Neuroprotective Role of Lactoferrin during Early Brain Development and Injury through Lifespan.
Early adverse fetal environments can significantly disturb central nervous system (CNS) development and subsequently alter brain maturation. Nutritional status is a major variable to be considered during development and increasing evidence links neonate and preterm infant impaired brain growth with neurological and psychiatric diseases in adulthood. Breastfeeding is one of the main components required for healthy newborn development due to the many "constitutive" elements breastmilk contains. Maternal intake of specific nutrients during lactation may alter milk composition, thus affecting newborn nutrition and, potentially, brain development. Lactoferrin (Lf) is a major protein present in colostrum and the main protein in human milk, which plays an important role in the benefits of breastfeeding during postnatal development. It has been demonstrated that Lf has antimicrobial, as well as anti-inflammatory properties, and is potentially able to reduce the incidence of sepsis and necrotizing enterocolitis (NEC), which are particularly frequent in premature births. The anti-inflammatory effects of Lf can reduce birth-related pathologies by decreasing the release of pro-inflammatory factors and inhibiting premature cervix maturation (also related to commensal microbiome abnormalities) that could contribute to disrupting brain development. Pre-clinical evidence shows that Lf protects the developing brain from neuronal injury, enhances brain connectivity and neurotrophin production, and decreases inflammation in models of perinatal inflammatory challenge, intrauterine growth restriction (IUGR) and neonatal hypoxia-ischemia (HI). In this context, Lf can provide nutritional support for brain development and cognition and prevent the origin of neuropsychiatric diseases later in life. In this narrative review, we consider the role of certain nutrients during neurodevelopment linking to the latest research on lactoferrin with respect to neonatology. We also discuss new evidence indicating that early neuroprotective pathways modulated by Lf could prevent neurodegeneration through anti-inflammatory and immunomodulatory processes.


A feasibility study evaluating a reservoir storage system for continuous oxygen delivery for children with hypoxemia in Kenya.
Supplemental oxygen is an essential treatment for childhood pneumonia but is often unavailable in low-resource settings or unreliable due to frequent and long-lasting power outages. We present a novel medium pressure reservoir (MPR) which delivers continuous oxygen to pediatric patients through power outages. An observational case series pilot study assessing the capacity, efficacy and user appraisal of a novel MPR device for use in low-resource pediatric wards. We designed and tested a MPR in a controlled preclinical setting, established feasibility of the device in two rural Kenyan hospitals, and sought user feedback and satisfaction using a standardized questionnaire. Preclinical data showed that the MPR was capable of bridging power outages and delivering a continuous flow of oxygen to a simulated patient. The MPR was then deployed for clinical testing in nine pediatric patients at Ahero and Suba Hospitals. Power was unavailable for 2% of the total time observed due to 11 power outages (median 4.6 min, IQR 3.6-13.0 min) that occurred during treatment with the MPR. Oxygen flowrates remained constant across all 11 power outages. Feedback on the MPR was uniformly positive; all respondents indicated that the MPR was easy to use and provided clinically significant help to their patients. We present a MPR oxygen delivery device that has the potential to mitigate power insecurity and improve the standard of care for hypoxemic pediatric patients in resource-limited settings.


The pertinence of the periodic selection phenomenon to prokaryote evolution.
A quarter of a century ago, it was pointed out that evolution can act in an important conservative way, in addition to its normal progressive mode. Evolution to a fitter form via changes at one locus means that the descendants of an individual with an improved locus or set of loci will supplant the previous population and carry with them the bulk of the total genotype of that original individual in asexual populations. Inasmuch as that individual is most likely to be wild type at most other loci, neutral and even other positively selected mutations will be reduced or eliminated from the population, if they are rare at the time of the evolutionary advance. In the present paper this problem has been set up for a computer simulation. The computations show the limits within which this effect functions and the conditions under which it does not. The conclusion is that it is likely that evolution at a locus proceeds in the course of many population replacements or revolutions, mostly via the rare occasions when the revolution carries a previously infrequent mutational type into abundance.


Rapid retroviral infection of human haemopoietic cells of different lineages: efficient transfer in fresh T cells.
In order to develop a clinically feasible gene marking approach, we have used the recently described PINCO retroviral expression system, composed of the enhanced green fluorescence protein (EGFP) cDNA driven by Moloney MLV LTR and packaged in the Phoenix amphotropic cell line. Two T, five B, one erythromyeloid and three myeloid cell lines were successfully infected with % GFP+ cells ranging from 4% to 79%, showing a lineage-dependent difference in infection susceptibility, with the myeloid cells being the least efficiently infected. We also infected normal mononuclear peripheral cells cultured in PHA and rhIL-2 for 2 d, and obtained an average of 30% GFP+ cells, all present within the CD3+ population, with CD4+ and CD8+ cells being equally infected. Finally, the tonsillar purified B population showed lower levels of infectivity (6%) whereas high susceptibility was shown by normal human umbilical vein endothelial cells (57%). Highly purified CD34+ cells were also susceptible, varying from 6% to 10% GFP+ cells. Immature myeloid/erythroid progenitors have been infected which stably expressed the GFP protein during further differentiation in culture. The GFP+ T cells were FACS-sorted rapidly upon infection, subsequently cultured and the fluorescence intensity monitored. In all cases the difference in percentage of GFP+ cells did not correlate with the percentage of S/G2/M cycling cells as determined at the moment of infection or with the expression levels of Ram-1 amphotrophic receptor. The improved safety of this retroviral system, the rapidity of the technique, the high efficiency of infection with respect to normal T lymphocytes (in this last case higher than previously reported) and the lack of need for in vitro selection make this system favourable for clinical development.


Docosahexaenoic acid may act as a neuroprotector for methylmercury-induced neurotoxicity in primary neural cell cultures.
The ability of docosahexaenoic acid (DHA) to modulate methylmercury (MeHg)-induced neurotoxicity was investigated in primary astrocytes and neurons from the cerebellum. Gas chromatography measurements indicated increased DHA content in both cell types after 24h supplementation. After individual or combined treatment with MeHg (10microM) and DHA (30 and 90microM), the cell-associated MeHg measurements were done using (14)C-labelled MeHg. In addition, mitochondrial activity was evaluated by MTT reduction, glutathione (GSH) content was measured with the fluorescent indicator monochlorobimane (MCB) and reactive oxygen species (ROS) were detected with the fluorescent indicator-chloro methyl derivative of di-chloro di-hydro fluorescein diacetate (CMH(2)DCFDA). For all the tested treatments, i.e. DHA, MeHg or DHA+MeHg treatment, the neurons differed significantly (p<0.001) from astrocytes exhibiting increased ROS production and decreased MTT activity. After MeHg and 30microM DHA treatment there were no changes in MTT or GSH content but significant decrease (p<0.001) in ROS was observed in both the cell types when compared to MeHg alone. The cell-associated MeHg measurements indicated reduced MeHg-accumulation in both cell types (p<0.05) upon 30microM DHA exposure. Taken together, this study, for the first time establishes that DHA pretreatment effectively reduces cell-associated MeHg and prooxidant response from MeHg in both cerebellar astrocytes and neurons and thus supports the hypothesis that fish-derived nutrients offer possible neuroprotection from MeHg.


Development of a symptomatic intracranial meningioma in a male-to-female transsexual after initiation of hormone therapy.
Transsexual patients are routinely treated with sex hormone therapy, which may be a risk factor for meningiomas, although the data are largely inconclusive. Here we describe a male-to-female transsexual patient treated with estradiol patches, who developed an occipital meningioma causing generalized seizures. This is the second report of a male-to-female transsexual patient who developed a symptomatic meningioma after sex hormone treatment, adding to the growing evidence that sex hormones contribute to the pathogenesis of meningiomas. Meningiomas may therefore complicate hormone therapy and sex hormones may be contraindicated in transsexual candidates with meningiomas identified upon screening.


Combined RNAi and localization for functionally dissecting long noncoding RNAs.
Whereas methods to comprehensively study cellular roles of protein-coding genes are available, techniques to systematically investigate long noncoding RNAs (lncRNAs), which have been implicated in diverse biological pathways, are limited. Here we report combined knockdown and localization analysis of noncoding RNAs (c-KLAN) that merges functional characterization and localization approaches to study lncRNAs. Using this technique we identified transcripts that regulate mouse embryonic stem cell identity.


Socioeconomic gradients in immune response to latent infection.
There is a strong relation between socioeconomic position and health outcomes, although the mechanisms are poorly understood. The authors used data from 1,503 California participants in the 1998-1999 Sacramento Area Latino Study on Aging aged 60-100 years to ask whether socioeconomic position is related to immune function as measured by the body's ability to keep latent herpesvirus antibody levels in a quiescent state. Individuals with lower educational levels had significantly higher levels of immunoglobulin G antibodies to cytomegalovirus and herpes simplex virus type 1. The odds ratio for being in a higher tertile of cytomegalovirus antibodies was 1.54 (95% confidence interval: 1.18, 2.01) for those in the lowest educational group, and the odds ratio for being in a higher tertile of herpes simplex virus type 1 was 1.63 (95% confidence interval: 1.25, 2.13). The relation between education and cytomegalovirus and herpes simplex virus type 1 antibody levels remained strong after controlling for baseline health conditions, smoking status, and body mass index. This is the first study known to show a relation between socioeconomic position and immune response to latent infection. It provides suggestive evidence that modulation of the immune system via latent infections may play a role in the observed associations between socioeconomic position and disease.


