[Morphologic changes in the chorio-allantoic membrane and organs of chick embryos inoculated with blood of patients with systemic lupus erythematosus (concerning the viral etiology of systemic lupus erythematosus)].
Morphological studies of 14 chorionallantoic membranes and organs of chick embryos which had been infected on the 7--8th day of incubation with leucocytic mass from patients with systemic lupus erythematosus were carried out. Corresponding virological and morphological control studies were performed. The changes observed were repeatedly reproduced in multiple inoculations (from the 2nd to the 16th passage). Apart from morphological changes, which may be listed among general pathological processes (impairment of the circulation, dystrophy, proliferation), changes testifying to a possible cytopathic effect disintegration of nuclei, formation of gigantic cells and multinuclear symplasts were also noted. The most pronounced changes, both in the chorionallantoic membrane and in internal organs, were observed on the 3rd--5th passage and on the 3rd--5th day of incubation following inoculation. They correlated with the clinical activity of the process in patients from whom the blood for inoculation had been taken. The data obtained justify the assumption concerning the existence in the blood of the patients with systemic lupus erythematosus a transplantable agent producing a cytopathic action, and may be considered as a new indirect corroborative evidence in favour of the concept of the viral nature of systemic lupus erythematosus.


Regulatory and scientific roles for biodistribution studies in aquatic species.
The advantage of focusing on biliary excretion of drugs and other xenobiotics is emphasized in this discussion of the regulatory and scientific roles for biodistribution studies in aquatic species. The role of the hepatobiliary system in the overall disposition of absorbed chemicals is briefly reviewed. The present survey includes 18 drugs, 6 petroleum hydrocarbons, and 16 different fish species. The fact that aquatic species concentrate most xenobiotics and their metabolites into bile to as much as several orders of magnitude underscores the advantage of using bile rather than tissue to determine whether aquatic species are being exposed to given chemicals. Until these advantages are recognized, analysis of edible muscle tissue remains the method of choice for assessment of human exposure to chemicals.


In vivo monitoring of the recruitment and activation of AP-1 by Arf1.
AP-1 is a clathrin adaptor recruited to the trans-Golgi Network where it can interact with specific signals found in the cytosolic tail of cargo proteins to incorporate them into clathrin-coated vesicles for trafficking. The small G protein Arf1 regulates the spatiotemporal recruitment of AP-1 and also drives a conformational change favoring an interaction with cargo proteins. A recent crystal structure and in vitro experiments highlighted potential residues mediating the AP-1/Arf1 interaction and the unlocking of the complex. We have used bioluminescence resonance energy transfer (BRET) to study the Arf1/AP-1 interaction and AP-1 conformational changes in vivo. We identified novel residues required for this interaction in addition to those predicted in the crystal structure. We also studied the conformational changes in AP-1 driven by Arf1 in live cells and found that opening of the complex is prerequisite for oligomerization. Using Arf1 knockout cells generated by CRISPR/Cas9, we demonstrated that residue 172 in Arf1 is necessary for AP-1 activation and is required for the efficient sorting of the lysosomal protein prosaposin. We have used BRET to study the in vivo activation of AP-1. The advantages of BRET include expressing full-length proteins in their native environment that have been fully post-translationally modified.


Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design.
Contemporary antiretroviral therapy (ART) is effective and tolerable for long periods of time but cannot eradicate human immunodeficiency virus type 1 (HIV-1) infection by either elimination of viral reservoirs or enhancement of HIV-1-specific immune responses. Boosting "protective" HIV-1-specific immune responses by active or passive immunization will therefore be necessary to control or eradicate HIV-1 infection and is currently the topic of intense investigation. Recently reported studies conducted in HIV patients and non-human primate (NHP) models of HIV-1 infection suggest that HIV-1-specific IgG antibody responses may contribute to the control of HIV-1 infection. However, production of IgG antibodies with virus neutralizing activity by vaccination remains problematic and while vaccine-induced natural killer cell-activating IgG antibodies have been shown to prevent the acquisition of HIV-1 infection, they may not be sufficient to control or eradicate established HIV-1 infection. It is, therefore, important to consider other functional characteristics of IgG antibody responses. IgG antibodies to viruses also mediate opsonophagocytic antibody responses against virions and capsids that enhance the function of phagocytic cells playing critical roles in antiviral immune responses, particularly conventional dendritic cells and plasmacytoid dendritic cells. Emerging evidence suggests that these antibody functions might contribute to the control of HIV-1 infection. In addition, IgG antibodies contribute to the intracellular degradation of viruses via binding to the cytosolic fragment crystallizable (Fc) receptor tripartite motif containing-21 (TRIM21). The functional activity of an IgG antibody response is influenced by the IgG subclass content, which affects binding to antigens and to Fcγ receptors on phagocytic cells and to TRIM21. The IgG subclass content and avidity of IgG antibodies is determined by germinal center (GC) reactions in follicles of lymphoid tissue. As HIV-1 infects cells in GCs and induces GC dysfunction, which may persist during ART, strategies for boosting HIV-1-specific IgG antibody responses should include early commencement of ART and possibly the use of particular antiretroviral drugs to optimize drug levels in lymphoid follicles. Finally, enhancing particular functions of HIV-1-specific IgG antibody responses by using adjuvants or cytokines to modulate the IgG subclass content of the antibody response might be investigated in NHP models of HIV-1 infection and during trials of therapeutic vaccines in HIV patients.


Language aptitude in the visuospatial modality: L2 British Sign Language acquisition and cognitive skills in British Sign Language-English interpreting students.
Sign language interpreting (SLI) is a cognitively challenging task performed mostly by second language learners (i.e., not raised using a sign language as a home language). SLI students must first gain language fluency in a new visuospatial modality and then move between spoken and signed modalities as they interpret. As a result, many students plateau before reaching working fluency, and SLI training program drop-out rates are high. However, we know little about the requisite skills to become a successful interpreter: the few existing studies investigating SLI aptitude in terms of linguistic and cognitive skills lack baseline measures. Here we report a 3-year exploratory longitudinal skills assessments study with British Sign Language (BSL)-English SLI students at two universities (n = 33). Our aims were two-fold: first, to better understand the prerequisite skills that lead to successful SLI outcomes; second, to better understand how signing and interpreting skills impact other aspects of cognition. A battery of tasks was completed at four time points to assess skills, including but not limited to: multimodal and unimodal working memory, 2-dimensional and 3-dimensional mental rotation (MR), and English comprehension. Dependent measures were BSL and SLI course grades, BSL reproduction tests, and consecutive SLI tasks. Results reveal that initial BSL proficiency and 2D-MR were associated with selection for the degree program, while visuospatial working memory was linked to continuing with the program. 3D-MR improved throughout the degree, alongside some limited gains in auditory, visuospatial, and multimodal working memory tasks. Visuospatial working memory and MR were the skills closest associated with BSL and SLI outcomes, particularly those tasks involving sign language production, thus, highlighting the importance of cognition related to the visuospatial modality. These preliminary data will inform SLI training programs, from applicant selection to curriculum design.


Epidural analgesia diminished pain but did not otherwise improve enhanced recovery after laparoscopic sigmoidectomy: a prospective randomized study.
The primary hypothesis for this study was that epidural analgesia reduces the use of opioids and thus advances bowel function and oral intake and shortens hospital stay after laparoscopic sigmoidectomy performed according to principles of enhanced recovery after surgery. For this study, 60 patients with complicated diverticular disease were randomized to the epidural anesthesia group or the control group before surgery. Postoperative oxycodone consumption, pain, and recovery parameters were followed for 14 days. The epidural group needed less oxycodone than the control group until 12 h postoperatively. They experienced significantly less pain related to coughing and motion until postoperative day 2. In the epidural group, fewer patients experienced significant pain, and the duration of postoperative pain was shorter. Postoperative oral intake, bowel function, hospital stay, and overall complication rate were similar in the two groups. However, the control group had more postoperative hematomas. Epidural analgesia significantly alleviates pain, reducing the need for opioids during the first 48 h after laparoscopic sigmoidectomy. However, epidural analgesia does not alter postoperative oral intake, mobilization, or length of hospital stay.


Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.
Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.


Biomarker-Guided Non-Adaptive Trial Designs in Phase II and Phase III: A Methodological Review.
Biomarker-guided treatment is a rapidly developing area of medicine, where treatment choice is personalised according to one or more of an individual's biomarker measurements. A number of biomarker-guided trial designs have been proposed in the past decade, including both adaptive and non-adaptive trial designs which test the effectiveness of a biomarker-guided approach to treatment with the aim of improving patient health. A better understanding of them is needed as challenges occur both in terms of trial design and analysis. We have undertaken a comprehensive literature review based on an in-depth search strategy with a view to providing the research community with clarity in definition, methodology and terminology of the various biomarker-guided trial designs (both adaptive and non-adaptive designs) from a total of 211 included papers. In the present paper, we focus on non-adaptive biomarker-guided trial designs for which we have identified five distinct main types mentioned in 100 papers. We have graphically displayed each non-adaptive trial design and provided an in-depth overview of their key characteristics. Substantial variability has been observed in terms of how trial designs are described and particularly in the terminology used by different authors. Our comprehensive review provides guidance for those designing biomarker-guided trials.


