Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts.
The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER-/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change.


Salazinic Acid and Norlobaridone from the Lichen Hypotrachyna cirrhata: Antioxidant Activity, α-Glucosidase Inhibitory and Molecular Docking Studies.
The present study was intended for the identification of secondary metabolites in acetone extract of the lichen Hypotrachyna cirrhata using UPLC-ESI-QToF-MS/MS and the detection of bioactive compounds. This study led to the identification of 22 metabolites based on their MS/MS spectra, accurate molecular masses, molecular formula from a comparison of the literature database (DNP), and fragmentation patterns. In addition, potent antioxidant and α-glucosidase inhibitory potentials of acetone extract of H. cirrhata motivated us to isolate 10 metabolites, which were characterized as salazinic acid (11), norlobaridone (12), atranorin (13), lecanoric acid (14), lichesterinic acid (15), protolichesterinic acid (16), methyl hematommate (17), iso-rhizonic acid (18), atranol (19), and methylatratate (20) based on their spectral data. All these isolates were assessed for their free radicals scavenging, radical-induced DNA damage, and intestinal α-glucosidase inhibitory activities. The results indicated that norlobaridone (12), lecanoric acid (14), methyl hematommate (17), and atranol (19) showed potent antioxidant activity, while depsidones (salazinic acid (11), norlobaridone (12)) and a monophenolic compound (iso-rhizonic acid, (18)) displayed significant intestinal α-glucosidase inhibitory activities (p < 0.001), which is comparable to standard acarbose. These results were further correlated with molecular docking studies, which indicated that the alkyl chain of norlobaridione (12) is hooked into the finger-like cavity of the allosteric pocket; moreover, it also established Van der Waals interactions with hydrophobic residues of the allosteric pocket. Thus, the potency of norlobaridone to inhibit α-glucosidase enzyme might be associated with its allosteric binding. Also, MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) binding free energies of salazinic acid (11) and norlobaridone (12) were superior to acarbose and may have contributed to their high activity compared to acarbose.


Attenuation of hind-limb ischemia in mice with endothelial-like cells derived from different sources of human stem cells.
Functional endothelial-like cells (EC) have been successfully derived from different cell sources and potentially used for treatment of cardiovascular diseases; however, their relative therapeutic efficacy remains unclear. We differentiated functional EC from human bone marrow mononuclear cells (BM-EC), human embryonic stem cells (hESC-EC) and human induced pluripotent stem cells (hiPSC-EC), and compared their in-vitro tube formation, migration and cytokine expression profiles, and in-vivo capacity to attenuate hind-limb ischemia in mice. Successful differentiation of BM-EC was only achieved in 1/6 patient with severe coronary artery disease. Nevertheless, BM-EC, hESC-EC and hiPSC-EC exhibited typical cobblestone morphology, had the ability of uptaking DiI-labeled acetylated low-density-lipoprotein, and binding of Ulex europaeus lectin. In-vitro functional assay demonstrated that hiPSC-EC and hESC-EC had similar capacity for tube formation and migration as human umbilical cord endothelial cells (HUVEC) and BM-EC (P>0.05). While increased expression of major angiogenic factors including epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor, placental growth factor and stromal derived factor-1 were observed in all EC cultures during hypoxia compared with normoxia (P<0.05), the magnitudes of cytokine up-regulation upon hypoxic were more dramatic in hiPSC-EC and hESC-EC (P<0.05). Compared with medium, transplanting BM-EC (n = 6), HUVEC (n = 6), hESC-EC (n = 8) or hiPSC-EC (n = 8) significantly attenuated severe hind-limb ischemia in mice via enhancement of neovascularization. In conclusion, functional EC can be generated from hECS and hiPSC with similar therapeutic efficacy for attenuation of severe hind-limb ischemia. Differentiation of functional BM-EC was more difficult to achieve in patients with cardiovascular diseases, and hESC-EC or iPSC-EC are readily available as "off-the-shelf" format for the treatment of tissue ischemia.


Sociology of the professions: what it means for podiatry.
The health professions have progressed and evolved considerably over the last few decades in response to demographic, technological, societal and political changes. They continue to do so as the volume and complexity of population health needs steadily increase. Role boundary expansion is among the key changes to the health professions, including podiatry to meet demand. Nonetheless podiatry's role boundary expansion has not been achieved swiftly or without resistance from neighbouring and dominant professions. This paper seeks to explain the nature of this resistance with respect to the sociology of the professions literature and to shed light on some of the factors and processes at play when role boundary changes arise in health care. Six of the most contemporaneously relevant sociology of the professions theories are summarised: Taxonomic, Marxian, Bourdieusian, Foucauldian, Boundary Work and Neo-Weberian paradigms. This review highlights that some paradigms are more relevant than others in the current socio-political landscape. It also illustrates that there is a common theme underlying each approach to defining the professions and their boundaries: competition. This may help health professionals, including podiatrists, to understand and manage the challenges and resistance experienced when professions attempt to expand role boundaries to meet increasing and changing population health needs.


Dietary patterns and the risk of breast cancer in Japanese women.
Components of the Japanese diet that might contribute to the relatively low breast cancer incidence in Japanese women have not been clarified in detail. To evaluate associations between broad dietary patterns and breast cancer risk in a Japanese population, the authors conducted a case-control study using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). Factor analysis (principal components) was used to derive food patterns based on the 31 food variables and allowed designation of four major dietary patterns: prudent, fatty, Japanese and salty. In total, 1885 breast cancer cases were included and 22,333 female non-cancer patients were recruited as the control group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined using multiple logistic regression analysis. After adjusting for potential confounders, there were no clear associations between the fatty, Japanese or salty dietary patterns and overall breast cancer risk. In contrast, an inverse association was evident for the prudent dietary. Women in the highest quartile of the prudent dietary pattern scores, had a 27% decreased risk of breast cancer compared with those in the lowest (95% CI: 0.63-0.84, p for trend < 0.0001). In addition, for women with a body mass index > or = 25, the highest quartile of the fatty factor score was associated with a 58% increment in breast cancer risk compared to the lowest quartile, with a significant linear trend (P = 0.027). The authors found the prudent dietary pattern to be negatively associated with breast cancer risk. In addition, the fatty and Japanese patterns may increase breast cancer risk among obese women.


Early childhood education and crime.
This article presents new evidence on the crime-reducing impacts of a high-quality, intensive early childhood program with long-term follow-up, evaluated by a randomized controlled trial. Proportionately, more women than men decrease their criminal activity after participating in the program. This gender difference arises because of the worse home environments for girls, with corresponding greater scope for improvement by the program. For both genders, treatment effects are larger for the least-advantaged children, as measured by their mother's education at baseline. The dollar value of the social cost of criminal activity averted is higher for men because they commit more costly violent crimes.


Myocardial infarct extension: incidence and relationship to survival.
Myocardial infarct extension, defined as reelevation or reappearance of creatine phosphokinase-MB (CK-MB) 48 hours after the onset of symptoms, was evaluated prospectively in 56 consecutive patients with acute myocardial infarction. Myocardial infarct extension occurred in eight patients (14%). The sensitivity, specificity and predictive accuracy in the diagnosis of myocardial infarct extension were 63%, 85% and 42%, respectively, for recurrent chest pain requiring morphine; 50%, 65% and 19% for recurrent ST-segment elevation on routine 12-lead ECGs; and 88%, 63% and 28% for reelevation of total CK. Three of the eight episodes of extension were clinically silent. Four of eight patients (50%) with extension died, compared with one of 46 patients (2%) without extension (p = 0.0009). CK-MB persisted for 72 hours or longer in 16 patients and identified seven of eight patients who subsequently had infarct extension. We conclude that myocardial infarct extension is an infrequent complication of acute myocardial infarction and is associated with a very high mortality rate. Persistence of CK-MB for 72 hours or more identifies a subgroup of patients at high risk for subsequent infarct extension and death.


The sexual brain, genes, and cognition: A machine-predicted brain sex score explains individual differences in cognitive intelligence and genetic influence in young children.
Sex impacts the development of the brain and cognition differently across individuals. However, the literature on brain sex dimorphism in humans is mixed. We aim to investigate the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive performance. To this end, we tested whether the individual difference in brain sex would be linked to that in cognitive performance that is influenced by genetic factors in prepubertal children (N = 9,658, ages 9-10 years old; the Adolescent Brain Cognitive Development study). To capture the interindividual variability of the brain, we estimated the probability of being male or female based on the brain morphometry and connectivity features using machine learning (herein called a brain sex score). The models accurately classified the biological sex with a test ROC-AUC of 93.32%. As a result, a greater brain sex score correlated significantly with greater intelligence (pfdr < .001, ηp2 = .011-.034; adjusted for covariates) and higher cognitive genome-wide polygenic scores (GPSs) (pfdr < .001, ηp2 < .005). Structural equation models revealed that the GPS-intelligence association was significantly modulated by the brain sex score, such that a brain with a higher maleness score (or a lower femaleness score) mediated a positive GPS effect on intelligence (indirect effects = .006-.009; p = .002-.022; sex-stratified analysis). The finding of the sex modulatory effect on the gene-brain-cognition relationship presents a likely biological pathway to the individual and sex differences in the brain and cognitive performance in preadolescence.