Molecular Genetics and Breeding for Nutrient Use Efficiency in Rice.
In the coming decades, rice production needs to be carried out sustainably to keep the balance between profitability margins and essential resource input costs. Many fertilizers, such as N, depend primarily on fossil fuels, whereas P comes from rock phosphates. How long these reserves will last and sustain agriculture remains to be seen. Therefore, current agricultural food production under such conditions remains an enormous and colossal challenge. Researchers have been trying to identify nutrient use-efficient varieties over the past few decades with limited success. The concept of nutrient use efficiency is being revisited to understand the molecular genetic basis, while much of it is not entirely understood yet. However, significant achievements have recently been observed at the molecular level in nitrogen and phosphorus use efficiency. Breeding teams are trying to incorporate these valuable QTLs and genes into their rice breeding programs. In this review, we seek to identify the achievements and the progress made so far in the fields of genetics, molecular breeding and biotechnology, especially for nutrient use efficiency in rice.


A Comprehensive Review on Ethnomedicinal, Pharmacological and Phytochemical Basis of Anticancer Medicinal Plants of Pakistan.
The widespread emergence of cancer and development of resistance to chemotherapeutic agents is increasing the interest of scientists in the use of ethnomedicinal preparations and isolated phytochemicals in the treatment and prevention of disease. Medicinal plants have been used in Pakistan since prehistoric times. The present review was designed to identify anticancer plants of ethnomedicinal significance and to summarize the anticancer activities carried out on these medicinal plants to establish the pharmacological and phytochemical basis of their use. Pakistani anticancer medicinal plants of ethnopharmacological significance were reviewed. Conservation status, worldwide distribution and ethno-botanical preparations of these medicinal plants were also tabulated. These medicinal plants and their isolated phytochemicals were also explored for their anticancer activities. It was revealed that there were 108 anticancer medicinal plants used to treat different neoplastic conditions on the folklore basis throughout Pakistan. Among these anticancer plants, 64 plants were found to be investigated previously for anticancer activity through in vivo and in vitro methods. Several ethnomedicinal plants have been validated for their anticancer activities through in vitro and animal models. These medicinal plants and phytochemicals resulted in the inhibition of initiation, progression or metastasis of neoplasm. Some medicinal plants (10) are endangered species. Half of folkloric Pakistani plants have been validated for use against various cancers through in vitro or in vivo methods. It is necessary to carry out further pharmacological and toxicological evaluation of these folkloric anticancer plants of Pakistan. It is also necessary to identify and isolate further potential phytochemicals so as to be evaluated in cancer patients.


Atypical Chemokine Receptor 1 (DARC/ACKR1) in Breast Tumors Is Associated with Survival, Circulating Chemokines, Tumor-Infiltrating Immune Cells, and African Ancestry.
Tumor-specific immune response is an important aspect of disease prognosis and ultimately impacts treatment decisions for innovative immunotherapies. The atypical chemokine receptor 1 (ACKR1 or DARC) gene plays a pivotal role in immune regulation and harbors several single-nucleotide variants (SNV) that are specific to sub-Saharan African ancestry. Using computational The Cancer Genome Atlas (TCGA) analysis, case-control clinical cohort Luminex assays, and CIBERSORT deconvolution, we identified distinct immune cell profile-associated DARC/ACKR1 tumor expression and race with increased macrophage subtypes and regulatory T cells in DARC/ACKR1-high tumors. In this study, we report the clinical relevance of DARC/ACKR1 tumor expression in breast cancer, in the context of a tumor immune response that may be associated with sub-Saharan African ancestry. Briefly, we found that for infiltrating carcinomas, African Americans have a higher proportion of DARC/ACKR1-negative tumors compared with white Americans, and DARC/ACKR1 tumor expression is correlated with proinflammatory chemokines, CCL2/MCP-1 (P <0.0001) and anticorrelated with CXCL8/IL8 (P <0.0001). Sub-Saharan African-specific DARC/ACKR1 alleles likely drive these correlations. Relapse-free survival (RFS) and overall survival (OS) were significantly longer in individuals with DARC/ACKR1-high tumors (P <1.0 × 10-16 and P <2.2 × 10-6, respectively) across all molecular tumor subtypes. DARC/AKCR1 regulates immune responses in tumors, and its expression is associated with sub-Saharan African-specific alleles. DARC/ACKR1-positive tumors will have a distinct immune response compared with DARC/AKCR1-negative tumors. This study has high relevance in cancer management, as we introduce a functional regulator of inflammatory chemokines that can determine an infiltrating tumor immune cell landscape that is distinct among patients of African ancestry.


Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.
Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).


[Grey zones on new oral anticoagulants in atrial fibrillation. Expert opinion].
Clinical guidelines, while representing an objective reference to perform appropriate treatment choices, contain grey zones, where recommendations are not supported by solid evidence. In a conference held in Bergamo in October 2018, an attempt was made to highlight some of the main grey zones in Cardiology and, through a comparison between experts, to draw shared conclusions that can illuminate our clinical practice. This manuscript contains the statements of the symposium concerning the controversies regarding new oral anticoagulants (NOACs) and atrial fibrillation (AF). The manuscript represents the organization of the meeting, with an initial review of current guidelines on this topic, followed by an expert presentation of pros (white) and cons (black) related to the identified "gaps of evidence". For every issue is then reported the response derived from the votes of the experts and the public, the discussion and, finally, the highlights, which are intended as practical "take home messages" to be used in everyday clinical practice. The first topic concerns the indication for anticoagulant therapy in patients with subclinical AF revealed by implanted devices. The second issue examines the opportunity to use NOACs in oncological patients with AF. The third gap evaluates the necessity of anticoagulating patients with AF and CHA2DS2-VASc 1 or CHA2DS2-VASc 2 if women. The last "gap in evidence" concerns the preference of triple or double therapy in patients with AF and acute coronary syndrome/coronary stenting. The work has also been implemented with evidences deriving from important randomized studies published after the date of the Conference.


Topical gentamicin-induced hearing loss: a mitochondrial ribosomal RNA study of genetic susceptibility.
Mitochondrial ribosomal RNA mutation has been shown to predispose affected individuals to aminoglycoside-induced hearing loss (AIHL). An A-to-G nucleotide substitution at the 1555 position within the 12S ribosomal RNA gene has been identified with a maternally inherited pattern in affected Asian pedigrees. The aim of this study was to identify the frequency of this DNA polymorphism in subjects who appear to show hypersensitivity to topical (middle ear) application of aminoglycoside. In this pilot study, 10 subjects with AIHL were recruited. Eight underwent vestibular ablative therapy with middle ear instillation of gentamicin for disabling vertigo, and two were treated with topical antibiotic drops for otitis media in the presence of a tympanic perforation. DNA samples were extracted, and polymerase chain reaction (PCR) technique was used for gene amplification and purification, searching for 1555 A-to-G substitution in the 12S ribosomal RNA gene. None of the subjects demonstrated this specific mutation.


Elevated Systemic Inflammatory Burden and Cardiovascular Risk in Young Adults with Endodontic Apical Lesions.
The aim of this study was to assess whether apical lesions are associated with inflammatory serum markers of cardiovascular risk, especially high-sensitivity C-reactive protein (hsCRP), in young adults. In this cross-sectional study, otherwise healthy individuals with apical lesions of endodontic origin (ALEOs) and a clinical diagnosis of asymptomatic apical periodontitis and controls aged between 18 and 40 years were included. Patients' sociodemographic characteristics, medical history, and classic cardiovascular risk factors were recorded, and the pathobiological determinants of atherosclerosis in youth score was calculated. Oral clinical and radiographic examinations were performed. Blood samples were collected to determine the lipid profile, glycated hemoglobin, hsCRP, immunoglobulin G, interleukin (IL)-6, IL-10, IL-12p70, matrix metalloproteinase 8, soluble vascular cellular adhesion molecule-1, soluble intercellular adhesion molecule-1, and soluble E-selectin. Bivariate and multivariate analyses adjusting for oral and classic cardiovascular risk factors were performed. hsCRP levels were significantly higher in ALEO patients versus controls (median = 2.54 vs 0.78), whereas the pathobiological determinants of atherosclerosis in youth score was comparable among the groups. Also, the levels of IL-6, matrix metalloproteinase 8, and soluble E-selectin were significantly higher in ALEO patients. hsCRP, IL-6, and IL-12 correlated with soluble adhesion molecules. Bivariate analysis based on hsCRP serum concentrations ≥1 mg/L showed an odds ratio (OR) = 6.8, and the risk increased 3.3 times for an additional ALEO. In multivariate analysis, ALEO was significantly associated with hsCRP levels ≥1 mg/L (OR = 5.1-12.8) independently of the adjustment model. ALEO also associated with CRP levels >3 mg/L, which was significant after the adjustment for covariates (OR = 4.0). ALEO is associated with the systemic inflammatory burden and cardiovascular risk determined by hsCRP, supporting a mechanistic link for cardiovascular diseases in young adults.


Binding of plasma fibronectin to monolayer human endothelium.
Interaction of exogenous plasma fibronectin with endothelium was examined using monolayer cultures of human umbilical vein endothelial cells. Plasma fibronectin was purified on gelatin-sepharose with 1 M arginine elution and iodinated with 125I by the solid phase glycoluril method. Endothelial monolayers were incubated with 0.5 to 15.0 mg/l (125I)fibronectin. Specificity of binding was 50 to 60% as determined by competition with 50-fold excess nonlabeled fibronectin. Binding reached maximal levels within 1 hour and without saturation over the concentration range. The bound glycoprotein showed minimal dissociation during subsequent incubation in media free of fibronectin.