Global trend analysis of diabetes mellitus incidence, mortality, and mortality-to-incidence ratio from 1990 to 2019.
Diabetes Mellitus (DM) is a common chronic disease and a public health challenge worldwide. The present study aimed to analyze the trend in DM incidence, mortality, and mortality-to-incidence ratio (MIR) world over 30 years. The age-standardized DM incidence and mortality rates for both genders and different countries of the world from 1990 to 2019 were extracted from the Global Burden of Disease (GBD) study and the Human Development Index (HDI) was obtained for all countries from the United Nations Development Program (UNDP) database. The mean trends for the indicators for developing countries, developed countries, and all countries were evaluated using Generalized Estimating Equations (GEE) and the spline model. The estimates showed that the global mean trend of DM incidence from 1990 to 2019 followed an upward trend with an annual increase of 3.73 cases per 100,000 people. The global mean of DM mortality followed an upward trend with an annual increase of 0.43 cases until 2005 followed by a downward trend after this year with an annual decrease of 0.14 and the global mean MIR followed a downward trend during the same period with an annual decrease of 0.001 per 100,000 people. Besides, the mean incidence of DM in developing countries followed an upward trend similar to the trend in developed countries. Additionally, the mean mortality rate due to DM in developing countries increased with a slope of 0.62 until 2005 and then decreased with a slope of 0.02, and the mean MIR trend in the developed and developing countries showed a downward trend. Thus, developed countries followed a relatively faster decrease in MIR than developing countries.The data from the present study show the increased incidence of DM has made it one of the most important health concerns in the world, and if this issue is not addressed, this disease can cause more concerns for communities in the coming years. This being so, more DM prevention and control programs need to be put into practice.


MR imaging of CNS involvement in children affected by chronic liver disease.
MR imaging sheds new light on CNS involvement in the course of acquired chronic liver disease; however, the exact pathogenetic mechanisms of hepatic encephalopathy and associated MR abnormalities remain unclear. Our purpose was to relate MR signal intensity abnormalities of the CNS to clinical, biochemical, and pathologic features of childhood-onset chronic liver disease. Twenty-one patients (12 male and nine female patients) were included in the study; two had Crigler-Najjar disease type 2, 17 had chronic liver disease of different causes, and two had idiopathic copper toxicosis. Twelve patients had histologically proved liver cirrhosis, with a median disease duration of 175 months at the time of MR study. None had clinical symptoms of hepatic encephalopathy. MR imaging was performed using spin-echo T1- and T2-weighted sequences. Eleven patients had abnormal MR imaging findings of the brain revealed by T1-weighted MR sequences; two of the 11 had idiopathic copper toxicosis. The affected sites were the hypothalamus and globus pallidus, presenting symmetrical and bilateral high signal intensities, or the pituitary gland, which appeared homogeneously hyperintense, or both findings. Eight of the 12 patients with cirrhosis had abnormal MR signals of the brain. In these, the median cirrhosis duration was shorter (169 months) than in the remaining four patients with normal MR signals (177 months). A significant correlation was found between abnormal MR signals of the brain and cirrhosis (P = .008) and factor V activity (P = .008). MR imaging confirms the presence of abnormal brain signals in the globus pallidus, hypothalamus, and pituitary gland in patients with childhood-onset liver disease in the absence of clinical symptoms of encephalopathy. Signal intensity abnormalities are likely caused by an as yet unidentified metabolic process partially correlated with the severity of liver disease.


Neuropathology of H5N1 virus infection in ferrets.
Highly pathogenic H5N1 virus remains a potential threat to humans. Over 289 fatalities have been reported in WHO confirmed human cases since 2003, and lack of effective vaccines and early treatments contribute to increasing numbers of cases and fatalities. H5N1 encephalitis is a recognized cause of death in Vietnamese cases, and brain pathology is described in other human cases and naturally infected animals. However, neither pathogenesis of H5N1 viral infection in human brain nor post-infection effects in survivors have been fully investigated. We report the brain pathology in a ferret model for active infection and 18-day survival stages. This model closely resembles the infection pattern and progression in human cases of influenza A, and our report is the first description of brain pathology for longer term (18-day) survival in ferrets. We analyzed viral replication, type and severity of meningoencephalitis, infected cell types, and cellular responses to infection. We found viral replication to very high titers in ferret brain, closely correlating with severity of meningoencephalitis. Viral antigens were detected predominantly in neurons, correlating with inflammatory lesions, and less frequently in astrocytes and ependymal cells during active infection. Mononuclear cell infiltrates were observed in early stages predominantly in cerebral cortex, brainstem, and leptomeninges, and less commonly in cerebellum and other areas. Astrogliosis was mild at day 4 post-infection, but robust by day 18. Early and continuous treatment with an antiviral agent (peramivir) inhibited virus production to non-detectable levels, reduced severity of brain injury, and promoted higher survival rates.


[Reversion induction in phage T4 mutants in Escherichia coli strains with defective RNA polymerase].
The reversion induction in mutants of phage T4 under the effect of base analogues in RNA-polymerase Escherichia coli mutants is studied. In double mutant E. coli rif-r stl-r strain phage T4 mutates several times more frequently than in the parental strain of E. coli RFS-522, containing an intact enzyme.


[Roles of human cytochrome P450 enzymes involved in drug metabolism and toxicological studies].
Multiple forms of cytochrome P450 (P450 or CYP) enzymes play important roles in the oxidation of structurally diverse xenobiotics and endobiotics. Interindividual variations in the level and activity of P450 enzymes were investigated in the human liver microsomes. Although the total P450 content was higher in Caucasian samples than in Japanese ones, the relative levels (percentage of total P450) of individual forms of P450 determined immunochemically were not very different. CYP3A (about 30% of total P450) and CYP2C (about 20%) enzymes were major forms. Different P450 enzymes in the human liver play major roles in a variety of drug oxidations and the hepatic contents of these P450 forms could be affective to determine which P450 enzymes play major roles in drug metabolism in individual humans. Recently recombinant P450 enzymes from different sources, e.g., microsomes of human lymphoblastoid cells, of yeast, and insect cells infected with baculovirus systems, and Escherichia coli membranes containing coexpressed P450 and reductase, have been widely used for drug metabolism research. However, the marker activities or kinetic parameters of human P450 enzymes reported are not always similar. Cytochrome b5 can enhance the activities of recombinant P450 systems in some cases using different mechanisms. These differences in activities may be a critical factor for understanding the roles of human P450 enzymes involved in drug metabolism. This review provides useful information for the study of drug biotransformation in humans and for the basis of drug toxicities and carcinogenesis.


Challenge of dogs with live enterotoxigenic Escherichia coli and effects of repeated challenges on fluid secretion in jejunal Thiry-Vella loops.
Dogs were evaluated as experimental models for the study of diarrheal disease produced by enterotoxigenic Escherichia coli. Although a suitable whole model for orogastric bacterial challenge could not be developed, chronic jejunal Thiry-Vella loops were used to study the secretory effects of multiple jejunal challenges with enterotoxin of either Vibrio cholerae or E. coli. The heat-stable and heat-labile E. coli enterotoxins could be differentiated clearly in this model. Sequential weekly challenges over a four-week period showed a significant decrease in loop secretory response to homologous enterotoxin, although levels of antitoxin in serum remained unchanged, a finding suggesting a local immune response. Dogs challenged with E. coli enterotoxin were markedly protected against subsequent challenge with V. cholerae enterotoxin; the converse was not true. Histologic studies of the loops showed only minimal atrophy, and results of absorption studies in the loops were normal. These studies suggest that mongrel dogs are resistant to colonization by enterotoxigenic E. coli and partially resistant to challenge with enterotoxin, perhaps on an immune basis due to prior antigenic exposure. Multiple challenges with enterotoxin effect a decreased secretory response; this finding also suggests a local immune mechanism.


A patent review of bisphosphonates in treating bone disease.
Bisphosphonates (BPs) are widely used to manage a variety of bone disorders, including osteoporosis, metastatic bone disease and myeloma bone disease. The nitrogen-containing BPs (NBPs) target osteoclast activity by disrupting protein prenylation via inhibition of farnesyl diphosphate synthase (FDPS). This review summarizes the recent advances in BPs with a focus on the latest patents (2015-2018). Patents involving novel BPs, new modes of BP delivery, as well as use of BPs to deliver other drugs to bone are discussed. A review of phosphonate-based drugs targeting geranylgeranyl diphosphate synthase (GGDPS) or geranylgeranyl transferase II (GGTase II) as alternative strategies to disrupt protein geranylgeranylation is provided. While the NBPs remain the mainstay of treatment for most bone disorders, further understanding of their pharmacological properties could lead to further refinement of their chemical structures and optimization of efficacy and safety profiles. In addition, the development of NBP analogs or drug delivery mechanisms that allow for nonbone tissue exposure could allow for the use of these drugs as direct anticancer agents. The development of GGDPS and GGTase II inhibitors represents alternative heterocycle phosphonate-based strategies to disrupt protein geranylgeranylation and may have potential as anticancer agents and/or as bone-targeted therapies.


