Cerebral hemodynamic responses induced by specific acupuncture sensations during needling at trigger points: a near-infrared spectroscopic study.
Acupuncture stimulation at specific points, or trigger points (TPs), elicits sensations called "de-qi". De-qi sensations relate to the clinical efficacy of the treatment. However, it is neither clear whether de-qi sensations are associated with TPs, nor clear whether acupuncture effects on brain activity are associated with TPs or de-qi. We recorded cerebral hemodynamic responses during acupuncture stimulation at TPs and non-TPs by functional near-infrared spectroscopy. The acupuncture needle was inserted into both TPs and non-TPs within the right extensor muscle in the forearm. Typical acupuncture needle manipulation was conducted eight times for 15 s. The subjects pressed a button if they felt a de-qi sensation. We investigated how hemodynamic responses related to de-qi sensations induced at TPs and non-TPs. We observed that acupuncture stimulations producing de-qi sensations significantly decreased the Oxy-Hb concentration in the supplementary motor area (SMA), pre-supplementary motor area, and anterior dorsomedial prefrontal cortex regardless of the point stimulated. The hemodynamic responses were statistically analyzed using a general linear model and a boxcar function approximating the hemodynamic response. We observed that hemodynamic responses best fit the boxcar function when an onset delay was introduced into the analyses, and that the latency of de-qi sensations correlated with the onset delay of the best-fit function applied to the SMA. Our findings suggest that de-qi sensations favorably predict acupuncture effects on cerebral hemodynamics regardless of the type of site stimulated. Also, the effect of acupuncture stimulation in producing de-qi sensation was partly mediated by the central nervous system including the SMA.


Costs of outpatient and inpatient MRSA screening and treatment strategies for patients at elective hospital admission - a decision tree analysis.
Nosocomial infections are among the most common complications in hospitals. A major part is caused by multidrug-resistant organisms (MDRO). MRSA is still the most prominent and frequent MDRO. The early detection of carriers of multidrug-resistant bacteria is an effective measure to reduce nosocomial infections caused by MDRO. For patients who are planning to go to the hospital, an outpatient screening for MDRO and pre-hospital decolonization is recommended. However, the effectiveness of such pre-admission MDRO management in preparation for a planned hospital stay has not yet been sufficiently scientifically examined from an economic perspective. A decision tree will be used to develop scenarios for MDRO screening and treatment in the context of the outpatient and inpatient sectors using MRSA-positive patients as an example. Subsequently, the expected costs for the respective strategy are presented. The decision tree analysis shows that the expected costs of outpatient MRSA management are €8.24 and that of inpatient MRSA management are €672.51. The forward displacement of the MRSA screening to the ambulatory sector and any subsequent outpatient decolonization for patients with a planned hospitalization is the most cost-effective strategy and should become a standard benefit. Excluding opportunity costs, the expected costs of inpatient MRSA management are €54.94.


Prejudiced learning: a connectionist account.
Connectionist simulation was employed to investigate processes that may underlie the relationships between prior expectancies or prejudices and the acquisition of attitudes, under conditions where learners can only discover the valence of attitude objects through directly experiencing them. We compared contexts analogous to learners holding either false negative expectancies ('prejudices') about a subclass of objects that were actually good or false positive expectancies about objects that were actually bad. We introduced expectancy-related bias either by altering the probability of approach, or by varying the rate of learning following experience with good or bad objects. Where feedback was contingent on approach, the false positive expectancies were corrected by experience, but negative prejudices resisted change, since the network avoided objects deemed to be bad, and so received less corrective feedback. These findings are discussed in relation to the effects of intergroup contact and expectancy-confirmation processes in reducing or sustaining prejudice.


The activation of TC10, a Rho small GTPase, contributes to v-Rel-mediated transformation.
v-Rel is the oncogenic member of the Rel/NF-kappaB family of transcription factors and transforms hematopoietic cells and fibroblasts. Differential display was employed to identify target genes that exhibit altered expression in v-Rel transformed cells. One of the cDNAs identified encodes the chicken ortholog of TC10, a member of the Rho small GTPase family. The expression of TC10 was increased in v-Rel-transformed chicken embryonic fibroblasts (CEFs) 3 to 6-fold relative to control cells at both the RNA and protein levels. An elevated level of active, GTP-bound TC10 was also detected in v-Rel-transformed cells relative to control cells. Expression of a dominant-negative TC10 mutant (TC10T32N) decreased the colony formation potential of v-Rel-transformed cells. Furthermore, overexpression of wild-type TC10 or a gain-of-function mutant (TC10Q76L) greatly enhanced the ability of v-Rel transformed CEFs to form colonies in soft agar. In addition to enhance the transformation potential of v-Rel, the overexpression of wild-type TC10 or the gain-of-function mutant alone enhanced the saturation density of CEFs and was sufficient for their anchorage-independent growth in vitro. These results indicate that elevated TC10 activity contributes to v-Rel-mediated transformation of CEFs and demonstrate for the first time that a Rho factor alone is capable of inducing the in vitro transformation of primary cells.


Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM.
The ligand for CD40 (CD40L) is a membrane protein on activated T cells that induces B cell proliferation and differentiation. Several mutations of the CD40L gene were reported responsible for defective class switching of B cells in an X-linked immunodeficiency with hyper IgM (X-HIM). We studied four affected males from three families and found three independent mutations including new mutations of CD40L gene. In every X-HIM patient tested, however, anti-CD40 plus IL-10 did not induce class switching from IgM to IgG or IgA, even in the presence of Staphylococcus aureus Cowan I strain (SAC). CD4+ T cell clones, expressing CD40L on their surface, also did not rescue IgG or IgA induction by X-HIM peripheral blood B cells in vitro. But signaling through CD40 induced both B cell proliferation and IgE secretion when IL-4 was added to the culture. Taken together, these results show that in vitro signaling through CD40 rescues IgE but not IgG or IgA secretion by peripheral blood X-HIM B cells and suggest that in vivo CD40 and CD40L interaction might be necessary for IgG and IgA differentiation in X-HIM.


Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence.
Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.


Maize NPF6 Proteins Are Homologs of Arabidopsis CHL1 That Are Selective for Both Nitrate and Chloride.
Nitrate uptake by plant cells requires both high- and low-affinity transport activities. Arabidopsis thaliana nitrate transporter 1/peptide transporter family (NPF) 6.3 is a dual-affinity plasma membrane transport protein that has both high- and low-affinity functions. At-NPF6.3 imports and senses nitrate and is regulated by phosphorylation at Thr-101 (T101). A detailed functional analysis of two maize (Zea mays) homologs of At-NPF6.3 (Zm-NPF6.6 and Zm-NPF6.4) showed that Zm-NPF6.6 was a pH-dependent nonbiphasic high-affinity nitrate-specific transport protein. By contrast, maize NPF6.4 was a low-affinity nitrate transporter with efflux activity. When supplied chloride, NPF6.4 switched to a high-affinity chloride selective transporter, while NPF6.6 had only a low-affinity chloride transport activity. Structural predictions identified a nitrate binding His (H362) in NPF6.6 but not in NPF6.4. Mutation of NPF6.4 Tyr-370 to His (Y370H) resulted in saturable high-affinity nitrate transport activity and nitrate selectivity. Loss of H362 in NPF6.6 (H362Y) eliminated both nitrate and chloride transport. Furthermore, alterations to Thr-104, a conserved phosphorylation site in NPF6.6, resulted in a similar high-affinity nitrate transport activity with increased Km, whereas equivalent changes in NPF6.4 (T106) disrupted high-affinity chloride transport activity. NPF6 proteins exhibit different substrate specificity in plants and regulate nitrate transport affinity/selectivity using a conserved His residue.


Early predictors of lumbar spine surgery after occupational back injury: results from a prospective study of workers in Washington State.
Prospective population-based cohort study. To identify early predictors of lumbar spine surgery within 3 years after occupational back injury. Back injuries are the most prevalent occupational injury in the United States. Few prospective studies have examined early predictors of spine surgery after work-related back injury. Using Disability Risk Identification Study Cohort (D-RISC) data, we examined the early predictors of lumbar spine surgery within 3 years among Washington State workers, with new workers compensation temporary total disability claims for back injuries. Baseline measures included worker-reported measures obtained approximately 3 weeks after claim submission. We used medical bill data to determine whether participants underwent surgery, covered by the claim, within 3 years. Baseline predictors (P < 0.10) of surgery in bivariate analyses were included in a multivariate logistic regression model predicting lumbar spine surgery. The area under the receiver operating characteristic curve of the model was used to determine the model's ability to identify correctly workers who underwent surgery. In the D-RISC sample of 1885 workers, 174 (9.2%) had a lumbar spine surgery within 3 years. Baseline variables associated with surgery (P < 0.05) in the multivariate model included higher Roland-Morris Disability Questionnaire scores, greater injury severity, and surgeon as first provider seen for the injury. Reduced odds of surgery were observed for those younger than 35 years, females, Hispanics, and those whose first provider was a chiropractor. Approximately 42.7% of workers who first saw a surgeon had surgery, in contrast to only 1.5% of those who saw a chiropractor. The area under the receiver operating characteristic curve of the multivariate model was 0.93 (95% confidence interval, 0.92-0.95), indicating excellent ability to discriminate between workers who would versus would not have surgery. Baseline variables in multiple domains predicted lumbar spine surgery. There was a very strong association between surgery and first provider seen for the injury even after adjustment for other important variables.


