Secretion of vascular endothelial growth factor/vascular permeability factor from human luteinized granulosa cells is human chorionic gonadotrophin dependent.
Vascularization is a prominent event during corpus luteum formation, providing low density lipoproteins for steroid biosynthesis and enabling transport of secreted steroids. The process of vascularization is controlled by specific regulators. Vascular endothelial growth factor (VEGF), otherwise named vascular permeability factor (VPF), induces endothelial cell proliferation as well as angiogenesis in vivo and increases capillary permeability. Here we report the expression of VEGF/VPF mRNA by cultured human luteinized granulosa cells (GC) for at least 10 days. Without HCG VEGF/VPF expression declined after day 4 and by day 10 was reduced to approximately 30% of the value at day 4. However, after culture in the presence of 1 U/ml human chorionic gonadotrophin (HCG), expression of VEGF/VPF mRNA by GC was four times greater than control experiments by day 10, and increased 100% from day 4 to day 10. Simultaneously, HCG supplementation increased VEGF/VPF secretion by GC. Medium VEGF/VPF on day 3 was 13 pM without and 11 pM with HCG. Medium VEGF/VPF on day 10 was 6 pM without HCG and 29 pM with HCG. These results suggest that vascularization of the corpus luteum is induced by HCG-mediated effects of VEGF/VPF.


Inguinal hernia containing a native orthotopic kidney.
We report a rare case of an inguinal hernia containing part of a native kidney and present a review of the literature with regard to urological findings in patients with inguinal hernias. This case involves an elderly man with known bilateral inguinal hernias with an incidental radiographic finding of a large right inguinal hernia containing the inferior pole of the right kidney. The patient was not symptomatic from the hernia and given his overall frailty, no surgical intervention was offered.


Optimal spectral coordination of subantennae in natural antennae as an efficient strategy for light harvesting in photosynthesis.
This work continues a series of our investigations on efficient strategies of functioning of natural light-harvesting antennae, initiated by a concept of rigorous optimization of photosynthetic apparatus by functional criterion, and deals with the problem of an optimal spectral coordination of subantennae in photosynthetic superantenna of the green bacterium Oscillochloris trichoides from a new family of green bacteria Oscillochloridaceae based in 2000. At present, two subantennae were identified surely: chlorosomal BChl c subantenna B750 and membrane BChl a subantennae B805-860. Some indirect experiments indicated on the presence of minor amounts of BChl a in isolated chlorosomes which allowed us to propose on the existence of an intermediate-energy subantenna which can connect the chlorosomal BChl c and the membrane BChl a ones. However, in the absorption spectra of isolated chlorosomes, this BChl a subantenna was not visually identified. This promoted us to perform a theoretical analysis of the optimality of spectral coordination of Oscillochloris trichoides subantennae. Using mathematical modeling for the functioning of the natural superantenna, we showed that an intermediate-energy subantenna, connecting B750 and B805-860 ones, allows one to control superantenna efficiency, i.e. to optimize the excitation energy transfer from B750 to B805 by functional criterion, and hence, the existence of such intermediate-energy subantenna is biologically expedient.


The ear is connected to the brain: some new directions in the study of children with cochlear implants at Indiana University.
Since the early 1980s, the DeVault Otologic Research Laboratory at the Indiana University School of Medicine has been on the forefront of research on speech and language outcomes in children with cochlear implants. This paper highlights work over the last decade that has moved beyond collecting speech and language outcome measures to focus more on investigating the underlying cognitive, social, and linguistic skills that predict speech and language outcomes. This recent work reflects our growing appreciation that early auditory deprivation can affect more than hearing and speech perception. The new directions include research on attention to speech, word learning, phonological development, social development, and neurocognitive processes. We have also expanded our subject populations to include infants and children with additional disabilities.


Accelerated degradation of poly(epsilon-caprolactone) by organic amines.
The solid-state degradation of poly(epsilon-caprolactone) catalyzed by primary, secondary and tertiary alkylamines was investigated. The degradation process was monitored by weight loss and molecular weight change measured by gel permeation chromatography. Degradation studies were conducted at 37 degrees C in methanol solutions of the alkylamines. Primary alkylamines caused rapid weight loss (i.e., approximately 90% weight loss in 30 days) that depended on alkylamine concentration, molar ratio of alkylamine to poly(epsilon-caprolactone) monomer and alkyl chain length. The secondary alkylamines caused less rapid polymer weight loss (i.e., approximately 90%) weight loss within 80 days). One tertiary alkylamine (N,N-diisopropylethylamine) showed little catalytic effect while a bicyclic tertiary alkylamine (quinuclidine) was about as catalytic as the primary alkylamines. The degradation products isolated when primary alkylamines were used include both esters and amides indicating that nucleophilic attack by the alkylamines competed with the amine-catalyzed methanolysis reaction. Only ester moieties could be identified in the products from reactions containing secondary and tertiary alkylamines, which indicated that they acted as nucleophilic catalysts. All of the primary alkylamines reduced poly(epsilon-caprolactone) molecular weight from about 25,000 to 10,000 within 10 days after which the molecular weight of the remaining solid leveled off even though weight loss continued.


Chromatin modifying activity of leukaemia associated fusion proteins.
The leukaemias, which are divided into chronic and acute forms, are malignant diseases of haematopoietic cells in which the proper balance between proliferation, differentiation and apoptosis is no longer operative. Genes, such as those of mixed-lineage leukaemia, AML1 and retinoic acid receptor alpha, have been found to be aberrantly fused to different partners, which often encode transcription factors or other chromatin modifying enzymes, in numerous types of acute lymphoid and myeloid leukaemias. These chimeric fusion oncoproteins, generated by reciprocal chromosomal translocations, are responsible for chromatin alterations on target genes whose expression is critical to stem cell development or lineage specification in haematopoiesis. Alterations in the 'histone code' or in the DNA methylation content occur as consequence of aberrant targeting of the corresponding enzymatic activities. Here, the author will review the most recent progress in the field, focusing on how fusion proteins generated by chromosomal translocation are responsible for chromatin alterations, gene deregulation and haematopoietic differentiation block and their implication for clinical treatment.


[RESEARCH PROGRESS OF HETEROTOPIC OSSIFICATION OF ELBOW JOINT AFTER TRAUMA].
To summarize the research progress of heterotopic ossification of the elbow joint after trauma. The recent domestic and foreign literature concerning heterotopic ossification of the elbow joint after trauma was analysed and summarized. The mechanism of heterotopic ossification of the elbow joint after trauma is mainly related to bone morphogenetic protein signal transduction disorder. Now there are many treatments of heterotopic ossification, including non-surgical treatment, prevention, and surgical treatment. Non-surgical treatment and prevention mainly aim at patients who have no elbow heterotopic ossification or who have mild limited elbow motion because of elbow heterotopic ossification after trauma, including drug therapy, radiation therapy, Chinese medicine therapy, and rehabilitation treatment. For patients with invalid non-surgical treatment, choosing surgical treatment is a must. Surgical treatment includes surgical resection, arthroscopic resection, and joint replacement, priority should be given first to surgical resection. Heterotopic ossification of the elbow joint is common and there is not a recognized standard treatment, comprehensive use of non-surgical treatment and surgical treatment is the future direction.


Evaluation of lung ventilation and carbon monoxide-diffusing capacity in patients with nonseminomatous testicular tumors treated with bleomycin.
Spirometric tests and CO transfer tests were systematically employed before, during, after the therapy and in the follow-up of 33 patients affected by seminomatous testicular tumours treated with 4-5 Einhorn courses (PVB). The aim was to demonstrate possible bleomycin-induced pulmonary toxicity and its relationship with the cumulative dose of the drug. Our patients, who never had clinical or radiological signs of pulmonary toxicity, did not show significant change in the functional respiratory tests throughout therapy, except for 6 patients who had a reduction in CO transfer of about 30% after the 2nd or 3rd course which persisted up to the end and during the follow-up. We did not find any correlation of such a reduction with predisposing factors.


Reconstitution of Ir genes, Ia antigens, and mixed lymphocyte reaction determinants by gene complementation.
By using clones of murine T cells reactive with alloantigens as well as soluble antigens, it has been possible to demonstrate that Ia antigens, Ir gene phenomena (defined as the ability of immune T cells to recognize antigen), and mixed lymphocyte reaction (MLR)-stimulating determinants encoded within the I-A subregion are different manifestations associated with same product. These studies utilized the I-Ab mutant mouse B6.C-H-2bm (bm12), whose defect in the normal expression of the cell surface products of the I-Ab subregion can be partially circumvented through trans-complementation by deriving hybrids between bm12 and mice expressing normal I-A subregion products. Such mice [e.g., (bm12 X B10.A)F1] express several serologically normal I-Ab products but have defects in certain I-A subregion gene products normally expressed on cells of H-2a X H-2b heterozygote mice that are used as restricting elements for antigen recognition by antigen-reactive T cell clones or recognized as alloantigens by alloreactive T cell clones. This defect in cell surface expression of certain normal I-Ab products on the mutant bm12 cells has allowed us to suggest that there exist trans-complementing products on H-2a X H-2b heterozygote mice consisting of Ab alpha Ak beta and Ak alpha Ab beta that restrict antigen recognition by cloned T cells, stimulate MLR responses by cloned T cells, and react with certain anti-Ia antisera.


MaXlab: a novel application for the cross comparison and integration of biological signatures from microarray studies.
Microarray gene expression datasets are continually being placed in public repositories. As a result, one of the most important emerging challenges is that which enables researchers to take full advantage of such previously accumulated data to discover or validate common genes in similar biological systems. In light of this we have designed the MaXlab software to not only cross-compare available array data from different laboratories but also extract further knowledge from gene expression patterns embedded within published data. More importantly MaXlab offers a flexible and automated solution applicable for microarray technologies including cDNA and Affymetrix gene chips generating expression profiles for common genes with biological significance. We have identified several sets of genes previously unknown to be commonly expressed across studies investigating related biological questions. Among them is the identification of 17 genes involved in the dysregulation of immune tolerance including the crucial transcription factor Egr2. In addition, we have identified 175 genes commonly expressed in basal and luminal breast tumours in response to the chemotherapeutic drug doxorubicin. The universal expression and characterisation of these encouraging genes identified through MaXlab suggests that they may play a common role in the mechanism of disease and hence act as an incentive for further investigation for identifying potential therapeutic targets. Overall, MaXlab is an attractive application for molecular biologists extracting the intersection between microarray datasets together with the gene expression profiles, from which biologists are able to infer further biological insights. The software together with file formats and additional material is freely available at http://www.immuno-software.org.