Regularization parameter based on incomplete variables for X-ray luminescence computed tomography.
X-ray luminescence computed tomography (XLCT) is an emerging molecular imaging technique for biological application. However, it is still a challenge to get a stable and accurate solution of the reconstruction of XLCT. This paper presents a regularization parameter selection strategy based on incomplete variables frame for XLCT. A residual information, which is derived from Karush-Kuhn-Tucker (KKT) equivalent condition, is employed to determine the regularization parameter. This residual contains the relevant information about the solution norm and gradient norm, which improved the recovered results. Simulation and phantom experiments are designed to test the performance of the algorithm.Clinical Relevance- The results have not yet been used in clinical relevance currently, we believed that this strategy will facilitate the development of the preclinical applications in FMT.


Building on the past--challenging the future: will genomics provide the solution to hypertension?
Hypertension is one of the major common polygenic and multifactorial diseases, and continues to constitute a major cause of morbidity and mortality worldwide. The pathophysiological mechanisms underlying hypertension have not been elucidated, which significantly limits our ability to treat and prevent hypertension. A frequently asked question is whether genomics will provide the solution to the many remaining unanswered questions as to the causes of hypertension. Genomics, an art by its own virtue, holds its promises, yet the questions we are asking of genomics must be well defined for genomics to meet at least some of our expectations. The hopes and promises of genomics are high and one of the major hopes is that genomics will improve our understanding of the pathophysiology of hypertension and enable us to classify hypertensive syndromes more succinctly and enhance our ability to provide patients with specific anti-hypertensive therapy as well as predict outcome. There is still much to be done but perseverance in the task and a firm belief in genomics and in the immense potential of the human genome is essential.


A robust curve-fitting procedure for the analysis of plasmid DNA strand break data from gel electrophoresis.
A robust method for fitting to the results of gel electrophoresis assays of damage to plasmid DNA caused by radiation is presented. This method makes use of nonlinear regression to fit analytically derived dose-response curves to observations of the supercoiled, open circular and linear plasmid forms simultaneously, allowing for more accurate results than fitting to individual forms. Comparisons with a commonly used analysis method show that while there is a relatively small benefit between the methods for data sets with small errors, the parameters generated by this method remain much more closely distributed around the true value in the face of increasing measurement uncertainties. This allows for parameters to be specified with greater confidence, reflected in a reduction of errors on fitted parameters. On test data sets, fitted uncertainties were reduced by 30%, similar to the improvement that would be offered by moving from triplicate to fivefold repeats (assuming standard errors). This method has been implemented in a popular spreadsheet package and made available online to improve its accessibility.


Aprotinin reduces blood loss during spinal surgery in children.
A prospective blinded, randomized controlled study compared the effect of a perioperative infusion of aprotinin versus placebo during long segment spinal fusions in children. To determine whether aprotinin decreases blood loss and transfusion requirements in pediatric patients with spinal deformities undergoing posterior spinal fusions of seven or greater segments. Blood loss is a major cause of morbidity during long segment spinal fusion. Several preoperative and intraoperative techniques are currently used to reduce blood loss and transfusion requirements. Aprotinin, an antifibrinolytic and anti-inflammatory agent, has been used to decrease blood loss in cardiac surgical patients. We designed a prospective, randomized, and blinded controlled study to evaluate aprotinin's efficacy in reducing bleeding during pediatric spine surgery. After obtaining informed written consent, we studied 44 children and adolescents who were anticipated to be at higher risk for major blood loss during posterior spinal fusion. Children were randomly assigned to receive high dose aprotinin or placebo infusion during the perioperative period. Patients were assessed for blood loss, transfusion requirements, days in the intensive care unit, and days in hospital. Demographics in the two groups of patients were similar. The study demonstrated a significant reduction in estimated blood loss (aprotinin 545 cc, placebo 930 cc) and transfusion requirements (aprotinin 1.1 U, placebo 2.2 U). The duration of intensive care unit admission was similar in the two groups, as was the time until discharge. This randomized, blinded study suggests that aprotinin significantly decreased blood loss and transfusion requirements in pediatric and adolescent scoliosis surgical patients at increased risk for intraoperative bleeding.


Functional Outcome and Complications in Management of Proximal Humerus Fractures Operated with Proximal Humerus Locking Plate.
Controversies exist in treatment of proximal humerus fractures as treatment options vary greatly from conservative management, closed pinning, stacked intramedullary nails, plating and hemi-arthroplasty. The purpose of this study is to study the fracture patterns of each case and document the functional outcome and complications post-operative in the management of proximal humerus fractures operated with proximal humerus plate. Thirty five patients with closed proximal humerus fractures, above 18 years old, admitted in our tertiary care hospital during the study period were enrolled. Patients underwent open reduction internal fixation with proximal humerus locking plate under general anaesthesia. Post-operative patients were assessed using Constant and DASH scores. Complications were recorded. In our study the absolute Constant score of the study population increases at three months and six months and was found to be significant. Mean Constant score for 4-part fractures was 45.6 which were inferior as compared to 2-part and 3-part fractures (43.1 and 44.6, respectively). The mean Constant score at six months was 51.80 +/- 6.71. All three types of proximal humerus fractures showed significant improvement in the mean DASH score over our study period of six months and was found to be significant. Mean DASH score at six months was 27.97+/-12.84. Out of the 35 cases in the study two had complications. One had implant failure (Neer's type 3, 60-year-old female) and one had varus collapse (Neer's type 3, 45-year-old male). Due to angular stability and effective maintenance of the intraoperative fracture reduction during follow-up period, early post-operative mobilisation is possible which helps the patient to attain better shoulder range of motion and return to activity faster.


[Chilean results of the international registry of risk factors and treatment of unstable angina and non ST elevation myocardial infarction: ACCORD (ACute CORonary syndrome Descriptive study)].
Guidelines for the management of unstable angina (UA) and non ST elevation myocardial infarction (NSTEMI) have been issued, however, current practices are unknown in Chile. To evaluate in a prospective cohort of NSTEMI patients the current practices, treatments and risk factors. One year prospective International non interventional registry, conducted in Chile between January 2005 and November 2006. Two hundred thirty three Chilean NSTEMI patients were enrolled. Mortality was 5.5% at the end of the follow-up. Mean age was 61.6 years, and 30.6% were female. Most of the patients had at least one risk factor (98%): hypertension (84%), previous myocardial infarction (33%), dyslipidemia (54%), diabetes (33%), current smoking (30%). Main procedures during the hospitalization were coronary angiogram (67%), angioplasty (33%; 88% with stent) and coronary bypass surgery (7%). During procedures, 31% of patients received clopidogrel, and 4.2% glycoprotein Ilb/IIIa antagonists. Medical management was selected for 60% of patients. In comparison to men, women received less interventional procedures despite having more risk factors. Treatments prescribed at discharge were aspirin (97%), clopidogrel (49%), beta blockers (78%), diuretics (21%), lipid lowering agents (78%), oral hypoglycemic agents (13%) and insulin (9%). At the end of the 1-year follow-up, treatments were aspirin (84%), beta blockers (72%), diuretics (19%), and dual antiplatelet therapy with clopidogrel (16%). A high prevalence of multiple risk factors for cardiovascular disease in Chilean patients with NSTEMI was observed. More aggressive primary and secondary preventive measures are urgently needed. Use of therapies proposed in the guidelines is high, but dual antiplatelet therapy is less than 50% at discharge and decreases during the one year-follow-up.


Assessment of suicide risk in mental health practice: shifting from prediction to therapeutic assessment, formulation, and risk management.
Suicide prevention in psychiatric practice has been dominated by efforts to predict risk of suicide in individual patients. However, traditional risk prediction measures have been shown repeatedly in studies from high income countries to be ineffective. Several factors might contribute to clinicians' preoccupation with risk prediction, which can have negative effects on patient care and also on clinicians where prediction is seen as failing. The model of therapeutic risk assessment, formulation, and management we outline in this article regards all patients with mental health problems as potentially at increased risk of suicide. It is aimed at reducing risk through use of a person-centred approach. We describe how a move towards therapeutic risk assessment, formulation, and risk management, including collaborative safety planning, could help clinicians develop a more tailored approach to managing risk for all patients, incorporating potentially therapeutic effects as well as helping to identify other risk reduction interventions. Such an approach could lead to enhanced patient safety and quality of care, which is more acceptable to patients.


A cross-sectional comparison of breastfeeding knowledge, attitudes, and perceived partners' support among expectant couples in Mekelle, Ethiopia.
Breastfeeding is considered the biological norm and essential to reduce infant morbidity and mortality. Mothers are responsible for breastfeeding but the support of others, including their partners is an influential determinant. The aim of this study was to compare antenatal breastfeeding knowledge, attitudes, and perceived breastfeeding support of expectant couples in Mekelle, Ethiopia. As part of a randomised controlled trial of an mHealth intervention, 128 couples in their third trimester from three selected health centres in Mekelle city were recruited to participate between September and October 2018. Couples who each had a personal mobile phone, read and spoke Tigrigna, and lived together were included. Baseline data on breastfeeding knowledge, attitudes, and perceived support (breastfeeding savvy, help, appreciation, presence and responsiveness) were collected using previously validated tools through interview by health workers. Compared to mothers, male partners were more likely to indicate their intention to provide breastfeeding appreciation (p = 0.02), breastfeeding presence (p = 0.002), and breastfeeding responsiveness (p = 0.04). The mothers' prenatal perception of their partners' intended breastfeeding support was lower than fathers' perceptions to support their partners. Multiparous mothers had more positive perceptions regarding their partners' breastfeeding savvy (p = 0.03), and breastfeeding help (p = 0.02) compared to primiparous mothers. Fathers in Ethiopia are potentially strong supporters of breastfeeding practice. Future breastfeeding interventions should promote the involvement of fathers in breastfeeding and encourage mothers to increase their partners' involvement in breastfeeding.