Post-translational protein arginylation in the normal nervous system and in neurodegeneration.
Post-translational arginylation of proteins is an important regulator of many physiological pathways in cells. This modification was originally noted in protein degradation during neurodegenerative processes, with an apparently different physiological relevance between central and peripheral nervous system. Subsequent studies have identified a steadily increasing number of proteins and proteolysis-derived polypeptides as arginyltransferase (ATE1) substrates, including β-amyloid, α-synuclein, and TDP43 proteolytic fragments. Arginylation is involved in signaling processes of proteins and polypeptides that are further ubiquitinated and degraded by the proteasome. In addition, it is also implicated in autophagy/lysosomal degradation pathway. Recent studies using mutant mouse strains deficient in ATE1 indicate additional roles of this modification in neuronal physiology. As ATE1 is capable of modifying proteins either at the N-terminus or middle-chain acidic residues, determining which proteins function are modulated by arginylation represents a big challenge. Here, we review studies addressing various roles of ATE1 activity in nervous system function, and suggest future research directions that will clarify the role of post-translational protein arginylation in brain development and various neurological disorders. Arginyltransferase (ATE1), the enzyme responsible for post-translational arginylation, modulates the functions of a wide variety of proteins and polypeptides, and is also involved in the main degradation pathways of intracellular proteins. Regulatory roles of ATE1 have been well defined for certain organs. However, its roles in nervous system development and neurodegenerative processes remain largely unknown, and present exciting opportunities for future research, as discussed in this review.


Control of radiative processes using tunable plasmonic nanopatch antennas.
The radiative processes associated with fluorophores and other radiating systems can be profoundly modified by their interaction with nanoplasmonic structures. Extreme electromagnetic environments can be created in plasmonic nanostructures or nanocavities, such as within the nanoscale gap region between two plasmonic nanoparticles, where the illuminating optical fields and the density of radiating modes are dramatically enhanced relative to vacuum. Unraveling the various mechanisms present in such coupled systems, and their impact on spontaneous emission and other radiative phenomena, however, requires a suitably reliable and precise means of tuning the plasmon resonance of the nanostructure while simultaneously preserving the electromagnetic characteristics of the enhancement region. Here, we achieve this control using a plasmonic platform consisting of colloidally synthesized nanocubes electromagnetically coupled to a metallic film. Each nanocube resembles a nanoscale patch antenna (or nanopatch) whose plasmon resonance can be changed independent of its local field enhancement. By varying the size of the nanopatch, we tune the plasmonic resonance by ∼ 200 nm, encompassing the excitation, absorption, and emission spectra corresponding to Cy5 fluorophores embedded within the gap region between nanopatch and film. By sweeping the plasmon resonance but keeping the field enhancements roughly fixed, we demonstrate fluorescence enhancements exceeding a factor of 30,000 with detector-limited enhancements of the spontaneous emission rate by a factor of 74. The experiments are supported by finite-element simulations that reveal design rules for optimized fluorescence enhancement or large Purcell factors.


Temporal variation and characterization of grunt sounds produced by Atlantic cod Gadus morhua and pollack Pollachius pollachius during the spawning season.
Fine-scale temporal patterning in grunt production and variation in grunt attributes in Atlantic cod Gadus morhua and pollack Pollachius pollachius was examined. Pollachius pollachius produced only a single sound type, the grunt, similar to that previously described for G. morhua. Sound production and egg production were correlated in P. pollachius but not in G. morhua. Only G. morhua displayed a strongly cyclical pattern, producing more grunts at night. Finer-scale temporal patterning in grunt production was observed in both species which produced significantly fewer grunts following a period of high grunt production. These quieter periods lasted up to 45 min for P. pollachius and up to 1 h in G. morhua. Grunts were not always produced in isolation but organized into bouts in both species. Longer bouts were more frequent during periods of increased sound activity and were linked with changes in grunt characteristics including increased grunt duration, pulse duration and repetition period of each pulse combined with decreased dominant frequency. This study provides the first evidence of acoustic signalling being used by spawning P. pollachius and presents the most detailed analysis of the complexity of gadoid sound production.


Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.
The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility.


Spleen stiffness measurements by acoustic radiation force impulse imaging after living donor liver transplantation in children: a potential quantitative index for venous complications.
Living donor liver transplantation in children often results in venous complications, leading to portal hypertension. Spleen stiffness measurements have been recently proposed as a new, noninvasive parameter for portal hypertension in cirrhotic patients. To evaluate the diagnostic value of spleen stiffness measurements by acoustic radiation force impulse (ARFI) imaging in diagnosing venous complications after pediatric living donor liver transplantation. We prospectively enrolled 69 patients after pediatric living donor liver transplantation using a left-side liver allograft. Around the time of the protocol liver biopsy examination, spleen stiffness measurements by ARFI imaging were performed via the left intercostal space at the center of the spleen parenchyma and repeated five times. Imaging examinations around the time of the spleen stiffness measurements were retrospectively reviewed. Regarding venous complications, significant portal and hepatic venous stenosis was defined as >50% stenosis on multiphasic computed tomography. After post hoc exclusion, 62 patients were studied. Portal and hepatic venous stenosis was identified in three and two patients, respectively. The median spleen stiffness values were 2.70 and 4.00 m/s in patients without and with venous complications, respectively (P < 0.001). Spleen stiffness measurements showed good diagnostic power for venous complications, and the cutoff value was determined as 2.93 m/s, with 100% sensitivity and 78.9% specificity. Spleen stiffness measurements decreased with the relief of venous stenosis resulting from an interventional radiology procedure. Spleen stiffness measurements by ARFI imaging might provide a useful quantitative index for venous complications after pediatric living donor liver transplantation.


Illness-related problems and coping among persons with low-grade glioma.
The literature reveals no qualitative study concerning the consequences of low-grade glioma in adults. The aim of the present study was to describe perceived illness-related problems in persons with low-grade glioma and the coping used in everyday living. The study was cross-sectional within a well-defined population. A semi-structured qualitative interview was conducted with each of 39 persons, and the data were subjected to inductive content analysis. There was a wide range of perceived problems, mainly concerning bodily functions, memory, cognition, emotion, communication and perception. Several coping strategies emerged, the most frequent being searching for a solution, which was often related to memory and communication problems. One characteristic of communication was the creation of new words. Other common strategies were refraining from and avoiding and laughing and joking. Caring about self involved prioritizing of personal needs. A striving to feel a sense of solidarity within seeking social affinity was coping with a novel content. The study provides vivid narratives about previously unreported phenomena, conveying a deeper understanding. The variety and endurance of problems revealed verifies the need of support from several professionals, including in the form of out-patient post-medical care.


Storing memories: the distinct phases of Polycomb-mediated silencing of Arabidopsis FLC.
Polycomb-mediated epigenetic silencing is central to correct growth and development in higher eukaryotes. The evolutionarily conserved Polycomb repressive complex 2 (PRC2) transcriptionally silences target genes through a mechanism requiring the histone modification H3K27me3. However, we still do not fully understand what defines Polycomb targets, how their expression state is switched from epigenetically ON to OFF and how silencing is subsequently maintained through many cell divisions. An excellent system in which to dissect the sequence of events underlying an epigenetic switch is the Arabidopsis FLC locus. Exposure to cold temperatures progressively induces a PRC2-dependent switch in an increasing proportion of cells, through a mechanism that is driven by the local chromatin environment. Temporally distinct phases of this silencing mechanism have been identified. First, the locus is transcriptionally silenced in a process involving cold-induced antisense transcripts; second, nucleation at the first exon/intron boundary of a Polycomb complex containing cold-induced accessory proteins induces a metastable epigenetically silenced state; third, a Polycomb complex with a distinct composition spreads across the locus in a process requiring DNA replication to deliver long-term epigenetic silencing. Detailed understanding from this system is likely to provide mechanistic insights important for epigenetic silencing in eukaryotes generally.


Facilitating evidence-based practice: process, strategies, and resources.
Occupational therapy practitioners may encounter challenges when they try to incorporate evidence into practice. To embrace evidence-based practice (EBP), clinicians must have readily available, relevant, and concisely summarized evidence. Although researchers have described the importance and process of EBP, less has been written about how to efficiently integrate evidence into practice. Clinicians may benefit from examples of reasoning, strategies, and resources to successfully integrate evidence. This article reviews the steps of EBP and offers recommendations to overcome common barriers. For EBP to become integrated into practice, greater communication and collaboration among all stakeholders must occur. EBP and knowledge translation require multiple processes and coordinated efforts. Therefore, everyone from practitioners to employers has a role in increasing EBP and transferring knowledge for practice. To encourage discussion and actions, the article provides implications and recommendations for practitioners, researchers, educators, organizations, and policymakers.