A three miRNAs signature predicts survival in cervical cancer using bioinformatics analysis.
Growing evidences showed that a large number of miRNAs were abnormally expressed in cervical cancer tissues and played irreplaceable roles in tumorigenesis, progression and metastasis. The aim of the present study was to identify the differential miRNAs expression between cervical cancer and normal cervical tissues by analyzing the high-throughput miRNA data downloaded from TCGA database. Additionally, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a three-miRNA signature that could effectively predict patient survival. According to the cut-off criteria (P < 0.05 and |log2FC| > 2.0), a total of 78 differentially expressed miRNAs were identified between cervical cancer tissues and matched normal tissues, including 37 up-regulated miRNAs and 41 down-regulated miRNAs. The Kaplan-Meier survival method revealed the prognostic function of the three miRNAs (miRNA-145, miRNA-200c, and miRNA-218-1). Univariate and multivariate Cox regression analysis showed that the three-miRNA signature was an independent prognostic factor in cervical cancer. The functional enrichment analysis suggested that the target genes of three miRNAs may be involved in various pathways related to cancer, including MAPK, AMPK, focal adhesion, cGMP-PKG, wnt, and mTOR signaling pathway. Taken together, the present study suggested that three-miRNA signature could be used as a prognostic marker in cervical cancer.


Temperature-sensitive mutants of murine leukemia virus. V. Impaired leukemogenic activity in vivo.
The in vivo biologic activities of a clonal isolate of the Rauscher strain of murine leukemia virus and several conditional lethal mutants with impaired replicative functions at the non-permissive temperature were investigated. The parental virus induced a rapidly developing lymphoid leukemia in a high percentage of NIH Swiss mice inoculated as newborns. Mice inoculated in parallel with temperature-sensitive mutant viruses showed no evidence of disease. The implications of these findings with regard to the requirements for type-C virus replication to permit oncogenic transformation of lymphoid cells in vivo are discussed.


Low blood pressure and five-year mortality in a Stockholm cohort of the very old: possible confounding by cognitive impairment and other factors.
Low blood pressure has often been reported to be related to excess mortality in people over the age of 75 years. This study examined whether other predictors may account for the association. A community-based cohort of 1810 people who were aged 75 years and older was followed for 5 years. The relative risk of death was 1.39 (95% confidence interval [CI] = 1.11, 1.73) for people with systolic pressure lower than 130 mm Hg and 1.21 (95% CI = 1.02, 1.43) for those with diastolic pressure lower than 75 mm Hg, compared with corresponding reference groups, when all other variables were simultaneously considered in Cox proportional hazards models. The observed association was present mainly in subjects with at least two of the three conditions (cardiovascular disease, limitation in activities of daily living, or cognitive impairment). The effect of low diastolic pressure on mortality was also significant in those with only cognitive impairment. Preexisting cardiovascular disease, limitation in activities of daily living, and, more important, cognitive impairment may be responsible for the association of low blood pressure with increased mortality in the very old in that they cause both reductions in blood pressure and excess deaths.


β-Carotene Concentration and Its Association with Inflammatory Biomarkers in Spanish Schoolchildren.
To examine the correlation between inflammatory biomarkers and plasma β-carotene levels in children. A total of 564 Spanish schoolchildren aged 9-12 were observed and studied. Plasma β-carotene levels were assessed by HPLC. A β-carotene level <4.83 µg/dL (0.09 µmol/L) was considered deficient. Plasma tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by immunoenzyme assays. Serum high-sensitivity C-reactive protein (hs-CRP) was tested by immunonephelometry. Subjects who were β-carotene-deficient (23.1% of the studied children) had higher IL-6 levels than subjects with normal β-carotene concentrations. The log-IL-6 and log-hs-CRP concentrations, but not the log-TNF-α level, were strongly and inversely related to the plasma log-β-carotene level (taking into account log-age, energy intake, log-triglycerides, gender, log-body mass index, log-β-carotene intake, energy from lipids and cholesterol as covariables). When the 3 inflammatory biomarkers were introduced into the regression model along with the corresponding covariables, only the log-IL-6 level was related to the plasma log-β-carotene level (β = -0.505 ± 0.078; p < 0.001). Inflammatory status, in particular IL-6 levels, appears to be negatively associated with plasma β-carotene levels in schoolchildren.


Plasmacytoid adenocarcinoma of the lung.
Plasmacytoid adenocarcinoma of the lung has not been reported. Herein reported is the first case of plasmacytoid adenocarcinoma of the lung. A 68-year-old man presented with cough and sputum. X-P and CT demonstrated a large tumor (10 x 10 x 9 cm) in the right upper lobe. CT-guided needle biopsy was performed. The biopsy showed plasmacytoid malignant cells. The malignant cells were small, had eccentrically located nuclei, perinuclear halo, and basophilic cytoplasm. No mucins were observed by mucins stains. Immunohistochemical study showed that the tumor cells were positive for pancytokeratin AE1/3, pancytokeratin CAM5.2, TTF-1, Ki-67 (labeling 70%), CA19-9, and p53. They were negative for neuron specific enolase, CEA, CD45, CD68, chromogranin, synaptophysin, surfactant apoprotein A, CDX-2, κ-chain, λ-chain, KIT, and PDGFRA. Since epithelial markers and adenocarcinoma markers were positive, the pathological diagnosis was plasmacytoid adenocarcinoma of lung. The patient is now treated with chemotherapy.


Discovery of a Plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase inhibitor (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) that reduces parasite growth in vitro.
A high-throughput screen of the NIH's MLSMR collection of ∼340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD). PfG6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum , the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of PfGluPho. The lead compound identified from this effort, (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC(50) = 889 nM). It is completely selective for the enzyme's human isoform, displays micromolar potency (IC(50) = 2.6 μM) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting PfG6PD in vivo are in progress.


Activation of cAMP signaling interferes with stress-induced p53 accumulation in ALL-derived cells by promoting the interaction between p53 and HDM2.
The tumor suppressor p53 provides an important barrier to the initiation and maintenance of cancers. As a consequence, p53 function must be inactivated for a tumor to develop. This is achieved by mutation in approximately 50% of cases and probably by functional inactivation in the remaining cases. We have previously shown that the second messenger cAMP can inhibit DNA damage-induced wild-type p53 accumulation in acute lymphoblastic leukemia cells, leading to a profound reduction of their apoptotic response. In the present article, we provide a mechanistic insight into the regulation of p53 levels by cAMP. We show that increased levels of cAMP augment the binding of p53 to its negative regulator HDM2, overriding the DNA damage-induced dissociation of p53 from HDM2. This results in maintained levels of p53 ubiquitination and proteasomal degradation, which in turn counteracts the DNA damage-induced stabilization of the p53 protein. The apoptosis inhibitory effect of cAMP is further shown to depend on this effect on p53 levels. These findings potentially implicate deregulation of cAMP signaling as a candidate mechanism used by transformed cells to quench the p53 response while retaining wild-type p53.


Autotransfusion Cell-Saver and Plasma Saver.
Early attempts at blood salvage during surgery shared many of the complications associated with the development of cardiopulmonary (heart-lung) bypass machines; especially, coagulopathy and air embolism. By the late 1970s, the technology had developed to the point where not only were the red blood cells salvaged, but washed and processed in a manner that prevented auto-immunisation, transfusion reactions, and transmission of diseases. Blood conservation became practical.


Nutritional needs in the professional practice of swimming: a review.
Swimming requires developing a high aerobic and anaerobic capacity for strength and technical efficiency. The purpose of this study was to establish the nutritional requirements and dietary strategies that can optimize swimming performance. Several related studies retrieved from the databases, Dialnet, Elsevier, Medline, Pubmed, and Web of Science, through keyword search strategies were reviewed. The recommended carbohydrate intake ranges between 6-10-12 g/kg/d, protein 2 g/kg/d, and fat should surpass 20-25% of the daily intake. Performance can be optimized with a hydration plan, as well as adequate periodization of supplements, such as caffeine, creatine, sodium bicarbonate, B-alanine, beetroot juice, Vitamin D, bovine colostrum, and HMB.


Proactive Hemocompatibility Platform Initiated by PAMAM Dendrimer Adapting to Key Components in Coagulation System.
Surface modification manipulates the application performance of materials, and thrombosis caused by material contact is a key risk factor of biomaterials failure in blood-contacting/implanting devices. Therefore, building a safe and effective hemocompatibility platform is still urgent. Owing to the unique properties of polyamidoamine (PAMAM) dendrimers, in this study, modified surfaces with varying dendrimer densities were interacted with elements maintaining blood homeostasis. These included the plasma proteins bovine serum albumin and fibrinogen, cells in blood (platelets and erythrocyte), as well as endothelial cells (ECs), and the objective was to evaluate the blood compatibility of the chosen materials. Whole blood test and dynamic blood circulation experiment by the arteriovenous shunt mode of rabbit were also conducted, based on the complexity and fluidity of blood. The PAMAM-modified substrates, particularly that with a high density of PAMAM (N1.0), adsorbed proteins with lessened fibrinogen adsorption, reduced platelet activation and aggregation, and suppressed clotting in whole blood and dynamic blood testing. Furthermore, the designed PAMAM dendrimer densities were safe and showed negligible erythrocyte lysis. Concurrently, PAMAM modification could maintain EC growth and did not trigger the release of procoagulant factors. These results suggest that the PAMAM-modified materials are compatible for maintaining blood homeostasis. Thus, PAMAM dendrimers can work as excellent surface modifiers for constructing a hemocompatibility platform and even a primer layer for desired functional design, promoting the service performance of blood-contacting devices.


