. Ro/SS-A autoantibodies tended to remain present in the blood after resolution of drug-induced SCLE skin lesions. A common link between the disparate group of drug structures implicated in triggering SCLE is their tendencies to produce photosensitivity and lichenoid drug reactions. This leads to the speculation that DI-SCLE could represent a photo-induced isomorphic/Köebner response in an immunogenetically predisposed host.


BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.
There is a clear association between germ-line BRCA1 mutations and inherited ovarian cancer; however, the association between BRCA1 mutations and sporadic ovarian cancer remains ambiguous. The frequency of BRCA1 promoter hypermethylation as an epigenetic means of BRCA1 inactivation was determined for a large, population-based cohort of ovarian cancer patients. BRCA1 promoter hypermethylation was determined by methylation-specific restriction digestion of tumor DNA, followed by Southern blot analysis and confirmed by methylation-specific PCR. BRCA1 promoter hypermethylation was observed in 12 of 98 ovarian tumors. BRCA1 methylation status of the primary tumor was conserved in six recurrent tumors after interim chemotherapy. None of the 12 tumors with BRCA1 promoter hypermethylation demonstrated BRCA1 protein expression by immunohistochemistry. BRCA1 methylation was only seen in ovarian cancer patients without a family history suggestive of a breast/ ovarian cancer syndrome. Therefore, the 12 BRCA1 methylated tumors represented 15% (12 of 81) of the sporadic cancers analyzed in this study. Although the clinical significance of BRCA1 promoter hypermethylation is yet to be determined, promoter hypermethylation may be an alternative to mutation in causing the inactivation of the BRCA1 tumor suppressor gene in sporadic ovarian cancer.


Fine-tuning solid-state luminescence in NPIs (1,8-naphthalimides): impact of the molecular environment and cumulative interactions.
An investigation of a series of seven angular "V" shaped NPIs (1-7) is presented. The effect of substitution of these structurally similar NPIs on their photophysical properties in the solution-state and the solid-state is presented and discussed in light of experimental and computational findings. Compounds 1-7 show negligible to intensely strong emission yields in their solid-state depending on the nature of substituents appended to the oxoaryl moiety. The solution and solid-state properties of the compounds can be directly correlated with their structural rigidity, nature of substituents and intermolecular interactions. The versatile solid-state structures of the NPI siblings are deeply affected by the pendant substituents. All of the NPIs (1-7) show antiparallel dimeric π-π stacking interactions in their solid-state which can further extend in a parallel, alternate, orthogonal or lateral fashion depending on the steric and electronic nature of the C-4' substituents. Structural investigations including Hirshfeld surface analysis methods reveal that where strongly interacting systems show weak to moderate emission in their condensed states, weakly interacting systems show strong emission yields under the same conditions. The nature of packing and extended structures also affects the emission colors of the NPIs in their solid-states. Furthermore, DFT computational studies were utilized to understand the molecular and cumulative electronic behaviors of the NPIs. The comprehensive studies provide insight into the condensed-state luminescence of aggregation-prone small molecules like NPIs and help to correlate the structure-property relationships.


Drug-Eluting Resorbable Scaffold versus Angioplasty for Infrapopliteal Artery Disease.
Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown. In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death. The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group. Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.).


Kinesthetic vs. visual focus: No evidence for effects of practice modality in representation types after action imagery practice and action execution practice.
Action-imagery practice (AIP) is assumed to result in partly different action representations than action-execution practice (AEP). The present study investigated whether focusing on either kinesthetic or visual aspects of a task during practice amplifies or diminishes such differences between AIP and AEP. In ten sessions, four groups, using either AIP or AEP with either kinesthetic or visual focus, practiced a twelve-element sequence in a unimanual serial reaction time task. Tests involved the practice sequence, a mirror sequence, and a different sequence, each performed with the practice and transfer hand. In AIP and AEP, in both hands, reaction times (RTs) were shorter in the practice sequence than in the different sequence, indicating effector-independent visual-spatial sequence representations. Further, RTs were shorter in the practice hand than in the transfer hand in the practice sequence (but not in the different sequence), indicating effector-dependent representations in AEP and AIP. Although the representation types did not differ, learning effects were stronger in AEP than in AIP. Thus, although to a lower extent than in AEP, effector-dependent representations can be acquired using AIP. Contrary to the expectations, the focus manipulation did not have an impact on the acquired representation types. Hence, modality instructions in AIP may not have such a strong impact as commonly assumed, at least in implicit sequence learning.


Structure-based thermodynamic scale of alpha-helix propensities in amino acids.
A structural parameterization of the folding energetics has been used to predict the effect of single amino acid mutations at exposed locations in alpha-helices. The results have been used to derive a structure-based thermodynamic scale of alpha-helix propensities for amino acids. The structure-based thermodynamic analysis was performed for four different systems for which structural and experimental thermodynamic data are available: T4 lysozyme [Blaber et al (1994) J. Mol. Biol.235, 600-624], barnase [Horovitz et al. (1992) J.Mol.Biol.227,560-568], a synthetic leucine zipper [O'Neil & Degrado (1990) Science 250, 646-651], and a synthetic peptide [Lyu et al. (1990) Science 250, 669-673]. These studies have permitted the optimization of the set of solvent-accessible surface areas (ASA) for all amino acids in the unfolded state. It is shown that a single set of structure/thermodynamic parameters accounts well for all the experimental data sets of helix propensities. For T4 lysozyme, the average value of the absolute difference between predicted and experimental delta G values is 0.09 kcal/mol, for barnase 0.14 kcal/mol, for the synthetic coiled-coil 0.11 kcal/mol, and for the synthetic peptide 0.08 kcal/mol. In addition, this approach predicts well the overall stability of the proteins and rationalizes the differences in alpha-helix propensities between amino acids. The excellent agreement observed between predicted and experimental delta G values for all amino acids validates the use of this structural parameterization in free energy calculations for folding or binding.


Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.
Mutations in the human Cu,Zn superoxide dismutase gene (SOD1) are found in 20% of kindreds with familial amyotrophic lateral sclerosis. Transgenic mice (line G1H) expressing a human SOD1 containing a mutation of Gly-93 --> Ala (G93A) develop a motor neuron disease similar to familial amyotrophic lateral sclerosis, but transgenic mice (line N1029) expressing a wild-type human SOD1 transgene do not. Because neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of amyotrophic lateral sclerosis, we asked whether mutant G1H and/or N1029 mice develop similar NF lesions. NF inclusions (i.e., spheroids, Lewy body-like inclusions) were first detected in spinal cord motor neurons of the G1H mice at 82 days of age about the time these mice first showed clinical evidence of disease. Other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulated in these spheroids. The onset of accumulations of ubiquitin immunoreactivity in the G1H mice paralleled the emergence of vacuoles and NF-rich spheroids in neurons, but they did not colocalize exclusively with spheroids. In contrast, NF inclusions were not seen in the N1029 mice until they were 132 days old, and ubiquitin immunoreactivity was not increased in the N1029 mice even at 199 days of age. Astrocytosis in spinal cord was associated with a marked increase in glial fibrillary acidic protein immunoreactivity in the G1H mice, but not in the N1029 mice. Finally, comparative studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis. These findings link a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with amyotrophic lateral sclerosis. Thus, neuronal cytoskeletal abnormalities may be implicated in the pathogenesis of human familial amyotrophic lateral sclerosis.