Linked vaccine adverse event data from VAERS for biomedical data analysis and longitudinal studies.
Vaccines have been one of the most successful public health interventions to date. The use of vaccination, however, sometimes comes with possible adverse events. The U.S. FDA/CDC Vaccine Adverse Event Reporting System (VAERS) currently contains more than 200,000 reports for post-vaccination events that occur after the administration of vaccines licensed in the United States. Although the data from the VAERS has been applied to many public health and vaccine safety studies, each individual report does not necessarily indicate a casuality relationship between the vaccine and the reported symptoms. Further statistical analysis and summarization needs to be done before this data can be leveraged. This paper introduces our efforts on representing the vaccine-symptom correlations and their corresponding meta-information extracted from the VAERS database using Resource Description Framework (RDF). Numbers of occurrences of vaccine-symptom pairs reported to the VAERS were summarized with corresponding proportional reporting ratios (PRR) calculated. All the data was stored in an RDF file. We then applied network analysis approaches to the RDF data to illustrate a use case of the data for longititual studies. We further dicussed our vision on integrating the data with vaccine information from other sources using RDF linked approach to facilitate more comprehensive analyses. The 1990-2013 data from VAERS has been extracted from the VAERS database. There are 83,148 unique vaccine-symptom pairs with 75 vaccine types and 5,865 different reported symptoms. The yearly and over PRR values for each reported vaccine-symptom pair were calculated. The network properties of networks consisting of significant vaccine-symptom associations (i.e., PRR larger than 1) were then investigated. The results indicated that vaccine-symptom association network is a dense network, with any given node connected to all other nodes through an average of approximately two other nodes and a maximum of five nodes.


Solvent exposures and Parkinson disease risk in twins.
Several case reports have linked solvent exposure to Parkinson disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design. Ninety-nine twin pairs discordant for PD ascertained from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job task-specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status. Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (odds ratio [OR], 6.1; 95% confidence interval [CI] 1.2-33; p = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl(4) ) tended toward significance (respectively: OR, 10.5; 95% CI, 0.97-113; p = 0.053; OR, 2.3; 95% CI, 0.9-6.1; p = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure. Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl(4) are also ubiquitous in the environment. Our findings require replication in other populations with well-characterized exposures, but the potential public health implications are substantial.


A Randomised Controlled Trial of Evidence Based Supported Employment for People Who have Recently been Homeless and have a Mental Illness.
Individual placement and support (IPS) has not been tested experimentally among people recently housed with a scattered-site Housing First program. Ninety recently housed people were randomized to IPS or usual services. Regression models estimated via GEE were used to compare employment outcomes. Over 8 months of follow-up with good fidelity, fifteen (34 %) people in the IPS group versus nine (22 %) in the control group found competitive employment (p = 0.16). Adjusted odds of obtaining competitive employment were greater in the IPS group (OR 2.42, 95 %CI 1.13-5.16). Other employment outcomes were not significantly different between groups. Satisfaction with services was greater in the group receiving IPS. In this study, IPS was a modestly useful adjunct to scattered-site Housing First for people with mental illness who have been homeless.


Liver disease in the immunocompromised patient.
This chapter reviews the most common diseases of the liver that are associated immunodeficiencies resulting from AIDS, chemotherapy and radiation, and bone marrow and solid organ transplantation. Conditions described include liver disease, infection, venoocclusive disease, graft versus host disease, and others.


Epidemiology of rotavirus diarrhea in the Highlands of Papua, New Guinea, in 1979, as revealed by electrophoresis of genome RNA.
Results of gel electrophoresis of rotavirus genome RNA from feces of children in two provinces in Papua, New Guinea, suggest that the epidemiology of rotavirus infection in small communities with a total population of 3,000 may differ from that in urban or closely settled rural areas.


Genome-wide identification of the Pinus tabuliformis CONSTANS-like gene family and their potential roles in reproductive cone development.
The CONSTANS-like (COL) genes, as a core transcription factor in the photoperiod regulation pathway, play a key role in plant reproduction development. However, their molecular characterization has rarely been studied in Pinus tabuliformis. Here, 10 PtCOL genes were identified in the P. tabuliformis genome and multiple sequence alignments have indicated that the PtCOL proteins contained highly conserved B-BOX1 and CCT domains. Sequence similarity analysis showed that PtCOL1 and PtCOL3 had the higher similarity with Norway spruce COLs (PaCOL2 and PaCOL1) and Arabidopsis COLs (AtCOL3, 4 and 5), respectively. Phylogeny and gene structure analyses revealed that PtCOLs were divided into three subgroups, each with identical or similar distributions of exons, introns, and motifs. Moreover, 10 PtCOLs were distributed on 6 chromosomes and PtCOL9 has syntenic gene pairs in both Ginkgo biloba and Sequoiadendron giganteum. Interestingly, in transcriptome profiles, most PtCOLs exhibited a diurnal oscillation pattern under both long (LD) and short (SD) day conditions. Additionally, PtCOLs were highly expressed in needles and female cones, and showed different spatial expression patterns. Among the ten PtCOLs, PtCOL1/3 heterologous overexpression Arabidopsis displayed a delayed-flowering phenotype under SD, indicating that they are likely to play a crucial role in the reproductive development. Additionally, PtCOL1 and PtCOL3 were not only capable of interacting with each other, but they were each capable of interacting with themselves. Furthermore, PtCOL1 and PtCOL3 were also involved in the MADS-box protein-protein interaction (PPI) network in P. tabuliformis cone development. Direct interactions of PtDAL11 with PtCOL1/3 impeded PtCOL1/3 translocation into the nucleus. In summary, this study provided comprehensive understanding for the functions of the PtCOL gene family and revealed their biological roles in the photoperiod-dependent P. tabuliformis cone development.


Dysregulation of Angiogenesis and Inflammatory Genes in Endometrial Mesenchymal Stem Cells and Their Contribution to Endometriosis.
Endometriosis is a common, chronic, inflammatory disorder in women, characterized by the presence of endometrial tissue outside the uterus cavity. The disease affects ~10% of women during their reproductive age. There is some debates on the pathogenesis of endometriosis and its mechanism among the scientists; therefore, different hypotheses have been suggested. According to Sampson theory, a possible mechanism for seeding ectopic endometriotic lesions is a dysregulation of endometrial mesenchymal stem cells (eMSCs). In the present study, we evaluated the expression of candidate genes in eMSCs obtained from endometriosis patients and compared them with non-endometriosis female patients. In addition, a bioinformatic analysis was conducted to uncover the genes in the list of our co-expression gene network in endometriosis. According to our results, the expression of vascular endothelial growth factor A, C-X-C-motif chemokine ligand 8, interleukin-6, and intercellular adhesion molecule-1 genes were up-regulated in the eMSCs isolated from endometriosis patients. There was no significant difference in the expression of the LaminB1 gene between the endometriosis and non-endometriosis patients. On the other hand, our bioinformatics analysis demonstrated that co-expressed genes were enriched in the cytokine signalling pathway. Our study provides valuable insights into the gene expression dysregulation in eMSCs derived from endometriosis patients and suggests a possible function for co-expressed networks in the pathogenesis of endometriosis. To confirm the results, more investigations are required.


Lameness in Early Lactation Is Associated with Lower Productive and Reproductive Performance in a Herd of Supplemented Grazing Dairy Cows.
The main aim of this study was to assess the associations between the timing of lameness clinical case occurrence in lactation with productive and reproductive performances in grazing Holstein cows. A cohort study was carried out on a dataset with records from a commercial dairy herd (Buenos Aires, Argentina) for cows that calved and were dried off from January 2010 through June 2017. The first recorded event of lameness per lactation was considered for the study. Criteria for lactation inclusion included not having uterine diseases, mastitis, or anovulatory cysts during the studied risk period (i.e., up to 200 DIM). Therefore, a total of 7156 out of 20,086 lactations were included in the statistical analysis. The association between lameness case occurrence in lactation (cows not lame (LG0) vs. lame cows between parturition and first service (LG1) vs. lame cows between first service and first pregnancy (LG2)) with productive (i.e., accumulated milk yield to 150 DIM (MILK150) and 300 DIM (MILK305)) and reproductive performances (hazard of insemination and pregnancy) was analyzed with linear regression models and proportional hazard regression models, respectively. Lame cows produced 161 and 183 kg less MILK150 and MILK305 than non-lame herd mates, respectively. Moreover, LG1 cows produced 216 kg less MILK150 and 200 kg less MILK305 than LG0 cows, and LG2 cows also produced 58 kg less MILK150 and 158 kg less MILK305 than LG0 cows. The LG1 cows had a lower hazard of service than LG0 cows (HR = 0.43, 95%CI = 0.39-0.47). Furthermore, LG1 cows had a lower hazard of pregnancy than LG0 cows (HR = 0.52, 95%CI = 0.46-0.59) and took longer to get pregnant than LG0 cows (median [95%CI], 139 [132-144] vs. 101 [99-103]). Moreover, LG2 cows had a much lower hazard of pregnancy than LG0 cows (HR = 0.08, 95%CI = 0.05-0.12) and much longer calving to first pregnancy interval than LG0 cows (188 [183-196] vs. 101 [99-103]). In conclusion, cows that become lame in early lactation produce less milk and have lower hazards of insemination and pregnancy than herd mates that are healthy or become lame later in lactation. In addition, cows that become lame immediately after the voluntarily waiting period have the poorest reproductive performance (i.e., they have the lowest hazard of pregnancy and the longest calving to pregnancy interval).