[Diagnostic problems of pulmonary embolism].
There is no pathognomonic sign for pulmonary embolism. The diagnosis must be made from the combination of anamnestic, clinical and paraclinical parameters. An essential purpose of the paper is the demonstration of the valency of these parameters. The clinical proof of the origin of embolism facilitates the establishment of the diagnosis, is, however, often not possible. The pulmonary embolism as well as the origin of embolism are most certainly to be proved by angiographic investigation methods. On account of the vital endangering by relapses as well as the necessity of a different and extensive therapy the securing of the diagnosis is necessary.


Superior Foville syndrome due to pontine hemorrhage: a case report.
The Superior Foville Syndrome is a rare clinical feature of stroke or brain hemorrhage. Few cases have been reported worldwide particularly in Africa. We report the case of a 20 years old patient resident in Senegal with no known medical history. He was admitted on August 2015 in the Neurology Department of Fann National Teaching Hospital for an abrupt onset of left body side weakness, acute headaches and rotatory vertigo five days before admission. The physical examination found a superior Foville Syndrome. And the brain CT scan shown hemorrhage at the right inferior part of the pons compressing the fourth ventricle. No cause of this hemorrhage stroke has been found. Superior Foville syndrome is a rare clinical presentation of stroke and presented a rich semiological feature of the posterior cerebral fossa.


A novel vest with dual functions for firefighters: combined effects of body cooling and cold fluid ingestion on the alleviation of heat strain.
This study investigated the separate and combined effects of skin cooling and cold fluid ingestion on the alleviation of heat strain when wearing protective firefighting clothing at an air temperature of 30°C with 50%RH. A vest with the dual functions of cooling and providing sports drink supply (1.2% body mass) was developed. Eight males participated in the following four conditions: control [CON], drinking only [DO], cooling only [CO], and both cooling and drinking [CD]. The results showed that rectal (Tre), mean skin temperature (Tsk) and heart rate (HR) during recovery were lower for CD than for CON (p<0.05), while no significant differences between the four conditions were found during exercise. CO significantly reduced mean Tsk and HR and improved thermal sensation, whereas DO was effective for relieving thirst and lowering HR in recovery. In summary, the combined effect of skin cooling and fluid ingestion was synergistically manifested in Tre, Tsk and thermal sensation in recovery.Practitioner Summary: The present results provide data on a novel vest that contributes to alleviating firefighters' heat strain. Because a cooling vest after melting may be a burden for firefighters, this study indicates a practical way to reduce the additional weight load of the vest by drinking the melted fluid of the cooling packs.


Hfq CLASH uncovers sRNA-target interaction networks linked to nutrient availability adaptation.
By shaping gene expression profiles, small RNAs (sRNAs) enable bacteria to efficiently adapt to changes in their environment. To better understand how Escherichia coli acclimatizes to nutrient availability, we performed UV cross-linking, ligation and sequencing of hybrids (CLASH) to uncover Hfq-associated RNA-RNA interactions at specific growth stages. We demonstrate that Hfq CLASH robustly captures bona fide RNA-RNA interactions. We identified hundreds of novel sRNA base-pairing interactions, including many sRNA-sRNA interactions and involving 3'UTR-derived sRNAs. We rediscovered known and identified novel sRNA seed sequences. The sRNA-mRNA interactions identified by CLASH have strong base-pairing potential and are highly enriched for complementary sequence motifs, even those supported by only a few reads. Yet, steady state levels of most mRNA targets were not significantly affected upon over-expression of the sRNA regulator. Our results reinforce the idea that the reproducibility of the interaction, not base-pairing potential, is a stronger predictor for a regulatory outcome.


Composed solutions of synchronized patterns in multiplex networks of Kuramoto oscillators.
Networks with different levels of interactions, including multilayer and multiplex networks, can display a rich diversity of dynamical behaviors and can be used to model and study a wide range of systems. Despite numerous efforts to investigate these networks, obtaining mathematical descriptions for the dynamics of multilayer and multiplex systems is still an open problem. Here, we combine ideas and concepts from linear algebra and graph theory with nonlinear dynamics to offer a novel approach to study multiplex networks of Kuramoto oscillators. Our approach allows us to study the dynamics of a large, multiplex network by decomposing it into two smaller systems: one representing the connection scheme within layers (intra-layer), and the other representing the connections between layers (inter-layer). Particularly, we use this approach to compose solutions for multiplex networks of Kuramoto oscillators. These solutions are given by a combination of solutions for the smaller systems given by the intra- and inter-layer systems, and in addition, our approach allows us to study the linear stability of these solutions.


Plasmonic Nanostructures-Decorated ZIF-8-Derived Nanoporous Carbon for Surface-Enhanced Raman Scattering.
Surface-enhanced Raman scattering (SERS) is considered to be a highly sensitive platform for chemical and biological sensing. Recently, owing to their high porosity and large surface area, metal-organic frameworks (MOFs) have attracted considerable attention in sensing applications. Porous carbon nanostructures are promising SERS substrates due to their strong broadband charge-transfer resonance and reproducible fabrication. Furthermore, an extraordinarily large enhancement of the electromagnetic field enables plasmonic nanomaterials to be ideal SERS substrates. Here, we demonstrate the porous Au@Ag nanostructure-decorated MOF-derived nanoporous carbon (NPC) for highly efficient SERS sensing. Specifically, this plasmonic nanomaterial-NPC composite offers high Raman signal enhancement with the ability to detect the model Raman reporter 2-naphthalenethiol (2-NT) at picomolar concentration levels.


The Pseudomonas syringae type III effector tyrosine phosphatase HopAO1 suppresses innate immunity in Arabidopsis thaliana.
The bacterial pathogen Pseudomonas syringae pv. tomato (Pst) strain DC3000 infects tomato and Arabidopsis plants, and is a model for studying the molecular basis of bacterial disease. Pst DC3000 secretes a battery of largely uncharacterized effector proteins into host cells via a type-III secretion system (TTSS). Little is currently known about the molecular mechanisms by which individual TTSS effectors promote virulence. The effector HopAO1 has similarity to protein tyrosine phosphatases, including a conserved catalytic site, and suppresses the hypersensitive response (HR) in some non-host plants. Whether HopAO1 has a similar effect in the host Arabidopsis is not clear. Here, we show that transgenic expression of HopAO1 in Arabidopsis suppresses callose deposition elicited by the Pst DC3000 hrpA mutant, and allows the normally non-pathogenic hrpA mutant to multiply within the leaf tissue. HopAO1 also suppresses resistance to Pst DC3000 induced by flg22, a pathogen-associated molecular pattern (PAMP). However, HopAO1 does not suppress the HR triggered by several classical avirulence genes. These results suggest that HopAO1 targets primarily PAMP-induced innate immunity in Arabidopsis. The virulence function of HopAO1 is dependent on an intact phosphatase catalytic site, as transgenic plants expressing a catalytically inactive derivative do not show these effects. Intriguingly, expression of the catalytically inactive HopAO1 has a dominant-negative effect on the function of the wild-type HopAO1. Analysis of mitogen-activated protein kinase (MAPK) activity suggests that HopAO1 targets a step downstream or independent of MAPK activation. Genome-wide expression analysis revealed that expression of several well-known defense genes was suppressed in hrpA mutant-infected HopAO1 transgenic plants.


The treatment of infected non-union of fractures of long bones. Study of sixty-four cases with a five to twenty-one-year follow-up.
The result of treatment of sixty-four patients with infected ununited fractures of long bone by debridement of soft tissue and bone and open suction-irrigation drainage, followed by rigid stabilization of the non-union and cancellous bone-grafting when indicated, was bone union in sixty cases, even in the presence of infection. The late results five to twenty-one years later showed good function despite the fact that prolonged periods of hospitalization were often required. The importance of local treatment of the infection prior to stabilizing the fracture fragments, and the use of cancellous bone grafts when necessary, are emphasized.


Interaction of macrophage-migration-inhibitory factor with haematin.
Macrophage-migration-inhibitory factor (MIF) is retained by S-hexylglutathione-agarose but is not specifically eluted in high yield. Human liver MIF was purified in high yield using retention by phenyl-agarose at low ionic strength and cation-exchange FPLC as described for bovine lens MIF [Rosengren, Bucala, Aman, Jacobsson, Odh, Metz and Rorsman (1996) Mol. Med. 2, 143-149]. The l-dopachrome methyl ester tautomerase activity of human liver MIF was not inhibited by a variety of glutathione S-conjugates, eicosanoids or glucocorticoids but was very sensitive to inhibition by haematin (IC50 100-200 nM). The inhibition was non-competitive and showed positive co-operativity (h=5.8). Similar sensitivity to haematin was obtained with purified recombinant human MIF. The sensitivity of MIF to haematin is approx. 1000-fold greater than for any previously described ligands, and is within its physiological range. Therefore the interaction is likely to be important in modulating the function of MIF in the initiation of immune responses.


Cyto-nuclear genomic dissociation and the African elephant species question.
Studies of skull morphology and of nuclear DNA have strongly concluded that African elephants comprise two species. Nonetheless, Debruyne (2005) has suggested a single-species model for Loxodonta based on the polyphyly of a single genetic locus, mitochondrial DNA (mtDNA). Discordant patterns between mitochondrial and nuclear DNA markers were subsequently reported in some African savanna elephant populations, further supporting a two-species model, and prompting us to re-examine here the geographic distribution of different elephant morphotypes and their relationship to nuclear and mtDNA phylogeographic patterns. We used exact tests to compare the distribution of forest elephant-typical and savanna elephant-typical characteristics across eight published datasets containing morphological, mtDNA or nuclear DNA data for African elephants. Among the elephants examined by Debruyne (2005), we found that patterns of forest vs. savanna characteristics were significantly different (p < 10(-5)) between mtDNA and morphology, suggesting the presence of cyto-nuclear genomic dissociation. We show that the eight African elephant continent-wide datasets compared, including that of Debruyne (2005), together support a two-species model with cyto-nuclear genomic dissociation rather than a one-species model, and together indicate that Africa harbors two species of elephant.