Cyclin and cyclin-dependent kinase substrate requirements for preventing rereplication reveal the need for concomitant activation and inhibition.
DNA replication initiation in S. cerevisiae is promoted by B-type cyclin-dependent kinase (Cdk) activity. In addition, once-per-cell-cycle replication is enforced by cyclin-Cdk-dependent phosphorylation of the prereplicative complex (pre-RC) components Mcm2-7, Cdc6, and Orc1-6. Several of these controls must be simultaneously blocked by mutation to obtain rereplication. We looked for but did not obtain strong evidence for cyclin specificity in the use of different mechanisms to control rereplication: both the S-phase cyclin Clb5 and the mitotic cyclins Clb1-4 were inferred to be capable of imposing ORC-based and MCM-based controls. We found evidence that the S-phase cyclin Clb6 could promote initiation of replication without blocking reinitiation, and this activity was highly toxic when the ability of other cyclins to block reinitiation was prevented by mutation. The failure of Clb6 to regulate reinitiation was due to rapid Clb6 proteolysis, since this toxic activity of Clb6 was lost when Clb6 was stabilized by mutation. Clb6-dependent toxicity is also relieved when early accumulation of mitotic cyclins is allowed to impose rereplication controls. Cell-cycle timing of rereplication control is crucial: sufficient rereplication block activity must be available as soon as firing begins. DNA rereplication induces DNA damage, and when rereplication controls are compromised, the DNA damage checkpoint factors Mre11 and Rad17 provide additional mechanisms that maintain viability and also prevent further rereplication, and this probably contributes to genome stability.


Informal urban green-space: comparison of quantity and characteristics in Brisbane, Australia and Sapporo, Japan.
Informal urban green-space (IGS) such as vacant lots, brownfields and street or railway verges is receiving growing attention from urban scholars. Research has shown IGS can provide recreational space for residents and habitat for flora and fauna, yet we know little about the quantity, spatial distribution, vegetation structure or accessibility of IGS. We also lack a commonly accepted definition of IGS and a method that can be used for its rapid quantitative assessment. This paper advances a definition and typology of IGS that has potential for global application. Based on this definition, IGS land use percentage in central Brisbane, Australia and Sapporo, Japan was systematically surveyed in a 10×10 km grid containing 121 sampling sites of 2,500 m2 per city, drawing on data recorded in the field and aerial photography. Spatial distribution, vegetation structure and accessibility of IGS were also analyzed. We found approximately 6.3% of the surveyed urban area in Brisbane and 4.8% in Sapporo consisted of IGS, a non-significant difference. The street verge IGS type (80.4% of all IGS) dominated in Brisbane, while lots (42.2%) and gaps (19.2%) were the two largest IGS types in Sapporo. IGS was widely distributed throughout both survey areas. Vegetation structure showed higher tree cover in Brisbane, but higher herb cover in Sapporo. In both cities over 80% of IGS was accessible or partly accessible. The amount of IGS we found suggests it could play a more important role than previously assumed for residents' recreation and nature experience as well as for fauna and flora, because it substantially increased the amount of potentially available greenspace in addition to parks and conservation greenspace. We argue that IGS has potential for recreation and conservation, but poses some challenges to urban planning. To address these challenges, we propose some directions for future research.


Cardiovascular biomarkers pro-atrial natriuretic peptide and pro-endothelin-1 to monitor ductus arteriosus evolution in very preterm infants.
The diagnostic and prognostic appraisal of patent ductus arteriosus (PDA) in preterm infants is still debatable. To compare plasma cardiovascular biomarkers with echocardiographic indices alongside ductus arteriosus (DA) evolution in very preterm infants within the first week of life. Mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) levels were prospectively measured on the second and sixth days of life (DOL) in 52 preterm infants born before 32weeks of gestation. Echocardiographic indices to define DA patency and significance were simultaneously obtained. Logistic regression and receiver operating characteristics (ROC) analyses were used to assess and quantify the biomarkers' diagnostic capacities. Thirty infants exhibited PDA on DOL 2; in 21 of these infants, DA was characterized as hemodynamically significant. Treatment failure after a first course of indomethacin was noted in 8 infants (DOL 6), whereas 7 participants underwent later surgical ligation. The diagnostic accuracy of cardiovascular biomarkers was moderate on DOL 2 but high on DOL 6. PDA was the only significant predictor of MR-proANP levels on DOL 6, independent of the effect of clinical confounders (regression coefficient 0.426, R(2) 0.60). Infants with MR-proANP ≥850pmol/l on DOL 2 had 3.9-fold higher risk (95% CI 1.01 to 14.5) of being diagnosed with significant DA, whereas infants with MR-proANP ≥700pmol/l on DOL 6 had 7.1-fold higher risk (1.9 to 27.2) for pharmaceutical treatment failure. The cardiovascular plasma biomarker MR-proANP is a promising candidate for monitoring PDA evolution in very preterm infants.


The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.
Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis.


Breast cancer incidence and overdiagnosis in Catalonia (Spain).
Early detection of breast cancer (BC) with mammography may cause overdiagnosis and overtreatment, detecting tumors which would remain undiagnosed during a lifetime. The aims of this study were: first, to model invasive BC incidence trends in Catalonia (Spain) taking into account reproductive and screening data; and second, to quantify the extent of BC overdiagnosis. We modeled the incidence of invasive BC using a Poisson regression model. Explanatory variables were: age at diagnosis and cohort characteristics (completed fertility rate, percentage of women that use mammography at age 50, and year of birth). This model also was used to estimate the background incidence in the absence of screening. We used a probabilistic model to estimate the expected BC incidence if women in the population used mammography as reported in health surveys. The difference between the observed and expected cumulative incidences provided an estimate of overdiagnosis. Incidence of invasive BC increased, especially in cohorts born from 1940 to 1955. The biggest increase was observed in these cohorts between the ages of 50 to 65 years, where the final BC incidence rates more than doubled the initial ones. Dissemination of mammography was significantly associated with BC incidence and overdiagnosis. Our estimates of overdiagnosis ranged from 0.4% to 46.6%, for women born around 1935 and 1950, respectively. Our results support the existence of overdiagnosis in Catalonia attributed to mammography usage, and the limited malignant potential of some tumors may play an important role. Women should be better informed about this risk. Research should be oriented towards personalized screening and risk assessment tools.


MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer.
The aim of the study was to evaluate the influence of the MDR1 C3435T polymorphism on the therapeutic response in 23 patients treated with cetuximab plus irinotecan for irinotecan refractory liver metastatic colorectal cancer considering their KRAS status. Indeed, irinotecan and its active metabolite (SN-38) are both substrates of P-glycoprotein (P-gp) encoded by MDR1. Patients received cetuximab and irinotecan up to progression. The overall survival was 55% at 10 months. Overall, four patients had an undetermined KRAS status and two patients with mutated KRAS were in progression disease. The response to treatment was observed after 3 months among the 17 wild-type KRAS patients. Two patients presented a progressive disease (1 TT and 1 CT), eight patients had a stable disease (5 CC and 3CT) and five patients had a partial response (3 CC and 2 CT). Importantly, 2 patients (2 TT) were in complete response and still alive 5 years after starting the treatment, which suggests that the combination of wild-type KRAS and MDR1 3435 TT may be a factor of good prognosis. These results suggest that EGFR inhibition by cetuximab may overcome this irinotecan resistance by abrogating drug efflux depending on MDR1 3435 polymorphism. Among patients resistant to irinotecan, it is still possible to use the association of cetuximab plus irinotecan to obtain a complete resection of hepatic metastases that is necessary to improve their survival.


Children and U.S. federal policy on health and health care: seen but not heard.
Children account for 73.5 million Americans (24%), but 8% of federal expenditures. Data on health and health care indicate that child well-being in the United States has been in decline since the most recent recession. Childhood poverty has reached its highest level in 20 years, 1 in 4 children lives in a food-insecure household, 7 million children lack health insurance, a child is abused or neglected every 47 seconds, and 1 in 3 children is overweight or obese. Five children are killed daily by firearms, 1 in 5 experiences a mental disorder, racial/ethnic disparities continue to be extensive and pervasive, and major sequester cuts and underfunding of pediatric research have damaged our global leadership in biomedical research and hobbled economic growth. In this analysis, we identify 10 urgent priorities for the health and health care of US children, including poverty, food insufficiency, lack of health insurance, child abuse and neglect, overweight and obesity, firearm deaths and injuries, mental health, racial/ethnic disparities, immigration, and research. Overwhelming, bipartisan support by voters exists for enhancing our nation's investments in children's health and well-being. Federal policy action steps are proposed to successfully address these priorities and ensure a healthy, productive future for US children and the nation.


A cost-effective sandwich electrochemiluminescence immunosensor for ultrasensitive detection of HIV-1 antibody using magnetic molecularly imprinted polymers as capture probes.
In this report, a rapid and cost-effective sandwich electrochemiluminescence (ECL) immunosensor was constructed for the ultrasensitive detection of human immunodeficiency virus type 1 antibody (anti-HIV-1) using magnetic molecularly imprinted polymers (MMIPs) as capture probes by combining surface and epitope imprinting techniques and antigen conjugated with horseradish peroxidase (HRP-HIV-1) as labels. First, 3-aminobenzeneboronic acid (APBA) was used as the functional monomer and cross-linking reagent, which was polymerized on the surface of silicate-coated magnetic iron oxide nanoparticles (Fe3O4@SiO2 NPs) in the presence of human immunoglobulin G (HIgG), as the template exhibiting the same Fc region but different Fab region to anti-HIV-1 after the addition of the initiator, ammonium persulfate. This process resulted in grafting a hydrophilic molecularly imprinted polymer (MIP) film on the Fe3O4@SiO2 NPs. Thus, MMIPs, which could be reused after eluting the template, were used to recognize and enrich ultra-trace levels of anti-HIV-1. Subsequently, a novel sandwich ECL immunosensor was formed through the immunoreaction between MMIPs conjugated with varied concentrations of anti-HIV-1 and HRP-HIV-1. By the catalysis of HRP immobilized onto HRP-HIV-1 on the ECL system of Luminol-H2O2, a linear response range of the anti-HIV-1 dilution ratio (standard positive serum) was achieved from 1:20,000 to 1:50, with a detection limit of 1:60,000 (S/N=3). The developed method provides a low-cost, simple, and sensitive way for the early diagnosis of HIV infected patients.