Temporal evolution of oscillations and synchrony in GPi/muscle pairs in Parkinson's disease.
Both standard spectral analysis and time-dependent phase correlation techniques were applied to 27 pairs of tremor-related single units in the globus pallidus internus (GPi) and EMG of patients with Parkinson's disease (PD) undergoing stereotactic neurosurgery. Over long time-scales (approximately 60 s), GPi tremor-related units were statistically coherent with restricted regions of the peripheral musculature displaying tremor. The distribution of pooled coherence across all pairs supports a classification of GPi cell/EMG oscillatory pairs into coherent or noncoherent. Analysis using approximately 2-s sliding windows shows that oscillatory activity in both GPi tremor units and muscles occurs intermittently over time. For brain/muscle pairs that are coherent, there is partial overlap in the times of oscillatory activity but, in most cases, no significant correlation between the times of oscillatory subepisodes in the two signals. Phase locking between coherent pairs occurs transiently; however, the phase delay is similar for different phase-locking subepisodes. Noncoherent pairs also show episodes of transient phase locking, but they occurred less frequently, and no preferred phase delay was seen across subepisodes. Tremor oscillations in pallidum and EMGs are punctuated by phase slips, which were classified as synchronizing or desynchronizing depending on their effect on phase locking. In coherent pairs, the incidence of synchronizing slips is higher than desynchronizing slips, whereas no significant difference was seen for noncoherent pairs. The results of this quantitative characterization of parkinsonian tremor provide a foundation for hypotheses about the structure and dynamical functioning of basal ganglia motor control networks involved in tremor generation.


Towards an Advanced Modeling of Hybrid Composite Cutting: Heat Discontinuity at Interface Region.
In this study, a thermomechanical model is developed to simulate a finite drilling set of Carbon Fibre Reinforced Polymers (CFRP)/Titanium (Ti) hybrid structures widely known for their energy saving performance. The model applies different heat fluxes at the trim plane of the two phases of the composite, owing to cutting forces, in order to simulate the temperature evolution at the workpiece during the cutting step. A user-defined subroutine VDFLUX was implemented to address the temperature-coupled displacement approach. A user-material subroutine VUMAT was developed to describe Hashin damage-coupled elasticity model for the CFRP phase while Johnson-Cook damage criteria was considered for describing the behavior of titanium phase. The two subroutines coordinate to evaluate sensitively the heat effects at the CFRP/Ti interface and within the subsurface of the structure at each increment. The proposed model has been first calibrated based on tensile standard tests. The material removal process was then investigated versus cutting conditions. Predictions show discontinuity in temperature field at interface that should further favor damage to localize especially at CFRP phase. The obtained results highlight the significant effects of fibre orientation in dominating cutting temperature and thermal effects over the whole hybrid structure.


Scleroderma: therapeutic options.
Although the cause of scleroderma remains elusive, pharmacologic advances and increased understanding of the pathophysiology of this disease provide therapeutic options. Therapy usually addresses the fibrotic, vascular, or immunologic alterations, but general measures can be helpful and should not be overlooked.


Engineering long shelf life multi-layer biologically active surfaces on microfluidic devices for point of care applications.
Although materials and engineered surfaces are broadly utilized in creating assays and devices with wide applications in diagnostics, preservation of these immuno-functionalized surfaces on microfluidic devices remains a significant challenge to create reliable repeatable assays that would facilitate patient care in resource-constrained settings at the point-of-care (POC), where reliable electricity and refrigeration are lacking. To address this challenge, we present an innovative approach to stabilize surfaces on-chip with multiple layers of immunochemistry. The functionality of microfluidic devices using the presented method is evaluated at room temperature for up to 6-month shelf life. We integrated the preserved microfluidic devices with a lensless complementary metal oxide semiconductor (CMOS) imaging platform to count CD4(+) T cells from a drop of unprocessed whole blood targeting applications at the POC such as HIV management and monitoring. The developed immunochemistry stabilization method can potentially be applied broadly to other diagnostic immuno-assays such as viral load measurements, chemotherapy monitoring, and biomarker detection for cancer patients at the POC.


Preclinical screening of the applicability of strontium as a marker for intestinal calcium absorption.
The applicability of stable strontium as a marker for measuring intestinal calcium absorption is mainly dependent on the validity of the assumption that calcium and strontium are absorbed with a constant ratio. Up to now, it is not clear whether this ratio is affected by intervention therapy. Therefore, preclinical screening of this ratio before and after treatment is indispensable for a clinical calcium absorption test based on the use of stable strontium as a marker. We studied the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D(3)], a potent enhancer of active intestinal calcium absorption, on the pharmacokinetics of both calcium-45 and strontium in adult male rats, in a short-term dose-finding study [0-50 ng 1,25(OH)2D(3)/100 g body weight] and also in a placebo-controlled study in which 12.5 ng 1,25(OH)2D(3)/100 g body weight were applied to assess the long-term pharmacokinetics. The mean bioavailability (true absorption) was 33% for calcium and 19% for strontium (ratio 1.7:1), whereas, after 1,25(OH)2D(3) pretreatment, it was 73 and 43% (ratio 1.7:1), respectively. These findings demonstrate that intestinal strontium absorption has, like intestinal calcium absorption, an active component. Moreover, they underscore the applicability of stable strontium as a tool for investigating calcium absorption under various conditions.


A coaxial cable Fabry-Perot interferometer for sensing applications.
This paper reports a novel coaxial cable Fabry-Perot interferometer for sensing applications. The sensor is fabricated by drilling two holes half-way into a coaxial cable. The device physics was described. The temperature and strain responses of the sensor were tested. The measurement error was calculated and analyzed.


Inferior vena cava occlusion secondary to aortic aneurysm.
A case of inferior vena caval thrombosis secondary to aortic aneurysm is presented with management guidelines. CT scanning, as well as conventional venography and arteriography, is very useful in understanding this process preoperatively. Intraoperative management should prevent pulmonary embolism and should anticipate the possibility of blood loss in excess of that which usually occurs with an uncomplicated aneurysm repair. Detailed review of the literature reveals this is a rare complication of aneurysm disease and a potentially lethal one.


In vivo expression of survivin and its splice variant survivin-2B: impact on clinical outcome in acute myeloid leukemia.
Survivin, a member of the inhibitor of apoptosis protein family, is expressed in most human cancers, but undetectable in normal differentiated adult tissue in vivo. Because of this cancer-related expression, survivin is a promising target for cancer therapy. To determine the expression and prognostic role of survivin in acute myeloid leukemia (AML), we investigated the mRNA expression pattern of survivin and of the splice variants survivin-2B and survivin-DeltaEx3 in adult (n = 74) and children (n = 31) with de novo AML using RT-PCR. Survivin was the predominant transcript variant in AML cells, whereas significantly lower levels of survivin-2B and survivin-DeltaEx3 were observed (p < or = 0.0001). Neither expression of survivin nor of any splice variant correlated with maturation stage (FAB subtypes, immunophenotype) or cytogenetic risk groups. For AML cases treated according to AMLCG92 (adult) and AML-BFM93 (children) protocols, respectively, expression patterns were correlated with clinical data: in adult AML (n = 51), low expression of survivin-2B correlated with a better overall survival (p = 0.05; mean survival time 19 months vs. 9 months) and a better eventfree survival (p < or = 0.01; 27 months vs. 10 months). In childhood AML (n = 31), high survivin-DeltaEx3 expression was associated with a shorter overall survival (p < or = 0.05; 24 months vs. 43 months). We conclude that certain survivin splice variants have potential prognostic impact for long-term therapy outcome in adult as well as childhood de novo AML.


Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1.
The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers.


Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Retain Activity against Multidrug-Resistant Pseudomonas aeruginosa In Vitro and In Vivo.
Most antimicrobials currently in the clinical pipeline are modifications of existing classes of antibiotics and are considered short-term solutions due to the emergence of resistance. Pseudomonas aeruginosa represents a major challenge for new antimicrobial drug discovery due to its versatile lifestyle, ability to develop resistance to most antibiotic classes, and capacity to form robust biofilms on surfaces and in certain hosts such as those living with cystic fibrosis (CF). A precision antibiotic approach to treating Pseudomonas could be achieved with an antisense method, specifically by using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Here, we demonstrate that PPMOs targeting acpP (acyl carrier protein), lpxC (UDP-(3-O-acyl)-N-acetylglucosamine deacetylase), and rpsJ (30S ribosomal protein S10) inhibited the in vitro growth of several multidrug-resistant clinical P. aeruginosa isolates at levels equivalent to those that were effective against sensitive strains. Lead PPMOs reduced established pseudomonal biofilms alone or in combination with tobramycin or piperacillin-tazobactam. Lead PPMO dosing alone or combined with tobramycin in an acute pneumonia model reduced lung bacterial burden in treated mice at 24 h and reduced morbidity up to 5 days postinfection. PPMOs reduced bacterial burden of extensively drug-resistant P. aeruginosa in the same model and resulted in superior survival compared to conventional antibiotics. These data suggest that lead PPMOs alone or in combination with clinically relevant antibiotics represent a promising therapeutic approach for combating P. aeruginosa infections.IMPORTANCE Numerous Gram-negative bacteria are becoming increasingly resistant to multiple, if not all, classes of existing antibiotics. Multidrug-resistant Pseudomonas aeruginosa bacteria are a major cause of health care-associated infections in a variety of clinical settings, endangering patients who are immunocompromised or those who suffer from chronic infections, such as people with cystic fibrosis (CF). Herein, we utilize antisense molecules that target mRNA of genes essential to bacterial growth, preventing the formation of the target proteins, including acpP, rpsJ, and lpxC We demonstrate here that antisense molecules targeted to essential genes, alone or in combination with clinically relevant antibiotics, were effective in reducing biofilms and protected mice in a lethal model of acute pneumonia.