What are the Particularities of Colorectal Surgery in Cirrhotic Patients.
This work's objective was to review the entire literature on colorectal surgery in order to best define the surgical indications and their management specificities. The literature analysis was carried out according to High Authority for Health (HAS) methodology, by consulting the PubMed database (Medline), from the beginning of January 1995 until the end of June 2015.


Two-stage three-channel Kondo physics for an FePc molecule on the Au(1 1 1) surface.
We study an impurity Anderson model to describe an iron phthalocyanine (FePc) molecule on Au(1 1 1), motivated by previous results of scanning tunneling spectroscopy (STS) and theoretical studies. The model hybridizes a spin doublet consisting in one hole at the [Formula: see text] orbital of iron and two degenerate doublets corresponding to one hole either in the 3d xz or in the 3d yz orbital (called π orbitals) with two degenerate Hund-rule triplets with one hole in the 3d z orbital and another one in a π orbital. We solve the model using a slave-boson mean-field approximation (SBMFA). For reasonable parameters we can describe very well the observed STS spectrum between sample bias -60 mV to 20 mV. For these parameters the Kondo effect takes place in two stages, with different energy scales [Formula: see text] corresponding to the Kondo temperatures related with the hopping of the z 2 and π orbitals respectively. There is a strong interference between the different channels and the Kondo temperatures, particularly the lowest one is strongly reduced compared with the value in the absence of the competing channel.


Identification of primary and sequential bioactivation pathways of carbamazepine in human liver microsomes using liquid chromatography/tandem mass spectrometry.
Carbamazepine (CBZ)-induced idiosyncratic toxicities are commonly believed to be related to the formation of reactive metabolites. CBZ is metabolized primarily into carbamazepine-10,11-epoxide (CBZE), 2-hydroxycarbamazepine (2-OHCBZ) and 3-hydroxycarbamazepine (3-OHCBZ), in human liver microsomes (HLM). Over the past two decades, the 2,3-arene oxidation has been commonly assumed to be the major bioactivation pathway of CBZ. Recently, CBZE has been also confirmed to be chemically reactive. In order to identify other possible primary and sequential CBZ bioactivation pathways, individual HLM incubations of CBZ, CBZE, 2-OHCBZ and 3-OHCBZ were conducted in the presence of glutathione (GSH). In the CBZ incubation, a variety of GSH adducts were formed via individual or combined pathways of 10,11-epoxidation, arene oxidation and iminoquinone formation. In the CBZE incubation, the only detected GSH adducts were CBZE-SG1 and CBZE-SG2, which represented the two most abundant conjugates observed in the CBZ incubation. In the incubation of either 2-OHCBZ or 3-OHCBZ, a number of sequential GSH adducts were observed. However, none of the 2-OHCBZ-derived GSH adducts were detected in the CBZ incubation. Meanwhile, several GSH adducts were only observed in the CBZ incubation. In conclusion, CBZ can be bioactivated in HLM via 10,11-epoxidation, 2,3-arene oxidation, and several other pathways. In addition, the sequential bioactivation of 3-OHCBZ appeared to play a more important role than that of either CBZE or 2-OHCBZ in the overall bioactivation of CBZ in HLM. The identification of several new bioactivation pathways of CBZ in HLM demonstrates that possible CBZ bioactivation can be more complex than previously thought.


Lymphatics and colorectal liver metastases: the case for sentinel node mapping.
Hepatic resection remains the treatment of choice for patients with colorectal liver metastases (CLM). Indications for hepatic resection have been extended to include extrahepatic lymph node groups, resulting in increased survival benefits. The identification of specific lymph pathways and involved nodes is necessary to support the development of guidelines for a more focused approach to the management of this disease. The feasibility of sentinel node mapping should be investigated to define specific lymphatic groups involved in CLM. Scientific papers published from 1950 to 2012 were sought and extracted from the MEDLINE, PubMed and University of Melbourne databases. Several studies have reported microscopic lymph node involvement in 10-15% of patients undergoing hepatic resection for CLM in which no macroscopic involvement was evident. In retrospect, over 80% of lymphadenectomies are proven unnecessary. Traditional imaging modalities have limited predictive value in detecting lymph node involvement. Sentinel node mapping has proved an extremely accurate tool in detecting lymph node involvement and can identify patients in whom lymphadenectomy may be beneficial. Current imaging techniques are inadequate to detect microscopic lymph node involvement in patients with resectable CLM. The use of sentinel node mapping is proposed to identify nodal groups involved and provide management strategies.


Exploratory plasma proteomic analysis in a randomized crossover trial of aspirin among healthy men and women.
Long-term use of aspirin is associated with lower risk of colorectal cancer and other cancers; however, the mechanism of chemopreventive effect of aspirin is not fully understood. Animal studies suggest that COX-2, NFκB signaling and Wnt/β-catenin pathways may play a role, but no clinical trials have systematically evaluated the biological response to aspirin in healthy humans. Using a high-density antibody array, we assessed the difference in plasma protein levels after 60 days of regular dose aspirin (325 mg/day) compared to placebo in a randomized double-blinded crossover trial of 44 healthy non-smoking men and women, aged 21-45 years. The plasma proteome was analyzed on an antibody microarray with ~3,300 full-length antibodies, printed in triplicate. Moderated paired t-tests were performed on individual antibodies, and gene-set analyses were performed based on KEGG and GO pathways. Among the 3,000 antibodies analyzed, statistically significant differences in plasma protein levels were observed for nine antibodies after adjusting for false discoveries (FDR adjusted p-value<0.1). The most significant protein was succinate dehydrogenase subunit C (SDHC), a key enzyme complex of the mitochondrial tricarboxylic acid (TCA) cycle. The other statistically significant proteins (NR2F1, MSI1, MYH1, FOXO1, KHDRBS3, NFKBIE, LYZ and IKZF1) are involved in multiple pathways, including DNA base-pair repair, inflammation and oncogenic pathways. None of the 258 KEGG and 1,139 GO pathways was found to be statistically significant after FDR adjustment. This study suggests several chemopreventive mechanisms of aspirin in humans, which have previously been reported to play a role in anti- or pro-carcinogenesis in cell systems; however, larger, confirmatory studies are needed.


Insight into the population dynamics of pathogenic bacteria causing grapevine crown gall in snowfall areas: snow cover protects the proliferation of pathogenic bacteria.
Grapevine crown gall (GCG) is a significant bacterial disease caused by tumorigenic Allorhizobium vitis (TAV) and is prevalent worldwide. TAV infects grapevines through wounds such as freezing injuries. Although grapevines typically avoid being wounded under snow cover, GCG occurs in many commercial vineyards in snowy regions. This study investigated the TAV population in GCG gall tissues, grapevine skins, and snow on grapevine skins from six infected vineyards located in Hokkaido, Japan, an area known for heavy snowfall. TAV was isolated not only from gall tissues but also from skins and snow on skins throughout the year. Hierarchical Bayesian model (HBM) analysis revealed that the number of TAV cells in gall tissues was affected by cultivar and low temperature, while those in skins were affected by location and low temperature. Additionally, Bayesian changepoint detection (BCD) showed that the number of TAV cells in gall and skin tissues increased during winter, including the snowfall season. Furthermore, the TAV population in grapevine skins under the snow was significantly higher than those above the snow, indicating that TAV under the snow is protected by the snow and can survive well during the snowfall season. This study highlights the ability of TAV to overwinter on/in galls and skins under the snow and act as inoculum for the next season.


Physicochemical and metabolic properties of modified metallothioneins.
Attempts to crosslink metallothionein through lysine residues have resulted in trapping of octameric structures. Two such polymers have been characterized. They are of a critical size for glomerular filtration, and unique tissue distributions of cadmium arise when they are injected into rats.


Increase of DNA damage and alteration of the DNA damage response in myelodysplastic syndromes and acute myeloid leukemias.
Increased DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability presumably implicated in pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We used immunofluorescence staining of γH2AX and 53BP1 for analyzing DNA double-strand breaks (DSB) in MDS and AML cell lines, in CD34+ selected cells of normal and MDS bone marrow (including three cases of chronic myelomonocytic leukemias) and in blasts of AML bone marrow. In addition, we screened for activation of the DDR by immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53. As compared to γH2AX foci levels in normal bone marrow samples (0.2 focus per CD34+ cell±0.0; mean±standard error of mean), increased levels of γH2AX foci were detected in 16/16 MDS bone marrow samples (2.8 foci per CD34+ cell±0.5), 18/18 AML bone marrow samples (5.5 foci per blast±0.5), 1/1 MDS cell line (6.4 foci per cell) and 6/6 AML cell lines (12.0 foci per cell±0.6). γH2AX and 53BP1 co-localized in all tested samples forming diffuse, clustered and marginal patterns. Further, DDR proteins were expressed heterogeneously suggesting impairment of the DDR. In summary, our results provide evidence for a continuous increase of DSB across the spectrum from MDS to AML in conjunction with an impaired DDR. Co-localization of γH2AX and 53BP1 indicates promotion of (in)effective nonhomologous end-joining repair mechanisms at sites of DSB. Moreover, γH2AX/53BP1 foci distribution presumably reveals a non-random spatial organization of the genome in MDS and AML.


Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation.
Proteostasis is one of the seven "pillars of aging research" identified by the Trans-NIH Geroscience Initiative and loss of proteostasis is associated with aging and age-related chronic disease. Accumulated protein damage and resultant cellular dysfunction are consequences of limited protein repair systems and slowed protein turnover. When relatively high rates of protein turnover are maintained despite advancing age, damaged proteins are more quickly degraded and replaced, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides necessary mechanistic insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with a number of murine models of slowed aging shows that, compared to controls, energetic resources are directed more toward somatic maintenance and proteostasis, and away from cell growth and proliferation. In particular, slowed aging models are associated with heightened mechanisms of mitochondrial proteostatic maintenance. Taking cell proliferation into account may explain the paradoxical findings that aging itself and slowed aging interventions can both be characterized by slower rates of protein synthesis.