Genetic Ancestry using Mitochondrial DNA in patients with Triple-negative breast cancer (GAMiT study).
Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P<.0001). Eight patients were BRCA1/2 mutation carriers. There were no differences noted among groups with regard to surgery, lymph node metastases, or survival. Analysis revealed Nigerian, Cameroon, or Sierra Leone ancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry). Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society.


Regulatory mechanism of smooth muscle contraction studied with gelsolin-treated strips of taenia caeci in guinea pig.
The potential roles of the regulatory proteins actin, tropomyosin (Tm), and caldesmon (CaD), i.e., the components of the thin filament, in smooth muscle have been extensively studied in several types of smooth muscles. However, controversy remains on the putative physiological significance of these proteins. In this study, we intended to determine the functional roles of Tm and CaD in the regulation of smooth muscle contraction by using a reconstitution system of the thin filaments. At appropriate conditions, the thin (actin) filaments within skinned smooth muscle strips of taenia caeci in guinea pigs could be selectively removed by an actin-severing protein, gelsolin, without irreversible damage to the contractile apparatus, and then the thin filaments were reconstituted with purified components of thin filaments, i.e., actin, Tm, and CaD. We found that the structural remodeling of actin filaments or thin filaments was functionally linked to the Ca(2+)-induced force development and reduction in muscle cross-sectional area (CSA). That is, after the reconstitution of the gelsolin-treated skinned smooth muscle strips with pure actin, the Ca(2+)-dependent force development was partially restored, but the Ca(2+)-induced reduction in CSA occurred once. In contrast, the reconstitution with actin, followed by Tm and CaD, restored not only the force generation but also both its Ca(2+) sensitivity and the reversible Ca(2+)-dependent reduction in CSA. We confirmed that both removal of the thin filaments by gelsolin treatment and reconstitution of the actin (thin) filaments with Tm and CaD caused no significant changes in the level of myosin regulatory light chain phosphorylation. We thus conclude that Tm and CaD are necessary for the full regulation of smooth muscle contraction in addition to the other regulatory systems, including the myosin-linked one.


The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study.
We sought to evaluate the value of the extent of microvascular damage as assessed with myocardial contrast echocardiography (MCE) in the prediction of left ventricular (LV) remodeling after ST-segment elevation myocardial infarction (STEMI) as compared with established clinical and angiographic parameters of reperfusion. Early identification of post-percutaneous coronary intervention microvascular dysfunction may help in tailoring appropriate pharmacological interventions in high-risk patients. The ideal method to establish effective microvascular reperfusion after percutaneous coronary intervention remains to be determined. A total of 110 patients with first successfully reperfused STEMI were enrolled in the AMICI (Acute Myocardial Infarction Contrast Imaging) multicenter study. After reperfusion, peak creatine kinase, ST-segment reduction, and Thrombolysis In Myocardial Infarction (TIMI) and myocardial blush grade were calculated. We evaluated perfusion defects with MCE by using continuous infusion of Sonovue (Bracco, Milan, Italy) in real-time imaging. The endocardial length of contrast defect (CD) on day 1 after reperfusion was calculated. Wall motion score index, the extent of wall motion abnormalities, LV end-diastolic volume, and ejection fraction after reperfusion and at follow-up also were calculated. Of 110 patients, 25% evolved in LV remodeling and 75% did not. Although peak creatine kinase, ST-segment reduction >70%, and myocardial blush grade were not different between groups, in patients exhibiting LV remodeling, TIMI flow grade 3 was less frequent (p < 0.001), wall motion score index was greater (p < 0.001), and CD was greater (p < 0.001). At multivariate analysis, only TIMI flow grade <3 and CD with a cutoff of >25% were independently associated with LV remodeling. Among patients with TIMI flow grade 3, CD was the only independent variable associated with LV remodeling. Among patients with TIMI flow grade 3, the extent of microvascular damage, detected and quantitated by MCE, is the most powerful independent predictor of LV remodeling after STEMI as compared with persistent ST-segment elevation and myocardial blush grade.


Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas.
In zebrafish, Müller glia (MG) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision1. In mammals, however, MG do not spontaneously re-enter the cell cycle to generate a population of stem or progenitor cells that differentiate into retinal neurons. Nevertheless, the regenerative machinery may exist in the mammalian retina, as retinal injury can stimulate MG proliferation followed by limited neurogenesis2-7. Therefore, there is still a fundamental question regarding whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas8. Here we report that following gene transfer of β-catenin, cell-cycle-reactivated MG can be reprogrammed to generate rod photoreceptors by subsequent gene transfer of transcription factors essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1rd17Gnat2cpfl3 double mutant mice, a model of congenital blindness9,10, throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas.


TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells.
Recent studies have revealed that murine bone marrow-derived cultured mast cells (BMMC), which are phenotypically immature mast cells, express functional TLR2 and TLR4 that recognize distinct pathogen-associated molecules. However, it remains relatively uncertain whether mast cells express other TLR. We recently established a method to obtain large numbers of murine fetal skin-derived cultured mast cells (FSMC); these cells exhibit important features of connective tissue type mast cells. Working with FSMC and BMMC, the TLR mRNA expression profiles were compared between both cell types. Although TLR2 and TLR4 mRNA were detected in both cells at comparable levels, TLR3, TLR7, and TLR9 mRNA were expressed by FSMC at higher levels than by BMMC, suggesting distinct TLR expression profiles among different mast cell populations. With respect to their functional aspects, FSMC, but not BMMC, dose dependently produced proinflammatory cytokines (TNF-alpha and IL-6) and chemokines (RANTES, MIP-1alpha, and MIP-2) in response to poly(I:C), R-848, and CpG oligodeoxynucleotide, which are TLR3, TLR7, and TLR9 activators, respectively. Interestingly, these TLR activators failed to induce degranulation and IL-13 production by both mast cells, although peptidoglycan and LPS (TLR2 and TLR4 activators, respectively) induced IL-13 production by both cells. Mast cells, thus, may have potential to recruit other immune cells to the infected sites by responding to various bacterial and viral components through TLR signaling pathways, presumably being involved in initiating innate immunity and subsequently linking innate and acquired immune responses.


Comprehensive analysis of the expression of the metastasis-associated gene 1 in human neoplastic tissue.
The metastasis-associated gene 1 (MTA1) is overexpressed in several human cancers. Recent reports suggest that MTA1 may play a role in cancer progression either through transcription repression and/or hormone receptor interactions. To analyze MTA1 expression levels in a wide variety of human tumors. We used Oncomine, an Internet-based compendium of expression array data, to query more than 90 expression array studies, and we evaluated tissue microarrays composed of more than 3200 samples representing 138 different localized neoplasms. Both analyses show that MTA1 is ubiquitously expressed in benign and malignant tumors. The highest levels of MTA1 expression were observed in diffuse B-cell lymphoma (mean staining intensity, 3.9/4), basal cell carcinomas (3.7/4), and consistently in tumors of neuroendocrine descent such as paraganglioma (3.7/4) and carcinoid tumor (3.1/4). This study characterizes MTA1 expression for the first time across a broad spectrum of primary tumors, demonstrating expression in both benign and malignant neoplasms in addition to showing an association with neuroendocrine differentiation. We also found evidence that MTA1 expression is associated with tissue invasion but may not be sufficient for the progression to metastatic stages.


A Bibliographic Analysis of the Most Cited Articles in Global Neurosurgery.
Global neurosurgery is the practice of neurosurgery with the primary purpose of delivering timely, safe, and affordable neurosurgical care to all who need it. The aim of this study is to identify the most frequently cited articles in global neurosurgery through a bibliographic review to characterize articles and trends around this growing topic. The top most-cited articles in global neurosurgery were determined by searching the Web of Science database using a priori search terms. Articles with at least 5 citations were selected, and there were no time period or language restrictions. The data were extracted from each included article and all characteristics were summarized. A total of 932 articles were identified using the search terms; 69 articles fulfilled inclusion criteria and 17 articles were selected that had more than 5 citations. The articles' number of citations ranged from 6 to 98 for the most-cited article. Authors from, or affiliated with, 14 countries contributed to the 17 articles, and the country that had the greatest representation was the United States. The main topic discussed was surgical capacity, the second topic was the treatment of different neurosurgical conditions, and volunteerism was the third topic. There is currently a deficit in both the amount of literature surrounding the topic of global neurosurgery and how much that literature is cited. Developing innovative ways to increase academic productivity within, or in collaboration with, low-middle income countries is essential to contribute to global neurosurgery.


Epidemiological patterns of hepatitis B virus (HBV) in highly endemic areas.
This paper uses meta-analysis of published data and a deterministic mathematical model of hepatitis B virus (HBV) transmission to describe the patterns of HBV infection in high endemicity areas. We describe the association between the prevalence of carriers and a simple measure of the rate of infection, the age at which half the population have been infected (A50), and assess the contribution of horizontal and perinatal transmission to this association. We found that the two main hyper-endemic areas of sub-Saharan Africa and east Asia have similar prevalences of carriers and values of A50, and that there is a negative nonlinear relationship between A50 and the prevalence of carriers in high endemicity areas (Spearman's Rank, P = 0.0086). We quantified the risk of perinatal transmission and the age-dependent of infection to allow a comparison between the main hyper-endemic areas. East Asia was found to have higher prevalences of HBeAg positive mothers and a greater risk of perinatal transmission from HBeAg positive mothers than sub-Saharan Africa, though the differences were not statistically significant. However, the two areas have similar magnitudes and age-dependent rates of horizontal transmission. Results of a simple compartmental model suggest that similar rates of horizontal transmission are sufficient to generate the similar patterns between A50 and the prevalences of carriers. Interrupting horizontal transmission by mass immunization is expected to have a significant, nonlinear impact on the rate of acquisition of new carriers.