Evaluation of Psychological Resilience, Alexithymia, and Impulsivity Characteristics in Persons Who Attempted Suicide with Drugs.
In this study, it was aimed to research the connection between psychological resilience, alexithymia, depression, anxiety and impulsivity in patients who attempted suicide with drugs. The patient group (n = 66) who attempted suicide with drugs and the control group (n = 66) without any psychiatric diagnosis were examined in the study. Sociodemographic data form, Psychological Resilience Scale, Toronto Alexithymia Scale (TAS-20), Beck Depression Inventory, Beck Anxiety Inventory, Barratt Impulsivity Scale (BIS-11) were used in the study. It was found that PRS dedication and challenge are significantly higher in the control group (p = .039 and p = .003, respectively). When the undiagnosed group who attempted suicide were compared with the control group, it was observed that there is a significant difference between BIS-11 total and TAS total after bonferonni correction (respectively; p = .002; p = .001), while, there is no statistically significant difference in terms of PRS total score (p = .483). It was observed that patients who attempted suicide with drugs had low levels of psychological resilience, high alexithymia levels. In the absence of an additional diagnosis of depression, psychological resilience did not differ in terms of suicide attempts. In the suicide group, those who did not receive any additional diagnosis were not more impulsive than those who were depressed.


New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis.
Periodic paralysis is classified into hypokalemic (hypoPP) and hyperkalemic (hyperPP) periodic paralysis according to variations of blood potassium levels during attacks. To describe new mutations in the muscle sodium channel gene SCN4A that cause periodic paralysis. A thorough clinical, electrophysiologic, and molecular study was performed of four unrelated families who presented with periodic paralysis. The nine affected members had episodes of muscle weakness reminiscent of both hyperPP and hypoPP. A provocative test with potassium chloride was positive in two patients. However, repeated and carefully performed tests of blood potassium levels during attacks resulted in normal potassium levels. Remarkably, two patients experienced hypokalemic episodes of paralysis related to peculiar provocative factors (corticosteroids and thyrotoxicosis). Similarly to hyperPP, electromyography in nine patients revealed increased compound muscle action potentials after short exercise and a delayed decline during rest after long exercise as well as myotonic discharges in one patient. With use of molecular genetic analysis of the gene SCN4A, three new mutations were found affecting codon 675. They resulted in an amino acid substitution of a highly conserved arginine (R) to either a glycine (G), a glutamine (Q), or a tryptophan (W). Interestingly, hypoPP is caused by both mutations affecting nearby codons as well as the change of an arginine into another amino acid. A potassium-sensitive and normokalemic type of periodic paralysis caused by new SCN4A mutations at codon 675 is reported.


Treatment in an outpatient setting for a patient with an infected, surgical wound with hypergranulation tissue.
The purpose of this article is to describe a multifaceted approach to wound care in an outpatient setting for a patient with an infected, nonhealing surgical wound with hypergranulation tissue following fasciotomy for acute compartment syndrome. A 44-year-old male underwent an anterior and lateral lower extremity compartment fasciotomy and developed a persistent right anterolateral lower leg wound. Thirty-six days after fasciotomy he came to the authors' clinic after 2 failed skin grafts with an infected wound covered in hypergranulation tissue. Treatment included sharp debridement, saline irrigation, patient education, and dressing changes during 9 treatment sessions. The patient's total wound surface area decreased from 5.2 cm x 17.3 cm to 4 cm x 15 cm with increased epithelialization from approximately 40% to 85% after 29 days of treatment. This article demonstrates the positive effect of a multifaceted approach for facilitation of wound healing in a lower extremity wound following fasciotomy.


Tumor-specific transcriptional targeting of suicide gene therapy.
Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog ([((1)31)I]-FIAU) serving as a substrate for HSV-tk. [((1)31)I]-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.


Physical fitness and hypertension in a population at risk for cardiovascular disease: the Henry Ford ExercIse Testing (FIT) Project.
Increased physical fitness is protective against cardiovascular disease. We hypothesized that increased fitness would be inversely associated with hypertension. We examined the association of fitness with prevalent and incident hypertension in 57 284 participants from The Henry Ford ExercIse Testing (FIT) Project (1991–2009). Fitness was measured during a clinician‐referred treadmill stress test. Incident hypertension was defined as a new diagnosis of hypertension on 3 separate consecutive encounters derived from electronic medical records or administrative claims files. Analyses were performed with logistic regression or Cox proportional hazards models and were adjusted for hypertension risk factors. The mean age overall was 53 years, with 49% women and 29% black. Mean peak metabolic equivalents (METs) achieved was 9.2 (SD, 3.0). Fitness was inversely associated with prevalent hypertension even after adjustment (≥12 METs versus <6 METs; OR: 0.73; 95% CI: 0.67, 0.80). During a median follow‐up period of 4.4 years (interquartile range: 2.2 to 7.7 years), there were 8053 new cases of hypertension (36.4% of 22 109 participants without baseline hypertension). The unadjusted 5‐year cumulative incidences across categories of METs (<6, 6 to 9, 10 to 11, and ≥12) were 49%, 41%, 30%, and 21%. After adjustment, participants achieving ≥12 METs had a 20% lower risk of incident hypertension compared to participants achieving <6 METs (HR: 0.80; 95% CI: 0.72, 0.89). This relationship was preserved across strata of age, sex, race, obesity, resting blood pressure, and diabetes. Higher fitness is associated with a lower probability of prevalent and incident hypertension independent of baseline risk factors.


A computational study on ligand assisted vs. ligand participation mechanisms for CO2 hydrogenation: importance of bifunctional ligand based catalysts.
CO2 hydrogenation products are not only useful chemical sources but also promising hydrogen storage materials. A DFT study has been carried out on the CO2 hydrogenation reaction catalyzed by a series of bifunctional aminomethyl based Mn(i) complexes. We find that the N-H functionality in the aminomethyl ligand shows a metal-ligand cooperation (MLC) mechanism for the CO2 hydrogenation reaction. Here, the N-H functionality assists the MLC mechanism by stabilizing the formate anion via N-HO hydrogen bonding interactions. This is opposite to the MLC mechanism proposed by Noyori for ketone hydrogenation, where the N-H functionality actively participates in the reaction mechanism via cleavage/formation of N-H/M-H bonds. Furthermore, the stabilized formate anion initiates heterolytic H2 cleavage, which requires a very low barrier compared to external base/ligand participation heterolytic H2 cleavage. Therefore, the bifunctional aminomethyl based Mn(i) complexes are promising for the CO2 hydrogenation reaction and our study may be very helpful for experimentalists for the development of efficient bifunctional ligand-based catalysts for the CO2 hydrogenation reaction.


[Muscular phosphorylase deficiency in two siblings].
The clinical manifestation of McArdle disease rarely occur in children. A brother and a sister aged 12 and 7 years respectively are presented. Both are sons of a consanguinous marriage. The clinical manifestations of the girl began when she was seven. The dominant clinical feature was her difficulty in performing physical exercises. At this time the brother was asymptomatic. There were no abnormalities on physical examination. The level of the serum CK was fluctuating at a level above normal in both patients. There was not lactic acidosis after exercise test. The level of lactic acid didn't rise after McArdle test with ischemia of the forearm in both, however the plasmatic ammonium rose six or seven times above the basal level. The electromyography showed in the girl electric silence without pain and stiffness after ischemia of the forearm. The muscle biopsy performed by a Bergström needle showed in both a subsarcolemmal glycogen accumulations. The histochemical reaction for phosphorylase was absent, the biochemical investigations confirmed the absence of this enzyme. A hyperproteique diet did not release the clinical manifestations of the patients.


Variable selection for optimal treatment decision.
In decision-making on optimal treatment strategies, it is of great importance to identify variables that are involved in the decision rule, i.e. those interacting with the treatment. Effective variable selection helps to improve the prediction accuracy and enhance the interpretability of the decision rule. We propose a new penalized regression framework which can simultaneously estimate the optimal treatment strategy and identify important variables. The advantages of the new approach include: (i) it does not require the estimation of the baseline mean function of the response, which greatly improves the robustness of the estimator; (ii) the convenient loss-based framework makes it easier to adopt shrinkage methods for variable selection, which greatly facilitates implementation and statistical inferences for the estimator. The new procedure can be easily implemented by existing state-of-art software packages like LARS. Theoretical properties of the new estimator are studied. Its empirical performance is evaluated using simulation studies and further illustrated with an application to an AIDS clinical trial.


[The nature of the hypermetabolism and tachycardia in cold adaptation and experimental hyperthyroidism].
The cross circulation method has been used to study contribution of humoral and nonhumoral components to the origin of hypermetabolism (increased level of basal metabolism) and tachycardia under adaptation to cold and experimental hyperthyroidism. Consumption of oxygen, heart rate and rectal temperature have been studied in periods prior to and during the cross circulation. It is shown that under experimental hyperthyroidism contribution of humoral and nonhumoral factors to the origin of hypermetabolism equals 22 and 78%, while that to genesis of tachycardia--44 and 56%, respectively. Under cold adaptation an increase of the basal metabolism level depends on humoral agents by 77% and on changes of the stationary character only by 23%. The nature of adaptation tachycardia is mainly, of the humoral origin (65%).