Neural Basis of Touch and Proprioception in Primate Cortex.
The sense of proprioception allows us to keep track of our limb posture and movements and the sense of touch provides us with information about objects with which we come into contact. In both senses, mechanoreceptors convert the deformation of tissues-skin, muscles, tendons, ligaments, or joints-into neural signals. Tactile and proprioceptive signals are then relayed by the peripheral nerves to the central nervous system, where they are processed to give rise to percepts of objects and of the state of our body. In this review, we first examine briefly the receptors that mediate touch and proprioception, their associated nerve fibers, and pathways they follow to the cerebral cortex. We then provide an overview of the different cortical areas that process tactile and proprioceptive information. Next, we discuss how various features of objects-their shape, motion, and texture, for example-are encoded in the various cortical fields, and the susceptibility of these neural codes to attention and other forms of higher-order modulation. Finally, we summarize recent efforts to restore the senses of touch and proprioception by electrically stimulating somatosensory cortex. © 2018 American Physiological Society. Compr Physiol 8:1575-1602, 2018.


Contractile inactivation in frog single denervated muscle fibers.
After preliminary conditioning depolarizations, single muscle fibers of the frog were tested for ability to contract in response to depolarization by 100 mM K+ Ringer solution. Denervated fibers (6-42 days) lose their ability to produce a 100 mM K+ contracture more rapidly than do control fibers. This decrease in 100 mM K+ contracture size (inactivation) is dependent on length of exposure to and magnitude of the conditioning depolarization and on the calcium concentration in the external medium. At 0.4 mM Ca++, the inactivation is 3 times faster than at 1.5 mM Ca++. The rate of contracture loss is not correlated with fiber diameter or the number of days after failure of neuromuscular transmission, and the preliminary conditioning depolarizations do not affect the rate of terminal relaxation from the 100 mM K+ contractures.


Langmuir monolayers with internal dipoles: Understanding phase behavior using Monte Carlo simulations.
A coarse-grained, rigid-rod model that includes steric interactions and an internal dipole is used to study monolayers of surfactant molecules tethered to a flat interface. Monte Carlo simulations are performed in the canonical ensemble for a range of high-density configurations with varying degrees of dipole strength. Both a melting transition and a tilting transition are observed, and the dependence of the transitions on the surfactant molecules' internal dipoles is examined. Simulation results indicate that at high packing densities, the monolayers exist in a frustrated state due to dipole-dipole repulsions and steric interactions. Tilting of the surfactant molecules increases the magnitude of the dipole-dipole attractions and lowers the overall system energy, but is limited by steric repulsions. In simulations with higher dipole strengths, the melting and tilting transitions are found to be coupled. The formation of nanodomains with increased collective tilt and positional order in these systems suggests a possible mechanism for the coupling.


Screening for Military Sexual Trauma Is Associated With Improved HIV Screening in Women Veterans.
To examine factors associated with HIV screening among women veterans receiving health care in the Department of Veterans Affairs. Cross-sectional study of women veterans receiving Veterans Affairs care between 2001 and 2014 derived from the Women Veteran's Cohort Study. Descriptive and bivariate statistics were calculated comparing patients with and without an HIV screen. Generalized estimating equations were conducted to estimate the odds of HIV screening among women screened for military sexual trauma (MST) and the subset with a positive MST screen. Multivariable analyses were adjusted for demographic characteristics, mental health diagnoses, pregnancy, HIV risk factors, and facility level clustering. Among the 113,796 women veterans in the sample, 84.3% were screened for MST and 13.2% were screened for HIV. Women screened for MST were over twice as likely to be tested for HIV (odds ratio, 2.8; 95% confidence interval, 2.2-3.5). A history of MST was inversely associated with HIV screening (odds ratio, 0.9; 95% confidence interval, 0.8-0.9). Women veterans screened for sexual trauma received more comprehensive preventive health care in the form of increased HIV screening.


Epidemiologic survey of traumatic dental injuries in children seen at the Federal University of Rio de Janeiro, Brazil.
This epidemiologic survey aimed at assessing the prevalence of traumatic dental injuries in children seen at the Federal University of Rio de Janeiro, Brazil. The records of a total of 111 children (aged 0 to 6 years) seen from 2004 to 2006 in the dental trauma clinic were surveyed, comprising a total of 201 traumatized primary teeth. Data pertaining to the child and to the trauma such as age, gender, etiology, teeth involved, type of traumatic injury, time elapsed between the trauma and seeking care, and the presence and kind of clinical and radiographic sequelae in the first visit were collected from the dental records. All variables studied were assessed by means of frequency analysis and the Chi-square test (p < 0.05). A higher prevalence of trauma was observed in boys (56.7%) and in the age group from 0-3 years (73.8%). The most affected teeth were the central incisors (84.7%) and the most common trauma etiology was a fall from the child's own height (63.0%). The supporting tissues were the most affected. Lateral luxation was the most frequent alteration observed (33.4%), followed by concussion (21.0%). Coronal discoloration (17.7%) and external resorption (18.3%) were, respectively, the most prevalent clinical and radiographic sequelae. Gender had no influence on the clinical (p = 0.54) and radiographic (p = 0.55) sequelae. Even though age had no influence on radiographic sequelae (p = 0.41), clinical sequelae were more prevalent in children aged 0 to 3 years (p = 0.03). In conclusion, traumatisms in primary teeth were more prevalent in boys, and in 0-3-year-old children. Luxation was the most frequent traumatic lesion, and coronal discoloration and external resorption were the most prevalent sequelae.


Cyclin-dependent kinase control of centrosome duplication.
Centrosomes nucleate microtubules and duplicate once per cell cycle. This duplication and subsequent segregation in mitosis results in maintenance of the one centrosome/cell ratio. Centrosome duplication occurs during the G1/S transition in somatic cells and must be coupled to the events of the nuclear cell cycle; failure to coordinate duplication and mitosis results in abnormal numbers of centrosomes and aberrant mitoses. Using both in vivo and in vitro assays, we show that centrosome duplication in Xenopus laevis embryos requires cyclin/cdk2 kinase activity. Injection of the cdk (cyclin-dependent kinase) inhibitor p21 into one blastomere of a dividing embryo blocks centrosome duplication in that blastomere; the related cdk inhibitor p27 has a similar effect. An in vitro system using Xenopus extracts carries out separation of the paired centrioles within the centrosome. This centriole separation activity is dependent on cyclin/cdk2 activity; depletion of either cdk2 or of the two activating cyclins, cyclin A and cyclin E, eliminates centriole separation activity. In addition, centriole separation is inhibited by the mitotic state, suggesting a mechanism of linking the cell cycle to periodic duplication of the centrosome.


Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Kidney Transplant Recipients with Post-transplant Diabetes Mellitus (PTDM)- a Systematic Review and Meta-Analysis.
Kidney transplant recipients may develop post-transplant diabetes mellitus (PTDM). Dipeptidyl peptidase 4(DPP-4) inhibitors are evolving agents in the management of patients with diabetes mellitus. To evaluate the efficacy and safety of DPP-4 inhibitors in the management of post-transplant diabetes mellitus (PTDM) in renal transplant recipients. We performed a systematic search of the electronic databases using keys words and Mesh terms. Data were extracted and reviewed using structured proforma. A comprehensive review of the eligible studies was performed independently by each of two reviewers; conflicts were resolved by the third reviewer. The primary efficacy endpoint was the difference in glycosylated hemoglobin (HbA1c) comparing any of the DPP-4 inhibitors to either placebo or other hypoglycaemic agent. The primary safety endpoints were the worsening of graft functions and change in Tacrolimus trough level. We performed the Random effect model using standardised mean difference. We identified seven studies that were eligible for the systematic review; only one study compared Sitagliptin to insulin Glargine. One study involved head to head comparison of three DPP-4 inhibitors. The other five studies were pooled in the meta-analysis. DPP-4 inhibitors had a favourable glycemic effect as measured by HbA1c when compared to either placebo or oral anti-hyperglycemic medications (standardised mean difference in HbA1c = -0.993, 95% CI= -1.303 to -0.683, P=0.001). DPP-4 inhibitors use did not result in significant change in eGFR ((standardised mean difference = 0.147, 95% CI= -0.139 - 0.433, p=0.312).) nor Tacrolimus level (standardised Mean Difference= 0.152, 95% CI= -0.172 to 0.477, P=0.354). Current evidence supports the short term efficacy and safety of DDP-4 inhibitor agents in the management of post transplantation diabetes mellitus (PTDM) in kidney transplant recipients. However, more RCTs are required to investigate the long-term safety and efficacy of these agents in kidney transplant recipients.