The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis.
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mϕs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE2 receptor EP2. However, human Mϕs also express EP4, a PGE2 receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mϕs have been unclear. EP4 antagonist addition to H37Ra-infected Mϕs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase-1 (mPGES-1), which are involved in PGE2 production. Moreover, H37Ra infection induced PGE2 production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected Mϕs, PGE2 production induced by pathogen recognition receptors/p38 MAPK signaling is up-regulated by EP4-triggered signaling to maintain an effective PGE2 concentration.


Genetically encoded fluorescent biosensors illuminate kinase signaling in cancer.
Protein kinase signaling networks stringently regulate cellular processes, such as proliferation, motility, and cell survival. These networks are also central to the evolution and progression of cancer. Accordingly, genetically encoded fluorescent biosensors capable of directly illuminating the spatiotemporal dynamics of kinase signaling in live cells are being increasingly used to investigate kinase signaling in cancer cells and tumor tissue sections. These biosensors enable visualization of biological processes and events directly in situ, preserving the native biological context and providing detailed insight into their localization and dynamics in cells. Herein, we first review common design strategies for kinase activity biosensors, including signaling targets, biosensor components, and fluorescent proteins involved. Subsequently, we discuss applications of biosensors to study the biology and management of cancer. These versatile molecular tools have been deployed to study oncogenic kinase signaling in living cells and image kinase activities in tumors or to decipher the mechanisms of anticancer drugs. We anticipate that the diversity and precision of genetically encoded biosensors will expand their use to further unravel the dysregulation of kinase signaling in cancer and the modes of actions of cancer-targeting drugs.


Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons.
Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to the development and maintenance of paclitaxel-induced pain.


New Evidence Supporting a Novel Conceptual Framework for Distinguishing Proportionate and Disproportionate Functional Mitral Regurgitation.
Traditionally, physicians distinguished between mitral regurgitation (MR) as a determinant of outcomes and MR as a biomarker of left-ventricular (LV) dysfunction by designating the lesions as primary or secondary, respectively. In primary MR, leaflet abnormalities cause the MR, resulting in modest increases in LV end-diastolic volume over time, whereas in patients with classic secondary MR, LV dysfunction and dilatation lead to MR without structural leaflet abnormalities. However, certain patients with global LV disease (eg, those with left bundle branch block or regional wall motion abnormalities) have the features of primary MR and might respond favorably to interventions that aim to restore the proper functioning of the mitral valve apparatus. A novel conceptual framework is proposed, which classifies patients with meaningful LV disease based on whether the severity of MR is proportionate or disproportionate to the LV end-diastolic volume. Treatments that reduce LV volumes (eg, neurohormonal antagonists) are effective in proportionate MR but not disproportionate MR. Conversely, procedures that restore mitral valve function (eg, cardiac resynchronization and mitral valve repair) are effective in patients with disproportionate MR but not in those with proportionate MR. The proposed framework explains the discordant findings in the Multicentre Randomized Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trials; differences in procedural success and medical therapy in the 2 studies cannot explain the different results. In addition, the small group of patients in the COAPT trial who had the features of proportionate MR and were similar to those enrolled in the MITRA-FR trial did not respond favorably to transcatheter mitral valve repair. The characterization of patients with functional MR into proportionate and disproportionate subtypes may explain the diverse range of responses to drug and device interventions that have been observed.


[Idiopathic inflammatory myopathies: main clinical and immunological variants, difficulties of differential diagnostics and therapy].
Idiopathic inflammatory myopathies are rare autoimmune diseases with inflammatory lesions in skeletal muscles. They include polymyositis, dermatomyositis, juvenile myositis and inclusion body myositis. These are clinically and immunologically heterogeneous conditions differently responding to therapy. The authors consider the main manifestations of polymyositis/dermatomyositis and principal differences between them. Therapy is based on the prescription of glucocorticoids in combination with immunesuppressors. Better understanding immunological, genetic, and molecular mechanisms opens up new prospects for the management of idiopathic inflammatory myopathies.


Rock2 controls TGFbeta signaling and inhibits mesoderm induction in zebrafish embryos.
The Rho-associated serine/threonine kinases Rock1 and Rock2 play important roles in cell contraction, adhesion, migration, proliferation and apoptosis. Here we report that Rock2 acts as a negative regulator of the TGFbeta signaling pathway. Mechanistically, Rock2 binds to and accelerates the lysosomal degradation of TGFbeta type I receptors internalized from the cell surface in mammalian cells. The inhibitory effect of Rock2 on TGFbeta signaling requires its kinase activity. In zebrafish embryos, injection of rock2a mRNA attenuates the expression of mesodermal markers during late blastulation and blocks the induction of mesoderm by ectopic Nodal signals. By contrast, overexpression of a dominant negative form of zebrafish rock2a, dnrock2a, has an opposite effect on mesoderm induction, suggesting that Rock2 proteins are endogenous inhibitors for mesoderm induction. Thus, our data have unraveled previously unidentified functions of Rock2, in controlling TGFbeta signaling as well as in regulating embryonic patterning.


FADS1 and FADS2 Polymorphisms Modulate Fatty Acid Metabolism and Dietary Impact on Health.
Variants in the FADS gene cluster modify the activity of polyunsaturated fatty acid (PUFA) desaturation and the lipid composition in human blood and tissue. FADS variants have been associated with plasma lipid concentrations, risk of cardiovascular diseases, overweight, eczema, pregnancy outcomes, and cognitive function. Studies on variations in the FADS genecluster provided some of the first examples for marked gene-diet interactions in modulating complex phenotypes, such as eczema, asthma, and cognition. Genotype distribution differs markedly among ethnicities, apparently reflecting an evolutionary advantage of genotypes enabling active long-chain PUFA synthesis when the introduction of agriculture provided diets rich in linoleic acid but with little arachidonic and eicosapentaenoic acids. Discovering differential effects of PUFA supply that depend on variation of FADS genotypes could open new opportunities for developing precision nutrition strategies based either on an individual's genotype or on genotype distributions in specific populations.


Cadaver donor screening for infectious agents in solid organ transplantation.
The transmission of infection by a cadaver donor organ can result not only in loss of the allograft but also in death of the immunosuppressed recipient. Despite the shortage of cadaver organ donors, every donor must be evaluated thoroughly for the potential transmission of infectious disease, because the consequences of the organ donor events can have a profound effect on the transplant outcome. This review summarizes current knowledge about serological screening of organ donors to determine the suitability of organs from cadaver donors for transplantation.


A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression.
MYC regulates multiple gene programs, raising questions about the potential selectivity and downstream transcriptional consequences of MYC inhibitors as cancer therapeutics. Here, we examined the effect of a small-molecule MYC inhibitor, MYCi975, on the MYC/MAX cistromes, epigenome, transcriptome, and tumorigenesis. Integrating these data revealed three major classes of MYCi975-modulated gene targets: type 1 (down-regulated), type 2 (up-regulated), and type 3 (unaltered). While cell cycle and signal transduction pathways were heavily targeted by MYCi, RNA biogenesis and core transcriptional pathway genes were spared. MYCi975 altered chromatin binding of MYC and the MYC network family proteins, and chromatin accessibility and H3K27 acetylation alterations revealed MYCi975 suppression of MYC-regulated lineage factors AR/ARv7, FOXA1, and FOXM1. Consequently, MYCi975 synergistically sensitized resistant prostate cancer cells to enzalutamide and estrogen receptor-positive breast cancer cells to 4-hydroxytamoxifen. Our results demonstrate that MYCi975 selectively inhibits MYC target gene expression and provide a mechanistic rationale for potential combination therapies.


Influence of N-methylation on a cation-pi interaction produces a remarkably stable beta-hairpin peptide.
The methylation of lysine in histone tails is a common posttranslational modification that functions in histone-regulated chromatin condensation, with binding of methylated lysine occurring in aromatic pockets on chromodomain proteins. We have synthesized a highly stable 12-residue beta-hairpin peptide that exploits the histone-related cation-pi interaction between a methylated lysine residue and a tryptophan residue. Thermodynamic analysis reveals significant entropic stabilization of the peptide due to methylation of the lysine residue. Chemical denaturation of the peptide demonstrates two-state behavior. In comparison to other reported, highly stable designed beta-hairpins, this peptide is the most thermally stable beta-hairpin reported to date. This study provides insight into the role of Lys methylation in histone proteins and more generally in mediating protein-protein interactions.