Rise and fall of outbreak-specific clone inside endemic pulsotype of Salmonella 4,[5],12:i:-; insights from high-resolution molecular surveillance in Emilia-Romagna, Italy, 2012 to 2015.
Background and aimEpidemiology of human non-typhoid salmonellosis is characterised by recurrent emergence of new clones of the pathogen over time. Some clonal lines of Salmonella have shaped epidemiology of the disease at global level, as happened for serotype Enteritidis or, more recently, for Salmonella 4,[5],12:i:-, a monophasic variant of serotype Typhimurium. The same clonal behaviour is recognisable at sub-serotype level where single outbreaks or more generalised epidemics are attributable to defined clones. The aim of this study was to understand the dynamics of a clone of Salmonella 4,[5],12:i:- over a 3-year period (2012-15) in a province of Northern Italy where the clone caused a large outbreak in 2013. Furthermore, the role of candidate outbreak sources was investigated and the accuracy of multilocus variable-number tandem repeat analysis (MLVA) was evaluated. Methods: we retrospectively investigated the outbreak through whole genome sequencing (WGS) and further monitored the outbreak clone for 2 years after its conclusion. Results: The study showed the transient nature of the clone in the population, possibly as a consequence of its occasional expansion in a food-processing facility. We demonstrated that important weaknesses characterise conventional typing methods applied to clonal pathogens such as Salmonella 4,[5],12:i:-, namely lack of accuracy for MLVA and inadequate resolution power for PFGE to be reliably used for clone tracking. Conclusions: The study provided evidence for the remarkable prevention potential of whole genome sequencing used as a routine tool in systems that integrate human, food and animal surveillance.


[The effect of surgical trauma on the metabolism of essential fatty acids in patients with cancer of the esophagus and stomach].
The dynamics of levels of essential fatty (linolic and arachidonic) acids in blood plasma and erythrocytes as well as that of free fatty acids fraction versus duration of surgery was assessed by gas chromatography in 49 patients with cancer of the esophagus and gastric cardia. Surgical procedures lasting longer than 5 hours are followed by overmobilization of essential fatty acids from body lipids their endogenous store being depleted. As a result, a double increase in the level of free arachidonic acid, an immediate prostaglandin precursor, develops to satisfy the body's augmented requirements in essential fatty acids due to application of aggressive surgical procedures.


Additive Value of Preoperative Sarcopenia and Lymphopenia for Prognosis Prediction in Localized Pancreatic Ductal Adenocarcinoma.
Surgical resection with adjuvant chemotherapy is the only treatment that can provide long term survival in localized pancreatic ductal adenocarcinoma (LPDAC). Notwithstanding, recurrence occurs in the vast majority of patients and a better stratification of preoperative therapies is required. This study aimed to investigate preoperative immunological and nutritional factors to predict relapse-free survival (RFS) in patients with LPDAC. Analyses were derived from all consecutive LPDAC patients treated with surgical resection at Besancon University Hospital, France, between January 2006 and December 2014 (n=146). Biological and nutritional parameters were recorded before and after surgery. The association of 24 baseline parameters with RFS was evaluated using univariate and multivariate Cox analyses. Based on the final model, a prognostic score was developed. Lymphocyte count and body composition were available for 94 patients. In multivariate analysis, preoperative lymphopenia and sarcopenia (or a low muscle mass) were identified as independent prognostic factors for RFS. The score determined three groups with a median RFS of 5.6 months (95% confidence interval [CI] = 4.3 to 9.6 months) for high-risk group, corresponding to patients with lymphopenia; 11.5 months (95%CI = 9.8 to 13.9 months), and 21.2 months (95%CI = 9.9 to 55.3 months), for intermediate-(patient with sarcopenia without lymphopenia), and low-risk groups (no risk factor), respectively (p <0.001). Preoperative sarcopenia predicts the occurrence of postoperative lymphopenia in patients with a preoperative lymphocyte count above 1,000/mm3 (p = 0.0029). Preoperative lymphopenia and sarcopenia are pejorative prognostic factors in LPDAC and should be considered in the preoperative evaluation to stratify death risk in patients with LPDAC.


Activation of thyroid hormone is transcriptionally regulated by epidermal growth factor in human placenta-derived JEG3 cells.
Human type II deiodinase is a master regulator of thyroid hormone activation in several tissues. In placenta, type II deiodinase mRNA levels and enzymatic activity are elevated only during the first trimester of pregnancy and then progressively decline. During this early stage, mitogens such as epidermal growth factor (EGF) have been shown to promote the proliferation of the trophoblast by acting through multiple mechanisms. Here we show that EGF modulates transcription of human type II deiodinase gene (Dio2) through distinct signaling pathways, leading to the assembly of a heterogeneous transcription factor complex. Gene expression and deiodination assays have shown that EGF promptly induces a short-lived Dio2 mRNA and enzymatic activity. The induction is mediated by ERK and p38 kinases, as demonstrated by selective inhibition or overexpression of different mitogen-activated kinases. Reporter assays of mutant constructs indicate that EGF-induced transcriptional activity on Dio2 promoter is mediated by the cAMP response element (CRE) and does not involve the activating protein 1 site. With functional and biochemical approaches, we have demonstrated that the EGF stimulation culminates with the assembly and recruitment over the Dio2 CRE of a composite complex, which consists of c-Jun, c-Fos, and CRE-binding protein. These results further support the hypothesis that placental iodothyronine metabolism is critical during early pregnancy.


Biomarkers of Rehabilitation Therapy Vary according to Stroke Severity.
Biomarkers that capture treatment effects could improve the precision of clinical decision making for restorative therapies. We examined the performance of candidate structural, functional, and angiogenesis-related MRI biomarkers before and after a 3-week course of standardized robotic therapy in 18 patients with chronic stroke and hypothesized that results vary significantly according to stroke severity. Patients were 4.1 ± 1 months poststroke, with baseline arm Fugl-Meyer scores of 20-60. When all patients were examined together, no imaging measure changed over time in a manner that correlated with treatment-induced motor gains. However, when also considering the interaction with baseline motor status, treatment-induced motor gains were significantly related to change in three functional connectivity measures: ipsilesional motor cortex connectivity with (1) contralesional motor cortex (p = 0.003), (2) contralesional dorsal premotor cortex (p = 0.005), and (3) ipsilesional dorsal premotor cortex (p = 0.004). In more impaired patients, larger treatment gains were associated with greater increases in functional connectivity, whereas in less impaired patients larger treatment gains were associated with greater decreases in functional connectivity. Functional connectivity measures performed best as biomarkers of treatment effects after stroke. The relationship between changes in functional connectivity and treatment gains varied according to baseline stroke severity. Biomarkers of restorative therapy effects are not one-size-fits-all after stroke.


Metabolomics Analysis on Obesity-Related Obstructive Sleep Apnea After Weight Loss Management: A Preliminary Study.
Roux-en-Y gastric bypass (RYGB) surgery is an effective type of weight loss management and may improve obesity-related obstructive sleep apnea (OSA). Obese subjects who meet the criteria for surgery with OSA were enrolled. We investigated the metabolomic effects of RYGB on OSA. Clinical data, serum measurements including indices of glycolipid metabolism, and polysomnography (PSG) measurements were collected at baseline and 6 months after RYGB surgery. Metabolomic analysis was performed using ultra-performance liquid chromatography-mass spectrometry. A group of 37 patients with obesity, type 2 diabetes (T2DM) and suspected OSA were enrolled of which 27 were OSA subjects. After RYGB surgery, metabolic outcomes and sleep parameters were all significantly improved. The OSA remission group had lower valine, isoleucine, and C24:1(cis-15) levels, and higher trimethylamine N-oxide, hippurate, and indole-3-propionic acid levels after RYGB surgery. A combination of preoperative indices (age, apnea-hypopnea index (AHI), fasting C-peptide level, and hippurate level) predicted the RYGB effect size in obese patients with T2DM and OSA, with an area under receiver operating characteristic curve of 0.947, specificity of 82.4%, and sensitivity of 100%. RYGB surgery may significantly improve the metabolic status of patients with obesity, T2DM and OSA. A combination of preoperative indices (age, AHI, fasting C peptide level, and hippurate level) may be useful for predicting the effect size of RYGB in obese patients with T2DM and OSA. The mechanisms underlying OSA remission need to be explored.


Transition-state stabilization by a secondary substrate-ligand interaction: a new design principle for highly efficient transition-metal catalysis.
A library of monodentate phosphane ligands, each bearing a guanidine receptor unit for carboxylates, was designed. Screening of the library gave some excellent catalysts for regioselective hydroformylation of beta,gamma-unsaturated carboxylic acids. A terminal alkene, but-3-enoic acid, was hydroformylated with a linear/branched (l/b) regioselectivity up to 41. An internal alkene, pent-3-enoic acid was hydroformylated with regioselectivity up to 18:1. Further substrate selectivity (e.g., acid vs. methyl ester) and reaction site selectivity (monofunctionalization of 2-vinylhept-2-enoic acid) were also achieved. Exploration of the structure-activity relationship and a practical and theoretical mechanistic study gave us an insight into the nature of the supramolecular guanidinium-carboxylate interaction within the catalytic system. This allowed us to identify a selective transition-state stabilization by a secondary substrate-ligand interaction as the basis for catalyst activity and selectivity.


Enhanced Ethanol-Sensing Properties Based on Modified NiO-ZnO p-n Heterojunction Nanotubes.
NiO/ZnO gas-sensing nanotube materials were prepared by electrospinning. The structure and morphology of the samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), energydispersive X-ray detection (EDX) and Brunauer-Emmett-Teller (BET) analysis. The template, PAN (peroxyacetyl nitrate) fibers, was completely removed, as evidenced by the EDX results. The final NiO/ZnO composite materials were composed of hexagonal wurtzite ZnO and cubic NiO and exhibited hollow tubular structures. In the composites, p-n heterojunctions were formed at the interface of NiO and ZnO. The results of gas sensitivity tests showed that the incorporation of NiO considerably improved the gas sensitivity of ZnO to ethanol. When the doping ratio was 0.125 mol/mol, the composites exhibited the highest sensitivity to ethanol (100.92 at 300 °C) and showed high selectivity.