Effects of a program of intervention on parental distress following infant death.
A longitudinal study of 144 parents (65 fathers, 79 mothers) was conducted to evaluate the effectiveness of a program of intervention in relieving the psychological distress of parents affected by infant death. Participants were assessed in terms of their psychiatric disturbance, depression, anxiety, physical symptoms, dyadic adjustment, and coping strategies. The experimental group (n = 84) was offered an intervention program comprising the use of specially designed resources and contact with a trained grief worker. A control group (n = 60) was given routine community care. Parental reactions were assessed at four to six weeks postloss (prior to the implementation of the intervention program), at six months postloss, and at 15 months postloss. A series of multivariate analyses of variance revealed that the intervention was effective in reducing the distress of parents, particularly those assessed prior to the intervention as being at high-risk of developing mourning difficulties. Effects of the intervention were noted in terms of parents' overall psychiatric disturbance, marital quality, and paternal coping strategies.


Congenital malformations at birth--a prospective study from south India.
Congenital malformations were studied prospectively from September 1989 to December 1992 covering 12,797 consecutive deliveries. The overall incidence of malformations was 3.7% and it was 3.2% among live births and 15.7% among still births. Three hundred and ninety seven birth defects were observed among 308 live births and 72 among 45 still births. The incidence of malformation was significantly higher among male babies (p < 0.001), still births (p < 0.001), low birth weights (p < 0.001) and preterm babies (p < 0.001). Consanguinity among parents of malformed babies was more common (p < 0.001). Musculo-skeletal malformations were the commonest (9.69 per 1000) followed by cutaneous (6.33 per 1000), genitourinary (5.47 per 1000), gastrointestinal (5.47 per 1000), central nervous system (3.99 per 1000) and cardiac anomalies (2.03 per 1000). Musculoskeletal, cutaneous and genitourinary malformations were common among live born babies while central nervous system and gastrointestinal defects were common among still born babies. Antenatal infections and ingestion of drugs were not found to be significant factors in the causation of birth defects.


Interobserver Variability in Applying American Society of Echocardiography/European Association of Cardiovascular Imaging 2016 Guidelines for Estimation of Left Ventricular Filling Pressure.
Assessment of left ventricular (LV) filling pressure is among the important components of a comprehensive echocardiographic report. Previous studies noted wide limits of agreement using 2009 American Society of Echocardiography/European Association of Echocardiography guidelines, but reproducibility of 2016 guidelines update in estimating LV filling pressure is unknown. Echocardiographic and hemodynamic data were obtained from 50 patients undergoing cardiac catheterization for clinical indications. Clinical and echocardiographic findings but not invasive hemodynamics were provided to 4 groups of observers, including experienced echocardiographers and cardiology fellows. Invasively acquired LV filling pressure was the gold standard. In group I of 8 experienced echocardiographers from the guidelines writing committee, sensitivity for elevated LV filling pressure was 92% for all observers, and specificity was 93±6%. Fleiss κ-value for the agreement in group I was 0.80. In group II of 4 fellows in training, sensitivity was 91±2%, and specificity was 95±2%. Fleiss κ-value for the agreement in group II was 0.94. In group III of 9 experienced echocardiographers who had not participated in drafting the guidelines, sensitivity was 88±5%, and specificity was 91±7%. Fleiss κ-value for the agreement in group III was 0.76. In group IV of 7 other fellows, sensitivity was 91±3%, and specificity was 92±5%. Fleiss κ-value for the agreement in group IV was 0.89. There is a good level of agreement and accuracy in the estimation of LV filling pressure using the American Society of Echocardiography/European Association of Cardiovascular Imaging 2016 recommendations update, irrespective of the experience level of the observer.


Air embolism during anaesthesia for arthography in a child.
An infant aged 5 months, weighing 6 kg and suffering from congenital dislocation of the hip joint, was subjected to air arthrography of the right hip joint under general anaesthesia. Air embolism occurred following injection of air into the joint. The clinical management is described. Resuscitation was successfully accomplished and the patient was discharged from hospital without untoward sequelae.


Environmental Source Tracking of Per- and Polyfluoroalkyl Substances within a Forensic Context: Current and Future Techniques.
The source tracking of per- and polyfluoroalkyl substances (PFASs) is a new and increasingly necessary subfield within environmental forensics. We define PFAS source tracking as the accurate characterization and differentiation of multiple sources contributing to PFAS contamination in the environment. PFAS source tracking should employ analytical measurements, multivariate analyses, and an understanding of PFAS fate and transport within the framework of a conceptual site model. Converging lines of evidence used to differentiate PFAS sources include: identification of PFASs strongly associated with unique sources; the ratios of PFAS homologues, classes, and isomers at a contaminated site; and a site's hydrogeochemical conditions. As the field of PFAS source tracking progresses, the development of new PFAS analytical standards and the wider availability of high-resolution mass spectral data will enhance currently available analytical capabilities. In addition, multivariate computational tools, including unsupervised (i.e., exploratory) and supervised (i.e., predictive) machine learning techniques, may lead to novel insights that define a targeted list of PFASs that will be useful for environmental PFAS source tracking. In this Perspective, we identify the current tools available and principal developments necessary to enable greater confidence in environmental source tracking to identify and apportion PFAS sources.


Endovascular therapy followed by stereotactic radiosurgery for cerebral arteriovenous malformations.
Pre-radiosurgical embolization was carried out using cyanoacrylate in seven of 13 patients with cerebral arteriovenous malformations (AVMs) treated by stereotactic radiosurgery (SRS) with a linear accelerator (LINAC). The aim of embolization before SRS was the reduction of AVM volume and/or the elimination of vascular structures bearing an increased risk of haemorrhage. Staged-volume SRS was also performed in two patients because of residual irregular shaped nidus of AVMs even after the embolizations. Complete obliteration of the AVM nidus on angiogram was presented in five patients with embolizations (including one with staged-volume SRS) and in three of six patients with SRS alone, during follow-up periods after radiosurgery. No patients experienced haemorrhagic events after SRS. Although transient neurological symptoms were observed after embolizations in two patients, no permanent neurological deficits were presented in all patients with SRS. Pre-radiosurgical embolization may allow the effective influence on irradiation therapy in relatively large AVMs and promote more frequent obliteration in more small sized AVMs compared to those with SRS alone. However, further study must be needed to determine whether staged-volume SRS provides a high rate of AVM obliteration and its safeness.


Effects of various suspending media on plaque formation by rickettsiae in tissue culture.
Effects of some media used for suspending rickettsiae during purification, for metabolic studies, and in titrations of infectious rickettsiae were examined with respect to the plaque-forming ability of Rickettsia rickettsi and R. typhi in primary chicken embryo tissue cultures and the infectivity of R. typhi in mice. Brain heart infusion broth (BHI) was found superior to all other media tested in preventing both a significant decrease in plaque-forming units (PFU) and a delay in plaque formation. Skim milk, egg yolk, and some metabolic media were effective in maintaining PFU at 0 C, but did not prevent a significant delay in plaque formation. However, infectivity of R. typhi for tissue culture and mice was markedly decreased when suspended in metabolic media at 26 C. Addition of BHI to the routine tissue culture overlay reversed the deleterious effects of sucrose-phosphate solutions. The effects of Mg(2+), Mn(2+), K(+), Na(+), sucrose, and glutamate were also examined. No significant differences were observed between R. rickettsi and R. typhi in their responses to different media. The results of this study suggest the necessity for a reappraisal of previous studies of metabolism and infectivity of rickettsiae in these media.


Ionoprinted Multi-Responsive Hydrogel Actuators.
We report multi-responsive and double-folding bilayer hydrogel sheet actuators, whose directional bending response is tuned by modulating the solvent quality and temperature and where locally crosslinked regions, induced by ionoprinting, enable the actuators to invert their bending axis. The sheets are made multi-responsive by combining two stimuli responsive gels that incur opposing and complementary swelling and shrinking responses to the same stimulus. The lower critical solution temperature (LCST) can be tuned to specific temperatures depending on the EtOH concentration, enabling the actuators to change direction isothermally. Higher EtOH concentrations cause upper critical solution temperature (UCST) behavior in the poly(N-isopropylacrylamide) (pNIPAAm) gel networks, which can induce an amplifying effect during bilayer bending. External ionoprints reliably and repeatedly invert the gel bilayer bending axis between water and EtOH. Placing the ionoprint at the gel/gel interface can lead to opposite shape conformations, but with no clear trend in the bending behavior. We hypothesize that this is due to the ionoprint passing through the neutral axis of the bilayer during shrinking in hot water. Finally, we demonstrate the ability of the actuators to achieve shapes unique to the specific external conditions towards developing more responsive and adaptive soft actuator devices.