Cognitive correlates of mathematical achievement in children with cerebral palsy and typically developing children.
Remarkably few studies have investigated the nature and origin of learning difficulties in children with cerebral palsy (CP). To investigate math achievement in terms of word-problem solving ability in children with CP and controls. Because of the potential importance of reading for word-problem solving, we investigated reading as well. Children with CP attending either special (n= 41) or mainstream schools (n= 16) and a control group of typically developing children in mainstream schools (n= 16). Group differences in third grade math and reading, controlled for IQ, were tested with analyses of co-variance (ANCOVAs). Hierarchical regression was used to investigate cognitive correlates of third grade math and reading. Predictors included verbal and non-verbal IQ measured in first grade, components of working memory (WM) and executive function (EF) measured in second grade, and arithmetic fact fluency and reading measured in third grade. Children with CP in special schools performed significantly worse than their peers on word-problem solving and reading. There was a trend towards worse performance in children with CP in mainstream schools compared to typically developing children. Impairments of non-verbal IQ and WM updating predicted future difficulties in both word-problem solving and reading. Impairments of visuospatial sketchpad and inhibition predicted future word-problem, but not reading difficulty. Conversely, deficits of phonological loop predicted reading but not word-problem difficulty. Concurrent arithmetic fact fluency and reading ability were both important for word-problem solving ability. These results could potentially help to predict which children are likely to develop specific learning difficulties, facilitating early intervention.


omniCLIP: probabilistic identification of protein-RNA interactions from CLIP-seq data.
CLIP-seq methods allow the generation of genome-wide maps of RNA binding protein - RNA interaction sites. However, due to differences between different CLIP-seq assays, existing computational approaches to analyze the data can only be applied to a subset of assays. Here, we present a probabilistic model called omniCLIP that can detect regulatory elements in RNAs from data of all CLIP-seq assays. omniCLIP jointly models data across replicates and can integrate background information. Therefore, omniCLIP greatly simplifies the data analysis, increases the reliability of results and paves the way for integrative studies based on data from different assays.


Imaging of small-scale features on 433 Eros from NEAR: evidence for a complex regolith.
On 25 October 2000, the Near Earth Asteroid Rendevous (NEAR)-Shoemaker spacecraft executed a low-altitude flyover of asteroid 433 Eros, making it possible to image the surface at a resolution of about 1 meter per pixel. The images reveal an evolved surface distinguished by an abundance of ejecta blocks, a dearth of small craters, and smooth material infilling some topographic lows. The subdued appearance of craters of different diameters and the variety of blocks and different degrees of their burial suggest that ejecta from several impact events blanketed the region imaged at closest approach and led to the building up of a substantial and complex regolith consisting of fine materials and abundant meter-sized blocks.


[DNA content of the nuclei of secondary giant cells of the rat trophoblast at different phases of the polytene nucleus cycle].
A cytophotometric study of DNA content has been made for secondary trophoblastic giant cells, which differ morphologically in relation to the stage of the cycle of the polytene nucleus. The ploidy rate varying from 16c to 512c. It is shown that the DNA content of the nuclei with polytene chromosomes in phase G is more stable, corresponding to the 2c multiple DNA content. Unlike, reticular nuclei in phase S do not present clear-cut peaks on a histogram of DNA. Ratios of nuclei with unequal ploidy differ depending on the structure of these nuclei.


Changes in Plasma Carotenoid Concentrations during the AntioxObesity Weight Reduction Program among Adults with Excessive Body Weight.
Plasma carotenoid concentrations are associated with antioxidant defense which might be disturbed in people with excessive body weight (EBW). This study aimed at evaluating the effect of a 6-week weight reduction program on plasma concentration of β-carotene, lycopene, and lutein/zeaxanthin in adults with EBW. A total of 130 adults were recruited for the study; 75 completed the program. Data on food consumption were collected with a 3-day recording method and a semi-quantitative FFQ. Body height, body weight (BW), waist circumference (WC), fat mass (FM), fat-free mass (FFM), abdominal subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were measured. Lipid profile, β-carotene, lycopene, and lutein/zeaxanthin were analyzed in blood. The AntioxObesity program resulted in a significant reduction in BW, WC, FM, SAT, and VAT. The mean plasma concentrations of β-carotene, lycopene, and lutein/zeaxanthin increased significantly after intervention. A reduction in FM above 4 kg significantly increased the concentration of β-carotene, lutein/zeaxanthin, and total carotenoids. An increase in carotenoid levels correlated with FM reduction, as fruit and vegetable intake remained unchanged. However, this effect may vary due to gender, HDL-cholesterol, body fat content, and obesity status in the weight loss process.


Phylogeny and molecular evolution of the first local monkeypox virus cluster in Guangdong Province, China.
The first local mpox outbreak in Guangdong Province, China occurred in June 2023. However, epidemiological data have failed to quickly identify the source and transmission of the outbreak. Here, phylogeny and molecular evolution of 10 monkeypox virus (MPXV) genome sequences from the Guangdong outbreak were characterized, revealing local silent transmissions that may have occurred in Guangdong whose mpox outbreaks suggested a molecular epidemiological correlation with Portugal and several regions of China during the same period. The lineage IIb C.1, which includes all 10 MPXV from Guangdong, shows consistent temporal continuity in both phylogenetic characteristics and unique molecular evolutionary mutation spectrum, reflected in the continuous increase of single nucleotide polymorphisms (SNPs) and shared mutations over time. Compared with the Japan MPXV, the Guangdong MPXV showed higher genomic nucleotide differences and separated 14 shared mutations from the B.1 lineage, comprising 6 non-synonymous mutations in genes linked to host regulation, virus infection, and virus life cycle. The unique mutation spectrum with temporal continuity in IIb C.1, related to apolipoprotein B mRNA-editing catalytic polypeptide-like 3, promotes rapid viral evolution and diversification. The findings contribute to understanding the ongoing mpox outbreak in China and offer insights for developing joint prevention and control strategies.


Serological interrelationships in avian mycoplasma serotypes.
A study of 18 standard avian mycoplasma and their antisera employing indirect haemagglutination test revealed distinct relationships among avian mycoplasma serotypes, so that they could be classified into 9 groups.


Functional network in the prefrontal cortex during episodic memory retrieval.
A recent consistent finding in neuroimaging studies of human memory is that the prefrontal cortex (PFC) is activated during episodic memory retrieval. To date, however, there has been no direct evidence to explain how activity in the right and left PFC and in the anterior and posterior PFC are functionally interconnected. The goal of the present study was to obtain such evidence by event-related functional magnetic resonance imaging (MRI) and the functional connectivity method. Subjects were first asked to try to remember a series of associate-word lists outside the MRI scanner in preparation for a later recognition test. In the MRI scanning phase, they were asked to make recognition judgments in regard to old words, semantically related lure words, and unrelated new words. The analysis of functional connectivity revealed that the posterior PFC in each hemisphere had strong functional interconnections with the contralateral posterior PFC, whereas the anterior PFC in each hemisphere had only weak functional interconnections with the contralateral anterior PFC. No strong functional interconnections were found between the anterior and posterior PFC in either hemisphere. These findings support the hypothesis of an associative contribution of the bilateral posterior PFC to episodic memory retrieval and a dissociative contribution of the bilateral anterior PFC.


Beta-lactamase inhibitors: agents to overcome bacterial resistance.
The extensive use of beta-lactam antibiotics in hospitals and community has created major resistance problems leading to increased morbidity, mortality and health-care costs. Resistance is most often mediated by -lactamases, which have emerged in both gram-positive and gram-negative bacteria. A novel approach to countering bacterial beta-lactamases is the delivery of a beta-lactam antibiotic in combination with a beta-lactamase inhibitor. Several such combinations are currently available, containing inhibitors clavulanic acid, sulbactam and tazobactam. These inhibitors are not, however, active against all beta-lactamases and the AmpC chromosomal enzymes that are hyperproduced by some enterobacteria and pseudomonas are a particular gap. Moreover, genes for these AmpC enzymes have begun to escape to plasmids. Consequently, there is a growing need for new broad-spectrum beta-lactamase inhibitors. This review offers an overview of synthetic beta-lactamase inhibitors, emphasizing information on their structures, and highlighting their activity against various beta-lactamases, particularly AmpC enzymes. Effective inhibition of AmpC enzymes are to be found among the penems and monobactams, but none of these has yet proved suitable for pharmaceutical development.


Silicon drift detectors as a tool for time-resolved fluorescence XAFS on low-concentrated samples in catalysis.
A silicon drift detector (SDD) was used for ex situ and time-resolved in situ fluorescence X-ray absorption fine structure (XAFS) on low-concentrated catalyst samples. For a single-element and a seven-element SDD the energy resolution and the peak-to-background ratio were verified at high count rates, sufficient for fluorescence XAFS. An experimental set-up including the seven-element SDD without any cooling and an in situ cell with gas supply and on-line gas analysis was developed. With this set-up the reduction and oxidation of a zeolite supported catalyst containing 0.3 wt% platinum was followed by fluorescence near-edge scans with a time resolution of 10 min each. From ex situ experiments on low-concentrated platinum- and gold-based catalysts fluorescence XAFS scans could be obtained with sufficient statistical quality for a quantitative analysis. Structural information on the gold and platinum particles could be extracted by both the Fourier transforms and the near-edge region of the XAFS spectra. Moreover, it was found that with the seven-element SDD concentrations of the element of interest as low as 100 ppm can be examined by fluorescence XAFS.


Perceptual significance of seat-dip effect related direct sound coloration in concert halls.
In concert halls, the spectrum of direct sound (here 0 to 15 ms) is influenced by the seat-dip effect that causes selective low frequency attenuation. The seat-dip effect has been considered to be detrimental to the acoustic quality of halls, yet there is little evidence about the perceptual significance of the effect. This paper studies the discrimination and preference of seat-dip effect related changes in the direct sound, with realistic auralization of multichannel anechoic orchestra recordings in halls measured with the loudspeaker orchestra. Comparisons are made with a free-field direct sound and direct sound magnitude changes typically associated with the seat-dip effect. Overall, the differences were not significantly audible, except with a subgroup of participants in one out of four halls, and two out of three comparisons. Furthermore, participants' preference for the uncolored direct sound was significant in the halls with less reflected energy, but non-significant in the halls with more reflected energy. The results imply that for most seats in adequately reverberant halls, typical seat-dip effect related coloration in the direct sound can be perceptually negligible.