Analysis of sagittal condylar path inclination in consideration of Fischer's angle.
This study investigated the sagittal condylar path during protrusive and lateral excursions by analysing the actually measured jaw movement data and re-evaluated the setting of the sagittal condylar path inclination in consideration of Fischer's angle. Protrusive and lateral excursions of 10 healthy subjects were measured using a three-dimensional mandibular movement analysing system. Condylar path inclinations at the hinge-axis point and the corresponding external point laterally extending from the condyle were evaluated in the sagittal plane. Fischer's angle was defined as the difference between the sagittal condylar inclinations during protrusive and lateral excursions on the non-working side, by keeping the corresponding horizontal distance from the intercuspal position (ICP) equivalent at the incisal point. Analysis was performed at three different magnitudes of excursions, where the incisal point was located at 1, 3 and 5 mm away from the ICP. There was no significant difference in the sagittal condylar path inclination or the Fischer's angle between two condylar reference points. However, they were significantly different across the three different magnitudes of excursions for both condylar reference points, i.e. sagittal condylar path inclination (P = 0.003 for protrusive excursion, and P < 0.001 for lateral excursion respectively; two-way repeated-measures anova), and Fischer's angle (P = 0.013, two-way repeated-measures anova) became smaller as the incisal point became distant from the ICP. Moreover, 3- and 5-mm eccentric positions were included in the 95% CI where Fischer's angle equals zero and were considered to be clinically acceptable to adjust the sagittal condylar inclination on the semiadjustable articulators.


Polyethylene glycol-mediated cell fusion.
Polyethylene glycol (PEG)-mediated cell fusion is a simple and efficient technique used widely for the production of somatic cell hybrids and for nuclear transfer in mammalian cloning. We describe a basic protocol of PEG-mediated cell fusion for the production of somatic cell hybrids. Fusion can be performed between adherent and suspension cells or between adherent cells or suspension cells. Either whole cells or microcells can be used as donors to fuse with recipient cells. Microcell fusion is particularly useful in transfer of a single or a limited number of chromosomes between various types of cells. Using this method, we have successfully introduced mammalian minichromosomes into a variety of vertebrate cells. The technique described here can be adapted for uses in other cell fusion involved research. This protocol, in principle, provides guidelines for further development of PEG mediated cell fusion technology.


Immune response: the key to bone resorption in periodontal disease.
Periodontal disease infection with oral biofilm microorganisms initiates host immune response and signs of periodontitis, including bone resorption. This review delineates some mechanisms underlying the host immune response in periodontal infection and alveolar bone resorption. Activated T lymphocytes have been historically implicated in experimental periodontal bone resorption. An experimental rat adoptive transfer/gingival challenge periodontal disease model has been demonstrated to require antigen-specific T lymphocytes and gingival instillation of antigen and LPS for bone resorption. Interference with costimulatory interactions between T cells and antigen-presenting cells abrogated bone resorption, further emphasizing the significance of immune response in periodontal disease. Receptor activator of nuclear factor kappaB ligand (RANKL), a critical osteoclast differentiation factor, is expressed on T lymphocytes in human periodontal disease as determined by immunohistochemical and confocal microscopic analyses. Interference with RANKL by systemic administration of osteoprotegerin (OPG), the decoy receptor for (and inhibitor of) RANKL, resulted in abrogation of periodontal bone resorption in the rat model. This finding indicated that T cell-mediated bone resorption is RANKL-dependent. In additional experiments, treatment of T cell-transferred rats with kaliotoxin (a scorpion venom potassium channel inhibitor) resulted in decreases in T-cell RANKL expression, diminished induction of RANKL-dependent osteoclastogenesis, and abrogation of bone resorption, implicating an important role of immune response/RANKL expression in osteoclastogenesis/bone resorption. In other experiments, adoptive transfer of antigen-specific, RANKL-expressing B cells, and infection with the antigen-bearing Actinobaccillus actinomycetemcomitans gave rise to periodontal bone resorption, indicating that B cells also have the capacity to mediate bone resorption, probably via RANKL expression. In humans, prominent T lymphocytes have been identified in periodontal disease, and diseased tissues showed elevated RANKL mRNA expression, as well as decreased OPG mRNA expression. Mononuclear cells from periodontal lesions involving T cells and B cells of patients induced osteoclastogenesis in vitro. In summary, a biofilm interface initiates immune cell infiltration, stimulating osteoclastogenesis/bone resorption in periodontal disease. This resorption can be ameliorated by inhibition of RANKL activity or by diminishing immune cell stimulation. These two procedures, if localized, have the potential to lead to the prevention or therapeutic management of periodontal disease and therefore require further study.


[Retroviral oncogenes and their cellular proto-oncogenes].
Recent data on the genome structure of transforming retroviruses and their cellular counterparts has been reviewed. Retroviruses are divided in several groups according to their oncogenic potential. Comparison of oncogenes and their protein products for most abundant transforming viruses are presented. Probable mechanisms of capture of cellular proto-oncogenes by retroviruses and the hypothesis of existence of endogenous transforming viruses are discussed. General features of cellular proto-oncogenes and possible ways of their activation resulting in neoplastic transformation are discussed. Some unresolved problems of retroviral carcinogenesis, in particular, the problem of existence of unidentified "X"-genes in retroviral genomes and involvement of constitutional viral genes in carcinogenesis are mentioned.


The carboxyl-terminal third of the dicarboxylate carrier is crucial for productive association with the inner membrane twin-pore translocase.
The carrier proteins of the mitochondrial inner membrane consist of three structurally related tandem repeats (modules). Several different, and in some cases contradictory, views exist on the role individual modules play in carrier transport across the mitochondrial membranes and how they promote protein insertion into the inner membrane. Thus, by use of specific translocation intermediates, we performed a detailed analysis of carrier biogenesis and assessed the physical association of carrier modules with the inner membrane translocation machinery. Here we have reported that each module of the dicarboxylate carrier contains sufficient targeting information for its transport across the outer mitochondrial membrane. The carboxyl-terminal module possesses major targeting information to facilitate the direct binding of the carrier protein to the inner membrane twin-pore translocase and subsequent insertion into the inner membrane in a membrane potential-dependent manner. We concluded that, in this case, a single structural repeat can drive inner membrane insertion, whereas all three related units contribute targeting information for outer membrane translocation.


Pediatric Spinal Ependymomas: An Epidemiologic Study.
Pediatric intramedullary spinal cord ependymomas represent a rare central nervous system neoplasm with few available data regarding incidence and outcomes. To this end, large population-based studies are needed to assess the epidemiology and survival risk factors associated with these tumors in the hope of better understanding these tumors as well as improving outcomes. This retrospective study was undertaken to explore factors that may influence survival in pediatric patients with intramedullary spinal cord ependymomas. Using the SEER (Surveillance Epidemiology and End Results) database, a prospective cancer registry, we retrospectively assessed survival in histologically confirmed spinal ependymomas in patients 17 years of age and younger. Survival was described with Kaplan-Meier curves, and a multivariate regression analysis was used to assess the association of several variables with survival, controlling for confounding variables. Invasive tumor extension (P < 0.001) was associated with decreased survival, whereas gross total resection (P = 0.028) correlated with better rates of survival. Age, gender, tumor size, tumor extension, the use and sequence of radiation therapy, or use of chemotherapy were not found to have a statistically significant association with survival outcomes. Invasive ependymomas occurring in the spine have a worse prognosis, whereas higher tumor grades do not clearly show worse rates of survival. Early diagnosis and surgery seem to be associated with improved survival and outcomes, whereas radiation therapy and chemotherapy have an unclear role.


Exchange of individual hydrogens for a protein in a crystal and in solution.
A preliminary comparison of the solvent exchange of individual hydrogens of a protein in solution and in a crystal has been possible by using data for lysozyme from 1H nuclear magnetic resonance and neutron diffraction studies. It is suggested that this approach enables a direct comparison of local dynamical behaviour in the two states. The results indicate markedly similar behaviour for many residues, but significant differences are indicated in several regions of the protein.


Decoding communities in networks.
According to a recent information-theoretical proposal, the problem of defining and identifying communities in networks can be interpreted as a classical communication task over a noisy channel: memberships of nodes are information bits erased by the channel, edges and nonedges in the network are parity bits introduced by the encoder but degraded through the channel, and a community identification algorithm is a decoder. The interpretation is perfectly equivalent to the one at the basis of well-known statistical inference algorithms for community detection. The only difference in the interpretation is that a noisy channel replaces a stochastic network model. However, the different perspective gives the opportunity to take advantage of the rich set of tools of coding theory to generate novel insights on the problem of community detection. In this paper, we illustrate two main applications of standard coding-theoretical methods to community detection. First, we leverage a state-of-the-art decoding technique to generate a family of quasioptimal community detection algorithms. Second and more important, we show that the Shannon's noisy-channel coding theorem can be invoked to establish a lower bound, here named as decodability bound, for the maximum amount of noise tolerable by an ideal decoder to achieve perfect detection of communities. When computed for well-established synthetic benchmarks, the decodability bound explains accurately the performance achieved by the best community detection algorithms existing on the market, telling us that only little room for their improvement is still potentially left.