Immunohistochemical localization of prostaglandin F2 alpha in reperfused gerbil brain.
Immunohistochemical localization of prostaglandin (PG) F2 alpha synthesized during recirculation following experimental forebrain ischemia was studied in Mongolian gerbils. The bilateral carotid arteries were clamped for 5 minutes, and the brains were frozen in situ after 5 minutes of recirculation. Sham-operated gerbils not subjected to arterial occlusion served as controls. Cryostat sections containing dorsal hippocampus 10 microns in thickness were incubated in rabbit anti-PGF2 alpha serum and stained with avidin-biotin-peroxidase complex after fixation in carbodi-imide and Zamboni's solution. In specimens from control animals, blood vessels were faintly stained with anti-PGF2 alpha serum, while neurons and glial cells were less intensely stained or unstained. Specimens from reperfused gerbils demonstrated strongly positive staining for PGF2 alpha in blood vessels, neurons (especially hippocampal pyramidal neurons), and glial cells. Staining for PGF2 alpha in the reperfused animals was substantially diminished by pretreatment with indomethacin (10 mg/kg, i.p.). The results indicate that recirculation after forebrain ischemia results in an increase in PGF2 alpha in neurons, glial cells, and blood vessels.


Catalyst Controlled Regiodivergent Arylboration of Dienes.
A method for the regiodivergent arylboration of dienes is presented. These reactions allow for the formation of a diverse range of synthetically versatile products from simple precursors. Through mechanistic studies, these reactions likely operate by initial addition of a Cu-Bpin complex across the diene followed by Pd-catalyzed cross coupling with an aryl halide or pseudohalide.


Fpg protein releases a ring-opened N-7 guanine adduct from DNA that has been modified by sulfur mustard.
Transfection of the Escherichia coli fpg gene into Chinese hamster ovary cells has been reported to enhance survival after exposure to aziridine (C. Cussac and F.Laval, 1996, Nucleic Acids Res., 24, 1742-1746). This result suggests that Fpg protein protects cells from toxicity by removing ring-opened N-7 guanine adducts from DNA, and raises the possibility that Fpg protein would offer protection from other agents that alkylate the N-7 position of guanine. Since the major adduct formed by sulfur mustard in DNA is 7-hydroxyethyl-thioethylguanine (HETEG), we have investigated the action of Fpg protein on the ring-opened form of this adduct (ro-HETEG). A substrate containing ro-HETEG was prepared by alkaline treatment of DNA modified by [14C]sulfur mustard. Fpg protein purified from an over-producing strain of E. coli released ro-HETEG from this substrate in an enzyme- and time-dependent manner, and at a rate that is similar to that at which it releases ring-opened 7-methylguanine. Thus, Fpg protein acts efficiently on ro-HETEG, and may offer some protection against the toxic action of sulfur mustard.


Vx3-Functionalized Alumina Nanoparticles Assisted Enrichment of Ubiquitinated Proteins from Cancer Cells for Enhanced Cancer Immunotherapy.
A simple and effective strategy was developed to enrich ubiquitinated proteins (UPs) from cancer cell lysate using the α-Al2O3 nanoparticles covalently linked with ubiquitin binding protein (Vx3) (denoted as α-Al2O3-Vx3) via a chemical linker. The functionalized α-Al2O3-Vx3 showed long-term stability and high efficiency for the enrichment of UPs from cancer cell lysates. Flow cytometry analysis results indicated dendritic cells (DCs) could more effectively phagocytize the covalently linked α-Al2O3-Vx3-UPs than the physical mixture of α-Al2O3 and Vx3-UPs (α-Al2O3/Vx3-UPs). Laser confocal microscopy images revealed that α-Al2O3-Vx3-UPs localized within the autophagosome of DCs, which then cross-presented α-Al2O3-Vx3-UPs to CD8+ T cells in an autophagosome-related cross-presentation pathway. Furthermore, α-Al2O3-Vx3-UPs enhanced more potent antitumor immune response and antitumor efficacy than α-Al2O3/cell lysate or α-Al2O3/Vx3-UPs. This work highlights the potential of using the Vx3 covalently linked α-Al2O3 as a simple and effective platform to enrich UPs from cancer cells for the development of highly efficient therapeutic cancer vaccines.


Innovative approaches in drug development.
This is the white paper on Innovative Approaches in Drug Development developed by the Biotechnology Industry Organization's (BIO) Clinical Trial Designs Workgroup. As recognized by the Food and Drug Administration's Critical Path Opportunities Report, the need to develop and apply innovative approaches to create new trial designs and clinical development programs is rapidly on the rise. Such novel approaches hold tremendous potential in the ability to refine mechanisms lying at the fundamental core of product safety and efficacy. The paper addresses the opportunities, challenges in pre-clinical and clinical trial design innovations; emphasizes the importance of safety database; and makes recommendations for carrying out the innovative approaches. The views expressed here in are solely those of the authors and do not reflect the official views of the Biotechnology Industry Organization.


Performance of an Adapted Version of the Timed Up-and-Go Test in People with Cognitive Impairments.
In clinical practice, older people with cognitive impairment may have difficulties to understand the instructions of the Timed Up-and-Go (TUGT) test and present a bad performance. The purpose of this study was to identify differences in the TUGT performance, in an adapted version, between older adults with preserved cognition (PC), mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to identify the association between the adapted TUGT performance and cognition among groups. A cross-sectional study was conducted with 118 community-dwelling older adults divided in three groups: PC (n = 40), MCI (n = 40) and AD (n = 38). The evaluation was composed by the adapted TUGT and cognitive assessment (Addenbrooke's Cognitive Examination and Frontal Assessment Battery). Only the cadence of TUGT presented significant difference between groups, specifically between AD versus MCI and PC groups. The main correlations were found between time of TUGT with fluency domain and global cognitive function, especially in the AD Group. The findings contribute to the understanding of how cognition interferes on functional mobility in older people with MCI and AD. The adapted TUGT is easy to perform in clinical practice and can be useful when assessing mobility in people with cognitive impairment.


Recurrent spontaneous bacterial peritonitis in a patient with polycythemia vera.
Spontaneous bacterial peritonitis (SBP) is an infectious process that usually occurs in patients with cirrhosis. There are few reports of SBP in patients with other pathologies such as nephrotic syndrome, acute and chronic hepatitis, cardiac ascites, and ascites secondary to neoplastic disease. We report a patient with polycythemia vera in whom recurrent episodes of SBP occurred 8 months following a portacaval shunt operation for Budd-Chiari syndrome. Conceivably, the polycythemia vera (PV) complicated by hepatic vein thrombosis and portacaval shunt resulted in significant loss of hepatic reticuloendothelial system function and predisposed the patient to bacterial peritonitis.


Polarization effects in interferograms of conical optical elements.
Analysis of a particular interferometer shows that severe polarization effects in interferograms of conical optical elements can be prevented. A simple formula is derived for correcting residual polarization effects due to spatially varying reflection coefficients. The formula can be used for estimating whether a correction is required. Several applications are discussed.


Corticotropin-releasing factor attenuates interleukin 1-induced sleep and fever in rabbits.
Interleukin 1 (IL-1), a key mediator of the acute phase response, stimulates hypothalamic corticotropin-releasing factor (CRF) release. The CRF-adrenocorticotrophic hormone (ACTH)-glucocorticoid axis is a feedback for peripheral production and action of IL-1. Effects of intracerebroventricularly administered CRF on rabbit sleepwake activity, brain temperature (Tbr), and behavior and on the central effects of IL-1 [fever and excess non-rapid-eye-movement sleep (NREMS)] were studied. CRF (0.1-1.25 micrograms) dose dependently decreased NREMS and enhanced wakefulness. IL-1-induced excess NREMS was inhibited by CRF. Rapid-eye-movement sleep (REMS) suppressed by IL-1 was partially restored by 0.1 or 0.5 microgram CRF, although CRF itself did not promote REMS. Behavioral effects of intracerebroventricular CRF were relatively small, although 1.25 micrograms abolished ingestion for 3 h, suppressed rearing behavior, and increased sitting behavior. Tbr increased after CRF injection alone. After IL-1 pretreatment, however, 0.1 and 0.5, but not 1.25, micrograms CRF reduced IL-1-induced fever after several hours. These results implicate IL-1-induced CRF release as part of a negative-feedback mechanism attenuating not only peripheral IL-1 actions but also its central effects.


Designed polar cosolvent-modified supercritical CO2 removing caffeine from and retaining catechins in green tea powder using response surface methodology.
This study examines cosolvent-modified supercritical carbon dioxide (SC-CO2) to remove caffeine from and to retain catechins in green tea powder. The response surface method was adopted to determine the optimal operation conditions in terms of the extraction efficiencies and concentration factors of caffeine and catechins during the extractions. When SC-CO2 was used at 333 K and 300 bar, 91.5% of the caffeine was removed and 80.8% of catechins were retained in the tea: 3600 g of carbon dioxide was used in the extraction of 4 g of tea soaked with 1 g of water. Under the same extraction conditions, 10 g of water was added to <800 g of carbon dioxide in an extraction that completely removed caffeine (that is, the caffeine extraction efficiency was 100%). The optimal result as predicted by three-factor response surface methodology and supported by experimental data was that in 1.5 h of extraction, 640 g of carbon dioxide at 323 K and 275 bar with the addition of 6 g of water extracted 71.9% of the caffeine while leaving 67.8% of the catechins in 8 g of tea. Experimental data indicated that supercritical carbon dioxide decaffeination increased the concentrations of caffeine in the SC-CO2 extracts at 353 K.