The chemotherapeutic agent doxorubicin induces brain senescence, with modulation by APOE genotype.
Many cancer patients experience serious cognitive problems related to their treatment, which can greatly affect their quality of life. The molecular mechanisms of this cancer chemotherapy-induced cognitive impairment (CICI) are unknown, thus slowing the development of preventative approaches. We hypothesized that cancer chemotherapies could induce cellular senescence in the brain, creating a pro-inflammatory environment and damaging normal brain communication. We tested this hypothesis using the common chemotherapeutic agent doxorubicin in two independent mouse models. In the first model, we used mice that express tdTomato under the pdkn2a (p16) promoter; p16 is a regulator of cellular senescence, and its upregulation is denoted by the presence of fluorescently tagged cells. Two weeks after exposure to three doses of 5 mg/kg doxorubicin, the number of tdTomato positive cells were increased nearly three-fold in both the cerebral cortex and the hippocampus. tdTomato staining co-localized with neurons, microglia, oligodendrocyte precursor cells, and endothelial cells, but not astrocytes. In the second model, we used APOE knock-in mice, since the APOE4 allele is a risk factor for CICI in humans and mouse models. We isolated RNA from the cerebral cortex of APOE3 and APOE4 mice from one to 21 days after a single dose of 10 mg/kg doxorubicin. Using NanoString analysis of over 700 genes related to neuroinflammation and RT-qPCR analysis of cerebral cortex transcripts, we found two-fold induction of four senescence-related genes at three weeks in the APOE4 mice compared to the APOE3 control mice: p21(cdkn1a), p16, Gadd45a, and Egr1. We conclude that doxorubicin promotes cellular senescence pathways in the brain, supporting the hypothesis that drugs to eliminate senescent cells could be useful in preventing CICI.


[Study of the dynamics of endogenous IL-6 in the culture erythroblastic islands].
It is found that in the process of cultivating the erythroblastic islets (EI) of rat bone marrow, the concentration of interleukin-6 (IL-6) increases in the culture medium. Stimulating erythropoiesis was observed on the 48th hour in cultures, the stimulation was characterized by the growth of endogenous erythropoietin and activation of formation of EI de novo and de repeto. The continuing increase in the concentration of IL-6 in the cultures at the 72nd hour of the experiment was accompanied by a decrease formation of islands de novo and a decrease in the absolute number of EI in culture.


Acquired progressive kinking of the hair: clinical features, pathological study, and follow-up of 7 patients.
Acquired progressive kinking of the hair (APKH) is a relatively rare condition, with fewer than 20 cases reported in the literature. Whether APKH is a separate entity or a variety of androgenetic alopecia is still controversial. This study reviews the clinical and pathological features and long-term follow-up of 7 patients with APKH. Since January 1989, we have diagnosed APKH in 7 males aged 15 to 22 years. All patients had strong family history for androgenetic alopecia. Hair kinking affected the frontotemporal region and/or the vertex where the hair appeared curly, frizzy, and lusterless. The pathological features of the affected scalp were consistent with the diagnosis of the early stages of androgenetic alopecia. In all patients, APKH evolved into androgenetic alopecia during the follow-up period. Mean follow-up was 4.5 years (range, 2-9 years). Treatment with topical minoxidil did not prevent development of hair thinning in the scalp areas affected by hair kinking. The term acquired progressive kinking of the hair encompasses a number of conditions characterized by acquired curling of the scalp hair. Acquired hair kinking on the androgen-dependent areas of the scalp represents a modality of onset of androgenetic alopecia associated with poor prognosis.


[Borrelia infections of the skin--progress of knowledge since the discovery of Lyme disease].
The description of Lyme disease in 1976 and the detection of its causative agent, the spirochete Borrelia burgdorferi (B. burgdorferi), in 1982 led to an increase in our knowledge of the course of B. burgdorferi infection and its clinical manifestations. The classic tick-borne dermatoses erythema chronicum migrans (ECM), lymphadenosis benigna cutis (LABC) and acrodermatitis chronica atrophicans (ACA) were proven by isolation of the spirochete from skin lesions to be caused by B. burgdorferi infection. In early disease (less than 1 year) ECM and LABC can develop locally at the site of infection (stage I), but both these skin manifestations can also occur together with multiple lesions after dissemination of the causative organism (stage II). ACA is typical for late infection (greater than 1 year, stage III). High titres of B. burgdorferi antibodies have been found in patients with localized sclerodermalike lesions (circumscribed scleroderma, lichen sclerosus et atrophicus, anetoderma), and frequent simultaneous occurrence of ACA suggests an association with late B. burgdorferi infection. Similarly, we found four cases of cutaneous B-cell lymphoma possibly arising from LABC in association with the same markers of late B. burgdorferi infection. Additionally, some cases of Schönlein-Henoch purpura and of Shulman syndrome may be associated with Lyme borreliosis. The disease is endemic in central Europe, and almost exclusively ticks of the Ixodes ricinus complex seem to transmit B. burgdorferi to humans, whereas the reservoir of infection seem to be rodents, especially mice. The main diagnostic tool is serological examination for B. burgdorferi antibodies, which will become detectable 3-6 weeks after infection. Enzyme-linked immunosorbent assay (ELISA) and the indirect immunofluorescence test (IFT) revealed similar sensitivity. In early disease, sensitivity for antibody detection could be improved by immunoblot technique and by flagellum-ELISA, which is specific for this early sensitizing B. burgdorferi antigen. For treatments, penicillin is no longer recommended as the drug of first choice, because low sensitivity of B. burgdorferi has been observed in vitro and in vivo. Tetracycline, doxycycline and amoxicillin p.o. are now preferred for the treatment of Lyme borreliosis, and in neurologic and cardiac abnormalities ceftriaxone i.v. is recommended. Treatment duration should be 14 days in early disease and 30 days in late disease.


[Specific response to benzo(a)pyrene treatment depending on mode of administration in rats].
Mathematical and statistical procedures were used to identify individual response in rats to benzo(a)pyrene (BP) treatment versus dose and regimen (single or repeated administration). Primary experimental data were suitably processed to exclude extreme values. A significant correlation was established between life-span and urine level of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (7,8-BP) after BP administration. It was found that, with single administration regimen, individual response to the carcinogenic agent correlated primarily with efficiency of excretion of the active forms of BP while in chronic experiment--with deactivation of the agent by enzymes.


Benefits of Adhering to the Canadian Physical Activity Guidelines for Adults with Multiple Sclerosis Beyond Aerobic Fitness and Strength.
The Canadian Physical Activity Guidelines for Adults with Multiple Sclerosis (PAGs) were released in 2013 but have yet to be validated. We aimed to test the effectiveness of the PAGs in improving fitness, mobility, fatigue symptoms, and quality of life (QOL) in a large cohort of adults with multiple sclerosis (MS). As part of an ongoing randomized controlled trial examining implementation of the PAGs, participants were randomized to either a direct referral group (physician referral to an exercise program following the PAGs; n = 42) or a control group (provided a print copy of the PAGs; n = 37). Physical activity behavior was assessed through weekly physical activity logs. Fitness, mobility, fatigue symptoms, and QOL were assessed at baseline and after 16 weeks. Participants were categorized as either PAG adherers (n = 30) or nonadherers (n = 49) to the PAGs based on achieving the weekly exercise recommendations at least 75% of the time. Adherence to the PAGs was twice as high in the referral group compared with the control group. Adherers experienced significantly greater improvements in peak oxygen consumption (29%), strength (7%-18%), mobility (16%), fatigue symptoms (-36%), and QOL (17%-22%) compared with nonadherers (P < .05). Following the PAGs for at least 12 of 16 weeks results in improvements in fitness, mobility, fatigue symptoms, and QOL, confirming their effectiveness for improving health in people with MS.


Analysis of the mobilization functions of the vancomycin resistance transposon Tn1549, a member of a new family of conjugative elements.
Conjugative transfer from Clostridium symbiosum to enterococci of Tn1549, which confers VanB-type vancomycin resistance, has been reported. This indicates the presence of a transfer origin (oriT) in the element. Transcription analysis of Tn1549 indicated that orf29, orf28, orfz, and orf27 were cotranscribed. A pACYC184 derivative containing 250 bp intergenic to orf29-orf30 of Tn1549 was mobilized in Escherichia coli recA::RP4::Delta nic provided that orf28 and orf29 were delivered simultaneously. These open reading frame (ORF) genes were able to promote mobilization in trans, but a cis-acting preference was observed. On the basis of a mobilization assay, a minimal 28-bp oriT was delimited, although the frequency of transfer was significantly reduced compared to that of a 130-bp oriT fragment. The minimal oriT contained an inverted repeat and a core, which was homologous to the cleavage sequence found in certain Gram-positive rolling-circle replicating (RCR) plasmids. While Orf29 was a mobilization accessory component similar to MobC proteins, Orf28 was identified as a relaxase belonging to a new phyletic cluster of the MOB(p) superfamily. The nick site was identified within oriT by an oligonucleotide cleavage assay. Closely related oriTs linked to mobilization genes were detected in data banks; they were found in various integrative and conjugative elements (ICEs) originating mainly from anaerobes. These results support the notion that Tn1549 is a member of a MOB(p) clade. Interestingly, the Tn1549-derived constructs were mobilized by RP4 in E. coli, suggesting that a relaxosome resulting from DNA cleavage by Orf28 interacted with the coupling protein TraG. This demonstrates the capacity of Tn1549 to be mobilized by a heterologous transfer system.