Simulated two-dimensional electronic spectroscopy of the eight-bacteriochlorophyll FMO complex.
The Fenna-Matthews-Olson (FMO) protein-pigment complex acts as a molecular wire conducting energy between the outer antenna system and the reaction center; it is an important photosynthetic system to study the transfer of excitonic energy. Recent crystallographic studies report the existence of an additional (eighth) bacteriochlorophyll a (BChl a) in some of the FMO monomers. To understand the functionality of this eighth BChl, we simulated the two-dimensional electronic spectra of both the 7-site (apo form) and the 8-site (holo form) variant of the FMO complex from green sulfur bacteria, Prosthecochloris aestuarii. By comparing the spectrum, it was found that the eighth BChl can affect two different excitonic energy transfer pathways: (1) it is directly involved in the first apo form pathway (6 → 3 → 1) by passing the excitonic energy to exciton 6; and (2) it facilitates an increase in the excitonic wave function overlap between excitons 4 and 5 in the second pathway (7 → 4,5 → 2 → 1) and thus increases the possible downward sampling routes across the BChls.


The measurement of compassionate leadership: Adaptation and Spanish validation of the compassionate leadership self-reported scale.
A culture of shared leadership is widespread among palliative care teams based on a commitment to valuing and including all people equally. As compassion is a core value for end-of-life care work, compassionate leadership may be the best way to lead in palliative care. The aims of this study were twofold: (1) to adapt and validate the Compassionate Leadership Self-reported Scale in a sample of palliative care professionals; and (2) to study the relation between compassionate leadership and associated concepts of self-compassion, awareness and self-care. A cross-sectional survey of 296 Spanish end-of-life care professionals was conducted. Analyses included descriptive statistics, a confirmatory factor analysis (CFA) with four-correlated factors, reliability estimates and a structural model. Results suggested there were medium to high levels of compassionate leadership in the sample. The CFA showed an adequate overall fit: χ2 (98) = 277.595 (p < 0.001); CFI = 0.986; SRMR = 0.047; RMSEA = 0.088 [0.076, 0.100]. Reliability estimates for four subscales of compassionate leadership (attending, understanding, empathising and helping) were also adequate, ranging from 0.72 to 0.96. Finally, the structural model predicting compassionate leadership suggested that the dimensions of attending and understanding were most highly related to positive self-compassion and awareness; empathising, to self-care and awareness; and helping, to positive self-compassion and self-care. The Compassionate Leadership Scale has adequate psychometric properties when used to assess compassionate leadership in the context of end-of-life care. Our results indicate that self-compassion, awareness and self-care are important correlates of such compassionate leadership.


Apparent [3H]1,25-dihydroxyvitamin D3 uptake by canine and rodent brain.
The brain uptake of [3H]1,25-dihydroxyvitamin D3 ([3H]1,25(OH)2D3) was studied during steady-state conditions using the multiple-indicator dilution technique in dogs. The fractional [3H]1,25(OH)2D3 uptake was evaluated at 0.8 +/- 0.15% during a single passage through the dog brain. Evaluation of the [3H]1,25(OH)2D3 uptake by the vitamin D-replete and vitamin D-depleted rat brain indicated that 30 min after its injection, the fractional uptake was not influenced by the vitamin D status of the animals or by the amount of [3H]-1,25(OH)2D3 injected. In the rodent the fractional [3H]-1,25(OH)2D3 brain accumulation was between 0.16 and 0.20%, whereas the brain-to-serum ratio varied between 5 and 6%. Protein-binding studies of serum [3H]1,25(OH)2D3 indicated that, at 37 degrees C, 94.8 +/- 0.4% of the hormone was protein bound 30 min after its intravenous injection. These observations suggest that 1,25(OH)2D3 is able to cross the blood-brain barrier. However, its limited brain uptake in relation to its serum concentration suggests that the hormone does not penetrate freely into the central nervous system and that its brain uptake may be related to the free circulating 1,25(OH)2D3 concentration perfusing the blood-brain barrier.


Generalizability of evidence-based assessment recommendations for pediatric bipolar disorder.
Bipolar disorder is frequently clinically diagnosed in youths who do not actually satisfy Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revision; DSM-IV-TR; American Psychiatric Association, 1994) criteria, yet cases that would satisfy full DSM-IV-TR criteria are often undetected clinically. Evidence-based assessment methods that incorporate Bayesian reasoning have demonstrated improved diagnostic accuracy and consistency; however, their clinical utility is largely unexplored. The present study examines the effectiveness of promising evidence-based decision-making strategies compared with the clinical gold standard. Participants were 562 youths, ages 5 to 17 and predominantly African American, drawn from a community mental health clinic. Research diagnoses combined a semistructured interview with youths' psychiatric, developmental, and family mental health histories. Independent Bayesian estimates that relied on published risk estimates from other samples discriminated bipolar diagnoses (area under curve = .75, p < .00005). The Bayes and confidence ratings correlated at rs = .30. Agreement about an evidence-based assessment intervention threshold model (wait/assess/treat) was κ = .24, p < .05. No potential moderators of agreement between the Bayesian estimates and confidence ratings, including type of bipolar illness, were significant. Bayesian risk estimates were highly correlated with logistic regression estimates using optimal sample weights (r = .81, p < .0005). Clinical and Bayesian approaches agree in terms of overall concordance and deciding next clinical action, even when Bayesian predictions are based on published estimates from clinically and demographically different samples. Evidence-based assessment methods may be useful in settings in which gold standard assessments cannot be routinely used, and they may help decrease rates of overdiagnosis while promoting earlier identification of true cases.


Design and Implementation of the Amenah Early Marriage Pilot Intervention Among Syrian Refugees in Lebanon.
Implementing and evaluating interventions in humanitarian settings in low- and middle-income countries presents unique challenges that are little addressed in the implementation literature. We document the process of developing, implementing, and evaluating the Amenah pilot intervention that aimed to mitigate the drivers of early marriage in a Syrian refugee community in Lebanon. Adolescent girls' vulnerability to early marriage increases following displacement due to poverty, insecurity, and school disruptions. We delineate how, as a local research team, we triangulated evidence from the international literature and formative community research to make informed decisions during the intervention's design and implementation phases. The pilot was delivered to 203 Syrian refugee schoolgirls aged 11-14 years during the 2017-2018 academic year. It consisted of 16 structured, interactive sessions with girls and a set of facilitated meetings with the girls' mothers, both of which were implemented by trained female community workers from the Syrian refugee community. Process evaluation results showed that sociodemographic factors predicted attendance among mothers, but relationships with peers in the intervention were the only significant predictor of attendance among girls. The primary outcomes of the pilot were attitudinal measures related to education and marriage. Attitudes toward education were highly positive at baseline and did not change over the course of the intervention. There were no significant changes in girls' ideal age at marriage. Among girls aged 13 and older at endline, the mean self-reported expected age at marriage increased slightly from 20.2 to 20.8 years (P<.05). Our results also suggest that girls may adjust their expected age at marriage downward as they become older and if they drop out of school. We reflect in the discussion on some of the challenges encountered and lessons learned for the benefit of researchers intending to conduct community-based interventions in displacement settings.


Effects of Genetic Polymorphisms of CYP2B6 on the Pharmacokinetics of Bupropion and Hydroxybupropion in Healthy Chinese Subjects.
BACKGROUND Bupropion (BUP) is an antidepressant and its pharmacological activity is mediated by its major metabolite, hydroxybupropion (HBUP). We investigated the effects of genetic polymorphisms of CYP2B6 on BUP and HBUP to provide certain evidence on the clinical rational administration of BUP. MATERIAL AND METHODS Plasma BUP and HBUP concentrations were assayed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS A total of 23 healthy volunteers (eleven participants with CYP2B6*1/*1, 7 participants with CYP2B6*1/*6, 3 participants with CYP2B6*4/*6, and 2 participants with CYP2B6*1/*4) received orally administered 150 mg of BUP according to protocol. Blood samples were obtained up to 96 hours after administration. The whole blood was subject to genotyping by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The concentration-time curve (AUC(0→96)), maximum plasma concentration (Cmax), and terminal half-life (t1/2) values of BUP in CYP2B6*1/*4 were lower than those of CYP2B6*1/*1. By contrast, the time to Cmax (tmax) value of the former was higher than that of the latter. The HBUP AUC(0→96) values in CYP2B6*4/*6 and CYP2B6*1/*4 increased to values 1.12-fold and 1.98-fold, compared with CYP2B6*1/*1 carriers. However, the HBUP AUC(0→96) value in CYP2B6*1/*1 was 1.51-fold higher than that in CYP2B6*1/*6. Similarly, the HBUP Cmax values in CYP2B6*4/*6 and CYP2B6*1/*4 increased by 1.12-fold and 1.97-fold, whereas the HBUP Cmax value in CYP2B6*1/*6 decreased to a value 1.64-fold lower than that in CYP2B6*1/*1. CONCLUSIONS Genetic polymorphisms of CYP2B6 influence the pharmacokinetic parameters of BUP and HBUP and thus establish rational BUP administration for Chinese patients in clinical settings.


FAT10, a ubiquitin-independent signal for proteasomal degradation.
FAT10 is a small ubiquitin-like modifier that is encoded in the major histocompatibility complex and is synergistically inducible by tumor necrosis factor alpha and gamma interferon. It is composed of two ubiquitin-like domains and possesses a free C-terminal diglycine motif that is required for the formation of FAT10 conjugates. Here we show that unconjugated FAT10 and a FAT10 conjugate were rapidly degraded by the proteasome at a similar rate. Fusion of FAT10 to the N terminus of very long-lived proteins enhanced their degradation rate as potently as fusion with ubiquitin did. FAT10-green fluorescent protein fusion proteins were not cleaved but entirely degraded, suggesting that FAT10-specific deconjugating enzymes were not present in the analyzed cell lines. Interestingly, the prevention of ubiquitylation of FAT10 by mutation of all lysines or by expression in ubiquitylation-deficient cells did not affect FAT10 degradation. Thus, conjugation with FAT10 is an alternative and ubiquitin-independent targeting mechanism for degradation by the proteasome, which, in contrast to polyubiquitylation, is cytokine inducible and irreversible.