Baseline population survey data on the prevalence of risk factors for coronary artery disease among Kuwaitis aged 15 years and older.
There are no baseline population survey data on the prevalence of risk factors for coronary artery disease (CAD) among normal, healthy Kuwaiti women upon which future interventional studies can be based. We collected data on the prevalence of excessive weight, obesity, diabetes mellitus, dyslipidemia, current smoking and physical inactivity for 7,609 apparently healthy Kuwaitis aged 15 years and older by means of a household survey. Using a structured questionnaire, we collected demographic data from the respondents, measured their body weight and height, and collected blood samples for measurement of glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoproteins A1 and B. The prevalence of obesity among adult Kuwaitis was 23.5%. It was higher among women (30.0%) than among men (17.5%). The combined prevalence of obesity and excessive weight in the population was 58% (63.4% among women and 53% among men). Diabetes mellitus and hypercholesterolemia were slightly higher in women than in men (21.8 vs 17.7 and 36.6 vs 30.2% respectively) while hypertriglyceridemia and low HDL-C were higher in men than in women (44.1 vs 33.8 and 52.2 vs 21.8% respectively). The prevalence of smoking was significantly higher in men (31.7%) than in women (1.4%), while the prevalence of physical inactivity was higher in women (71.4%) than in men (50.6%). We conclude that Kuwaiti women, like men, have high risk factors for CAD and should receive equal attention in future programs to prevent CAD death among Kuwaitis.


Occupational Safety and Health and Healthy Housing: A Review of Opportunities and Challenges.
Occupational safety and health (OSH) risks in construction of healthy housing (HH) have not been examined and collaboration between HH and OSH professionals is inadequate. The World Health Organization is developing international HH guidelines and the International Labour Organization is working to improve OSH in construction globally. We searched for exemplary reports (including gray literature) on construction hazards; preventive measures for occupants and workers; OSH frameworks, laws, and regulations; definitions; and HH. Healthy housing construction typically improves ventilation, moisture and mold, pest control, injury hazards, cleanability, maintenance, accessibility, thermal conditioning, and avoidance of toxic building materials. To date, this work is done without explicit requirements for worker health. Construction is among the most hazardous sectors around the globe, although protective measures are well known, including engineering and administrative controls and provision of personal protective equipment. Residential construction, renovation, repair, and maintenance are fragmented, consisting mostly of small companies without proper OSH training, equipment, and knowledge of HH principles. Residential construction is often undertaken by informal or unauthorized workers, putting them at high risk. Reduced exposure to toxic building materials is an example of a benefit for both workers and occupants if OSH and HH collaboration can be improved. By recognizing that homes under new construction or renovation are both a workplace and a residence, HH and OSH initiatives can apply public health principles to occupants and workers simultaneously. This article publishes key definitions, hazards and interventions common to both fields. A global increase in residential construction and renewed global interest in HH poses both risks and opportunities for primary prevention. Policy and practice interventions can benefit the health of occupants and those who work on their homes. Improvements in legislation, regulation, and international frameworks are needed to maximize OSH and HH collaboration and realize significant cobenefits. Occupational safety and health and HH standards should include requirements to protect both workers and occupants. Because homes can also be workplaces, both workers and housing occupants will receive important cobenefits when OSH and HH standards use proven interventions to protect workers and occupants.


Recombinant annexin-2 inhibits the progress of diabetic nephropathy in a diabetic mouse model via recovery of hypercoagulability.
Diabetic nephropathy, a major complication of diabetes mellitus that leads to mortality, has been shown to involve a dysregulation of the coagulation system. Annexin-2, a co-receptor for plasminogen and tissue plasminogen activator on endothelial cells, is one of the molecules required to maintain the antithrombogenic properties of endothelial cells. Previously, we showed that recombinant annexin-2 protein (rAN II) modulated impaired fibrinolytic activity in the carotid arteries of rats. In the present study, to investigate its protective effects against diabetic nephropathy, rAN II was administered to KK-Ay mice, a murine model of type 2 diabetes, for eight weeks, and albuminuria, kidney size, and histological glomerular lesions were investigated. The mean weight of kidneys from KK-Ay mice treated with rAN II was significantly less than that of those treated with PBS (control) (p < 0.02). Furthermore, the level of albuminuria observed in rAN II-treated KK-Ay mice was significantly less than that of the control group (rAN II, 0.90+/-0.12 microg/day; PBS, 1.55+/-0.31 microg/day; p < 0.01); also, the area of diffuse glomerular lesions was significantly smaller (rAN II, 41.51+/-4.54%; PBS, 81.81+/-8.10%; p < 0.01). Bleeding time, prothrombin time (PT), and active partial thromboplastin time (APTT) did not significantly differ between the two groups. Our results suggest that rAN II may inhibit the progression of diabetic nephropathy in KK-Ay mice without influencing the coagulation system, indicating that annexin-2 may be considered as a possible new therapeutic tool for patients with diabetic nephropathy.


Effect of all-trans retinoic acid (ATRA) on syndecan-1 expression and its chemoprotective effect in benzo(α)pyrene-induced lung cancer mice model.
All-trans retinoic acid (ATRA), an active metabolite of retinal, has been shown to exert anti-cancer activities in a number of cancer cells and tissues. Syndecan-1 is a proteoglycan, mediate cell-cell adhesion and prevent invasion in epithelial cells. The aim of the present study was to examine the level of syndecan-1 expression and the chemopreventive effect of ATRA during lung cancer development in BALB/c mice. Syndecan-1 expression was examined by immunohistochemistry using mouse monoclonal anti-human syndecan-1 antibody. In this study, benzo(α)pyrene [B(α)P] was used to induce lung cancer. The results indicated that ATRA has anti-cancer effect against B(α)P-induced lung tumor development as induced by number of tumor nodules and histopathologic report. The loss of syndecan-1 expression in the epithelial cell membrane is associated with tumor cell growth and invasiveness. Our study for syndecan-1 indicated a chemoprotective effect of ATRA against changes in lung epithelial cell membrane syndecan-1 expression in B(α)P-induced lung cancer model. Therefore ATRA could serve as effective chemotherapeutic agent against cancer invasion/metastasis, at least in the lungs.


Growth requirements of T cell hybridomas obtained by the fusion between a mouse cytolytic T cell line and the rat tumor C58NTD.
T23 are hybrids derived from the fusion between an IL-2-dependent mouse cell line, C10 and the rat lymphoma C58NTD. Supernatants from exponentially growing T23 cells induce the growth of CTLL2, and IL-2-dependent cell line, suggesting that these hybrids secrete interleukin 2. Addition of recombinant IL-2 to slowly growing T23 cells increases the rate of growth. Using an 125I IL-2 binding assay, a low number of cell surface IL-2 receptors were detected. T23 hybrids contain mouse but not rat IL-2 receptor genes as revealed by Southern blot analysis. These receptors are functional because the growth of exponentially growing hybrids is inhibited by an anti-mouse IL-2 receptor antibody. These data suggest an autocrine-like mechanism as responsible for the growth of these T cell hybridomas.


[Criteria for the health surveillance of WMSDs in exposed working populations].
In the light of the experiences and guidelines developed by other countries and of Italian legislative and operational conditions, the authors outline a strategy for a health surveillance programme for work-related musculo-skeletal disorders of the upper limbs. In particular, the paper defines the various aims of the health surveillance programme and identifies significant relevant criteria for its implementation (i.e. existence of risks or effects). A screening schedule is presented based on successive investigations (1st and 2nd level surveillance); the authors discuss the principal methods used for processing the results of the health surveillance programme, in collective (i.e. statistical comparisons; planning of periodical investigations) and individual terms (job fitness judgements; reporting of suspected occupational diseases.


[A case of ectodermal dysplasia].
A case of a 10-year old boy with anhidrotic ectodermal dyspasia is reported. The classic triad has been established--hypodontia, hypotrichosis and anhidrosis, confirmed by biopsy. The patient's genealogy was studied, revealing inheritance by C-chromosome. The early treatment results in functional, aesthetic and psychological effect. The prostheses should periodicaly be changed so as to guarantee the proper development of the jaws.


Frequency of prescription opioid misuse and suicidal ideation, planning, and attempts.
The goal of this study was to examine the relationship between past-year frequency of prescription opioid misuse and past-year suicidal ideation, suicide planning, and suicide attempts. Secondary data analyses were conducted using data from 41,053 participants of the 2014 National Survey of Drug Use and Health. Past-year frequency of prescription opioid misuse was grouped into 4 categories: none, less than monthly (1-11 times), monthly to weekly (12-51 times), and weekly or more (52 times or more). Binomial logistic regression analyses adjusted for demographics, overall health rating, depression, anxiety, and substance use disorders to test the associations between frequency of prescription opioid misuse and suicide-related variables. Compared to those who did not endorse prescription opioid misuse in the past year, prescription opioid misuse was significantly associated with suicidal ideation, suicide planning, and suicide attempts for each frequency of use category in unadjusted models (p < 0.05). In adjusted models, frequency of prescription opioid misuse remained significantly associated with suicidal ideation (p < 0.05 for each frequency category); however, only the group reporting weekly or more use on average was associated with suicide planning and attempts (p < 0.05). The findings provide novel specificity regarding prescription opioid use in relation to suicide-related outcomes further supporting enhanced access to suicide prevention and nonpharmacological approaches to pain management across various settings.


[Analytical method for methoprene in foods using HPLC].
We studied the determination of methoprene in foods by high-performance liquid chromatography (HPLC). The sample was extracted with acetonitrile and the extract was salted out by adding sodium chloride, allowing the acetonitrile layer to separate. The acetonitrile solution was washed with hexane saturated with acetonitrile, cleaned up on a Florisil column and determined by HPLC. The recovery of methoprene from spiked samples was 74.6-82.8%. In an evaluation of this method by 6 analytical laboratories, mean recoveries from spiked samples ranged from 79.4% to 84.6%. Repeatability relative standard deviation values were 2.3-8.8% and reproducibility relative standard deviation values were 8.8-23.6%. The detection limits were 0.001-0.02 microg/g and below the detection limit of the Notified Analytical Method.