Two-stage hepatectomy with radioembolization for bilateral colorectal liver metastases: A case report.
Two-stage hepatectomy (TSH) is a well-established surgical technique, used to treat bilateral colorectal liver metastases (CRLM) with a small future liver remnant (FLR). However, in classical TSH, drop-out is reported to be around 25%-40%, due to insufficient FLR increase or progression of disease. Trans-arterial radioembolization (TARE) has been described to control locally tumor growth of liver malignancies such as hepatocellular carcinoma, but it has been also reported to induce a certain degree of contralateral liver hypertrophy, even if at a lower rate compared to portal vein embolization or ligation. Herein we report the case of a 75-year-old female patient, where TSH and TARE were combined to treat bilateral CRLM. According to computed tomography (CT)-scan, the patient had a hepatic lesion in segment VI-VII and two other confluent lesions in segment II-III. Therefore, one-stage posterior right sectionectomy plus left lateral sectionectomy (LLS) was planned. The liver volumetry estimated a FLR of 38% (segments I-IV-V-VIII). However, due to a more than initially planned, extended right resection, simultaneous LLS was not performed and the patient underwent selective TARE to segments II-III after the first surgery. The CT-scan performed after TARE showed a reduction of the treated lesion and a FLR increase of 55%. Carcinoembryonic antigen and CA 19.9 decreased significantly. Nearly three months later after the first surgery, LLS was performed and the patient was discharged without any postoperative complications. According to this specific experience, TARE was used to induce liver hypertrophy and simultaneously control cancer progression in TSH settings for bilateral CRLM.


Ionizing radiation and genetic risks. XII. The concept of "potential recoverability correction factor" (PRCF) and its use for predicting the risk of radiation-inducible genetic disease in human live births.
Genetic risks of radiation exposure of humans are generally expressed as expected increases in the frequencies of genetic diseases over those that occur naturally in the population as a result of spontaneous mutations. Since human data on radiation-induced germ cell mutations and genetic diseases remain scanty, the rates derived from the induced frequencies of mutations in mouse genes are used for this purpose. Such an extrapolation from mouse data to the risk of genetic diseases will be valid only if the average rates of inducible mutations in human genes of interest and the average rates of induced mutations in mice are similar. Advances in knowledge of human genetic diseases and in molecular studies of radiation-induced mutations in experimental systems now question the validity of the above extrapolation. In fact, they (i) support the view that only in a limited number of genes in the human genome, induced mutations may be compatible with viability and hence recoverable in live births and (ii) suggest that the average rate of induced mutations in human genes of interest from the disease point of view will be lower than that assumed from mouse results. Since, at present, there is no alternative to the use of mouse data on induced mutation rates, there is a need to bridge the gap between these and the risk of potentially inducible genetic diseases in human live births. In this paper, we advance the concept of what we refer to here as "the potential recoverability correction factor" (PRCF) to bridge the above gap in risk estimation and present a method to estimate PRCF. In developing the concept of PRCF, we first used the available information on radiation-induced mutations recovered in experimental studies to define some criteria for assessing potential recoverability of induced mutations and then applied these to human genes on a gene-by-gene basis. The analysis permitted us to estimate unweighted PRCFs (i.e. the fraction of genes among the total studied that might contribute to recoverable induced mutations) and weighted PRCFs (i.e. PRCFs weighted by the incidences of the respective diseases). The estimates are: 0.15 (weighted) to 0.30 (unweighted) for autosomal dominant and X-linked diseases and 0.02 (weighted) to 0.09 (unweighted) for chronic multifactorial diseases. The PRCF calculations are unnecessary for autosomal recessive diseases since the risks projected for the first few generations even without using PRCFs are already very small. For congenital abnormalities, PRCFs cannot be reliably estimated. With the incorporation of PRCF into the equation used for predicting risk, the risk per unit dose becomes the product of four quantities (risk per unit dose=Px(1/DD)xMCxPRCF) where P is the baseline frequency of the genetic disease, 1/DD is the relative mutation risk per unit dose, MC is the mutation component and PRCF is the disease-class-specific potential recoverability correction factor instead of the first three (as has been the case thus far). Since PRCF is a fraction, it is obvious that the estimate of risk obtained with the revised risk equation will be smaller than previously calculated values.


Interplay of transcriptomics and proteomics.
Despite the obvious attractions of parallel profiling of transcripts and proteins on a global 'omic' scale, there are practical and biological differences involved in their application. Transcriptomics is now a robust, high-throughput, cost-effective technology capable of simultaneously quantifying tens of thousands of defined mRNA species in a miniaturized, automated format. Conversely, proteomic analysis is currently much more limited in breadth and depth of coverage owing to variations in protein abundance, hydrophobicity, stability, size and charge. Nevertheless, transcriptomic and proteomic data can be compared and contrasted provided the studies are carefully designed and interpreted. Differential splicing, post-translational modifications and data integration are among some of the future challenges to tackle.


Lethal Effects of Imergard WP, a Perlite-based Dust, on Amblyomma americanum (Ixodida: Ixodidae) Larvae and Nymphs.
As resistance in economically and medically important ixodids (hard ticks, Ixodida: Ixodidae) to conventional synthetic toxin-based acaricides has become increasingly widespread, research efforts to identify alternative control tactics have intensified. Laboratory bioassays on the lone star tick, Amblyomma americanum (L.), as a model for other ixodid species, were conducted to assess the efficiency of Imergard WP perlite-based dust versus CimeXa, a silica gel-based insecticidal product that is highly effective against ixodid larvae and nymphs. Each of the two inert desiccant dusts immobilized A. americanum larvae and nymphs within 4-6 h, and killed 100% of the ixodids by 24 h after contact by brief immersion in dry dusts, and after they crawled ≈7.3 cm across a filter paper disc treated with the dusts. Contact by crawling on a dried aqueous film of the dusts, however, did not immobilize and kill the ixodids by 24 h. Similar to silica gel-based desiccant dust, dry perlite-based Imergard WP dust might prophylactically protect cattle and other animals from medically and agriculturally important ixodid pests. Perlite can potentially be stored indefinitely, it can retain its lethal properties for as long as adequate amounts remain on a substrate, and it might be acceptable for limited application in environmentally sensitive habitats.


Orexins/hypocretins: pain regulation and cellular actions.
Orexin A and B (also named hypocretin 1 and 2) are 33 and 28 amino acid-containing neuropeptides, respectively, derived from prepro-orexin (prepro-hypocretin) which is localized in the the lateral and perifonical areas of the hypothalamus. Two G-protein coupled receptor subtypes, OX1 and OX2, were identified. Orexin-containing fibers and OX receptors are widely distributed in the central nervous system. Orexins have been implicated in the arousal, rewarding, energy homeostasis, autonomic central control and antinociceptive systems. Subtype-selective peptide agonists and antagonists and non-peptide antagonists, but not non-peptide agonists, have been developed. This review summarizes the studies investigating the antinociceptive effects of orexins in various animal models of pain, including trigeminovascular pain, and their cellular mechanisms. Orexins are antinociceptive at both spinal and supraspinal levels. The antinociceptive effect of orexin A is comparable to opioids but orexin B is less or not effective. This effect is opioid-independent and mainly mediated through OX1 receptors. Some animal studies suggest that endogenous orexins may be released during postoperative and inflammatory, but not acute, pain states, or during some stress conditions, which may contribute to stress-induced analgesia. Purinergic P(2X) and glycine receptors are proposed to be involved in orexin-induced spinal antinociception. The supraspinal sites of actions might involve the posterior hypothalamus, which contributes to the trigeminovascular nociception, and the ventrolateral periaqueductal gray, which mediates descending pain inhibition. Endocannobinoids and nociceptin/orphanin FQ were found to interplay with orexins in nocicpetive processing. Further studies are required to elucidate the receptor subtype-specific mechanism(s) and clinical implications of orexin-induced antinociception.


Persistent hyperglycemia in severe traumatic brain injury: an independent predictor of outcome.
In patients with severe traumatic brain injury (TBI), admission hyperglycemia is associated with poor outcome. The effect of persistent hyperglycemia (PH) on outcome in severe TBI, however, remains unknown. We performed a retrospective review of all blunt trauma patients with severe TBI (head Abbreviated Injury Score > or = 3) admitted to the intensive care unit at a Level I trauma center from January 1998 through December 2005. Admission and daily intensive care unit blood glucose levels up to the end of the first week were measured. PH was defined as an average daily blood glucose > or = 150 mg/dL on all days for the first week of the hospital stay. TBI patients with and without PH were compared with respect to baseline demographics, injury characteristics, and outcomes. Independent risk factors for mortality were identified using logistic regression analysis. One hundred and five (12.6%) out of 834 severe TBI patients had PH. Patients with PH were older, more severely injured, and had worse head injury compared with patients without PH. After adjusting for significant risk factors, PH was identified as an independent risk factor for mortality (odds ratio (OR): 4.91 [95% confidence interval (CI), 2.88-8.56, P < 0.0001]). PH is associated with significantly higher mortality rates in severe TBI patients.