DanteR: an extensible R-based tool for quantitative analysis of -omics data.
The size and complex nature of mass spectrometry-based proteomics datasets motivate development of specialized software for statistical data analysis and exploration. We present DanteR, a graphical R package that features extensive statistical and diagnostic functions for quantitative proteomics data analysis, including normalization, imputation, hypothesis testing, interactive visualization and peptide-to-protein rollup. More importantly, users can easily extend the existing functionality by including their own algorithms under the Add-On tab. DanteR and its associated user guide are available for download free of charge at http://omics.pnl.gov/software/. We have an updated binary source for the DanteR package up on our website together with a vignettes document. For Windows, a single click automatically installs DanteR along with the R programming environment. For Linux and Mac OS X, users must install R and then follow instructions on the DanteR website for package installation. firstname.lastname@example.com.


Pelamis: experience from concept to connection.
The development of the Pelamis wave energy converter from its conceptual origins to its commercial deployment is reviewed. The early emphasis on designing for survivability and favourable power absorption characteristics focused attention towards a self-referenced articulated line-absorber in an attenuator orientation. A novel joint and control system allow the machine to be actively tuned to provide a resonant response power amplification in small and moderate seas. In severe seas, the machine is left in its default or natural condition, which is benign and non-resonant. Hydraulic rams at the joints provide the primary power take-off with medium-term storage in high-pressure accumulators yielding smooth electricity generation. Land-based modular construction requiring minimal weather windows for rapid offshore installation is an essential engineering feature necessary for viable commercialization. The second-generation Pelamis designs built for E.ON and ScottishPower Renewables are presented, and the scope for further cost reduction and performance enhancements are explained.


Formative evaluation of standardized training for CT colonographic image interpretation by novice readers.
To introduce an educational intervention-specifically, a specialized training course-and perform a formative evaluation of the effect of the intervention on novice reader interpretation of computed tomography (CT) colonographic data. The study was institutional review board approved. Ten normal and 50 abnormal cases, those of 60 patients with 93 polyps-61 polyps 6-9 mm in diameter and 32 polyps 10 mm or larger-were selected from a previously published trial. Seven novice readers underwent initial training that consisted of a 1-day course, reading assignments, a self-study computer module (with 61 limited data sets), observation of an expert interpreting three cases, and full interpretation of 10 cases with unblinding after each case. After training, the observers independently interpreted 60 cases by means of primary two-dimensional reading with unblinding after each case. For each case, the reading time and the location and maximal diameter of the polyp(s) were recorded. A t test was used to evaluate the observers' improvements, and empirical receiver operating characteristic (ROC) curves were constructed. By-patient sensitivities and specificities were determined for each observer. The lowest by-patient sensitivity at the 6 mm or larger polyp threshold was 86%, with 90% specificity. Four observers had 100% by-patient sensitivity at the 10 mm or larger polyp threshold, with 82%-97% specificity. For polyps 10 mm or larger, mean sensitivity and specificity were 98% and 92%, respectively. For the last 20 cases, the average interpretation time per case was 25 minutes. The range of areas under the ROC curve across observers was low: 0.86-0.95. In the described polyp-enriched cohort, novice CT colonographic data readers achieved high sensitivity and good specificity at formative evaluation of a comprehensive training program. Use of a similar comprehensive training method might reduce interreader variability in interpretation accuracy and be useful for reader certification.


Phylogenetic analysis of kindlins suggests subfunctionalization of an ancestral unduplicated kindlin into three paralogs in vertebrates.
Kindlin proteins represent a newly discovered family of evolutionarily conserved FERM domain-containing proteins. This family includes three highly conserved proteins: Kindlin-1, Kindlin-2 and Kindlin-3. All three Kindlin proteins are associated with focal adhesions and are involved in integrin activation. The FERM domain of each Kindlin is bipartite and plays a key role in integrin activation. We herein explore for the first time the evolutionary history of these proteins. The phylogeny of the Kindlins suggests a single ancestral Kindlin protein present in even the earliest metazoan ie, hydra. This protein then underwent duplication events in insects and also experienced genome duplication in vertebrates, leading to the Kindlin family. A comparative study of the Kindlin paralogs showed that Kindlin-2 is the slowest evolving protein among the three family members. The analysis of synonymous and non-synonymous substitutions in orthologous Kindlin sequences in different species showed that all three Kindlins have been evolving under the influence of purifying selection. The expression pattern of Kindlins along with phylogenetic studies supports the subfunctionalization model of gene duplication.


Mammalian twisted gastrulation is essential for skeleto-lymphogenesis.
Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.


Structure and expression of human fibroblast growth factor-10.
We isolated the cDNA encoding a novel member of the human fibroblast growth factor (FGF) family from the lung. The cDNA encodes a protein of 208 amino acids with high sequence homology (95.6%) to rat FGF-10, indicating that the protein is human FGF-10. Human FGF-10 as well as rat FGF-10 has a hydrophobic amino terminus ( approximately 40 amino acids), which may serve as a signal sequence. The apparent evolutionary relationships of human FGFs indicate that FGF-10 is closest to FGF-7. Chromosomal localization of the human FGF-10 gene was examined by in situ hybridization. The gene was found to map to the 5p12-p13 region. Human FGF-10 (amino acids 40 to 208 with a methionine residue at the amino terminus) was produced in Escherichia coli and purified from the cell lysate. Recombinant human FGF-10 (approximately 19 kDa) showed mitogenic activity for fetal rat keratinizing epidermal cells, but essentially no activity for NIH/3T3 cells, fibroblasts. The specificity of mitogenic activity of FGF-10 is similar to that of FGF-7 but distinct from that of bFGF. In structure and biological activity, FGF-10 is similar to FGF-7.


Deep annotation of Populus trichocarpa microRNAs from diverse tissue sets.
Populus trichocarpa is an important woody model organism whose entire genome has been sequenced. This resource has facilitated the annotation of microRNAs (miRNAs), which are short non-coding RNAs with critical regulatory functions. However, despite their developmental importance, P. trichocarpa miRNAs have yet to be annotated from numerous important tissues. Here we significantly expand the breadth of tissue sampling and sequencing depth for miRNA annotation in P. trichocarpa using high-throughput smallRNA (sRNA) sequencing. miRNA annotation was performed using three individual next-generation sRNA sequencing runs from separate leaves, xylem, and mechanically treated xylem, as well as a fourth run using a pooled sample containing vegetative apices, male flowers, female flowers, female apical buds, and male apical and lateral buds. A total of 276 miRNAs were identified from these datasets, including 155 previously unannotated miRNAs, most of which are P. trichocarpa specific. Importantly, we identified several xylem-enriched miRNAs predicted to target genes known to be important in secondary growth, including the critical reaction wood enzyme xyloglucan endo-transglycosylase/hydrolase and vascular-related transcription factors. This study provides a thorough genome-wide annotation of miRNAs in P. trichocarpa through deep sRNA sequencing from diverse tissue sets. Our data significantly expands the P. trichocarpa miRNA repertoire, which will facilitate a broad range of research in this major model system.


Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire.
To assess the determinants and responsiveness of the Norwegian version of the Child Health Questionnaire (CHQ) in patients with early juvenile idiopathic arthritis (JIA) and to compare health status in patients and controls. A total of 116 children (median age 8.4 yrs) with JIA and < 2.5 years of disease duration (median 11.0 mo) were examined by a pediatric rheumatologist and reassessed after a median of 10.0 months. Physical and psychosocial health were assessed by means of the CHQ, which provides summary scores for physical and psychosocial health, the Childhood Health Assessment Questionnaire (CHAQ), and the Child Behavior Checklist (CBCL, n = 32). Matched controls (n = 116), randomly selected from the general population, completed the CHQ at baseline. The patients with JIA had poorer physical health and slightly impaired psychosocial health compared with the controls [41.2 +/- 13.6 vs 55.2 +/- 7.3 (p < 0.001) and 51.0 +/- 7.5 vs 54.1 +/- 5.7 (p = 0.002), respectively]. The most important determinants of the CHQ physical summary score were the child's pain, morning stiffness, the CHAQ disability index, erythrocyte sedimentation rate (ESR), overall well-being, and physician's global assessment of disease activity. The psychosocial summary score correlated with the CBCL level of internalizing, externalizing, and total behavior problems. The standardized response mean for the physical summary score was large (0.96) for those who improved, and moderate (-0.60) for those who became worse. The CHQ discriminated between patients with early JIA and controls. The most important determinants of the CHQ physical summary score were the child's pain, morning stiffness, CHAQ, ESR, overall well-being, and physician's global assessment of disease activity. The CHQ was sensitive to clinical changes in children with JIA.