Immunological studies of T-cell receptors. II. Limited polymorphism of idiotypic determinants on T-cell receptors specific for major histocompatibility complex alloantigens.
These studies explore the extent of genetic polymorphism in the expression of anti-MHC receptors by T cells in different strains of rats. This question was approached with the use of the model of specifically induced GVH resistance in F1 rats which has been shown to reflect a specific T-cell mediated immune response against parental strain T cell anti-MHC receptors specific for host alloantigens. When A/B F1 rats derived from MHC incompatibile matings are immunized with lymphocytes from one parental strain (A they display a specific resistance to anti-B GVH reactivity caused by T cells from that parental strain, but not anti-AGVH reactions from the other. In addition, they resist anti-B GHV reactivity by T cells from third-party donors (C, D, E,...), a finding taken to indicate that the idiotypes of anti-MHC receptors on T cells, recognized by other T cells, show little or no polymorphism. This conclusion suggests that anti-MHC receptors are shared in the species and may be encoded, at least partially, by germ-line genes.


Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors.
Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.


A Reappraisal of the Purported Gastric Pellet with Pterosaurian Bones from the Upper Triassic of Italy.
A small accumulation of bones from the Norian (Upper Triassic) of the Seazza Brook Valley (Carnic Prealps, Northern Italy) was originally (1989) identified as a gastric pellet made of pterosaur skeletal elements. The specimen has been reported in literature as one of the very few cases of gastric ejecta containing pterosaur bones since then. However, the detailed analysis of the bones preserved in the pellet, their study by X-ray microCT, and the comparison with those of basal pterosaurs do not support a referral to the Pterosauria. Comparison with the osteology of a large sample of Middle-Late Triassic reptiles shows some affinity with the protorosaurians, mainly with Langobardisaurus pandolfii that was found in the same formation as the pellet. However, differences with this species suggest that the bones belong to a similar but distinct taxon. The interpretation as a gastric pellet is confirmed.


The social determinants of health, health equity, and human rights.
This article explores the benefits of a rights-based approach to health according greater attention to the social determinants of health, health equity, and the power structure. It uses the report issued by the World Health Organization Commission on Social Determinants of Health (CSDH), "Closing the gap in a generation: Health equity through action on the social determinants of health," as a lens through which to address these issues. After presenting a brief overview of the CSDH report, the article compares the document with a rights-based approach to health on three topics: 1) the social determinants of health and the underlying determinants of health; 2) health inequalities and inequities; and 3) power, money, and resources. The article argues that the right to health requires greater attention to the social determinants of health, health inequalities, and power dynamics than these topics have received to date.


Histone H2A variants confer specific properties to nucleosomes and impact on chromatin accessibility.
In eukaryotes, variants of core histone H2A are selectively incorporated in distinct functional domains of chromatin and are distinguished by conserved sequences of their C-terminal tail, the L1 loop and the docking domain, suggesting that each variant confers specific properties to the nucleosome. Chromatin of flowering plants contains four types of H2A variants, which biochemical properties have not been characterized. We report that in contrast with animals, in Arabidopsis thaliana H2A variants define only four major types of homotypic nucleosomes containing exclusively H2A, H2A.Z, H2A.X or H2A.W. In vitro assays show that the L1 loop and the docking domain confer distinct stability of the nucleosome. In vivo and in vitro assays suggest that the L1 loop and the docking domain cooperate with the C-terminal tail to regulate chromatin accessibility. Based on these findings we conclude that the type of H2A variant in the nucleosome impacts on its interaction with DNA and propose that H2A variants regulate the dynamics of chromatin accessibility. In plants, the predominance of homotypic nucleosomes with specific physical properties and their specific localization to distinct domains suggest that H2A variants play a dominant role in chromatin dynamics and function.


FishMap: a community resource for zebrafish genomics.
An enormous amount of information on a genomics scale is available for zebrafish (Danio rerio), which is a well-studied model organism for human diseases. However, a majority of this annotation is scattered in obscure data sources. There have been limited efforts to present it on a unified and integrated platform, which would help to understand the biological processes in this organism better. FishMap is a unified and centralized resource for storage, retrieval, and display of genomic information of zebrafish. The datasets have been methodically collected from various resources and supplementary information of publications and mapped to the zebrafish genome. The data are organized into nine major sections, which include comparative genomics, mapping and sequencing, gene and gene predictions, expression and regulation, and variation and repeats. A number of unique sections have been incorporated, which include tracks on noncoding gene annotation, location of retrovirus/transposon integrations in the genome, and their flanking genomic sequences and novel transcripts. The datasets are linked to related data sources. FishMap is built on the Gbrowse, which is a part of the Generic Model Organism Database Consortium Project. The resource also features a Web-based BLAST server for sequence homology search and a gene ID converter that would enable users to sift through different interchangeable gene annotation identifier systems. The database is amenable to programmatic access through the Distributed Annotation System as well as BioMoby protocols, thus making it a central community resource that can be integrated with existing data mining and analysis workflows. We hope that FishMap would be an integral resource for community participation in zebrafish genomics. The resource is freely available at http://miracle.igib.res.in/fishmap, or at http://fishmap.igib.res.in.


Growth hormone responses to 3 different exercise bouts in 18- to 25- and 40- to 50-year-old men.
Exercise is a potent stimulus for growth hormone (GH) release, although aging appears to attenuate this response. The aim of this study was to investigate GH responses to different exercise stimuli in young and early middle-aged men. Eight men aged 18-25 y and 8 men aged 40-50 y completed 3 trials, at least 7 days apart, in a random order: 30 s cycle-ergometer sprint (sprint), 30 min resistance exercise bout (resistance), 30 min cycle at 70% maximal oxygen consumption (endurance). Blood samples were taken pre-, during, and post-exercise, and area under the GH vs. time curve was calculated for a total of 120 min. Mean blood lactate concentrations and percentage heart rate maximum at which the participants were working were not different between groups in any of the trials. In both groups, blood lactate concentrations were significantly lower in the endurance trial than in the sprint and resistance trials. There were no significant differences in resting GH concentration between groups or trials. GH AUC was significantly greater in the young group than the early middle-aged group, in both sprint (531 (+/-347) vs. 81 (+/-54) microg.L-1 per 120 min, p = 0.003) and endurance trials (842 (+/-616) vs. 177 (+/-137) microg.L-1 per 120 min, p = 0.010). Endurance exercise elicits a greater GH response than sprint and resistance exercise; however, aging per se, factors associated with aging, or an inability to achieve a sufficient absolute exercise intensity results in a smaller GH response to an exercise stimulus in early middle-aged men.


Multichromophoric hybrid species made of perylene bisimide derivatives and Ru(ii) and Os(ii) polypyridine subunits.
Herein, the synthesis and the photophysical and redox properties of a new perylene bisimide (PBI) species (L), bearing two 1,10-phenanthroline (phen) ligands at the two imide positions of the PBI, and its dinuclear Ru(ii) and Os(ii) complexes, [(bpy)2Ru(μ-L)Ru(bpy)2](PF6)4 (Ru2; bpy = 2,2'-bipyridine) and [(Me2-bpy)2Os(μ-L)Os(Me2-bpy)2](PF6)4 (Os2; Me2-bpy = (4,4'-dimethyl)-2,2'-bipyridine), are reported. The absorption spectra of the compounds are dominated by the structured bands of the PBI subunit due to the lowest-energy spin-allowed π-π* transition. The spin-allowed MLCT transitions in Ru2 and Os2 are inferred by the absorption at 350-470 nm, where the PBI absorption is negligible. The absorption band extends towards the red region for Os2 due to the spin-forbidden MLCT transitions, intensified by the heavy osmium center. The reduction processes of the compounds are dominated by two successive mono-electronic PBI-based processes, which in the metal complexes are slightly shifted compared to the free ligand. On oxidation, both metal complexes undergo an apparent bi-electronic process (at 1.31 V vs. SCE for Ru2 and 0.77 V for Os2), attributed to the simultaneous one-electron oxidation of the two weakly-interacting metal centers. In Ru2 and Os2, the intense fluorescence of L subunit (λmax, 535 nm; τ, 4.3 ns; Φ, 0.91) is fully quenched, mainly by photoinduced electron transfer from the metal centers, on the ps timescale (time constant, 11 ps in Ru2 and 3 ps in Os2). Such photoinduced electron transfer leads to the formation of a charge-separated state, which directly decays to the ground state in about 70 ps in Os2, but produces the triplet π-π* state of the PBI subunit in 35 ps in Ru2. The results provide information on the excited-state processes of the hybrid species combining two dominant classes of chromophore/luminophore species, the PBI and the metal polypyridine complexes, and can be used for future design on new hybrid species with made-to-order properties.


Primordial follicle activation as new treatment for primary ovarian insufficiency.
Primordial follicle activation is a process in which individual primordial follicles leave their dormant state and enter a growth phase. While existing hormone stimulation strategies targeted the growing follicles, the remaining dormant primordial follicles were ruled out from clinical use. Recently, in vitro activation (IVA), which is a method for controlling primordial follicle activation, has provided an innovative technology for primary ovarian insufficiency (POI) patients. IVA was developed based on Hippo signaling and phosphatase and tensin homolog (PTEN)/phosphatidylinositol- 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box O3 (FOXO3) signaling modulation. With this method, dormant primordial follicles are activated to enter growth phase and developed into competent oocytes. IVA has been successfully applied in POI patients who only have a few remaining remnant primordial follicles in the ovary, and healthy pregnancies and deliveries have been reported. IVA may also provide a promising option for fertility preservation in cancer patients and prepubertal girls whose fertility preservation choices are limited to tissue cryopreservation. Here, we review the basic mechanisms, translational studies, and current clinical results for IVA. Limitations and further study requirements that could potentially optimize IVA for future use will also be discussed.