Calcium antagonists in N-methyl d-aspartate-induced retinal injury.
To detect the neuroprotective role of nimodipine and dantrolene in N-methyl- d-aspartate (NMDA)-induced retinal injury. In this study we used two calcium antagonists which have two different modes of action, nimodipine and dantrolene, to prevent NMDA-induced retinal ischemia in guinea pigs. In 40 animals we injected nimodipine (n=10), dantrolene (n=10), a combination of both (n=10) or sterile 0.9% NaCl solution as a placebo (n=10) before intravitreal injection of NMDA. We enucleated one eye of each animal after 48 hours and performed histopathologic examination. We also measured malondialdehyde (MDA) levels in retinal homogenates as a marker of ischemic injury. Our results indicate that ganglion cells of the retina were preserved mostly by nimodipine, followed by combined nimodipine-dantrolene, and dantrolene respectively. The ganglion cell count was statistically significantly higher in cases where we used calcium antagonists than in the control group (p<0.05). We also found that MDA was significantly reduced by calcium antagonists compared to the control group (p<0.05). Our data show that nimodipine and dantrolene both have potential neuroprotective effects; nimodipine preserved retinal ganglion cells to a greater extent than dantrolene from NMDA-induced retinal injury.


Functional responses of the hippocampus to hyperexcitability depend on directed, neuron-specific KCNQ2 K+ channel plasticity.
M-type (KCNQ2/3) K+ channels play dominant roles in regulation of active and passive neuronal discharge properties such as resting membrane potential, spike-frequency adaptation, and hyper-excitatory states. However, plasticity of M-channel expression and function in nongenetic forms of epileptogenesis are still not well understood. Using transgenic mice with an EGFP reporter to detect expression maps of KCNQ2 mRNA, we assayed hyperexcitability-induced alterations in KCNQ2 transcription across subregions of the hippocampus. Pilocarpine and pentylenetetrazol chemoconvulsant models of seizure induction were used, and brain tissue examined 48 hr later. We observed increases in KCNQ2 mRNA in CA1 and CA3 pyramidal neurons after chemoconvulsant-induced hyperexcitability at 48 hr, but no significant change was observed in dentate gyrus (DG) granule cells. Using chromogenic in situ hybridization assays, changes to KCNQ3 transcription were not detected after hyper-excitation challenge, but the results for KCNQ2 paralleled those using the KCNQ2-mRNA reporter mice. In mice 7 days after pilocarpine challenge, levels of KCNQ2 mRNA were similar in all regions to those from control mice. In brain-slice electrophysiology recordings, CA1 pyramidal neurons demonstrated increased M-current amplitudes 48 hr after hyperexcitability; however, there were no significant changes to DG granule cell M-current amplitude. Traumatic brain injury induced significantly greater KCNQ2 expression in the hippocampal hemisphere that was ipsilateral to the trauma. In vivo, after a secondary challenge with subconvulsant dose of pentylenetetrazole, control mice were susceptible to tonic-clonic seizures, whereas mice administered the M-channel opener retigabine were protected from such seizures. This study demonstrates that increased excitatory activity promotes KCNQ2 upregulation in the hippocampus in a cell-type specific manner. Such novel ion channel expressional plasticity may serve as a compensatory mechanism after a hyperexcitable event, at least in the short term. The upregulation described could be potentially leveraged in anticonvulsant enhancement of KCNQ2 channels as therapeutic target for preventing onset of epileptogenic seizures.


BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.
Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.


Goals of Care Among Parents of Children Receiving Palliative Care.
While knowing the goals of care (GOCs) for children receiving pediatric palliative care (PPC) are crucial for guiding the care they receive, how parents prioritize these goals and how their priorities may change over time is not known. To determine parental prioritization of GOCs and patterns of change over time for parents of children receiving palliative care. A Pediatric Palliative Care Research Network's Shared Data and Research cohort study with data collected at 0, 2, 6, 12, 18, and 24 months in hospital, outpatient, or home settings from April 10, 2017, to February 15, 2022, at 7 PPC programs based at children's hospitals across the US. Participants included parents of patients, birth to 30 years of age, who received PPC services. Analyses were adjusted for demographic characteristics, number of complex chronic conditions, and time enrolled in PPC. Parents' importance scores, as measured using a discrete choice experiment, of 5 preselected GOCs: seeking quality of life (QOL), health, comfort, disease modification, or life extension. Importance scores for the 5 GOCs summed to 100. A total of 680 parents of 603 patients reported on GOCs. Median patient age was 4.4 (IQR, 0.8-13.2) years and 320 patients were male (53.1%). At baseline, parents scored QOL as the most important goal (mean score, 31.5 [SD, 8.4]), followed by health (26.3 [SD, 7.5]), comfort (22.4 [SD, 11.7]), disease modification (10.9 [SD, 9.2]), and life extension (8.9 [SD, 9.9]). Importantly, parents varied substantially in their baseline scores for each goal (IQRs more than 9.4), but across patients in different complex chronic conditions categories, the mean scores varied only slightly (means differ 8.7 or less). For each additional study month since PPC initiation, QOL was scored higher by 0.06 (95% CI, 0.04-0.08) and comfort scored higher by 0.3 (95% CI, 0-0.06), while the importance score for life extension decreased by 0.07 (95% CI, 0.04-0.09) and disease modification by 0.02 (95% CI, 0-0.04); health scores did not significantly differ from PPC initiation. Parents of children receiving PPC placed the highest value on QOL, but with considerable individual-level variation and substantial change over time. These findings emphasize the importance of reassessing GOCs with parents to guide appropriate clinical intervention.


Subwavelength plasmonics for graded-index optics on a chip.
Planar plasmonic devices are becoming attractive for myriad applications, owing to their potential compatibility with standard microelectronics technology and the capability for densely integrating a large variety of plasmonic devices on a chip. Mitigating the challenges of using plasmonics in on-chip configurations requires precise control over the properties of plasmonic modes, in particular their shape and size. Here we achieve this goal by demonstrating a planar plasmonic graded-index lens focusing surface plasmons propagating along the device. The plasmonic mode is manipulated by carving subwavelength features into a dielectric layer positioned on top of a uniform metal film, allowing the local effective index of the plasmonic mode to be controlled using a single binary lithographic step. Focusing and divergence of surface plasmons is demonstrated experimentally. The demonstrated approach can be used for manipulating the propagation of surface plasmons, e.g., for beam steering, splitting, cloaking, mode matching, and beam shaping applications.


Evaluation of vortex flow in left ventricle by echo-dynamography and phase contrast magnetic resonance angiography.
Echo-dynamography (EDG) is a method for visualizing left ventricular (LV) blood flow based on cardiac Doppler measurement in which blood flow component perpendicular to the ultrasonic beam is deduced by applying fluid dynamics theories to two-dimensional (2D) distribution of blood flow component along the ultrasonic beam. EDG has been validated by numerical simulation and particle image velocimetry of model circulation. However, these validations were too simple to reproduce unstable and asymmetrical flow in a beating heart. In the present study, EDG is compared with three-directional (3D) blood flow distribution on the same plane obtained with phase contrast magnetic resonance angiography (PCMRA) for clinical validation. Moreover, the location and vorticity of the vortex flow in LV are measured quantitatively and the relation to echocardiographic parameters of systolic and diastolic functions is discussed. 3D components of blood flow on a plane were obtained with triple scans of the same plane with ECG trigger and breath holding; 1) phase encode (x-axis), 2) read out (y-axis) and 3) slice selection (z-axis). After the acquisition of MRA dataset, color Doppler dataset of the same plane was acquired and 2D velocity distribution was obtained with EDG in MATLAB programs. EDG and PCMRA showed similar velocity vector distribution and formation of LV vortex flow. The vortex at mid diastolic phase was strongly affected by early diastolic filling while the vortex at isometric contraction was affected by atrial filling. EDG gained a new insight on systolic-diastolic coupling from the view point of LV blood flow such as LV vortex formation.


Human COQ9 Rescues a coq9 Yeast Mutant by Enhancing Coenzyme Q Biosynthesis from 4-Hydroxybenzoic Acid and Stabilizing the CoQ-Synthome.
Coq9 is required for the stability of a mitochondrial multi-subunit complex, termed the CoQ-synthome, and the deamination step of Q intermediates that derive from para-aminobenzoic acid (pABA) in yeast. In human, mutations in the COQ9 gene cause neonatal-onset primary Q10 deficiency. In this study, we determined whether expression of human COQ9 could complement yeast coq9 point or null mutants. We found that expression of human COQ9 rescues the growth of the temperature-sensitive yeast mutant, coq9-ts19, on a non-fermentable carbon source and increases the content of Q6, by enhancing Q biosynthesis from 4-hydroxybenzoic acid (4HB). To study the mechanism for the rescue by human COQ9, we determined the steady-state levels of yeast Coq polypeptides in the mitochondria of the temperature-sensitive yeast coq9 mutant expressing human COQ9. We show that the expression of human COQ9 significantly increased steady-state levels of yeast Coq4, Coq6, Coq7, and Coq9 at permissive temperature. Human COQ9 polypeptide levels persisted at non-permissive temperature. A small amount of the human COQ9 co-purified with tagged Coq6, Coq6-CNAP, indicating that human COQ9 interacts with the yeast Q-biosynthetic complex. These findings suggest that human COQ9 rescues the yeast coq9 temperature-sensitive mutant by stabilizing the CoQ-synthome and increasing Q biosynthesis from 4HB. This finding provides a powerful approach to studying the function of human COQ9 using yeast as a model.