Balancing Noncovalent Interactions in the Self-Assembly of Nonplanar Aromatic Carboxylic Acid MOF Linkers at the Solution/Solid Interface: HOPG vs Au(111).
This study explores directed noncovalent bonding in the self-assembly of nonplanar aromatic carboxylic acids on gold and graphite surfaces. It is the first step in developing a new design strategy to create two-dimensional surface metal-organic frameworks (SURFMOFs). The acid molecules used are tetraphenylethene-based and are typically employed in the synthesis of three-dimensional (3D) MOF crystalline solids. They include tetraphenylethene tetracarboxylic acid, tetraphenylethene bisphenyl carboxylic acid, and tetraphenylethene tetrakis-phenyl carboxylic acid. The two-dimensional structures formed from these molecules on highly ordered pyrolytic graphite (HOPG) and Au(111) are studied by scanning tunneling microscopy in a solution environment. The process of monolayer formation and final surface linker structures are found to be strongly dependent on the combination of the molecule and substrate used and are discussed in terms of intermolecular and molecule-substrate interactions, bonding geometry, and symmetry of the acid molecules. In the case of linker self-assembly on HOPG, the molecule-substrate interactions play a significant role in the resulting surface structure. When the acid molecules are adsorbed on Au(111), the intermolecular interactions tend to dominate over the weaker molecule-substrate bonding. Additionally, the interplay of π-π interactions and hydrogen bonding that directs the surface self-assembly on different supports can be modified by varying the linker concentration. This is particularly applicable for the case of the acid molecules adsorbing on the Au(111) substrate. Precise control over predesigned surface structures and orientation of the nonplanar aromatic carboxylic linkers open up an exciting prospect for manipulating the direction of SURFMOF growth in two dimensions and potentially in 3D.


Changes in chondrogenic phenotype and gene expression profiles associated with the in vitro expansion of human synovium-derived cells.
We undertook this study to characterize changes in the proliferative capacities, chondrogenic phenotypes, and gene expression profiles of human synovium-derived progenitor cells from osteoarthritic patients during in vitro expansion. Cells isolated from osteoarthritic synovia were cultured, and growth rates during serial passages were evaluated. Surface molecule expressions were determined by flow cytometry and cytogenetic analyses were performed. After chondrogenic differentiation in cell pellets, we evaluated type II collagen and glycosaminoglycan (GAG) synthesis. To assess whether the in vitro expansion of synovium-derived cells affects gene expression, we performed microarray analyses on cells at passage 0, 1, 2, 4, 6, and 8. Synovium-derived cells were rapidly expanded in vitro through passage 8 (about 130 days), and after passage 6, the proliferation rates decreased slightly with a wide range of individual variations. The expressions of CD166, CD49a, and CD106 decreased, whereas those of CD10, CD29, CD44, CD73, CD90, and CD105 showed no significant change. Karyotype analysis revealed no evidence of chromosome abnormalities. The staining of type II collagen and GAG in differentiated cell pellets showed rapid weakening. Genome-wide microarray analysis showed that synovium-derived cells from late passages over-expressed genes associated with cell cycle prolongation and cell aging, and less-expressed genes associated with cell growth stimulation. The in vitro expansion of synovium-derived cells was accompanied with decreased proliferative capacity and the chondrogenic phenotype, which might be modulated by change in gene expression patterns.


[Combined effect of epinephrine and chalone extracted from Ehrlich ascites carcinoma administered during different time of day on cell division in the tumor].
The biphasic circadian rhythm of mitotic activity has been demonstrated in a 5-day Ehrlich's ascites carcinoma (EAC) in mice. Adrenaline injected intraperitoneally in a dose of 1.5 micrograms/g bw produced an inhibitory effect on cell division that lasted over 4 hours and reached maximum at injection to mice during light time of the day. EAC extract in a dose of 1 ml also inhibited the mitosis during 4 hours, but the greatest fall in the mitotic activity was observed during the minimum mitotic activity in the control animals. Combined administration of adrenaline and the extract resulted in the phenomenon of prolonged inhibition of cell division, that persisted for maximum 6-8 hours, if the preparations were injected in the middle of the day light time. Of definite importance was the rhythm of changes in the sensitivity of proliferating tumor cells.


Physiology and behavior under food limitation support an escape, not preparative, response in the nomadic pine siskin (Spinus pinus).
Migration allows animals to use resources that are variable in time and/or space, with different migratory strategies depending on the predictability of resource variation. When food varies seasonally, obligate migrants anticipate and prepare for migration. In contrast, facultative migrants, whose movements are unpredictable in timing and destination, may prepare for either migration or escape when resources are depleted. We propose and test two alternative hypotheses regarding the behavioral and physiological responses of facultative migrants to declining food availability. (1) The prepare hypothesis predicts that facultative migrants prepare for departure by increasing fuel stores in response to declining food availability, and elevations of baseline corticosterone (CORT) facilitate increased activity. (2) The escape hypothesis predicts that facultative migrants do not prepare for departure, body condition declines as food availability declines, and stress-induced levels of CORT induce escape behavior when both energetic condition and food resources are low. We conducted a 16-day experiment, measuring body composition (using quantitative magnetic resonance), activity (using force perches) and baseline CORT in pine siskins (Spinus pinus) given ad libitum food or a slow decline, fast decline or randomly changing amount of food. Our results support the escape hypothesis: body condition declined as food declined, decreases in body and fat mass were associated with increases in baseline CORT, and activity increased only when food availability was low. This work suggests that facultative migration in autumn allows birds to escape low-resource areas and that the underlying physiological mechanisms differ from those driving both seasonal, obligate migrations and spring nomadic movements.


Role of the paraventricular hypothalamic nucleus in the dependence of the pituitary-adrenocortical system reaction on stress factor strength.
The influence of paraventricular hypothalamic nucleus lesion on the stress factor strength, i.e. on the pituitary-adrenocortical system (PACS) reaction dependence, was studied in chronic experiments on rabbits. It was shown that with the electric skin stimulation the increase in current strength from 0.3 to 0.7 mA results in elevation of corticosteroid level in plasma. With further increase of current strength to 0.9-1.1 mA the stress-induced rise in corticosteroids reduces and Wedensky pessimum is observed. Bilateral lesion of the paraventricular hypothalamic nucleus results in reduction of the amplitude of response to all strengths of stimulation, increase in stimulation threshold and decrease in the rate of PACS involvement into the response to stress factor action. However, the pessimal PACS inhibition is preserved after the paraventricular nucleus lesion.


Forms of selenium in vitamin-mineral mixes differentially affect serum alkaline phosphatase activity, and serum albumin and blood urea nitrogen concentrations, of steers grazing endophyte-infected tall fescue.
The goal of this study was to test the hypothesis that sodium selenite (ISe), SEL-PLEX (OSe), vs. a 1:1 blend (MIX) of ISe and OSe in a basal vitamin-mineral mix would differentially affect serological and hepatic parameters of growing steers grazing toxic endophyte-infected tall fescue-mixed forage pasture. Predominately Angus steers (BW = 183 ± 34 kg) were randomly selected from herds of fall-calving cows grazing endophyte-infected tall fescue-mixed pasture and consuming vitamin-mineral mixes that contained 35 ppm Se as ISe, OSe, and MIX forms. Steers were weaned, depleted of Se for 98 d, and subjected to summer-long common grazing of an endophyte-infected tall fescue-mixed pasture (0.51 ppm total ergovaline + ergovalinine; 10.1 ha). Steers were assigned (n = 8 per treatment) to the same Se form treatments upon which they were raised. Se treatments were administered by daily top-dressing 85 g of vitamin-mineral mix onto 0.23 kg soyhulls, using in-pasture Calan gates. The PROC MIXED procedure of SAS was used to assess the effect of Se form treatments on serum parameters at day 0, 22, 43, 64, and 86. After slaughter, the effect of Se treatment on hepatic alkaline phosphatase (tissue nonspecific isoform, TNALP) mRNA, protein, and albumin protein content was assessed using the PROC GLM procedure of SAS. Fisher's protected LSD procedure was used to separate treatment means. Partial correlation analysis was used to evaluate the relationship among whole blood Se concentration and serum parameters, accounting for the effect of time. Across periods, MIX steers had more (P ≤ 0.04) serum albumin than OSe and ISe steers, respectively. However, the relative hepatic bovine serum albumin protein content was not affected (P = 0.28) by Se treatments. Serum alkaline phosphatase activity was greater (P ≤ 0.01) in MIX and OSe steers. Similarly, hepatic TNALP protein content in MIX steers was greater (P = 0.01) than ISe steers. Partial correlation analysis revealed that serum albumin, blood urea nitrogen, and alkaline phosphatase activity were correlated (r ≥ 0.23, P ≤ 0.02) with whole blood Se concentration. In summary, consumption of 3 mg Se/d as OSe or MIX forms of Se in vitamin-mineral mixes increased serum albumin concentration and alkaline phosphatase activity, the reduction of which is associated with fescue toxicosis. We conclude that the organic forms of Se ameliorated the depression of 2 of known serological biomarkers of fescue toxicosis.


Low-cost high-sensitivity strain and temperature sensing using graded-index multimode fibers.
We report a low-loss, low-cost high-sensitivity all-fiber strain and temperature sensor based on mode interference in graded-index multimode fibers. Blueshifts with strain and temperature sensitivities of 18.6 pm/microstrain and 58.5 pm/ degrees C have been observed. Experimental results show that smaller core diameter graded-index fibers display greater strain-induced peak wavelength shifts than larger core diameter fibers.


Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer's Disease?
Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.