Coinfection of leprosy and tuberculosis.
Leprosy and tuberculosis (TB) are endemic to India, however, their coinfection is not frequently encountered in clinical practice. Here, we report a 32-year-old female patient who presented with a history of high-grade intermittent fever, cough and painless skin lesions since a month, along with bilateral claw hand (on examination). The haematological profile was suggestive of anaemia of chronic disease, chest radiograph showed consolidation, sputum smears were positive for Mycobacterium tuberculosis, and skin slit smear confirmed leprosy. The patient was prescribed WHO recommended multidrug therapy for multibacillary leprosy with three drugs. Additionally, prednisolone was added to her regimen for 2 weeks to treat the type 2 lepra reaction. For treatment of TB, she was placed on the standard 6-month short course chemotherapy. She was lost to follow-up, and attempts were made to contact her. Later, it came to our notice that she had discontinued medications and passed away 3 months after diagnosis.


Decision-making Increases Episodic Memory via Postencoding Consolidation.
The ability for individuals to actively make decisions engages regions within the mesolimbic system and enhances memory for chosen items. In other behavioral contexts, mesolimbic engagement has been shown to enhance episodic memory by supporting consolidation. However, research has yet to investigate how consolidation may support interactions between decision-making and episodic memory. Across two studies, participants encoded items that were covered by occluder screens and could either actively decide which of two items to uncover or an item was preselected by the experimenter. In Study 1, we show that active decision-making reduces forgetting rates across an immediate and 24-hr memory test, a behavioral marker of consolidation. In Study 2, we use functional neuroimaging to characterize putative neural markers of memory consolidation by measuring interactions between the hippocampus and perirhinal cortex (PRC) during a postencoding period that reexposed participants to elements of the decision-making context without exposing them to memoranda. We show that choice-related striatal engagement is associated with increased postencoding hippocampal-PRC interactions. Finally, we show that a previous reported relationship between choice-related striatal engagement and long-term memory is accounted for by these postencoding hippocampal-PRC interactions. Together, these findings support a model by which actively deciding to encode information enhances memory consolidation to preserve episodic memory for outcomes, a process that may be facilitated by reexposure to the original decision-making context.


Surface cytotoxic T lymphocyte-associated antigen 4 partitions within lipid rafts and relocates to the immunological synapse under conditions of inhibition of T cell activation.
T cell activation through the T cell receptor (TCR) involves partitioning of receptors into discrete membrane compartments known as lipid rafts, and the formation of an immunological synapse (IS) between the T cell and antigen-presenting cell (APC). Compartmentalization of negative regulators of T cell activation such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is unknown. Recent crystal structures of B7-ligated CTLA-4 suggest that it may form lattices within the IS which could explain the mechanism of action of this molecule. Here, we show that after T cell stimulation, CTLA-4 coclusters with the TCR and the lipid raft ganglioside GM1 within the IS. Using subcellular fractionation, we show that most lipid raft-associated CTLA-4 is on the T cell surface. Such compartmentalization is dependent on the cytoplasmic tail of CTLA-4 and can be forced with a glycosylphosphatidylinositol-anchor in CTLA-4. The level of CTLA-4 within lipid rafts increases under conditions of APC-dependent TCR-CTLA-4 coligation and T cell inactivation. However, raft localization, although necessary for inhibition of T cell activation, is not sufficient for CTLA-4-mediated negative signaling. These data demonstrate that CTLA-4 within lipid rafts migrates to the IS where it can potentially form lattice structures and inhibit T cell activation.


Iron-induced lipid peroxidation in rat liver is accompanied by preferential induction of glutathione S-transferase 8-8 isozyme.
Since previous studies from this laboratory have suggested that glutathione S-transferase (GST) 8-8 of rat belongs to a distinct subgroup of GST isozymes which may be involved in the detoxification of the products of lipid peroxidation (Zimniak et al., J. Biol. Chem. 269, 992-1000, 1994), during the present studies we examined the effect of iron-induced lipid peroxidation on the expression of GST 8-8 in rat liver. Rats treated with 100 mg/kg body wt iron showed a significant increase in lipid peroxidation in liver. This was accompanied by a concomitant increase in the expression of GST 8-8 in liver as observed in isoelectrophoretic analysis of rat liver GSTs, and an increase in GST activity toward 4-HNE, a toxic product of lipid peroxidation toward which GST 8-8 displays high specific activity. Western blot studies using polyclonal antibodies specifically recognizing GST 8-8 also indicated that, among the GST isozymes of rat liver, GST 8-8 was preferentially induced upon iron treatment. These findings were further confirmed by purifying and quantitating GST 8-8 protein from the controls and iron-treated rats. Significant differences in the specific activities of GST 8-8 purified from the controls and iron-treated rats were observed, indicating that more than one GST isozyme related to GST 8-8 may be present in rat liver. This observation is consistent with the observed heterogeneity in mouse mGSTA4-4 which is an ortholog of rat GST 8-8. Iron treatment also caused significant increase in GSH levels probably because of de novo synthesis as indicated by an increase in gamma-glutamyl cysteine synthetase activity. The results of these studies suggest that GST 8-8, and possibly other related GST isozymes, may play an important role in defense mechanisms against lipid peroxidation.


Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling.
Primary rodent neurons and immortalised cell lines have overwhelmingly been used for in vitro studies of traumatic injury to peripheral and central neurons, but have some limitations of physiological accuracy. Motor neurons (MN) derived from human induced pluripotent stem cells (iPSCs) enable the generation of cell models with features relevant to human physiology. To facilitate this, it is desirable that MN protocols both rapidly and efficiently differentiate human iPSCs into electrophysiologically active MNs. In this study, we present a simple, rapid protocol for differentiation of human iPSCs into functional spinal (lower) MNs, involving only adherent culture and use of small molecules for directed differentiation, with the ultimate aim of rapid production of electrophysiologically functional cells for short-term neural injury experiments. We show successful differentiation in two unrelated iPSC lines, by quantifying neural-specific marker expression, and by evaluating cell functionality at different maturation stages by calcium imaging and patch clamping. Differentiated neurons were shown to be electrophysiologically altered by uniaxial mechanical deformation. Spontaneous network activity decreased with applied stretch, indicating aberrant network connectivity. These results demonstrate the feasibility of this rapid, simple protocol for differentiating iPSC-derived MNs, suitable for in vitro neural injury studies focussing on electrophysiological alterations caused by mechanical deformation or trauma.


Effects of Sleep Fragmentation and Induced Mood on Pain Tolerance and Pain Sensitivity in Young Healthy Adults.
Background: Experimental research exploring the sleep/pain-relationship has typically focused on total or partial sleep deprivation, hereby failing to reproduce the mere fragmented sleep pattern typically observed in patients with chronic pain. Further, little research is done on how affect moderates the sleep-pain relationship after sleep fragmentation. The present study sought to clarify the relationship between pain, sleep and positive and negative affect. Methods: In an experimental counterbalanced crossover design, 35 healthy young adults were subjected to several pain measures after one night of fragmented sleep, compared to one control night of normal sleep, both conducted in their own homes, and respectively, positive and negative affect induction using validated film clips and facial feedback procedures. Sleep was monitored using sleep diaries. Results: Increased pain sensitivity after one night of experimentally induced sleep fragmentation was found, compared to after one control night of undisturbed sleep. No main effects of induced affect on pain were found, and sleep x induced affect interaction was not significant. Conclusion: The present study supports the adverse effect of sleep fragmentation on pain sensitivity, however, affect was not found to be a moderator in the sleep-pain relationship. The results underline the need for further research within this field.


OMP-ZsGreen fluorescent protein transgenic mice for visualisation of olfactory sensory neurons in vivo and in vitro.
Research into the biology of the mammalian olfactory system would be greatly enhanced by transgenic reporter mice with cell-specific fluorescence. To this end we previously generated a mouse whose olfactory ensheathing cells (OECs) express DsRed driven by the S100ß promoter. We present here a transgenic reporter mouse whose olfactory sensory neurons express ZsGreen, driven by the olfactory marker protein (OMP) promoter. ZsGreen was very strongly expressed throughout the cytoplasm of olfactory sensory neurons labelling them in living cells and after fixation. Labelled sensory neurons were seen in all olfactory regions in the nose and fluorescent axons coursed through the lamina propria and into the main and accessory bulbs. We developed methods for culturing embryonic and postnatal olfactory sensory neurons using these mice to visualise living cells in vitro. ZsGreen was expressed along the length of axons providing exceptional detail of the growth cones. The ZsGreen fluorescence was very stable, without fading during frequent imaging. The combination of OMP-ZsGreen and S100ß-DsRed transgenic mice is ideal for developmental studies and neuron-glia assays and they can be bred with mutant mice to dissect the roles of various molecules in neurogenesis, differentiation, axon growth and targeting and other aspects of olfactory sensory neuron and glia biology.


The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells.
Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent substantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice. In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas. Importantly, loss of Cul3 expression was also detected in a large series of human liver cancers and correlated directly with tumor de-differentiation. The expression of Cul3 during hepatic differentiation therefore safeguards against the formation of progenitor cells that carry a great potential for transformation into tumor-initiating cells.