"The patient is speaking": discovering the patient voice in ophthalmology.
Eye disease can be devastating. The most feared impact is sight loss, but in a number of ophthalmic conditions, there can be wide-ranging systemic, psychological, emotional and social effects of both the disease and its treatment. External tests of visual function, such as visual acuity, are inadequate to understand the overall impact of ophthalmic disease on a patient's functional vision or daily life. This can lead to a discordance between the patient's priorities and perspective on the one hand and the efforts of clinicians and other stakeholders on the other hand. In this review, we discuss how the patient is uniquely placed to understand the impact of the disease and can use that position to transform ophthalmic care at the individual and collective level, from research to care delivery. We highlight how the "patient voice" can contribute to key areas, including priority setting in the research agenda, communicating the wide-ranging impact of disease and its treatment as assessed through qualitative research, identifying the outcome measures that matter to the patient through core outcome set development and reporting these outcomes through appropriate patient-reported outcome measures. We also consider the increasing power of the patient voice on health institutions, ranging from broadcasting an individual's experience of care he/she has received to patient societies influencing future health policy. Finally, we reflect on the challenges that need to be overcome for the patient voice to increasingly influence and improve the delivery of eye care in the future.


Differential localization and independent acquisition of the H3K9me2 and H3K9me3 chromatin modifications in the Caenorhabditis elegans adult germ line.
Histone methylation is a prominent feature of eukaryotic chromatin that modulates multiple aspects of chromosome function. Methyl modification can occur on several different amino acid residues and in distinct mono-, di-, and tri-methyl states. However, the interplay among these distinct modification states is not well understood. Here we investigate the relationships between dimethyl and trimethyl modifications on lysine 9 of histone H3 (H3K9me2 and H3K9me3) in the adult Caenorhabditis elegans germ line. Simultaneous immunofluorescence reveals very different temporal/spatial localization patterns for H3K9me2 and H3K9me3. While H3K9me2 is enriched on unpaired sex chromosomes and undergoes dynamic changes as germ cells progress through meiotic prophase, we demonstrate here that H3K9me3 is not enriched on unpaired sex chromosomes and localizes to all chromosomes in all germ cells in adult hermaphrodites and until the primary spermatocyte stage in males. Moreover, high-copy transgene arrays carrying somatic-cell specific promoters are highly enriched for H3K9me3 (but not H3K9me2) and correlate with DAPI-faint chromatin domains. We further demonstrate that the H3K9me2 and H3K9me3 marks are acquired independently. MET-2, a member of the SETDB histone methyltransferase (HMTase) family, is required for all detectable germline H3K9me2 but is dispensable for H3K9me3 in adult germ cells. Conversely, we show that the HMTase MES-2, an E(z) homolog responsible for H3K27 methylation in adult germ cells, is required for much of the germline H3K9me3 but is dispensable for H3K9me2. Phenotypic analysis of met-2 mutants indicates that MET-2 is nonessential for fertility but inhibits ectopic germ cell proliferation and contributes to the fidelity of chromosome inheritance. Our demonstration of the differential localization and independent acquisition of H3K9me2 and H3K9me3 implies that the trimethyl modification of H3K9 is not built upon the dimethyl modification in this context. Further, these and other data support a model in which these two modifications function independently in adult C. elegans germ cells.


Functional characterization of the dimer linkage structure RNA of Moloney murine sarcoma virus.
Several determinants that appear to promote the dimerization of murine retroviral genomic RNA have been identified. The interaction between these determinants has not been extensively examined. Previously, we proposed that dimerization of the Moloney murine sarcoma virus genomic RNAs relies upon the concentration-dependent interactions of a conserved palindrome that is initiated by separate G-rich stretches (H. Ly, D. P. Nierlich, J. C. Olsen, and A. H. Kaplan, J. Virol. 73:7255-7261, 1999). The cooperative action of these two elements was examined using a combination of genetic and antisense approaches. Dimerization of RNA molecules carrying both the palindrome and G-rich sequences was completely inhibited by an oligonucleotide complementary to the palindrome; molecules lacking the palindrome could not dimerize in the presence of oligomers that hybridize to two G-rich sequences. The results of spontaneous dimerization experiments also demonstrated that RNA molecules lacking either of the two stretches of guanines dimerized much more slowly than the full-length molecule which includes the dimer linkage structure (DLS). However, the addition of an oligonucleotide complementary to the remaining stretch of guanines restored the kinetics of dimerization to wild-type levels. The ability of this oligomer to rescue the kinetics of dimerization was dependent on the presence of the palindrome, suggesting that interactions within the G-rich regions produce changes in the palindrome that allow dimerization to proceed with maximum efficiency. Further, unsuccessful attempts to produce heterodimers between constructs lacking various combinations of these elements indicate that the G-rich regions and the palindrome do not interact directly. Finally, we demonstrate that both of these elements are important in maintaining efficient viral replication. Modified antisense oligonucleotides targeting the DLS were found to reduce the level of viral vector titer production. The reduction in viral titer is due to a decrease in the efficiency of viral genomic RNA encapsidation. Overall, our data support a dynamic model of retroviral RNA dimerization in which discrete dimerization elements act in a concerted fashion.


Appraising the role of circulating concentrations of micronutrients in attention deficit hyperactivity disorder: a Mendelian randomization study.
Previous observational researches have discovered a connection between circulating concentrations of micronutrients and attention deficit hyperactivity disorder (ADHD). However, the results may be influenced by confounding factors and reverse causation. This study aims to explore the causal relationship between circulating concentrations of micronutrients and ADHD using Mendelian randomization (MR). In a two-sample MR context, we used summary data from the major European genome-wide association studies (GWAS) for these illnesses to assess the genetically anticipated effects of circulating concentrations of micronutrients on ADHD risk. In order to achieve this, we took single nucleotide polymorphisms (SNPs) from the GWAS that were highly related with concentrations of nine micronutrients. The corresponding data for ADHD were extracted from the Psychiatric Genomics Consortium. Inverse-variance weighted (IVW) method was used as the main MR analysis, and the reliability of the study's conclusions was assessed using sensitivity analyses. Our MR analyses showed that the copper level may be associated with a reduced risk of ADHD. However, the significance of the research results is weak. There were no clear relationships between other micronutrients and ADHD. Our sensitivity studies confirmed the findings of the primary IVW MR analyses. According to this study, there may be some association between copper level and ADHD, but the significance of the research results is weak, and it is recommended that copper level should be used as a long-term monitoring indicator for further research. The results provide a new idea for the further study of ADHD, and provide guidance for the prevention and treatment of ADHD.


Phase-dependent reversal of reflexes mediated by the thoracocoxal muscle receptor organ in the crayfish, Pacifastacus leniusculus.
Both negative feedback, resistance reflexes and positive feedback, assistance reflexes are mediated by the thoracocoxal muscle receptor organ (TCMRO) in the crayfish, depending on the central excitability of the preparation. In this paper we present evidence that the velocity-sensitive afferent T fiber of the TCMRO may elicit either resistance or assistance reflexes in different preparations. In preparations displaying assistance reflexes, the S and T fibers of the TCMRO exert reciprocal effects on leg motor neurons (MNs). The S fiber excites promotor MNs (negative feedback) and inhibits remotor MNs, the T fiber excites remotor MNs (positive feedback) and inhibits promotor MNs. During reciprocal motor output of promotor and remotor MNs, reflexes mediated by the TCMRO are modulated in a phase-dependent manner. The TCMRO excites promotor MNs during their active phases (negative feedback) but inhibits them during their reciprocal phases. Remotor MNs are excited by the TCMRO during their active phases (positive feedback). It is proposed that depolarizing central inputs that occur in the S and T fibers at opposite phases of the motor output cycle (21) facilitate the output effects of each afferent in alternation, effectively mediating a phase-dependent shift between the effects of one afferent and the other. The implications of central modulation of reflex pathways and the possible functions of positive and negative feedback reflexes during locomotion are discussed.


Dietary practices of South African ultradistance runners.
Training (T) and prerace (PR) dietary intakes of male and female athletes participating in a 90-km ultramarathon and the usual diets of matched, sedentary controls were investigated using 24-hr dietary records. Supplement use, mean weekly training distance, and race performance times were recorded. Macro- and micronutrient intakes were analyzed using computerized nutritional analysis programs. Total mean energy intake in the T and PR diets of the runners was 10.1 and 12.8 MJ in the men (n = 150) and 7.5 and 9.1 MJ in the women (n = 23). Mean relative contribution of CHO to the runners' total kilojoule intake increased from 50.0 and 49.5% in the T diets to 57.7 (p < .05; n = 153) and 56.4% (p < .05; n = 23) in the PR diets of male and female runners, respectively, and energy-boosting supplements were included in the PR diets of 48% of female and 59% of male runners. Seventy-eight percent of female and 62% of male runners used vitamin and mineral supplements in their T diets as opposed to 39% of female and 28% of male controls. No statistically significant relationship was found between total kilojoule, CHO, fat, protein, and selected micronutrient intake during the 3 days before the race and performance in the 90-km event in runners of homogenous training status and gender.


Genetic variation atapolipoprotein E locus in Ethiopia: an E5 variant corresponds to two different mutant alleles: E*5 (Glu212Lys) and E*5 (Gln204Lys; Cys112Arg).
A previous investigation on apolipoprotein E polymorphism in the Ethiopian population highlighted the presence of a further variant allele named E*5 in addition to the three common alleles. The variant is considered rare elsewhere but has a frequency of more than 1% in this population. Now characterized by gene sequencing and restriction isotyping in many members of the families of the original carriers, the variant isoform has actually been found to be determined by two different gene mutations. Effectively rare in Ethiopians, one of the two, E5 (Gln204Lys, Cys 112Arg), has never been described before. The other, E5 (Glu212Lys), previously described in a subject of Turkish origin, is present at the polymorphic level only in the Ethiopian population. No subjects bearing these variants had anomalous lipid or apolipoprotein patterns. In the course of the present investigation both have been found to occur as rare variants in the southern Italian population as well. The occurrence of the two variants in the populations of Ethiopia and of the Mediterranean basin could be explained by taking into account the relevant Caucasoid contribution to the Ethiopian gene pool.