Association between COVID-19 vaccination and critical outcomes among older adults with dementia: a comparative cohort study.
As COVID-19 vaccines became available, understanding their potential benefits in vulnerable populations has gained significance. This study explored the advantages of COVID-19 vaccination in individuals with cognitive disorders by analyzing health-related variables and outcomes. A prospective cohort study analyzed electronic medical records of 25,733 older adults with cognitive disorders and 65,544 older adults without cognitive disorders from March 2020 to February 2022. COVID-19 vaccination status was the primary exposure variable, categorized as fully vaccinated or unvaccinated. The primary outcomes measured were all-cause mortality and hospitalization rates within 14 and 400 days post-vaccination. Data on vaccination status, demographics, comorbidities, testing history, and clinical outcomes were collected from electronic health records. The study was ethically approved by the relevant medical facility's Institutional Review Board (0075-22-MHS). Vaccinated individuals had significantly lower mortality rates in both groups. In the research group, the mortality rate was 52% (n = 1852) for unvaccinated individuals and 7% (n = 1,241) for vaccinated individuals (p < 0.001). Similarly, in the control group, the mortality rate was 13.58% (n = 1,508) for unvaccinated individuals and 1.85% (n = 936) for vaccinated individuals (p < 0.001), despite higher COVID-19 positivity rates. In the research group, 30.26% (n = 1,072) of unvaccinated individuals tested positive for COVID-19, compared to 37.16% (n = 6,492) of vaccinated individuals (p < 0.001). In the control group, 17.31% (n = 1922) of unvaccinated individuals were COVID-19 positive, while 37.25% (n = 18,873) of vaccinated individuals tested positive (p < 0.001). Vaccination also showed potential benefits in mental health support. The usage of antipsychotic drugs was lower in vaccinated individuals (28.43%, n = 4,967) compared to unvaccinated individuals (37.48%, n = 1,328; 95% CI [0.92-1.28], p < 0.001). Moreover, vaccinated individuals had lower antipsychotic drug prescription rates (23.88%, n = 4,171) compared to unvaccinated individuals (27.83%, n = 968; 95% CI [-1.02 to -0.63], p < 0.001). Vaccination appeared to have a positive impact on managing conditions like diabetes, with 38.63% (n = 6,748) of vaccinated individuals having diabetes compared to 41.55% (n = 1,472) of unvaccinated individuals (95% CI [0.24, 0.48], p < 0.001). The findings highlight the importance of vaccination in safeguarding vulnerable populations during the pandemic and call for further research to optimize healthcare strategies for individuals with cognitive disorders.


Stereoselective transport of histidine in rat lung microvascular endothelial cells.
The transport characteristics of L- and D-histidine through the blood-lung barrier were studied in cultured rat lung microvascular endothelial cells (LMECs). L-Histidine uptake was a saturable process. The addition of metabolic inhibitors [2,4-dinitrophenol (DNP) and rotenone] reduced the uptake rate of L-histidine. Ouabain, an inhibitor of Na(+)-K(+)-ATPase, also reduced uptake of L-histidine. Moreover, the initial L-histidine uptake rate was reduced by the substitution of Na(+) with choline chloride and choline bicarbonate in the incubation buffer. The system N substrate, L-glutamic acid gamma-monohydroxamate, also inhibited uptake of L-histidine. However, system N-mediated transport was not pH sensitive. These results demonstrated that L-histidine is actively taken up by a system N transport mechanism into rat LMECs, with energy supplied by Na(+). Moreover, the Na(+)-independent system L substrate, 2-amino-2-norbornanecarboxylic acid (BCH), had an inhibitory effect on L-histidine uptake in Na(+) removal, indicating facilitated diffusion by a Na(+)-independent system L transport into the rat LMECs. These results provide evidence for there being at least two pathways for L-histidine uptake into rat LMECs, a Na(+)-dependent system N and Na(+)-independent system L process. On the other hand, the uptake of D-histidine into rat LMECs was not reduced by the addition of DNP, rotenone, or ouabain, or by Na(+) replacement. Although the uptake of D-histidine was reduced in the presence of BCH, the addition of L-glutamic acid gamma-monohydroxamate did not significantly decrease uptake of D-histidine. These results suggest that the uptake of D-histidine by rat LMECs has different characteristics compared with its isomer, L-histidine, indicating that system N transport did not involve D-histidine uptake.


Regulation of breast cancer metastasis by IGF signaling.
The insulin-like growth factors (IGFs) signaling via the type I insulin-like growth factor receptor (IGF-1R) regulate multiple aspects of malignancy. The importance of IGF-1R in regulating the malignant phenotype is currently being validated in numerous clinical trials for cancer including breast cancer. This review discusses the regulation of breast cancer metastasis by IGF-1R. IGF-1R stimulates invasion and survival in anchorage independent conditions. The regulation of metastasis independently of tumor growth by IGF-1R is also discussed. Finally, the impact of this on clinical trial design and outcomes, and the need for biomarkers, other than reduction in tumor size, are discussed in light of the fact that inhibition of metastasis is not measured in conventional clinical trial design.


In heavy drinkers fatty acid ethyl esters in the serum are increased for 44 hr after ethanol consumption.
Fatty acid ethyl esters (FAEEs) have been proposed as a marker of ethanol consumption because they can be detected for up to 24 hr after a moderate intake of ethanol, even though blood ethanol remains increased for only 8 hr. Therefore, this study investigated whether FAEEs can be found during a time period exceeding 24 hr in a group of patients who were hospitalized for ethanol detoxification. A second aim was to study the distribution of FAEEs between lipoproteins during that time. Serum samples of 12 patients with acute ethanol intoxication were assayed for FAEEs. Blood samples were drawn 8.2, 20.2, 32.2, and 44.2 hr after hospitalization. FAEEs were quantified by gas chromatography-mass spectrometry. Ethanol was no longer detectable after 20.2 hr from hospitalization, whereas FAEEs were still found after 32.2 and 44.2 hr. These late FAEEs were significantly higher than the FAEEs in 15 different healthy men who had abstained from ethanol for 4.5 days (p < 0.001 and p = 0.001). FAEEs were associated mainly with lipid-free serum but tended to accumulate in very-low-density lipoprotein in patients with moderate hypertriglyceridemia. In heavy drinkers, the FAEEs were increased after ethanol consumption for at least 44 hr. It remains to be studied whether they originate from a single ethanol intake or, in addition, from a slow release out of body storage compartments.


Determination of the attenuation properties of laboratory gloves exposed to an ultraviolet transilluminator.
The transmission of ultraviolet radiation (UVR) from an ultraviolet transilluminator through three types of laboratory gloves (latex, nitrile, vinyl) was determined using two independent methods. First, transmittance was measured with a radiometer equipped with UVA and actinic UV detectors. Second, a spectrophotometer was used to determine the UVR transmittance vs. wavelength (250-440 nm); this data was then used to compute the effective attenuation of the glove material. The average UVA percent transmittance using the radiometer method with an unstretched glove was 73.4%, 0.18%, and 1.10% for vinyl, nitrile, and latex, respectively. The average actinic percent transmittance for an unstretched glove was 13.3%, 0.015%, and 0.024% for vinyl, nitrile, and latex, respectively. Slight increases in UVR transmittance resulted from stretching the gloves by 30% or wetting them with saline. Six hours of UVR exposure decreased transmittance of vinyl gloves and increased transmittance by latex gloves. Results from the spectrophotometer method and radiometer methods of determining UVR transmittance agreed that vinyl gloves had the highest transmittance; however, the spectrophotometer method greatly overestimated UV glove attenuation due to the effect of light scattering by the glove material. The study suggests that in some circumstances, vinyl gloves will provide inadequate protection against workplace ultraviolet radiation.


The Susceptibility of Leukemia Cells to Arsenic Trioxide-induced Apoptosis is Determined by Cellular Reactive Oxygen Species Level.
To explore the relationship between the susceptibility to arsenic trioxide (As(2)O(3))-induced apoptosis of leukemia cells and the level of reactive oxygen species (ROS) of cells, flow cytometry and electron microscopy were applied to identify apoptosis, and dihydrorhodamine123 was used to display the ROS level of cells. As(2)O(3) alone or in combination with 2,3-dimethoxy-1,4-naphthoquinone (DMNQ, 2.5 &mgr;mol/L for NB4 cells, 10 &mgr;mol/L for U937 cells) were used to induce cell apoptosis. The results showed that NB4 cells possessed higher level of ROS than U937 cells. DMNQ raised ROS levels of NB4 and U937 cells, sensitized U937 cells to As(2)O(3)-induced apoptosis, and enhanced the efficacy of As(2)O(3)-induced apoptosis of NB4 cells. Catalase reversed the effect of DMNQ on NB4 and U937 cells. It was concluded that the susceptibility of leukemia cells to arsenic trioxide-induced apoptosis is determined by ROS level in the cells.


Overexpression of microRNA-30a contributes to the development of aortic dissection by targeting lysyl oxidase.
To explore the role of microRNA (miR)-30a in the development of aortic dissection. Human aortic specimens of aortic dissections and aneurysms were harvested. Aortic specimens from donors for heart transplantation served as controls. Rat aortic vascular smooth muscle cells (VSMCs) were transfected with agomiR-30a or antagomiR-30a, and control cells were incubated with empty vectors. Rats were pretreated with agomiR-30a or antagomiR-30a (5 × 107 transfection units every 3 days for 4 weeks), and empty vectors were infused to controls. Acute aortic dissection was induced by subcutaneous infusion of angiotensin II (1 μg · kg-1 · min-1 for 24 hours). Protein expressions of lysyl oxidase (LOX) and elastin and gene expression of miR-30a were measured in VSMCs and human and rat aortic specimens by Western blot analysis and quantitative real-time polymerase chain reaction. Gene expression of miR-30a was much higher, and protein abundance of LOX and elastin was significantly lower, in the aortic dissection specimens (P < .05 vs controls). Transfection of agomiR-30a markedly decreased the luciferase activity of LOX in VSMCs of wild type, but not of LOX 3'-UTR mutant (P = .002). In cultured VSMCs, transfection of agomiR-30a dramatically enhanced the gene expression of miR-30a and down-regulated the protein abundance of LOX and elastin (P < .05 vs controls). Pretreatment with agomiR-30a in vivo enhanced miR-30a expression and down-regulated the protein abundance of LOX and elastin in rat aortas (P < .05 vs controls). The rate of dissection was significantly higher in rats pretreated with agomiR-30a (P = .003 vs controls). Overexpression of miR-30a contributes to the development of aortic dissection, possibly by targeting LOX.