Inpatient costs for people with type 1 and type 2 diabetes in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group.
The rising prevalence of diabetes worldwide has increased interest in the cost of diabetes. Inpatient costs for all people with diabetes in Scotland were investigated. The Scottish Care Information-Diabetes Collaboration (SCI-DC), a real-time clinical information system of almost all diagnosed cases of diabetes in Scotland, UK, was linked to data on all hospital admissions for people with diabetes. Inpatient stay costs were estimated using the 2007-2008 Scottish National Tariff. The probability of hospital admission and total annual cost of admissions were estimated in relation to age, sex, type of diabetes, history of vascular admission, HbA(1c), creatinine, body mass index and diabetes duration. In Scotland during 2005-2007, 24,750 people with type 1 and 195,433 people with type 2 diabetes were identified, accounting for approximately 4.3% of the total Scottish population (5.1 million). The estimated total annual cost of admissions for all people diagnosed with type 1 and type 2 diabetes was £26 million and £275 million, respectively, approximately 12% of the total Scottish inpatient expenditure (£2.4 billion). Sex, increasing age, serum creatinine, previous vascular history and HbA(1c) (the latter differentially in type 1 and type 2) were all associated with likelihood and total annual cost of admission. Diabetes inpatient expenditure accounted for 12% of the total Scottish inpatient expenditure, whilst people with diabetes account for 4.3% of the population. Of the modifiable risk factors, HbA(1c) was the most important driver of cost in type 1 diabetes.


Survival of Bonded Space Maintainers: A Systematic Review.
This systematic review was aimed at evaluating the average survival time and the various factors which determine the longevity of bonded space maintainers. Although a meta-analysis could not be performed from the available literature, this review emphasizes the various factors contributing to the success of bonded space maintainers and its relevance during the planning of bonded space maintainers. The study selection criteria included in-vivo randomized and non-randomized clinical trials performed which was published in English. The databases searched were Pubmed, EBSCOhost and Google scholar, wherein the articles published from 1st January 1995 to 31st December 2015 were selected in the review. From the existing data, it can be concluded that the average survival period of bonded space maintainers is 11.2 months. However, there is a necessity for additional clinical trials with strict protocols to better the level of evidence. From the various articles included in the review, the longevity of bonded space maintainers was found to be comparable to the banded space maintainers. Hence, the bonded space maintainers can be a suitable alternative to the banded space maintainers in pediatric dentistry.How to cite this article: Deshpande SS, Bendgude VD, Kokkali VV. Survival of Bonded Space Maintainers: A Systematic Review Int J Clin Pediatr Dent. 2018;11(5):440-445.


Identification and Functional Characterization of Cis-Regulatory Elements Controlling Expression of the Porcine ADRB2 Gene.
The beta-2 adrenergic receptor (beta-2 AR) modulates metabolic processes in skeletal muscle, liver, and adipose tissue in response to catecholamine stimulation. We showed previously that expression of the porcine beta-2 AR gene (ADRB2) is affected by cis-regulatory polymorphisms. These are most likely responsible for the association of ADRB2 with economically relevant muscle-related traits in pigs. The present study focused on characterization of promoter elements involved in basal transcriptional regulation of the porcine ADRB2 in different cell types to aid identification of its cis-regulatory polymorphisms. Based on in silico analysis, luciferase reporter gene assays and gel shift assays were performed using COS-7, HepG2, C2C12, and 3T3-L1 cells. Deletion mapping of the 5´ flanking region (-1324 to +33) of ADRB2 revealed the region between -307 and -269 to be the minimal promoter, including regulatory elements essential for the basal transcriptional activity in all four tested cell types. Directly upstream (-400 to -323) we identified an important enhancer element required for maximal promoter activity. In silico analysis and gel shift assays revealed that this GC-rich element harbors two evolutionarily conserved binding sites of Sp1, a constitutive transcriptional activator. Significant transcriptional activation of the porcine ADRB2 promoter was demonstrated by overexpression of Sp1. Our results demonstrate, for the first time, an important role of Sp1 and of the responsive enhancer element in the regulation of ADRB2 expression. Polymorphisms located in this domain of the porcine ADRB2 promoter represent candidate causal cis-regulatory variants.


Natural atypical Listeria innocua strains with Listeria monocytogenes pathogenicity island 1 genes.
Identification of bona fide Listeria isolates into the six species of the genus normally requires only a few tests. Aberrant isolates do occur, but even then only one or two extra confirmatory tests are generally needed for identification to species level. We have discovered a hemolytic-positive, rhamnose and xylose fermentation-negative Listeria strain with surprising recalcitrance to identification to the species level due to contradictory results in standard confirmatory tests. The issue had to be resolved by using total DNA-DNA hybridization testing and then confirmed by further specific PCR-based tests including a Listeria microarray assay. The results show that this isolate is indeed a novel one. Its discovery provides the first fully documented instance of a hemolytic Listeria innocua strain. This species, by definition, is typically nonhemolytic. The L. innocua isolate contains all the members of the PrfA-regulated virulence gene cluster (Listeria pathogenicity island 1) of L. monocytogenes. It is avirulent in the mouse pathogenicity test. Avirulence is likely at least partly due to the absence of the L. monocytogenes-specific allele of iap, as well as the absence of inlA, inlB, inlC, and daaA. At least two of the virulence cluster genes, hly and plcA, which encode the L. monocytogenes hemolysin (listeriolysin O) and inositol-specific phospholipase C, respectively, are phenotypically expressed in this L. innocua strain. The detection by PCR assays of specific L. innocua genes (lin0198, lin0372, lin0419, lin0558, lin1068, lin1073, lin1074, lin2454, and lin2693) and noncoding intergenic regions (lin0454-lin0455 and nadA-lin2134) in the strain is consistent with its L. innocua DNA-DNA hybridization identity. Additional distinctly different hemolytic L. innocua strains were also studied.


Comparative Analysis of African and Asian Lineage-Derived Zika Virus Strains Reveals Differences in Activation of and Sensitivity to Antiviral Innate Immunity.
In recent years, Asian lineage Zika virus (ZIKV) strains emerged to cause pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZVS). The reasons for the enhanced spread and severe disease caused by newly emerging strains are not fully understood. Here we compared viral sequences, viral replication, and innate immune signaling induction of three different ZIKV strains derived from African and Asian lineages and West Nile virus, another flavivirus. We found pronounced differences in activation of innate immune signaling and inhibition of viral replication across ZIKV strains. The newly emerged Asian ZIKV strain Brazil Fortaleza 2015, which is associated with a higher rate of neurodevelopmental disorders like microcephaly, induced much weaker and delayed innate immune signaling in infected cells. However, superinfection studies to assess control of innate immune signaling induced by Sendai virus argue against an active block of IRF3 activation by the Brazilian strain of ZIKV and rather suggest an evasion of detection by host cell pattern recognition receptors. Compared to the Asian strain FSS13025 isolated in Cambodia, both ZIKV Uganda MR766 and ZIKV Brazil Fortaleza appear less sensitive to the interferon-induced antiviral response. ZIKV infection studies of cells lacking the different RIG-I-like receptors identified RIG-I as the major cytosolic pattern recognition receptor for detection of ZIKV.IMPORTANCE Zika Virus (ZIKV), discovered in 1947, is divided into African and Asian lineages. Pandemic outbreaks caused by currently emerging Asian lineage strains are accompanied by high rates of neurological disorders and exemplify the global health burden associated with this virus. Here we compared virological and innate immunological aspects of two ZIKV strains from the Asian lineage, an emerging Brazilian strain and a less-pathogenic Cambodian strain, and the prototypic African lineage ZIKV strain from Uganda. Compared to the replication of other ZIKV strains, the replication of ZIKV Brazil was less sensitive to the antiviral actions of interferon (IFN), while infection with this strain induced weaker and delayed innate immune responses in vitro Our data suggest that ZIKV Brazil directs a passive strategy of innate immune evasion that is reminiscent of a stealth virus. Such strain-specific properties likely contribute to differential pathogenesis and should be taken into consideration when choosing virus strains for future molecular studies.


Photoacoustic emission from fluorescent nanodiamonds enhanced with gold nanoparticles.
Fluorescent nanodiamonds (FNDs) have drawn much attention in recent years for biomedical imaging applications due to their desired physical properties including excellent photostability, high biocompatibility, extended far-red fluorescence emission, and ease of surface functionalization. Here we explore a new feature of FNDs, i.e. their photoacoustic emission capability, which may lead to potential applications of using FNDs as a dual imaging contrast agent for combined fluorescence and photoacoustic imaging modalities. We observed significant enhancement of photoacoustic emission from FNDs when they were conjugated with gold nanoparticles (GNPs).