Origin of ancient potash evaporites: clues from the modem nonmarine qaidam basin of Western china.
Modern potash salt deposits and associated brines of the Qaidam Basin, western China, demonstrate that some anomalous marine evaporites may have formed from nonmarine brines instead of seawater. Qaidam Basin brines are derived from meteoric river inflow mixed with small amounts of CaCl spring inflow similar in composition to many saline formation waters and hydrothermal brines. Evaporation of springenriched inflow yields a predicted mineral sequence including carnallite, bischofite, and tachyhydrite that is identical to several anomalous marine evaporites. Other mixtures of river and spring inflow produce the salt assemblage expected from evaporation of seawater.


Characterization of a chimeric human dopamine D3/D2 receptor functionally coupled to adenylyl cyclase in Chinese hamster ovary cells.
Dopamine D3 receptor pharmacology differs from that of the dopamine D2 receptor despite a high degree of receptor sequence similarity. The greatest divergence of the primary sequences of D3 and D2 receptors occurs in the predicted third intracellular loops of the receptors, a region implicated in G protein binding and function. To determine whether this domain specifies the distinct ligand binding and signal transduction characteristics of the D3 receptor, we developed a chimeric receptor, replacing the third intracellular loop of the human D3 receptor with the third intracellular loop of the human D2 receptor. The pharmacology of the chimeric receptor expressed in Chinese hamster ovary cells was examined and compared with that of human dopamine D2 and D3 receptors expressed in the same cell line. The chimeric receptor retained characteristic human D3 receptor binding; the D2 third intracellular loop present in the chimeric receptor did not reduce high affinity agonist binding, characteristic of the D3 receptor, or make high affinity sites sensitive to GTP analogs. Unlike the native human D3 receptor, the chimeric receptor was negatively coupled to adenylyl cyclase through a pertussis toxin-sensitive pathway, apparently mediated by the D2 third intracellular loop. The ability of D3 ligand binding domains to produce a D2 functional response implies that the third intracellular loop of the D3 receptor is unable to mediate this D2 response in Chinese hamster ovary cells. The inhibition of adenylyl cyclase seen with the chimeric receptor is less than the inhibition produced by D2 receptor coupling, suggesting that additional sequences in the D2 receptor contribute to normal G protein coupling.


Ratiometric fluorescence off-on-off sensor for Cu2+ in aqueous buffer by a lower rim triazole linked benzimidazole conjugate of calix[4]arene.
A benzimidazole appended triazole linked 1,3-diconjugate of calix[4]arene (L) has been synthesized and characterized. The conjugate L has been found to recognize Cu(2+) among the thirteen different metal ions studied by exhibiting ratiometric fluorescence changes through newly generated excimer band at ∼380 nm. Fluorescence off-on-off behavior has been clearly demonstrated on the basis of the binding variability of Cu(2+) to L. The binding has been elicited through the changes observed in the fluorescence, ESI MS and (1)H NMR titrations. All the other metal ions studied do not show any new band and further do not interfere with the recognition of Cu(2+) by L, even when these are present in the same medium. The structural features of both the mono- and di-nuclear complexes were established by DFT computational calculations and found to display highly distorted geometry about the copper centers that deviate from both the tetrahedral and the square planar.


Role of inhibin in normal and high-risk pregnancy.
Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B. Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion. The fetoplacental unit produces inhibin throughout pregnancy. Inhibin A is the predominant molecular form of inhibin in maternal circulation from 4 weeks of gestation. Although the precise biological function of inhibin A in pregnancy is unclear, it is evident from recent studies that inhibin A could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life. The possible clinical applications for the measurement of inhibin A in early pregnancy could be in predicting miscarriage, Down's syndrome, preeclampsia, and fetal growth restriction in the first and/or second trimester before the onset of the clinical symptoms. The source of inhibins, factors controlling inhibin production, the possible functions of inhibin, and the use of inhibin measurement in normal and high-risk pregnancy are reviewed.


In vitro evaluation of potential benefits of a silica-rich thermal water (Monfortinho Thermal Water) in hyperkeratotic skin conditions.
Thermal therapy has gained popularity over the years, and Portugal is one of the richest European countries in mineral therapeutic waters. The interest in the use of these natural mineral waters (NMW) for dermatologic purposes is continuously growing but there is a lack of scientific studies supporting its health benefits. The study aims to investigate the effect of a silica-rich NMW in skin cell homeostasis using two representative cell lines of the epidermis and dermis, keratinocytes and fibroblasts, respectively, in addition to a macrophage cell line. Mouse skin fibroblasts, macrophages and human keratinocytes were exposed to culture medium prepared with NMW. Cell metabolism (MTT or resazurin assays) and cell proliferation (trypan blue exclusion dye assay) were investigated. Migration (scratch-wound assay) and senescence (β-galactosidase activity assay) of fibroblasts were also studied. Exposure to NMW compromised the cell metabolic state of all the cell lines tested. This impairment was more pronounced in skin keratinocytes (60% reduction) relatively to skin fibroblasts (45% reduction) or macrophages (25% reduction). Proliferation of macrophages was reduced threefold upon exposure to thermal water, compared to controls. No differences were observed in migration between fibroblasts exposed to NMW and controls, while a potentiation of senescence of these cells was observed. Our results shed light in the bioactive effects of a silica-rich NMW supporting its therapeutic use. A reduction in both cell metabolism and proliferation of keratinocytes and macrophages supports the empirical clinical benefits of this NMW in hyperkeratotic conditions, such as psoriasis and atopic dermatitis.


Impact of Dry Eye Symptoms and Daily Activities in a Modern Office.
Modern offices and the use of electronic devices are increasing factors in work-related eye symptoms. However, symptoms of eye fatigue or dry eye sensation can be mixed and confusing. This study surveys the eye symptoms reported during a working day at modern offices to investigate the possible inhibition on daily work activities. Two online digital surveys were sent to three different work locations, by direct e-mail. Survey A consisted of 14 questions that investigated eye symptoms experienced during daily activities at work and the impact on daily activities. Survey B consisted of four general questions, the Dutch Ocular Surface Disease Index, the Work Productivity and Activity Index, and the Illness Perception Questionnaire. A total of 505 participants completed survey A, and 213 completed survey B. The participants reported that a high proportion of their day was spent working on a computer (60%). The majority experienced an air draft (79.1%) and had no adjustable light (81.5%) at their workspace. Dry eye-related symptoms were reported at a significantly higher frequency at work than at home (P < .001). Up to 70% experienced some inhibition of daily activity at work due to eye symptoms, with more than 5% experiencing symptoms most or all of the time. Indoor environment, work environment, and general health were perceived as the main reasons for developing dry eye. Compared with males, females showed a statistically significant higher Ocular Surface Disease Index score (P < .001) and experienced more inhibition and adverse effects on daily life and work productivity. This investigation shows that dry eye symptoms have a negative impact on daily activities at work. These findings suggest that multidisciplinary understanding of the negative impact of dry eye by a range of specialists will be of help in managing work-related dry eye.


Frequency-based analysis of the early rapid filling pressure-flow relation elucidates diastolic efficiency mechanisms.
Stiffness- and relaxation-based diastolic function (DF) assessment can characterize the presence, severity, and mechanism of dysfunction. Although frequency-based characterization of arterial function is routine (input impedance, characteristic impedance, arterial wave reflection), DF assessment via frequency-based methods incorporating optimization/efficiency criteria is lacking. By definition, optimal filling maximizes (E wave) volume and minimizes "loss" at constant stored elastic strain energy (which initiates mechanical, recoil-driven filling). In thermodynamic terms, optimal filling delivers all oscillatory power (rate of work) at the lowest harmonic. To assess early rapid filling optimization, simultaneous micromanometric left ventricular pressure and echocardiographic transmitral flow (Doppler E wave) were Fourier analyzed in 31 subjects. A validated kinematic filling model provided closed-form expressions for E wave contours and model parameters. Relaxation-based DF impairment is indicated by prolonged E wave deceleration time (DT). Optimization was assessed via regression between the dimensionless ratio of 2nd (Q2) and 3rd flow harmonics (Q3) to the lowest harmonic (Q1), i.e., (Q2/Q1) or (Q3/Q1) vs. DT or c, the filling model's viscosity/damping (energy loss) parameter. Results show that DT prolongation or increased c generated increased oscillatory power at higher harmonics (Q2/Q1 = 0.00091DT + 0.09837, r = 0.70; Q3/Q1 = 0.00053DT + 0.02747, r = 0.60; Q2/Q1 = 0.00614c + 0.15527, r = 0.91; Q3/Q1 = 0.00396c + 0.05373, r = 0.87). Because ideal filling is achieved when all oscillatory power is delivered at the lowest harmonic, the observed increase in power at higher harmonics is a measure of filling inefficiency. We conclude that frequency-based analysis facilitates assessment of filling efficiency and elucidates the mechanism by which diastolic dysfunction associated with prolonged DT impairs optimal filling.