Microporous carbon nanoplates from regenerated silk proteins for supercapacitors.
Novel carbon-based microporous nanoplates containing numerous heteroatoms (H-CMNs) are fabricated from regenerated silk fibroin by the carbonization and activation of KOH. The H-CMNs exhibit superior electrochemical performance, displaying a specific capacitance of 264 F/g in aqueous electrolytes, a specific energy of 133 Wh/kg, a specific power of 217 kW/kg, and a stable cycle life over 10000 cycles.


Cell density downregulates DNA synthesis and proliferation during osteogenesis in vitro.
The classical models of in vitro cell culture comprise fibroblasts and epithelial cells. Osteogenic cells represent another interesting cell model; however, it is not known whether during osteogenesis cell density regulates cell growth as seen in cultures of fibroblasts and epithelial cells. We selected MC3T3-E1 cells for study because they are an osteogenic cell line that, when subcultured, grow to confluence and form multilayers of cells in conventional cultures by continued proliferation, as do fibroblasts. Once maximum cell density is obtained, proliferation is down regulated resulting in a mixed population of quiescent and dividing cells. We used this model to determine whether downregulation of proliferation as expressed by cell number and DNA synthesis is cell density-dependent. MC3T3-E1 cells were cultured over a period of 34 days to determine their kinetics, viability, ability to synthesize DNA, distribution within phases of the cell cycle and cell number-response relationships. Our results show that (1) viability ranged between 92% and 96% and the cell number 2.5 x 10(5) per cm2 once cultures reached steady state, (2) most cells entered the G0/G1 phase of the cell cycle on day 7, (3) there was no correlation between the proportion of cells in S phase and downregulation of DNA synthesis, (4) a direct relationship exists between cell density and downregulation of DNA synthesis on day 8, (5) the minimum time for cells to be cultured before downregulation of DNA synthesis begins is independent of cell number, and (6) downregulation of DNA synthesis is reversible. These results suggest that density-dependent downregulation of DNA synthesis may be a mechanism of growth control for osteogenic cells in vitro that operates more like density-dependent growth control in cultures of fibroblasts rather than epithelial cells.


Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the "3 + 7" induction regimen for acute myeloid leukemia.
Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re-induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re-induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re-induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to <5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3-year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long-term survivors than the Day 14th BM count (66% vs. 30%, P = 0.0001 and 48% vs. 37%, respectively, P = 0.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re-induction based on such early evaluation should be prospectively studied.


Nutrition, Gut Microbiota, and Alzheimer's Disease.
Nutrition is known to play an important role in the pathogenesis of Alzheimer's disease. Evidence is obtained that the gut microbiota is a key player in these processes. Dietary changes (both adverse and beneficial) may influence the microbiome composition, thereby affecting the gut-brain axis and the subsequent risk for Alzheimer's disease progression. In this review, the research findings that support the role of intestinal microbiota in connection between nutritional factors and the risk for Alzheimer's disease onset and progression are summarized. The mechanisms potentially involved in these processes as well as the potential of probiotics and prebiotics in therapeutic modulation of contributed pathways are discussed.


Conditioned taste aversions and neophobia in rats with hippocampal lesions.
In the first experiment extensive hippocampal lesions retarded, but did not prohibit, the conditioning of a strong taste aversion to physiological saline (the conditioned stimulus; CS) when illness (the unconditioned stimulus; UCS) was induced by injecting rats with apomorphine 15 min following ingestion of the saline. In the second experiment hippocampal lesions reduced the aversiveness of novelty in a drinking fluid for the thirsty rat. It was suggested that the mild impairment of taste aversion learning in the rats with hippocampal lesions was not the result of destruction of mnemonic mechanisms that serve to span the long CS-UCS interval but rather that the reduced intensity of the aversion resulted from a lesion-altered neophobic disposition that weakened the saliency of the novel flavor CS.


Validation of a Quality of Life Instrument in Spanish Patients With Rheumatic Diseases: The Rosser Classification System.
The aim of this study was to assess the reliability and validity of the Spanish version of the Rosser classification system for disease states in patients with musculoskeletal disorders. Our study was based on a questionnaire validation design. Patients were attended at an outpatient rheumatology clinic at Hospital Clínico San Carlos, Madrid, Spain. The Rosser classification system was completed by the physician from the research team (PMQ) and by the patient (HMQ). Criterion standards: The EuroQol-5D for the HMQ and the physician global estimate (DOCGL) for the PMQ. Internal consistency reliability was assessed using Cronbach α. Test-retest reliability and interobserver reliability were analyzed using the intraclass correlation coefficient. The criterion validity between HMQ and EuroQol-5D and between PMQ and DOCGL was assessed using the Spearman correlation coefficient. The full analysis was based on 4 samples of patients (104 to 266 patients), most of whom were middle-aged women. For HMQ, Cronbach α was 0.70. Test-retest reproducibility was 0.7. With respect to criterion validity, significant correlations in the expected direction were observed. For PMQ, Cronbach α was 0.70, indicating excellent intraobserver and interobserver reliability. With respect to criterion validity, strong correlations were observed between the PMQ and the DOCGL. The Rosser classification system showed satisfactory reliability and suitable criterion validity for patients with musculoskeletal disorders. The instrument seems to be suitable for clinical decision making and research.


Bioavailability and single-dose pharmacokinetics of intramuscular phenytoin.
Comparison of phenytoin plasma concentrations in an intravenous and intramuscular crossover study in 12 healthy ambulant, male subjects indicates that phenytoin administered intramuscularly is absorbed over a period of approximately five days. A model simulating precipitation and redissolution of the drug at the injection site has been shown to satisfactorily fit observed plasma concentration data following intramuscular administration. It is proposed that this model will be useful in the selection of an appropriate dosing regimen in situations in which intramuscular administration of phenytoin is indicated.


Acinetobacter baumannii Repeatedly Evolves a Hypermutator Phenotype in Response to Tigecycline That Effectively Surveys Evolutionary Trajectories to Resistance.
The evolution of hypermutators in response to antibiotic treatment in both clinical and laboratory settings provides a unique context for the study of adaptive evolution. With increased mutation rates, the number of hitchhiker mutations within an evolving hypermutator population is remarkably high and presents substantial challenges in determining which mutations are adaptive. Intriguingly however, hypermutators also provide an opportunity to explore deeply the accessible evolutionary trajectories that lead to increased organism fitness, in this case the evolution of antibiotic resistance to the clinically relevant antibiotic tigecycline by the hospital pathogen Acinetobacter baumannii. Using a continuous culture system, AB210M, a clinically derived strain of A. baumannii, was evolved to tigecycline resistance. Analysis of the adapted populations showed that nearly all the successful lineages became hypermutators via movement of a mobile element to inactivate mutS. In addition, metagenomic analysis of population samples revealed another 896 mutations that occurred at a frequency greater than 5% in the population, while 38 phenotypically distinct individual colonies harbored a total of 1712 mutations. These mutations were scattered throughout the genome and affected ~40% of the coding sequences. The most highly mutated gene was adeS, a known tigecycline-resistance gene; however, adeS was not solely responsible for the high level of TGC resistance. Sixteen other genes stood out as potentially relevant to increased resistance. The five most prominent candidate genes (adeS, rpsJ, rrf, msbA, and gna) consistently re-emerged in subsequent replicate population studies suggesting they are likely to play a role in adaptation to tigecycline. Interestingly, the repeated evolution of a hypermutator phenotype in response to antibiotic stress illustrates not only a highly adaptive strategy to resistance, but also a remarkably efficient survey of successful evolutionary trajectories.


Setting the scene: Historical overview of challenges and what led to advances in comprehensive care in developed countries, the Canadian experience.
The history of the development of comprehensive care for hemophilia and other inherited bleeding disorders in Canada has been long and full of challenges. From limited in-patient treatment with plasma and cryoprecipitate in a few major centres in the 1950s and 1960s, a network of Hemophilia Treatment Centres (HTCs) offering multi-disciplinary comprehensive care, home infusion and prophylaxis was established across the country by the late 1970s and early 1980s, only to be shaken by the widespread contamination of factor concentrates with HIV and HCV in the 1970s and 1980s. In recent years the mission of HTCs has expanded to better serve people with von Willebrand disease, rare factor deficiencies and other rare bleeding disorders, and more fully recognize the needs of women with bleeding disorders. In 2020, challenges remain, notably maintaining the resources and expertise in HTCs and gaining access to the latest innovations in treatments.


FAT10 Induces cancer cell migration by stabilizing phosphorylated ABI3/NESH.
The WAVE regulatory complex (WRC) is involved in various cellular processes by regulating actin polymerization. The dysregulation of WRC components is associated with cancer development. ABI family member 3 (ABI3)/new molecule including SH3 (NESH) is one of the WRC components and it has been reported that ABI3 phosphorylation can affect WRC function. Although several residues of ABI3 have been reported to be possible phosphorylation sites, it is still unclear which residues are important for the function of ABI3. Furthermore, it is unclear how the phosphorylated form of ABI3 is regulated. Here, we demonstrate that ABI3 is stabilized by its interaction with human leukocyte antigen-F adjacent transcript 10 (FAT10). Using phospho-dead or phospho-mimetic mutants of ABI3, we showed that serine 213 and 216 are important phosphorylation sites of ABI3. In particular, FAT10 has a higher affinity for the phosphorylated form of ABI3 than the non-phosphorylated form, and it stabilizes the phosphorylated form more than the non-phosphorylated form through this differential affinity. The interaction between FAT10 and the phosphorylated form of ABI3 promoted cancer cell migration. Therefore, our results suggest that FAT10 stabilizes the phosphorylated form of ABI3, which may lead to WRC activation, thereby promoting cancer cell migration.


ENTEROMEGALY AND CARDIOMEGALY IN CHAGAS DISEASE.
Chagas disease due to a trypanosome infection may lead to extensive destruction of ganglion cells in the peripheral autonomic system and may result in gross enlargement of the oesophagus, colon, and heart. From studies on nerve cell counts it is concluded that the number of ganglion cells in the oesophagus must be reduced to less than half to produce functional disturbances in the oesophagus and to one tenth to produce a megaoesophagus. Problems of terminology are discussed.