Safety and Efficacy of Bipolar Versus Monopolar Transurethral Resection of the Prostate: A Comparative Study.
Transurethral resection of the prostate (TURP) is considered gold standard for surgical treatment of benign prostatic hyperplasia (BPH). In this study, we aimed to compare post-operative clinical outcomes and adverse effects between monopolar and bipolar TURPs. The study included 590 patients who underwent TURP by a single urologist (E.H.) between June 2006 and June 2014 with a diagnosis of BPH. Patients were divided into two groups as monopolar TURP (group 1, n = 300) and bipolar TURP (group 2, n = 290). Patients receiving oral anticoagulants or aspirin and those with prostate cancer diagnosis were not included in the study. Data regarding pre-operative age, International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), post voiding residual urine volume (PVR), serum prostate specific antigen (PSA) levels and prostate volume (Vp) of the patients were gathered from medical records. Groups were compared in terms of catheterization, operation time, hemoglobin (Hb) decrease, and IPSS, Qmax, and PVR values at post-operative 12th month follow-up visit. From pre-operative to post-operative period, IPSS, Qmax and PVR showed significant improvements within both groups (P < .001). When groups were compared with each other, bipolar TURP group had significantly lesser catheterization time and hemoglobin decrease than monopolar TURP group, while no significant differences were detected regarding all other variables. Bipolar and monopolar TURPs are both effective and safe treatment modality for BPH. Bipolar TURP is superior to conventional monopolar TURP in terms of catheterization time and Hb decrease.


New candidates in the differential diagnosis of malignant mesothelioma from benign mesothelial hyperplasia and adenocarcinoma; DARS2 and suprabasin.
Malignant mesothelioma (MM) is a primary malignant tumour with a very bad prognosis, which develops from the mesothelial cells lining the serosal surfaces. Because MM can show a wide variety of histological patterns and its cytomorphological features are quite extensive, it is often confused with lung adenocarcinomas (LAC) and reactive mesothelial hyperplasia (RMH). The immunohistochemical examination method is the most useful method for discrimination. In this study, we aimed to determine the value of suprabasin and DARS2 markers in the differential diagnosis of RMH, MM and LAC. Thirty MM, 30 LAC and 30 RMH samples selected from the archive of Fırat University Hospital Pathology Department Laboratory were included in this study. Suprabasin and DARS2 markers were applied to the samples immunohistochemically and their place in the differential diagnosis was examined. Although DARS2 expression was observed in RMH, MM and adenocarcinoma samples, Suprabasin expression was only observed in adenocarcinoma. There was a significant difference between the groups in terms of DARS2 and Suprabasin expression. No suprabasin expression was detected in MM and RMH. Suprabasin and DARS2 may be proposed as new biomarkers to differentiate MM from LAC.


The effect of X-irradiation on Na-K ATPase and cation distribution in rabbit lens.
The Na-K ATPase activity of rabbit lens was measured at various times after exposure to a single dose of 2000 rads of X-ray and was compared with that in contralateral control eyes. A decrease in enzyme activity in both whole lens and in isolated capsule-epithelium was first observed 3 to 4 weeks after irradiation and became increasingly marked at 7.5 weeks after X-ray. These findings are consistent with our earlier observations that active transport of cations is reduced in these lenses and support the view that loss of membrane ATPase is responsible for the impairment of the cation pump in X-irradiated lenses. Despite a significant loss of the enzyme, X-irradiated lenses were able to maintain near normal levels of total cations (Na+ + K+), thus accounting for their normal hydration. The results of the changes in lens Na+ and K+ levels revealed that between 4 and 7.5 weeks after X-ray, the gain in Na+ was compensated by an equivalent loss of K+. A breakdown of this relationship of 1:1 exchange of Na+ for K+ is accompanied by a disproportionate increase in Na+ and water.


Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition.
AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus1. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes2. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.


Boron in sillimanite.
Sillimanite in six granulite-facies, kornerupine-bearing rocks contains 0.035 to 0.43 percent B(2)O(3) and 0.02 to 0.23 percent MgO (by weight). Substitution of boron for silicon and magnesium for aluminum is coupled such that the ratio of magnesium to boron is about 0.5. Sillimanite incorporates more than 0.1 percent B(2)O(3) only at high temperatures in a boron-rich environment at very low partial pressures of water. In the amphibolite facies, the sillimanite boron contents are too low to appreciably affect the stability relations of sillimanite with kyanite and andalusite.


Structural basis of X-ray-induced transient photobleaching in a photoactivatable green fluorescent protein.
We have observed the photoactivatable fluorescent protein IrisFP in a transient dark state with near-atomic resolution. This dark state is assigned to a radical species that either relaxes to the ground state or evolves into a permanently bleached chromophore. We took advantage of X-rays to populate the radical, which presumably forms under illumination with visible light by an electron-transfer reaction in the triplet state. The combined X-ray diffraction and in crystallo UV-vis absorption, fluorescence, and Raman data reveal that radical formation in IrisFP involves pronounced but reversible distortion of the chromophore, suggesting a transient loss of pi conjugation. These results reveal that the methylene bridge of the chromophore is the Achilles' heel of fluorescent proteins and help unravel the mechanisms of blinking and photobleaching in FPs, which are of importance in the rational design of photostable variants.


In situ study of the photodegradation of carbofuran deposited on TiO2 film under UV light, using ATR-FTIR coupled to HS-MCR-ALS.
The in situ study of the photodegradation of carbofuran deposited on a TiO2 catalyst film under UV light was carried out using the ATR-FTIR technique. The data were analyzed using a Hard-Soft Multivariate Curve Resolution-Alternating Least Squares (HS-MCR-ALS) methodology. Using S-MCR-ALS, four factors were deduced from the evolving factor analysis of the data, and their concentrations and spectra were determined. These results were used to draw qualitative and quantitative analyses of the major products of carbofuran photodegradation. The results of this analysis were in good agreement with GC-MS results and with reported mechanisms. Hard-MCR-ALS was then used to refine the spectra and concentrations, using a multistep kinetic model. The rate constant for the first step in the photodegradation of carbofuran was found to be 2.9 × 10(-3) min(-1). The higher magnitude of the correlation (96.87%), the explained variance (99.87%) and LOF (3.01), are good indicators of the reliability of the outcome of this approach. This method has been shown to be an efficient approach to study in situ photodegradation of pesticides on a solid surface.


[Study of glutamine solution use efficiency in pediatric patients with heavy thermic burns and concomitant injuries in the intensive care unit].
Comparing analysis of randomized study was conducted. 40 Pediatric patients (2-15 years old) with heavy thermic burns and concomitant injuries were recruited into the study to assess the glutamine solution intravenous use efficiency. Parenteral feeding and feeding with glutamine solution intravenous use were clinicaly and laboratory compared Duration of mechanical ventilation decreased in group of feeding with glutamine solution intravenous use. Preliminary results of the study recommend to include glutamine in the programs of parentreral feeding.


The effects of challenge or social buffering on cortisol, testosterone, and antler growth in captive red deer (Cervus elaphus) males.
We equipped 17 captive red deer males (Cervus elaphus) with GPS collars to measure inter-individual distances throughout the 5-months of the antler growth period. We expected some individuals to associate regularly with others while others would not. We predicted that males aggregating with others within a socially stable environment (Associates) would benefit from a form of "social buffering" and would likely have lowered cortisol (C) and testosterone (T) concentrations. Males only irregularly joining social groupings would experience elevated levels of aggression; according to the "Challenge hypothesis", their T and C concentrations should increase. Interacting with a higher proportion of Associates did indeed reduce C concentrations. Conversely, avoiding Associates and challenging other males stimulated the T secretion. Admittedly, males avoiding regular proximity to others tended to develop the largest antlers. They probably benefited from frequent successful agonistic threats to conspecifics, resulting in elevated T concentrations. Regular association with tolerant, conspecifics and "social buffering" did not seem sufficient for producing larger antlers despite reducing C concentrations. Alternative social strategies were adopted within the same group of individuals and showed how the trade-off between these strategies could have an essential impact on C and T concentrations.


Insulin resistance, cystatin C, and mortality among older adults.
Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes. We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥ 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR). A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6-41) and 11% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4-43) and 4% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models. Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.


A comparison of triple-therapy with double-therapy immunosuppression in cadaveric renal transplantation.
Triple-therapy (low-dose cyclosporine-azathioprine-prednisone) immunosuppression regimen was compared with double-therapy (cyclosporine-prednisone) in 91 consecutive nonrandomized adult cadaveric renal transplant recipients. Both groups were comparable with respect to ethnic diversity, prior transplants, and diabetes. The majority of patients with delayed function (ATN) were maintained on triple therapy, and the use of antilymphocyte agents was more common in the triple-therapy group (52% vs. 7%; P = 0.0001). Triple-therapy patients experienced increased acute rejection episodes (1.4 vs. 0.8 per patient, P = 0.03), required more courses of additional steroid pulse therapy (4.3 vs. 1.6 per patient; P = 0.001), and developed serious infections more frequently (37% vs. 15%; P = 0.05), especially CMV infections (17% vs. 0; P = 0.03), compared with double-therapy patients. However, the increased overall infection rate and CMV infection rate were observed only in those patients who received antilymphocyte agents compared with those who did not (46% vs. 21%; P = 0.02 for all infections, 26% vs. 4%; P = 0.006 for CMV). Additional steroid pulse therapy was associated with increased CMV infections (24% vs. 0; P = 0.03) but not with overall infections. One-year allograft and patient survival were equivalent in both groups. Exclusion of ATN patients from analysis did not alter the findings. This experience confirms the overall efficacy of triple-therapy immunosuppression in renal transplant recipients but suggests that triple therapy may be associated with more acute rejection episodes, greater immunosuppression requirements, and a resultant increase in infections, especially CMV.