Long-term benefit of transoral incisionless fundoplication using the esophyx device for the management of gastroesophageal reflux disease responsive to medical therapy.
Transoral incisionless fundoplication (TIF) using the EsophyX device has been shown to be effective and safe in patients with Gastroesophageal reflux disease (GERD); however, the subset of patients that would mostly benefit from this technique remains unknown. The aim of this study was to evaluate the long-term efficacy and safety of the TIF procedure in patients with a history of esophagitis or proven chronic GERD who have achieved symptom control with the administration of proton pump inhibitors (PPIs) but did not wish to continue receiving medications for life. Forty-five patients with typical GERD symptoms (heartburn, regurgitation, chest pain) and a history of esophagitis grade A and B or proven GERD by esophageal pH monitoring underwent TIF using Esophyx. Patients with eosphagitis C and D or those with large hiatal hernias (>2 cm in length) were excluded. The primary clinical effectiveness measure was GERD symptom elimination at follow up based on normalization of the GERD health related quality of life (GERD-HRQL) questionnaire. After a median follow up period of 59 months (36-75) the median GERD-HRQL scores improved significantly from 27 (2-45) at baseline to 4 (0-26) (P < 0.001) in the 44 patients completing the study. Heartburn was eliminated in 12 out of the 21 patients included (57.1%), regurgitation was eliminated in 15 out of the 17 patients included (88.2%) and finally chest pain was eliminated in 5 patients out of the six patients included (83.3%). Overall, 32 patients out of the 44 patients (72.7%) that completed the study follow up reported elimination of their main symptom, without the need for PPI administration (none PPI usage). Furthermore, six more patients (13.6%), five with heartburn, and one with regurgitation reported half PPI dose taken for <50% of the preceding follow up period (occasional PPI usage), while six more patients (four with heartburn, one with regurgitation, and one with chest pain) reported full or half PPI dose taken for more than 50% of the preceding follow up period (daily PPI usage). Creation of an esophagogastric fundoplication using the EsophyX device abolished reflux symptoms in 72.7% of PPI-responsive GERD patients at a median 59 month follow-up.


[Heart disease, pregnancy and anticoagulant therapy].
Pregnancy is a hypercoagulable state. Some women with cardiac disease and mechanical valve prosthesis are at increased risk of arterial thromboembolic phenomena. These women are maintained on oral anticoagulants and require effective permanent prophylaxis during pregnancy. The use of oral anticoagulants during pregnancy is controversial because of the risks of embriopathy (Chondrodysplasia punctata) in fetuses who are exposed to coumarin between the 6th and 9th week of gestation, the risk of neurological disorders all through pregnancy, and a higher incidence of abortion and stillbirths. The exact incidence of these complications is unknown. Most of this information comes from North American reports, when much higher mean daily doses of coumarin were administered, and they were probably overemphasised. Reports from Europe, Asia and our own, show that both embriopathy and central nervous system malformations are probably dose-related and that the risks of abnormality to the fetus are small. The ACC Antithrombotic Consensus (1998) recommends the use of subcutaneous heparin all through pregnancy or until the 13th week of gestation. Heparin does not cross the placenta, however there is a higher risk of maternal bleeding, abortion and stillbirths. With the use of small dose of heparin and of therapeutic heparin doses there is a risk of prosthesis thrombosis. Anticoagulant treatment of patients with prosthetic heart valves during pregnancy remains controversial. Subcutaneous heparin prophylaxis is feasible but the use of well controlled oral anticoagulants appear to offer lower risks of maternal and fetal complications.


Genome-wide studies highlight indirect links between human replication origins and gene regulation.
To get insights into the regulation of replication initiation, we systematically mapped replication origins along 1% of the human genome in HeLa cells. We identified 283 origins, 10 times more than previously known. Origin density is strongly correlated with genomic landscapes, with clusters of closely spaced origins in GC-rich regions and no origins in large GC-poor regions. Origin sequences are evolutionarily conserved, and half of them map within or near CpG islands. Most of the origins overlap transcriptional regulatory elements, providing further evidence of a connection with gene regulation. Moreover, we identify c-JUN and c-FOS as important regulators of origin selection. Half of the identified replication initiation sites do not have an open chromatin configuration, showing the absence of a direct link with gene regulation. Replication timing analyses coupled with our origin mapping suggest that a relatively strict origin-timing program regulates the replication of the human genome.


Mother-infant and father-infant attachment among alcoholic families.
This study examined the association between fathers' alcoholism and other risk factors such as parental depression, family conflict, infant temperament, and parent-infant attachment. The quality of parent-infant interactions was hypothesized to be a proximal mediator of the associations among alcoholism and other risk factors and attachment. The participants were 223 families (104 nonalcoholic families and 119 alcoholic families) with 12-month-old infants recruited through birth records. Infants in families with two parents with alcohol problem had significantly higher rates of insecure attachment with both parents. Structural Equations Modeling indicated that the fathers' alcohol problem was associated with lower paternal sensitivity (higher negative affect, lower positive engagement, and lower sensitive responding) during father-infant play interactions, and this in tum was associated with higher risk for infant attachment insecurity with fathers. The association between the fathers' alcohol problem and infant attachment security with the mother was mediated by matemal depression, and matemal alcohol problems and family conflict were associated with maternal sensitivity during play interactions. These results indicate that the fathers' alcoholism is associated with higher family risk including the quality of the parent-infant relationship; infant attachment develops in a family context; and this context has a significant association with attachment security.


Potential Distribution and the Risks of Bactericera cockerelli and Its Associated Plant Pathogen Candidatus Liberibacter Solanacearum for Global Potato Production.
The tomato potato psyllid (TPP), Bactericera cockerelli, is a psyllid native to North America that has recently invaded New Zealand and Australia. The potential for economic losses accompanying invasions of TPP and its associated bacterial plant pathogen Candidatus Liberibacter solanacearum (CLso), has caused much concern. Here, we employed ecological niche models to predict environments suitable for TPP/CLso on a global scale and then evaluated the extent to which global potato cultivation is at risk. In addition, at a finer scale the risk to the Australian potato acreage was evaluated. A total of 86 MaxEnt models were built using various combinations of settings and climatic predictors, and the best model based on model evaluation metrics was selected. Climatically suitable habitats were identified in Eurasia, Africa, South America, and Australasia. Intersecting the predicted suitability map with land use data showed that 79.06% of the global potato cultivation acreage, 96.14% of the potato production acreage in South America and Eurasia, and all the Australian potato cropping areas are at risk. The information generated by this study increases knowledge of the ecology of TPP/CLso and can be used by government agencies to make decisions about preventing the spread of TPP and CLso across the globe.


Surgical and radiotherapeutic approaches for myelofibrosis with myeloid metaplasia.
Sequestration of circulating immature myeloid progenitors in the chronic myeloproliferative disorder myelofibrosis with myeloid metaplasia (MMM) leads to extramedullary hematopoiesis (EMH), as well as end organ enlargement and dysfunction. When medical therapy is inadequate to control symptomatic myeloproliferation, both surgical resection and/or external beam radiotherapy may provide palliative cytoreduction in specific situations. Therapeutic splenectomy may provide relief of pain, mass effect, an improvement in cytopenias, or even palliation of portal hypertension. However, the risks of perioperative and long-term complications limit the use of splenectomy in MMM to specific candidates. In addition to splenectomy, portal hypertension has been palliated by either elective esophageal variceal ligation or porto-systemic shunting (through either open or invasive radiographic means). External beam radiotherapy can provide palliative cytoreduction in afflicted organs, with the greatest benefit seen in the lungs and spine. Splenic radiation also can provide a decrease in the size of the organ but carries the risk of myelosuppression and potentially increases the risk associated with subsequent splenectomy. Hepatic and abdominal radiation may palliate hepatomegaly and/or ascites, but cytopenias are common and responses brief. Novel therapies aimed at the pathogenesis of the disorder are needed for more efficacious and targeted therapy of MMM.


The application of in vivo confocal scanning laser microscopy in the diagnosis and evaluation of treatment responses in Mooren's ulcer.
To evaluate the extent of corneal inflammation and the response to treatment in patients with Mooren's ulcer, by in vivo confocal microscopy (IVCM). Twenty-two eyes of 15 patients with Mooren's ulcer were enrolled in this prospective study. All subjects underwent routine ophthalmic examinations, IVCM, and conjunctival histopathologic examination of specimens in patients undergoing conjunctival excision. Eyes with active ulcer were treated with topical corticosteroids and additional therapy, depending on the signs and symptoms. Eyes in remission continued to receive the previous treatment protocols. The relation between the severity of ulcer and inflammation status as assessed by IVCM was also studied. The endpoints were inflammatory cell density (ICD), counted by IVCM, and the extent of the limbal arc involved with ulcers. Ten eyes had active corneal ulcers, and 12 eyes had been in remission for the past year. The mean ICD of eyes with active ulcers before treatment was 2092.7 ± 1538.6 cells/mm(2) (range, 835.3-7832.7; 95% CI, 3232.5-952.9). Nine of the eyes improved at 8 weeks, with a decrease in ICD to 249.1 ± 109.0 cells/mm(2) (range, 100.3-595.3; 95% CI, 329.8-168.3). One eye had corneal perforation, and ICD immediately before perforation was 1677.6 ± 247.6 cells/mm(2). The mean ICD of 12 eyes in remission was 357.5 ± 266.8 cells/mm(2) (range, 12.7-1127.0; 95% CI, 555.2-159.8). The correlation of the ICD and the extent of limbal involvement with ulcers was strong (R(2) = 0.8119). ICD evaluated by IVCM is a useful and promising parameter for evaluation of the degree of inflammation in eyes with Mooren's ulcer and for assessment of response to treatment.


Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.
Metabotropic glutamate receptor subtype 5 (mGlu5) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu5 PAMs do not activate mGlu5 directly but selectively potentiate activation of mGlu5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu5 activation and achieving optimal in vivo effects. Using specially engineered mGlu5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate. Both in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations. Loss of the absolute dependence of mGlu5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia.