Oocyte vitrification induces loss of DNA methylation and histone acetylation in the resulting embryos derived using ICSI in dromedary camel.
Oocyte cryopreservation has become an important component of assisted reproductive technology with increasing implication in female fertility preservation and animal reproduction. However, the possible adverse effects of oocyte cryopreservation on epigenetic status of the resulting embryos is still an open question. This study evaluated the effects of MII-oocyte vitrification on gene transcripts linked to epigenetic reprogramming in association with the developmental competence and epigenetic status of the resulting embryos at 2-cell and blastocyst stages in dromedary camel. The cleavage rate of vitrified oocytes following intracytoplasmic sperm injection was significantly increased compared with the control (98.2 ± 2 vs. 72.7 ± 4.1%, respectively), possibly due to the higher susceptibility of vitrified oocytes to spontaneous activation. Nonetheless, the competence of cleaved embryos derived from vitrified oocytes for development to the blastocyst and hatched blastocyst was significantly reduced compared with the control (7.7 ± 1.2 and 11.1 ± 11.1 compared with 28.1 ± 2.6 and 52.4 ± 9.9%, respectively). The relative transcript abundances of epigenetic reprogramming genes DNMT1, DNMT3B, HDAC1, and SUV39H1 were all significantly reduced in vitrified oocytes relative to the control. Evaluation of the epigenetic marks showed significant reductions in the levels of DNA methylation (6.1 ± 0.3 vs. 9.9 ± 0.5, respectively) and H3K9 acetylation (7.8 ± 0.2 vs. 10.7 ± 0.3, respectively) in 2-cell embryos in the vitrification group relative to the control. Development to the blastocyst stage partially adjusted the effects that oocyte vitrification had on the epigenetic status of embryos (DNA methylation: 4.9 ± 0.4 vs. 6.2 ± 0.6; H3K9 acetylation: 5.8 ± 0.3 vs. 8 ± 0.9, respectively). To conclude, oocyte vitrification may interfere with the critical stages of epigenetic reprogramming during preimplantation embryo development.


Representing dynamic biological networks with multi-scale probabilistic models.
Dynamic models analyzing gene regulation and metabolism face challenges when adapted to modeling signal transduction networks. During signal transduction, molecular reactions and mechanisms occur in different spatial and temporal frames and involve feedbacks. This impedes the straight-forward use of methods based on Boolean networks, Bayesian approaches, and differential equations. We propose a new approach, ProbRules, that combines probabilities and logical rules to represent the dynamics of a system across multiple scales. We demonstrate that ProbRules models can represent various network motifs of biological systems. As an example of a comprehensive model of signal transduction, we provide a Wnt network that shows remarkable robustness under a range of phenotypical and pathological conditions. Its simulation allows the clarification of controversially discussed molecular mechanisms of Wnt signaling by predicting wet-lab measurements. ProbRules provides an avenue in current computational modeling by enabling systems biologists to integrate vast amounts of available data on different scales.


Relationship between noninvasive coronary angiography with multi-slice computed tomography and myocardial perfusion imaging.
The aim of this study was to perform a head-to-head comparison between multi-slice computed tomography (MSCT) and myocardial perfusion imaging (MPI) in patients with an intermediate likelihood of coronary artery disease (CAD) and to compare non-invasive findings to invasive coronary angiography. Multi-slice computed tomography detects atherosclerosis, whereas MPI detects ischemia; how these 2 techniques compare in patients with an intermediate likelihood of CAD is unknown. A total of 114 patients, mainly with intermediate likelihood of CAD, underwent both MSCT and MPI. The MSCT studies were classified as having no CAD, nonobstructive (<50% luminal narrowing) CAD, or obstructive CAD. Myocardial perfusion imaging examinations were classified as showing normal or abnormal (reversible and/or fixed defects). In a subset of 58 patients, invasive coronary angiography was performed. On the basis of the MSCT data, 41 patients (36%) were classified as having no CAD, of whom 90% had normal MPI. A total of 33 patients (29%) showed non-obstructive CAD, whereas at least 1 significant (> or =50% luminal narrowing) lesion was observed in the remaining 40 patients (35%). Only 45% of patients with an abnormal MSCT had abnormal MPI; even in patients with obstructive CAD on MSCT, 50% still had a normal MPI. In the subset of patients undergoing invasive angiography, the agreement with MSCT was excellent (90%). Myocardial perfusion imaging and MSCT provide different and complementary information on CAD, namely, detection of atherosclerosis versus detection of ischemia. As compared to invasive angiography, MSCT has a high accuracy for detecting CAD in patients with an intermediate likelihood of CAD.


How glutaminyl-tRNA synthetase selects glutamine.
Aminoacyl-tRNA synthetases covalently link a specific amino acid to the correct tRNA. The fidelity of this reaction is essential for accurate protein synthesis. Each synthetase has a specific molecular mechanism to distinguish the correct pair of substrates from the pool of amino acids and isologous tRNA molecules. In the case of glutaminyl-tRNA synthetase (GlnRS) the prior binding of tRNA is required for activation of glutamine by ATP. A complete understanding of amino acid specificity in GlnRS requires the determination of the structure of the synthetase with both tRNA and substrates bound. A stable glutaminly-adenylate analog, which inhibits GlnRS with a Ki of 1.32 microM, was synthesized and cocrystallized with GlnRS and tRNA2Gln. The crystal structure of this ternary complex has been refined at 2.4 A resolution and shows the interactions made between glutamine and its binding site. To select against glutamic acid or glutamate, both hydrogen atoms of the nitrogen of the glutamine sidechain are recognized. The hydroxyl group of Tyr211 and a water molecule are responsible for this recognition; both are obligate hydrogen-bond acceptors due to a network of interacting sidechains and water molecules. The prior binding of tRNAGln that is required for amino acid activation may result from the terminal nucleotide, A76, packing against and orienting Tyr211, which forms part of the amino acid binding site.


Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons.
Lead is a persistent environmental pollutant and exposure to high environmental levels causes various deleterious toxicities, especially to the central nervous system (CNS). The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor that is devoid of the glutamate receptor 2 (GluR2) subunit is Ca2+-permeable, which increases the neuronal vulnerability to excitotoxicity. We have previously reported that long-term exposure of rat cortical neurons to lead acetate induces decrease of GluR2 expression. However, it is not clarified whether lead-induced GluR2 decrease is involved in neurotoxicity. Therefore, we investigated the contribution of GluR2 non-containing AMPA receptor to lead-induced neurotoxic events. Although the expression of four AMPA receptor subunits (GluR1, GluR2, GluR3, and GluR4) was decreased by lead exposure, the decrease in GluR2 expression was remarkable among four subunits. Lead-induced neuronal cell death was rescued by three glutamate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a non-selective AMPA receptor blocker), MK-801 (N-methyl-D-aspartate (NMDA) receptor blocker), and 1-naphthyl acetyl spermine (NAS, a specific Ca2+-permeable AMPA receptor blocker). Lead exposure activated extracellular signal-regulated protein kinase (ERK) 1/2, which was significantly ameliorated by CNQX. In addition, lead exposure activated p38 mitogen-activated protein kinase (MAPK p38), and protein kinase C (PKC), which was partially ameliorated by CNQX. Our findings indicate that Ca2+-permeable AMPA receptors resulting from GluR2 decrease may be involved in lead-induced neurotoxicity.


Genome Editing of Human Primary Keratinocytes by CRISPR/Cas9 Reveals an Essential Role of the NLRP1 Inflammasome in UVB Sensing.
By forming a protective barrier, epidermal keratinocytes represent the first line of defense against environmental insults. UVB radiation of the sun is a major challenge for the skin and can induce inflammation, aging, and eventually skin cancer. UVB induces an immune response in human keratinocytes resulting in activation and secretion of the proinflammatory cytokines proIL-1β and -18. This is mediated by an assembly of protein complexes, termed inflammasomes. However, the mechanisms underlying sensing of UVB by keratinocytes, and particularly the types of inflammasomes required for cytokine secretion, are a matter of debate. To address these questions, we established a protocol that allows the generation of CRISPR/Cas9-targeted human primary keratinocytes. Our experiments showed an essential role of the NLRP1 rather than the NLRP3 inflammasome in UVB sensing and subsequent IL-1β and -18 secretion by keratinocytes. Moreover, NLRP1 but not NLRP3 was required for inflammasome activation in response to nigericin, a potassium ionophore and well-established NLRP3 activator in immune cells. Because the CRISPR/Cas9-targeted cells retained their full differentiation capacity, genome editing of human primary keratinocytes might be useful for numerous research and medical applications.


[Trapping of large and giant paraclinoid aneurysm based on intraoperative flowmetry test].
Four cases of giant or large paraclinoid aneurysms of the internal carotid artery successfully trapped after assessing blood flow using a flowmeter are presented. In all cases, the initial plan for clipping was changed to aneurysm trapping due to various reasons. The collateral blood flow was assessed using the flowmetry test, the original procedure of measuring volumetric blood flow in the middle cerebral artery using an ultrasonic flowmeter. We analyze the reasons for clipping refusal, the procedure of measuring blood flow, treatment outcomes, and catamnestic data. The risks of reconstructive surgeries involving the internal carotid artery are discussed and the literature data are analyzed. Conclusions. Ultrasonic flowmetry is a simple and safe method for intraoperative control over blood circulation, which may play the key role in complicated surgical cases.


Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias.
The MLL-partial tandem duplication (PTD) associates with high-risk cytogenetically normal acute myeloid leukemia (AML). Concurrent presence of FLT3-internal tandem duplication (ITD) is observed in 25% of patients with MLL-PTD AML. However, mice expressing either Mll-PTD or Flt3-ITD do not develop AML, suggesting that 2 mutations are necessary for the AML phenotype. Thus, we generated a mouse expressing both Mll-PTD and Flt3-ITD. Mll(PTD/WT):Flt3(ITD/WT) mice developed acute leukemia with 100% penetrance, at a median of 49 weeks. As in human MLL-PTD and/or the FLT3-ITD AML, mouse blasts exhibited normal cytogenetics, decreased Mll-WT-to-Mll-PTD ratio, loss of the Flt3-WT allele, and increased total Flt3. Highlighting the adverse impact of FLT3-ITD dosage on patient survival, mice with homozygous Flt3-ITD alleles, Mll(PTD/WT):Flt3(ITD/ITD), demonstrated a nearly 30-week reduction in latency to overt AML. Here we demonstrate, for the first time, that Mll-PTD contributes to leukemogenesis as a gain-of-function mutation and describe a novel murine model closely recapitulating human AML.


Apathy syndrome treated successfully with modafinil.
The treatment of apathy is often complicated and difficult. The authors present a case of apathy syndrome that was treated successfully with modafinil. An 87-year-old widowed Brazilian woman presented with loss of interest and pleasure in activities. Her level of apathy, as evaluated by the Brazilian care giver version of the apathy scale, was 25 (a score higher than 18 points is associated with an apathy syndrome). No diagnosis of depression or sleep disorder was noted. After 2 years with many different antidepressants, modafinil treatment was started at 100 mg/day. One month after the initiation of modafinil therapy, the patient reported feeling more motivation, and she also returned to her favorite physical activity, which was swimming (400 m/day). Apathy scale revealed an improvement (18 points). Actigraphic analysis was performed, and no sleep disturbances were noted before or after treatment. Modafinil may be a promising option in the treatment of apathy.


In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer.
Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein-protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.


Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression.
Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40-120 mg/day) with placebo for 8-9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (< or =19; n=682), moderate (n=1099), or severe (> or =25; n=446) groups. Duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in all three cohorts. Significant improvement was seen in HAMD17 items 1 (depressed mood), 3 (suicide), 7 (work and activities), and 10 (psychic anxiety) regardless of severity. The HAMD17 anxiety subscale and items 13 (somatic symptoms-general) and 15 (hypochondriasis) showed significant improvement only in moderately and severely ill patients. Significant improvement in the HAMD17 Maier subscale was seen in all groups by week 1. In all three groups, placebo was significantly superior to duloxetine at early visits on HAMD17 item 12 (somatic symptoms-GI). Mildly and severely ill patients exhibited significant reduction in visual analog scale overall pain severity at the study endpoint. The studies contained fewer patients with very mild or very severe illness, limiting our ability to draw conclusions in these patient populations. Duloxetine demonstrated superior efficacy in the treatment of major depressive disorder, when compared with placebo, regardless of the baseline severity of depressive symptoms, although effect sizes were largest in the most severely depressed patients.


Diabetes diminishes the portal-systemic collateral vascular response to vasopressin via vasopressin receptor and Gα proteins regulations in cirrhotic rats.
Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP) in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL)-induced cirrhosis received vehicle (citrate buffer) or streptozotocin (diabetic, BDL/STZ). The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist) and overcome by NaF (a G protein activator). The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation.


New techniques and devices for difficult airway management.
The purpose of this review is to compare old conventional techniques and devices for difficult airway management and new sophisticated techniques and devices. Recent techniques and devices are defined as the American Society of Anesthesiology (ASA) practice guidelines for the management of difficult airway, published in 1992, reviewed in 1993 and updated in 2003. According to ASA, the techniques for difficult airway management are divided into techniques for difficult intubation and techniques for difficult ventilation. Awake fiberoptic intubation is the technique of choice for difficult airway management prescribed by the World Health Organization document for patient safety in the operating theater. Conventional techniques for intubation used direct visualization. The new generation of devices does not require direct visualization of the vocal cords for endotracheal tube placement. They allow better glottis view and successful endotracheal placement of the tube with indirect laryngoscopy. New intubation devices such as video laryngoscopes facilitate endotracheal intubation by indirect visualization of glottis structures without aligning the oral, pharyngeal and laryngeal axes in patients with cervical spine abnormality. Video laryngoscopes such as V-Mac and C-Mac, Glide scope, McGrath, Airway Scope, Airtraq, Bonfils and Bullard laryngoscope are widely available at the market. Airway gadgets are lighted stylets and endotracheal tube guides. The principal conclusion of this review is that utilization of these devices can be easily learned. The technique of indirect laryngoscopy is currently used for managing difficult airway in the operating room as well as for securing the airway in daily anesthesia routine.


Mn(II) sub-nanometric site stabilization in noble, N-doped carbonaceous materials for electrochemical CO2 reduction.
The preparation of stable and efficient electrocatalysts comprising abundant and non-critical row-materials is of paramount importance for their industrial implementation. Herein, we present a simple synthetic route to prepare Mn(II) sub-nanometric active sites over a highly N-doped noble carbonaceous support. This support not only promotes a strong stabilization of the Mn(II) sites, improving its stability against oxidation, but also provides a convenient coordination environment in the Mn(II) sites able to produce CO, HCOOH and CH3COOH from electrochemical CO2 reduction.


Amino acid sensing mechanisms: an Achilles heel in cancer?
The act of increasing mass, either in non-dividing cells or in dividing cells seeking to provide new material for daughter cells, depends upon the continued presence of extracellular nutrients in order to conserve mass. For amino acid nutrients, it appears that their insufficiency for new protein synthesis is actively monitored by both prokaryotic and eukaryotic cells, eliciting appropriate cellular responses that may depend not only on bulk nutrient supply, but also on the abundance of specific amino acids.


Thanatophoric dwarfism in a Nigerian child.
We describe a lethal variety of congenital short-limbed dwarfism (Thanatophoric dwarfism) characterized by marked shortening of the extremities, macrocephaly with associated hydrocephalus and a narrow thorax, delivered by a 25-year-old woman in our hospital. Experience with this form of abnormality is rare and even an isolated case report will heighten awareness and assist with further management and counselling of parents.


Drugs for hypertension. Seven classes to choose from.
A wide variety of drugs are available for treatment of hypertension. Diuretics, long the sole therapy, can control blood pressure in more than 40% of patients. If a diuretic alone proves inadequate, a beta-adrenergic blocking agent, vasodilator, and central-acting sympathetic inhibitor may be added, as needed, in the familiar four-step program. A calcium channel blocker, with its vasodilating effects, or an angiotensin-converting enzyme inhibitor may be considered in appropriate situations. Selection among these agents should be based on knowledge of their pharmacologic action, duration of action, and side effects. With careful selection, blood pressure can be better controlled, side effects minimized, and patient compliance improved.


The distribution of TPX2 in dividing leaf cells of the fern Asplenium nidus.
Plant cell division requires the dynamic organisation of several microtubule arrays. The mechanisms of regulation of the above arrays are under rigorous research. Among several factors that are involved in plant microtubule dynamics, the Targeting Protein for Xklp2 (TPX2) has been found to play a role in spindle organisation, in combination with Aurora kinases, in dividing cells of angiosperms. Microtubule organisation in dividing cells of ferns exhibits certain peculiarities. Accordingly, the presence and distribution of a TPX2 homologue might be helpful in understanding the patterns and regulatory mechanisms of microtubule arrays in this plant group. In this study, a putative TPX2 homologue was identified using Western blotting in the fern Asplenium nidus. It was found, using immunostaining and CLSM, that it is co-localised with perinuclear preprophase microtubules and the prophase spindle, and follows the microtubule pattern during metaphase/anaphase and telophase. During cytokinesis, while in angiosperms TPX2 is degraded, in A. nidus the TPX2 signal persists, co-localising with the phragmoplast. In early post-cytokinetic cells, a TPX2 signal is present on the nuclear surface facing the daughter cell wall and, thereafter it is co-localised with the fern-specific microtubule aggregation that lines the new wall, which is possibly involved in cortical microtubule assembly.


Fibronectin in human hepatocellular carcinoma (HCC) and HCC cell lines.
The localization of fibronectin (FN) in human hepatocellular carcinoma (HCC) was studied in thirty-six HCC tumors (19 autopsy and 17 surgical specimens), two xenografted tumors of HCC to BALB/c mice and three HCC cell lines. The synthesis of FN was also examined in three HCC cell lines. FN was demonstrated on the endothelial surface of the blood spaces of cancerous tissue. Cytoplasmic and intercellular localization of FN was also observed. But there was no correlation between the localization pattern of FN and metastasis. In the two xenografted HCC tumors, FN was found in association with the blood vessels of the tumor tissue and between the HCC tumor cells. In all 3 HCC cell lines, FN was localized on the surface and in the cytoplasm of some HCC cells. FN was detected in the serum-free culture media of three HCC cell lines by immunoelectroblotting. The electrophoretic pattern of FN synthesized by these cell lines was different from that of plasma-FN and resembled that of cellular-FN synthesized by normal liver fibroblasts.


Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation.
Epileptogenesis is a common consequence of brain insults, however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy (TLE), and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3 g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.


Lavandula angustifolia mill. (Lamiaceae) ethanol extract and its main constituents as promising agents for the treatment of metabolic disorders: chemical profile, in vitro biological studies, and molecular docking.
Lavandula angustifolia Mill. (lavender) is one of the most used medicinal plants. Herein, we chemically characterised and investigated the antioxidant properties and the capability to inhibit key enzymes for the treatment of type 2 diabetes (TD2) and obesity such as pancreatic lipase, α-glucosidase, and α-amylase of the ethanolic extract of two lavender samples (La1 and La2) from southern Italy. Both extracts significantly inhibited α-glucosidase, while La1 inhibited α-amylase and lipase more effectively than La2. To investigate whether these properties could be due to a direct interaction of the main constituents of the extracts with the targeted enzymes, molecular docking studies have been performed. As a result, the selected compounds were able to interact with the key residues of the binding site of the three proteins, thus supporting biological data. Current findings indicate the new potential of lavender ethanolic extract for the development of novel agents for T2D and obesity.


Comprehensive Geriatric Assessment in the era of telemedicine.
The aging global population poses significant medical and social challenges, necessitating efforts to promote healthy aging. Comprehensive Geriatric Assessment (CGA) is a multidimensional diagnostic approach for older adults that aims to improve overall health. Remote CGA, facilitated by technological advancements, offers convenience and other potential advantages. It enables early disease detection, monitors chronic disease progression, delivers personalized care, and optimizes healthcare resources for better health outcomes in older individuals. However, remote CGA also has limitations, including technological requirements, data security, and the need for comprehensive evaluation and simplicity. Collaborative efforts are essential to developing a digital home-based CGA platform that addresses accessibility issues and tailors the assessment process to meet the needs of older adults. Continuous optimization of remote CGA can become a pivotal tool for advancing geriatric care and ensuring the well-being of the aging population. Geriatr Gerontol Int 2023; ••: ••-••.


Cisplatin and Vinorelbine -Mediated Electrochemotherapeutic Approach Against Multidrug Resistant Small Cell Lung Cancer (H69AR) In Vitro.
Small cell lung cancer (SCLC) originates from neuroendocrine branchial cells (15-20%). It is regarded as distinct from other lung cancers due to its biological and clinical features. In most cases of SCLC, surgery or radiotherapy alone is not an effective cure. The aim of our study was to examine the cytotoxic effects of chemotherapy supported by electroporation (EP) on a resistant SCLC model, in vitro. The multidrug resistant small lung cell line H69AR was used to evaluate the cytotoxic effects of cisplatin (CPPD) and vinorelbine (Navirel®; NAV) at lower doses when used with EP. Cells were treated with different concentrations of CPPD and NAV, alone or in combination with the following EP parameters: 400-1200 V/cm, 8 pulses of 100 μs duration, at 1Hz. The cell viability was estimated by MTT assay after 24 and 48 h. Apoptotic cells were detected by neutral comet assay and immunofluorescence assay with PARP-6. CPPD and NAV alone showed a dose-dependent effect on cell viability. Cytostatic drugs combined with EP revealed increased anticancer activity. Lower doses of CPPD or NAV delivered by EP were as effective as higher doses of these drugs without EP. The electrochemotherapeutic protocols increased the number of apoptotic cells and increased immunoreactivity of PARP-6. Our results indicated higher sensitivity of H69AR cells to NAV supported by EP. In SCLC cells, an increased anticancer activity was potentiated by exposure of cells to high intensity electric pulses and low drug doses. It is suggested that this method could be effectively applied in the treatment of lung cancer.


Immune Responses in Cecal Tonsils of Marek's Disease Virus-Infected Chickens.
Marek's disease (MD) is a lymphoproliferative disease of domestic chickens that is caused by a highly cell-associated oncogenic α-herpesvirus, Marek's disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. Clinical signs of MD include depression, crippling, weight loss, bursal/thymic atrophy, neurologic disorders, and rapid onset of T cell lymphomas that infiltrate lymphoid tissues, visceral organs, and peripheral nerves. The cecal tonsils (CTs) are considered the largest lymphoid aggregates of avian gut-associated lymphoid tissue. Along with Peyer's patches, CTs elicit protective immune responses against bacterial and viral pathogens in the intestinal tract of avian species. In this study, we investigated the effect of MDV infection on toll-like receptor (TLR) gene expression in CTs of MD-susceptible (72) and resistant (63) chicken lines. Real-time PCR gene expression profiling revealed that of the 10 TLRs tested, TLR2A, TLR3, TLR5, and TLR15 displayed significant differential expression patterns at different time points postinoculation. The expression levels of the remaining six genes were minimally affected by MDV infection in either line. Immunohistochemical analysis showed a severe depletion of B cells and CD4+ T cells in the CTs of susceptible line at 5 days postinfection (dpi), which recovered by 21 dpi. The destruction of B and T cells in the CTs of the resistant line was minimal at 5 dpi, which also recovered by 21 dpi. A significant infiltration of macrophages was observed after the depletion of B and T cells in the infected birds of both lines that could account for the differential TLR gene expression in the infected birds. The data presented provide further insight into the mechanism of MDV pathogenesis and tissue-specific immunologic responses to viral infection.


eHealth provides a novel opportunity to exploit the advantages of the Nordic countries in psychiatric genetic research, building on the public health care system, biobanks, and registries.
Nordic countries have played an important role in the recent progress in psychiatric genetics, both with large well-characterized samples and expertise. The Nordic countries have research advantages due to the organization of their societies, including system of personal identifiers, national health registries with information about diseases, treatment and prescriptions, and a public health system with geographical catchment areas. For psychiatric genetic research, the large biobanks and population surveys are a unique added value. Further, the population is motivated to participate in research, and there is a trust in the institutions of the society. These factors have been important for Nordic contributions to biomedical research, and particularly psychiatric genetics. In the era of eHealth, the situation seems even more advantageous for Nordic countries. The system with public health care makes it easy to implement national measures, and most of the Nordic health care sector is already based on electronic information. The potential advantages regarding informed consent, large scale recruitment and follow-up, and longitudinal cohort studies are tremendous. New precision medicine approaches can be tested within the health care system, with an integrated approach, using large hospitals or regions of the country as a test beds. However, data protection and legal framework have to be clarified. In order to succeed, it is important to keep the people's trust, and maintain the high ethical standards and systems for secure data management. Then the full potential of the Nordic countries can be leveraged in the new era of precision medicine including psychiatric genetics.


Natural polymorphisms of integrase among HIV type 1-infected South African patients.
An HIV-1 subtype C specific assay was established for integrase genotyping from 51 integrase inhibitor-naive patient plasma samples and 22 antiretroviral drug-naive primary viral isolates from South Africa. Seventy-one of the 73 samples were classified as HIV-1 subtype C and two samples were unique AC and CG recombinants in integrase. Amino acid sequence analysis revealed there were no primary mutations (Y143R/C/H, Q148H/R/K, and N155H/S) associated with reduced susceptibility to the integrase inhibitors raltegravir and elvitegravir. However, one sample had the T97A mutation, three samples had the E157Q and V165I mutations, and the majority of samples contained the polymorphic mutation V72I. The expected finding of no major integrase mutations conferring resistance to integrase inhibitors suggests that this new antiretroviral drug class will be effective in our region where HIV-1 subtype C predominates. However, the impact of E157Q and other naturally occurring polymorphisms warrants further phenotypic investigation.


Intraoperative retrograde type I aortic dissection in a patient with chronic type IIIb dissecting aneurysm.
Iatrogenic acute aortic dissection of the ascending aorta during cardiac surgery is a rare but potentially fatal complication. We describe the emergency repair of iatrogenic acute aortic dissection of the ascending aorta during distal arch replacement in a patient with a chronic type IIIb dissecting aneurysm. We scheduled distal arch and descending aortic aneurysm repair through a left anterolateral thoracotomy with a femoro-femoral bypass. While trimming the proximal suture line, retrograde aortic dissection occurred from the cross-clamped site to the aortic root. Transesophageal echocardiography revealed aortic dissection at the ascending aorta. As soon as the additional median sternotomy was established, the ascending aorta was transected and antegrade selective cerebral perfusion was applied without waiting for further cooling. Total arch replacement with descending aortic and root replacements then proceeded. The patient recovered uneventfully after extensive surgical replacement of the thoracic aorta and remains asymptomatic at two years after the procedure. To prevent possible neurological complications, this patient was managed by selective antegrade cerebral perfusion at 31 degrees C because we could not afford to wait for the induction of deep hypothermia. Successful management of iatrogenic acute aortic dissection depends on immediate recognition and the appropriate choice of surgical repair.


The Application of Gas Dwell Time Control for Rapid Single Wall Carbon Nanotube Forest Synthesis to Acetylene Feedstock.
One aspect of carbon nanotube (CNT) synthesis that remains an obstacle to realize industrial mass production is the growth efficiency. Many approaches have been reported to improve the efficiency, either by lengthening the catalyst lifetime or by increasing the growth rate. We investigated the applicability of dwell time and carbon flux control to optimize yield, growth rate, and catalyst lifetime of water-assisted chemical vapor deposition of single-walled carbon nanotube (SWCNT) forests using acetylene as a carbon feedstock. Our results show that although acetylene is a precursor to CNT synthesis and possesses a high reactivity, the SWCNT forest growth efficiency is highly sensitive to dwell time and carbon flux similar to ethylene. Through a systematic study spanning a wide range of dwell time and carbon flux levels, the relationship of the height, growth rate, and catalyst lifetime is found. Further, for the optimum conditions for 10 min growth, SWCNT forests with ~2500 μm height, ~350 μm/min initial growth rates and extended lifetimes could be achieved by increasing the dwell time to ~5 s, demonstrating the generality of dwell time control to highly reactive gases.


Privacy and disclosure in medical genetics examined in an ethics of care.
The progress of genetic knowledge magnifies existing ethical problems in medical genetics. Among the most troubling types of problems -- for medicine, patients, and the larger society -- are those of privacy and disclosure. Examples of the range of problems involving privacy and disclosure are: 1) disclosure of false paternity to an unsuspecting husband; 2) disclosure of a patient's genetic make-up to his or her unknowing spouse; 3) disclosure of information, against a patient's wishes, to relatives at genetic risk; 4) disclosure of ambiguous test results; 5) disclosure of adventitious nonmedical information, e.g., fetal sex; and 6) disclosure to institutional third parties, such as employers and insurers....


Synthetic musk fragrances in Lake Erie and Lake Ontario sediment cores.
Two sediment cores collected from Lake Ontario and Lake Erie were sectioned, dated, and analyzed for five polycyclic musk fragrances and two nitro musk fragrances. The polycyclic musk fragrances were HHCB (Galaxolide), AHTN (Tonalide), ATII (Traseolide), ADBI (Celestolide), and AHMI (Phantolide). The nitro musk fragrances were musk ketone and musk xylene. Chemical analysis was performed by gas chromatography/mass spectrometry (GC/MS), and results from Lake Erie were confirmed using gas chromatography/triple-quadrupole mass spectrometry (GC/MS/MS). The chemical signals observed at the two sampling locations were different from each other primarily because of large differences in the sedimentation rates at the two sampling locations. HHCB was detected in the Lake Erie core whereas six compounds were detected in the Lake Ontario core. Using measured fragrance and 210Pb activity, the burden of synthetic musk fragrances estimated from these sediment cores is 1900 kg in Lake Erie and 18 000 kg in Lake Ontario. The input of these compounds to the lakes is increasing. The HHCB accumulation rates in Lake Erie for 1979-2003 and 1990-2003 correspond to doubling times of 16 +/- 4 and 8 +/- 2 years, respectively. The results reflect current U.S. production trends for the sum of all fragrance compounds.


[Construction and primary application of two HBV-HLA-A*2402-peptide tetramers].
To construct two soluble HLA-A*2402-peptide tetramers and detect the HBV-specific cytotoxic T lymphocytes (CTLs) with the constructed HLA-A*2402-peptide tetramers. After proteins HLA-A*2402-BSP and beta2m were made an effective prokanyotical expression, the purified proteins were refolded into HLA-A*2402-beta2m-peptide complexes in the presence of two antigenic peptides (Hepatitis B virus Pol756-764 or Core117-125) with dilution method. Then the complexes were biotinylated by BirA enzyme and purified by gel-filtration chromatography. The tetramers were generated by mixing the complex with PE-Streptavidin in the molar ratio of 5:1. FCM can and cell quest software were used to analyze the stained PBMCs. Two biotinylated HBV-HLA-A*2402-peptide complexes were identified by Western blot and they were shown to have natural conformation by Dot-ELISA and ELISA. The constructed HLA-A*2402-peptide tetramers can detect the HBV-specific CTLs in the patients with self-limited acute HBV infection.


An exploratory study of industry perspectives to inform undergraduate nutrition employability initiatives.
The aim of this study was to explore nutrition professionals' perspectives of nutrition graduates' employability skills, and knowledge and skills required in the industry to understand gaps in undergraduate nutrition curriculum. Nutrition professionals (n = 26) across Australia were approached to participate in semi-structured interviews via telephone in 2018. Interviews were transcribed verbatim, data analysed using thematic analysis, and results interpreted and discussed. Nine participants across six work environments completed interviews. Common work roles were identified in their diverse areas of practice: nutrition educators, food developers, team members, and business leaders. Nutrition professionals identified that, in addition to evidence-based discipline knowledge, key skills and knowledge needed for their roles were interpersonal communication, including writing and listening. Participants highlighted the need for employability skills to be embedded within curriculum with emphasis on professional skills, business skills and discipline-specific skills in communicating complex science messages to a range of audiences. Networking, and formal and informal work-integrated learning were viewed as important vehicles for developing required skills. Participants expected that universities develop curriculum to address gaps; however, reflection by the academic researchers suggested this should be a joint role. Early career planning, professional skill development, work experience and networking opportunities should enhance graduate employability.


Heterogeneity of the arterial tree in essential hypertension: a noninvasive study of the terminal aorta and the common carotid artery.
The diameter and the stiffness of the distal portion of the abdominal aorta and of the common carotid artery were evaluated noninvasively in 72 subjects with mild to moderate hypertension by comparing 39 normotensive controls of same age and sex distribution. For each arterial segment, pulsatile changes of diameter were determined by a newly described echotracking technique and pulse pressure was evaluated by applanation tonometry and oscillometric methods. In both territories, distensibility of hypertensive subjects was significantly reduced but compliance was reduced only at the aortic level. Diastolic diameter was increased at the carotid but not at the aortic site. Multiple regression analysis indicated that whereas compliance and distensibility were strongly influenced by BP in the terminal aorta, age was the predominant factor influencing carotid arterial stiffness. Following 30 days of converting enzyme inhibition, the decrease of BP was associated with a normalisation of aortic compliance and distensibility whereas no change was observed at the site of the carotid artery. The study provides evidence that the response of the arteries to the changes of BP differ in the various parts of the arterial tree. This factor may influence the drug effect produced by chronic converting enzyme inhibition.


Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor.
Prospective epidemiologic studies indicate that the risk for advanced prostate cancer is increased among men with high levels of serum calcium. Because serum calcium levels are influenced by the calcium-sensing receptor (CaSR), we examined prostate cancer in African-American men in relation to three single nucleotide polymorphisms (SNPs) in the CaSR gene, A986S, R990G and Q1011E. This is the first study of CaSR polymorphisms and risk of prostate cancer. The CaSR genotypes were not associated with prostate cancer overall. However, we observed significant heterogeneity by disease stage for the Q1011E polymorphism (p = 0.02). Advanced cases were significantly less likely than controls or localized cases to be homozygous for the minor allele of the Q1011E polymorphism (1 vs. 5%). Cases with advanced disease were six times less likely to carry two copies of the minor allele than were controls (OR = 0.16, p = 0.02) or localized cases (OR = 0.15, p = 0.01) and were significantly older at diagnosis (68.8 ± 5.7 vs. 64.0 ± 9.0 y for the QQ and EE genotypes, p = 0.004). We genotyped three CaSR SNPs for 458 African-American prostate cancer cases and 248 controls from a population-based case-control study, the California Collaborative Prostate Cancer Study. The CaSR Q1011E minor allele, which is common in populations with African ancestry, may be associated with a less aggressive form of prostate cancer among African-American men.


Impact of morbid obesity in surgical management of endometrial cancer: surgical morbidity, clinical and pathological aspects.
To evaluate the effect of body mass index (BMI) on clinical, surgical, pathologic features, and surgical morbidity in the management of patients with endometrial cancer. All endometrial cancer patients who were surgically treated in our institution between January 1, 2003 and January 1, 2006 were eligible for the study. Forty-two out of 60 patients were included in the analysis from our cancer database. The patients were divided into three groups: BMI < 30, BMI 30-40, BMI > 40. Statistical analysis was performed by SPSS for Windows (version 11; SPSS, Inc., Chicago, IL). Lymphadenectomy as part of surgical staging was performed in 90.5% of all patients. Although patients with a BMI > 40 were less likely to have positive lymph vascular space invasion (LVSI) (p = 0.042), chance of deep myometrial invasion and positive lymph nodes (18%) were the same as for patients with a BMI < 30. Patients with a BMI > 40 had statistically longer operating times when compared to patients with a BMI < 40 (p = 0.039). Wound separation rate was statistically higher in the morbidly obese patients (p = 0.01). Average number of lymph nodes removed, hospital days, intraoperative and overall postoperative complication rates did not differ among the three groups (p > 0.05). This study confirms that comprehensive surgical staging can be performed adequately and safely in obese and morbidly obese endometrial cancer patients with no difference in length of hospital stay, intraoperative or postoperative complications. As a result adjuvant treatment of morbidly obese patients can be planned accordingly preventing under or over treatment.


Cellular expression of eve1 suggests its requirement for the differentiation of the ameloblasts and for the initiation and morphogenesis of the first tooth in the zebrafish (Danio rerio).
even-skipped-related (evx) genes encode homeodomain-containing transcription factors that are involved in a series of developmental processes such as posterior body patterning and neurodifferentiation. Although evx1 and evx2 were not reported to be expressed during mammalian tooth development, we present here evidence that eve1, the closest paralog of evx1 in the actinopterygian lineage, is expressed during pharyngeal tooth formation in the zebrafish, Danio rerio. We have performed whole-mount in situ hybridization on zebrafish embryos and larvae ranging from 24 to 192 hours postfertilization (hpf). A detailed analysis of serial sections through the pharyngeal region of whole-mount hybridized and control specimens indicates that only dental epithelial cells express eve1. eve1 transcription was activated at 48 hpf, in the placode of the first tooth (i.e., the initiation site of tooth 4V(1)), and maintained in the dental epithelium throughout morphogenesis. Then, by 72 hpf, eve1 expression was restricted to the differentiating ameloblasts of the enamel organ during early differentiation stage, and this expression decreased as soon as matrix was deposited. In subsequent primary teeth (3 V(1) and 5 V(1)) as well as in their successors (replacement teeth 4V(2), 3V(2), and 5V(2)), eve1 expression was restricted to the differentiating ameloblasts and, again, disappeared when matrix was deposited. Therefore, in the zebrafish, eve1 expression in the pharyngeal region is correlated with two key steps of tooth development: initiation and morphogenesis of the first tooth, and ameloblast differentiation of all developing teeth.


Glutathione and glutathione S-transferases in human squamous cell carcinomas of the larynx and GSTM1 dependent risk.
The aim of the present study was to establish the risk of squamous cell carcinoma (SCC) of the larynx associated with the congenital absence of glutathione S-transferase M1 (GSTM1), and to describe the expression of the isoenzymes GSTA1/2, GSTP1-1, and GSTM1 and glutathione (GSH) content in healthy and tumoral larynx tissue. Blood samples from 160 SCC male patients and 158 controls were phenotyped for GSTM1 by ELISA. Using 37 paired samples (normal and tumour specimens) from cancer patients we carried out a descriptive study of enzyme activity by ELISA (GSTs) and Ellman's as say (GSH) RESULTS: GSTM1 null phenotype was more common in the SCC group than in controls (OR 1.9, CIs 1.18-3.05, p = 0.004). Total GST activity was higher in tumour samples than in matched healthy tissue (2.2-fold, p-0.00001), being largely determined by GSTP1-1 (1.9-fold increased in malignant tissue; p = 0.0003). The GSH content was also significantly higher in SCC than in normal mucosa (1.9-fold, p = 0.0007). We confirmed the GSTM1-dependent risk for larynx cancer among smokers. The overexpression of the GST/GSH system in tumours reported here indicates their possible role in chemoresistance to pharmacological therapy.


Characterization of a C-Terminal SUMO-Interacting Motif Present in Select PIAS-Family Proteins.
The human PIAS proteins are small ubiquitin-like modifier (SUMO) E3 ligases that participate in important cellular functions. Several of these functions depend on a conserved SUMO-interacting motif (SIM) located in the central region of all PIAS proteins (SIM1). Recently, it was determined that Siz2, a yeast homolog of PIAS proteins, possesses a second SIM at its C terminus (SIM2). Sequence alignment indicates that a SIM2 is also present in PIAS1-3, but not PIAS4. Using biochemical and structural studies, we demonstrate PIAS-SIM2 binds to SUMO1, but that phosphorylation of the PIAS-SIM2 or acetylation of SUMO1 alter this interaction in a manner distinct from what is observed for the PIAS-SIM1. We also show that the PIAS-SIM2 plays a key role in formation of a UBC9-PIAS1-SUMO1 complex. These results provide insights into how post-translational modifications selectively regulate the specificity of multiple SIMs found in the PIAS proteins by exploiting the plasticity built into the SUMO-SIM binding interface.


Thermogenic protein UCP1 and UCP3 expression in non-small cell lung cancer: relation with glycolysis and anaerobic metabolism.
Uncoupling protein 1 (UCP1) is a proton transporter/channel residing on the inner mitochondrial membrane and is involved in cellular heat production. Using immunohistochemistry, we investigated the expression of UCP1 and UCP3 in a series of 98 patients with non-small cell lung cancer (NSCLC) treated with surgery. Expression patterns were correlated with histopathological variables, prognosis, and the expression of enzymes/proteins related to cell metabolism. Bronchial epithelium did not express UCP1 or UCP3, while alveolar cells strongly expressed UCP1. In tumors, strong expression of UCP1 and UCP3 was recorded in 43/98 (43.8%) and 27/98 (27.6%) cases, respectively. UCP1 was significantly associated with squamous cell histology (P = 0.05), whilst UCP3 was more frequently overexpressed in large cell carcinomas (P = 0.08), and was inversely related to necrosis (P = 0.009). In linear regression analysis, UCP1 was directly related to markers of glycolysis [hexokinase (HXKII) and phosphofructokinase (PFK1)] and anaerobic glucose metabolism [pyruvate dehydrogenase kinase (PDK1) and lactate dehydrogenase (LDH5)]. UCP3 was directly linked with a glucose transporter (GLUT2), monocarboxylate transporter (MCT2), glycolysis markers (PFK1 and aldolase), and with the phosphorylation of pyruvate dehydrogenase (pPDH). Kaplan-Meier survival analysis showed that UCP3 was significantly related to poor prognosis in squamous cell carcinomas (P = 0.04). UCP1 and UCP3 are overexpressed in a large subgroup of non-small cell lung tumors and their expression coincides with increased glucose absorption, intensified glycolysis, and anaerobic glucose usage. Whether UCPs are targets for therapeutic interventions in lung cancer is a hypothesis that demands further investigation.


Myxozoans infecting the sharptooth catfish, Clarias gariepinus in the Okavango River and Delta, Botswana, including descriptions of two new species, Henneguya samochimensis sp. n. and Myxobolus gariepinus sp. n.
During a recent investigation of parasites infecting fishes from the Okavango River and Delta, Botswana (southern Africa) fourteen sharptooth catfish, Clarias gariepinus (Burchell, 1822) (Siluriformes: Clariidae) were examined for the presence of myxozoan infections. Results revealed the presence of two species of the genus Henneguya Thélohan, 1895 and one species of the genus Myxobolus Bütschli, 1882 infecting this fish host. Two of the sampled fish exhibited large plasmodia of Henneguya suprabranchiae Landsberg, 1987 in the cartilage of the accessory breathing organ, another two individuals were infected with H. samochimensis sp. n. plasmodia in the gills and another three individuals revealed an infection with Myxobolus gariepinus sp. n. plasmodia in the ovaries.


Immuno-histological changes in lupus nephritis in female patients: a four-year study.
The objective of this study was to classify renal biopsies of all female patients diagnosed to have systemic lupus erythematosus at the College of Medicine, King Abdul Aziz University Hospital, Jeddah, Saudi Arabia over a period of four years between 19th January 2002 and 30th April 2006. Lupus nephritis was classified according to the modified WHO classification. The immunofluorescence pattern was also studied. All the study patients were examined, investigated, treated and followed-up in our center. We observed that class IV lupus nephritis was the most commonly seen lesion and IgG showed strong positivity in most of the cases. We believe that a more elaborate study is needed to explain the relatively high female to male ratio noticed in our study.


Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption.
Tissue inhibitor of metalloproteases (TIMPs) are inhibitors of matrix metalloproteinases (MMPs) that regulate tissue extracellular matrix (ECM) turnover. TIMP4 is highly expressed in adipose tissue, its levels are further elevated following high-fat diet, but its role in obesity is unknown. Eight-week old wild-type (WT) and Timp4-knockout (Timp4 -/-) mice received chow or high fat diet (HFD) for twelve weeks. Timp4 -/- mice exhibited a higher food intake but lower body fat gain. Adipose tissue of Timp4 -/- -HFD mice showed reduced hypertrophy and fibrosis compared to WT-HFD mice. Timp4 -/- -HFD mice were also protected from HFD-induced liver and skeletal muscle triglyceride accumulation and dyslipidemia. Timp4 -/--HFD mice exhibited reduced basic metabolic rate and energy expenditure, but increased respiratory exchange ratio. Increased free fatty acid excretion was detected in Timp4 -/--HFD compared to WT-HFD mice. CD36 protein, the major fatty acid transporter in the small intestine, increased with HFD in WT but not in Timp4 -/- mice, despite a similar rise in Cd36 mRNA in both genotypes. Consistently, HFD increased enterocyte lipid content only in WT but not in Timp4 -/- mice. Our study reveals that absence of TIMP4 can impair lipid absorption and the high fat diet-induced obesity in mice possibly by regulating the proteolytic processing of CD36 protein in the intestinal enterocytes.


Neurovascular and Clinical Outcomes of the Percutaneous Endoscopically Assisted Calcaneal Osteotomy (PECO) Technique to Correct Hindfoot Malalignment.
Standard open calcaneal osteotomies to correct hindfoot malalignment have been associated with high complication rates, including nerve damage and wound infection. This has resulted in the development of minimally invasive techniques such as the percutaneous endoscopically assisted calcaneal osteotomy (PECO), which in cadaver studies has been shown to be potentially safer than open surgeries. The aim of this study was to demonstrate the safety and effectiveness of PECO in a clinical setting, with regard to neurovascular injury rates, infection, and short-term radiographic and functional outcomes. Forty-one (41) patients with planovalgus or cavovarus foot deformities underwent treatment using PECO. Outcomes were analyzed at 6 months and primarily included neurovascular outcomes and wound infection rates. Secondarily, radiographic and functional (visual analog scale for pain [VAS], 36-Item Short Form Medical Outcomes Survey [SF-36], and Foot Function Index [FFI] scores) outcomes were also assessed. There were no reported cases of superficial wound infections, lateral calcaneal or sural nerve dysesthesia. Minor complications occurred in 6/41 feet. The mean postoperative hindfoot correction was 8.3 ± 2.2 mm (range: 6-15mm) compared to preoperative status. Compared to preoperative status, significant improvements ( P = .001 for all) were seen in the VAS, SF-36, and FFI at 6 months postoperatively. PECO resulted in minimal complications with no lateral calcaneal or sural nerve dysesthesias and no wound complications. It also resulted in significant improvements in postoperative radiographic and functional outcomes from baseline to 6-months postoperatively, demonstrating its use as a safe and effective means of treating hindfoot malalignment. Level IV, retrospective case series.


Renal excretion of citrate in patients with chronic renal failure or nephrolithiasis.
Using a specific citrate lyase method, renal excretion of citrate was studied in 32 normal Chinese males, 30 nondialysed uremic male patients and 35 male subjects who had a history of nephrolithiasis. Patients with uremia or nephrolithiasis were found to have a lower urinary citrate excretion. Tubular reabsorption of citrate was markedly decreased in uremic patients, but in stone patients, the increased renal tubular reabsorption of citrate was only found in patients with hypocitraturia, whose renal citrate excretion was below 650 mumol/day and whose urinary magnesium was also low. Hypocitraturia was found in 45% (16/35) of the patients with renal stones whether their filtered load of citrate was normal or subnormal. Urinary citrate excretion was correlated with renal creatinine clearance in both normal subjects and in patients with renal stones or chronic renal failure. However, urinary phosphate correlating with urinary citrate was only found in normal subjects and in patients with kidney stones. In normal subjects, we found a positive correlation between urinary citrate and phosphate, but in stone patients, we found a negative correlation. Hypercalciuria and hyperoxalaturia were noted in some stone formers, who had, moreover, a lower urinary citrate and ascorbate excretion level. Mean urinary ascorbate excretion in patients with renal stones was markedly below that in normal subjects. Thus, we suggest that low urinary citrate excretion may be prevalent in patients with renal stones or chronic renal failure, and that hypocitraturia can be found in some stone formers, whose tubular reabsorption of citrate may be increased.


Evaluation of ascorbic acid as suppressor of cyclophosphamide induced lipid peroxidation using common laboratory markers.
The present study deals with exploration of lipid peroxidation induction capacity of cyclophosphamide, an anticancer drug, and in vitro evaluation of ascorbic acid as a suppressor of cyclophosphamide induced lipid peroxidation. Goat liver homogenate has been used as the lipid source. This evaluation was done by measuring the malondialdehyde, 4-hydroxy-2-nonenal, reduced glutathione and nitric oxide content of the tissue as markers of lipid peroxidation. The study revealed that ascorbic acid could suppress the drug induced lipid peroxidation to a significant extent.


Metabolomics and Transcriptomics Analyses Reveals the Molecular Regulatory Mechanisms of Walnut (Juglans regia L.) Embryos in Response to Shade Treatment.
The walnut is an important nut that has numerous uses worldwide. However, due to dwarf and close plantation methods as well as continuous cloudy or rainy days that occur during periods of walnut oil accumulation, the walnut fruit exhibits varying degrees of stress under low-light conditions. However, the effects of shade on metabolites and genes in walnut embryos remain unclear in the literature. The purpose of this study is to investigate the lipid biosynthesis process that occurs in walnut embryos under shade treatment via the use of metabolomics and transcriptomics analyses. The results indicate that the oil content decreases significantly under shaded conditions, while the protein content increases significantly. The expression levels of fatty acid desaturase 2 (FAD2) and stearoyl-ACP-desaturase (SAD) involved in the lipid biosynthesis mechanism were significantly reduced in the shaded group, which resulted in reductions in oleic (C18:1), linoleic (C18:2), and α-linolenic (C18:3) acids. The reduced oil content was consistent with the downregulation of genes associated with the lipid biosynthesis mechanism. In the amino acid biosynthesis process, the upregulated cysteine synthase (cscK) and anthranilate synthase beta subunit 2 (trpG) genes promoted the accumulation of L-aspartic acid and L-citrulline. The increase in protein content was consistent with the upregulation of genes related to amino acid biosynthesis. Thus, our study provides new insights into the regulatory mechanisms of shade underlying overall walnut fruit quality.


Interagency collaboration: head start and a school of nursing.
Agency collaboration is gaining importance for schools of nursing as changes in health care systems focus on the community as a principal environment for health care delivery. Nursing faculty seeking settings in the community to prepare future nurses find Head Start especially interesting as a model of comprehensive care for low-income families. The skill required to develop successful collaboration between community agencies and schools of nursing is often underestimated. Polivka in a conceptual framework for community interageacy collaboration identifies factors to consider. Successful collaborative relationships require that goals be achieved, that relationships be satisfying, and that outcomes have value for all collaborators.


Blood lead levels in children living near abandoned metal-recovery plants.
Following the identification of high levels of lead in the soils of residences near two abandoned Montreal metal-recovery plants, blood lead concentrations were analyzed for children living or cared for in the affected neighbourhood. Overall, the distribution of blood lead levels (geometric mean = .27 mumol/L, range .11-1.01) among the 52 children sampled was similar to those of children of other Quebec localities without known point sources of lead. Nevertheless, multiple regression analysis did suggest a modest influence of the concentration of lead in children's own yards (as measured by actual soil samples or as estimated by a geostatistical modeling procedure) on their blood lead level (.05 mumol/l rise for a 1000 ppm increase in soil lead, 95% C.I.-.01, .11). This estimate of the influence of soil on blood lead is at the lower end of the range reported by others. We suggest that these Montreal results demonstrate the modest effects of lead-contaminated soil when its access is limited by grass cover and/or when the emissions which produced it have ceased.


Efficacy of venlafaxine in patients with major depressive disorder who have unsustained or no response to selective serotonin reuptake inhibitors: an open-label, uncontrolled study.
Approximately half of patients who are prescribed selective serotonin re-uptake inhibitors (SSRIs) either do not respond to treatment or do not experience a sustained response. The purpose of this study was to assess the efficacy of venlafaxine immediate-release (IR) and extended-release (XR) in outpatients who either did not respond to SSRI treatment or did not maintain a sustained response. Outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depressive disorder who were previously treated with an SSRI (fluoxetine > or = 20 mg/d; sertraline > or = 50 mg/d; paroxetine > or = 20 mg/d) for > or = 6 weeks, but demonstrated an inadequate or unsustained response, were switched to venlafaxine (IR or XR formulation, 50-400 mg/d, titrated from 37.5 mg/d) for > or = 6 weeks. Response at 6 to 8 weeks was defined as total score < or = 10 on the modified 25-item Hamilton Depression (HAM-D25) rating scale or total score > or = 5 on the 21-item Patient Global Improvement (PGI-21) scale. Remission was defined as a HAM-D25 total score < or = 8 or PGI-21 score > or = 7. Tests were administered by an unblinded, board-certified psychiatrist. A total of 73 patients (54 women, 19 men; mean age, 38.6 years) were enrolled and treated with venlafaxine IR (n = 63) or venlafaxine XR (n = 10); 33 were SSRI nonresponders and 36 had an unsustained response to SSRI treatment. Four patients receiving venlafaxine IR discontinued due to drug-related adverse events (agitation, sedation, or nausea). Data from these patients were excluded from the analysis. After 6 to 8 weeks of treatment, 94.2% (65/69) of patients were considered responders (HAM-D25 or PGI-21 criteria); 91.3% (63/69) of patients responded to treatment as assessed by both measures. Eighty-seven percent (60/69) and 85.5% (59/69) of patients achieved remission based on HAM-D,5 and PGI-21 criteria, respectively. Response/remission rates were comparable among patients treated with SSRIs, regardless of whether patients had failed to respond to treatment with 1 or 2 SSRIs. Venlafaxine IR/venlafaxine XR may be effective in outpatients with major depressive disorder who do not respond or have an unsustained response to SSRIs. However, randomized, controlled trials are needed before any conclusions can be drawn about the efficacy of this agent in this population.


Tobacco harm reduction: are smokers becoming more hardcore?
We undertook a systematic review to identify and summarise studies on hardcore smoking and hardening to: determine the degree of variability in definitions of hardcore smoking and hardening; assess the evidence for claims that smokers are becoming increasingly hardened within the context of harm reduction as a policy initiative; and identify the determining characteristics of a hardcore smoker. We searched five electronic databases from 1970 to mid-April 2018 using the search term "smok* AND hard* AND (tobacco OR cigar* OR nicotin*)". We included studies if they included a definition of hardcore smokers and/or hardening, and provided a prevalence rate for hard core smokers or empirical evidence for hardening. Definitions of hardcore smoker varied substantially across studies. Hardening was not evident in the general smoking population and we found mounting evidence of softening occurring in smoking populations. These results indicate that hardening of smokers is not occurring and that calls for policy interventions on this basis should be challenged.


Epigenetic weapons in plant-herbivore interactions: Sulforaphane disrupts histone deacetylases, gene expression, and larval development in Spodoptera exigua while the specialist feeder Trichoplusia ni is largely resistant to these effects.
Cruciferous plants produce sulforaphane (SFN), an inhibitor of nuclear histone deacetylases (HDACs). In humans and other mammals, the consumption of SFN alters enzyme activities, DNA-histone binding, and gene expression within minutes. However, the ability of SFN to act as an HDAC inhibitor in nature, disrupting the epigenetic machinery of insects feeding on these plants, has not been explored. Here, we demonstrate that SFN consumed in the diet inhibits the activity of HDAC enzymes and slows the development of the generalist grazer Spodoptera exigua, in a dose-dependent fashion. After consuming SFN for seven days, the activities of HDAC enzymes in S. exigua were reduced by 50%. Similarly, larval mass was reduced by 50% and pupation was delayed by 2-5 days, with no additional mortality. Similar results were obtained when SFN was applied topically to eggs. RNA-seq analyses confirm that SFN altered the expression of thousands of genes in S. exigua. Genes associated with energy conversion pathways were significantly downregulated while those encoding for ribosomal proteins were dramatically upregulated in response to the consumption of SFN. In contrast, the co-evolved specialist feeder Trichoplusia ni was not negatively impacted by SFN, whether it was consumed in their diet at natural concentrations or applied topically to eggs. The activities of HDAC enzymes were not inhibited and development was not disrupted. In fact, SFN exposure sometimes accelerated T. ni development. RNA-seq analyses revealed that the consumption of SFN alters gene expression in T. ni in similar ways, but to a lesser degree, compared to S. exigua. This apparent resistance of T. ni can be overwhelmed by unnaturally high levels of SFN or by exposure to more powerful pharmaceutical HDAC inhibitors. These results demonstrate that dietary SFN interferes with the epigenetic machinery of insects, supporting the hypothesis that plant-derived HDAC inhibitors serve as "epigenetic weapons" against herbivores.


Magnesium role in cardiovascular diseases.
Magnesium is one of the four major cations in the human body and the second most abundant within the cell. Observational studies have shown the fundamental role of magnesium in treatment of different cardiovascular disorders, connected with magnesium deficiency. As co-factor of many enzymes, especially those involved in phosphate transfer, it plays a role in regulation of intracellular reactions in the organism. By influence on sodium pump and calcium pump, it regulates flowing of Na+, Ca2+, K+ ions through channels in cell membrane and therefore: decreases lack of K+ ions, protects the cell from Ca2+ ions overloading, inhibits sodium influx into the cell, equalizes pH of cell by maintaining the correct level of acidosis, increases bioelectrical potential and supplies energy for calcium pump and sodium pump. Moreover, magnesium controls the level of triglycerides (rebuilds integration of cell membrane), attends in local autonomic control of circulation, which helps to maintain the balance of peripheral movement, corrects activity of conduction and stimulogenic system of the heart. Still carried out intensive research into the influence of magnesium on the human organism function may show unknown so far aspects of this element action on the cardiovascular system.


Fitness costs associated with the acquisition of antibiotic resistance.
Acquisition of antibiotic resistance is a relevant problem for human health. The selection and spread of antibiotic-resistant organisms not only compromise the treatment of infectious diseases, but also the implementation of different therapeutic procedures as organ transplantation, advanced surgery or chemotherapy, all of which require proficient methods for avoiding infections. It has been generally accepted that the acquisition of antibiotic resistance will produce a general metabolic burden: in the absence of selection, the resistant organisms would be outcompeted by the susceptible ones. If that was always true, discontinuation of antibiotic use would render the disappearance of resistant microorganisms. However, several studies have shown that, once resistance emerges, the recovery of a fully susceptible population even in the absence of antibiotics is not easy. In the present study, we review updated information on the effect of the acquisition of antibiotic resistance in bacterial physiology as well as on the mechanisms that allow the compensation of the fitness costs associated with the acquisition of resistance.


Pharmacogenetics of Potassium Channel Blockers.
The QT interval on surface electrocardiograms provides a model of a multicomponent integrated readout of many biological systems, including ion channels, modulatory subunits, signaling systems that modulate their activity, and mechanisms that regulate the expression of their responsible genes. The problem of drug exposure causing exaggerated QT interval prolongation and torsades de pointes highlights the multicomponent nature of cardiac repolarization and the way in which simple perturbations can yield exaggerated responses. Future directions will involve cellular approaches coupled to evolving technologies that can interrogate multicellular systems and provide a sophisticated view of mechanisms in this previously idiosyncratic drug reaction.


Risk Factors for Mortality among Adult HIV/AIDS Patients Following Antiretroviral Therapy in Southwestern Ethiopia: An Assessment through Survival Models.
Introduction: Efforts have been made to reduce HIV/AIDS-related mortality by delivering antiretroviral therapy (ART) treatment. However, HIV patients in resource-poor settings are still dying, even if they are on ART treatment. This study aimed to explore the factors associated with HIV/AIDS-related mortality in Southwestern Ethiopia. Method: A non-concurrent retrospective cohort study which collected data from the clinical records of adult HIV/AIDS patients, who initiated ART treatment and were followed between January 2006 and December 2010, was conducted, to explore the factors associated with HIV/AIDS-related mortality at Jimma University Specialized Hospital (JUSH). Survival times (i.e., the time from the onset of ART treatment to the death or censoring) and different characteristics of patients were retrospectively examined. A best-fit model was chosen for the survival data, after the comparison between native semi-parametric Cox regression and parametric survival models (i.e., exponential, Weibull, and log-logistic). Result: A total of 456 HIV patients were included in the study, mostly females (312, 68.4%), with a median age of 30 years (inter-quartile range (IQR): 23-37 years). Estimated follow-up until December 2010 accounted for 1245 person-years at risk (PYAR) and resulted in 66 (14.5%) deaths and 390 censored individuals, representing a median survival time of 34.0 months ( IQR: 22.8-42.0 months). The overall mortality rate was 5.3/100 PYAR: 6.5/100 PYAR for males and 4.8/100 PYAR for females. The Weibull survival model was the best model for fitting the data (lowest AIC). The main factors associated with mortality were: baseline age (>35 years old, AHR = 3.8, 95% CI: 1.6-9.1), baseline weight (AHR = 0.93, 95% CI: 0.90-0.97), baseline WHO stage IV (AHR = 6.2, 95% CI: 2.2-14.2), and low adherence to ART treatment (AHR = 4.2, 95% CI: 2.5-7.1). Conclusion: An effective reduction in HIV/AIDS mortality could be achieved through timely ART treatment onset and maintaining high levels of treatment adherence.


Construct validity and factor structure of survey-based assessment of cost-related medication burden.
Millions of Americans are burdened by out-of-pocket prescription costs. Although many survey measures have been developed to assess this burden, the construct validity and the factor structure of these instruments have not been rigorously assessed. To characterize the factor structure and the construct validity of items assessing cost-related medication burden. We applied exploratory factor and confirmatory factor analyses to the 2009 Medicare Current Beneficiary Survey, focusing on 10 items assessing cost-related mediation burden among a nationally representative sample of community-dwelling Medicare beneficiaries. The fit of competing models was compared using several indices. The study population (N=8777) was predominantly aged over 65 years (83.3%), female (54.4%), and white (84.3%). Two distinct factors were present for the medication cost-reduction strategies: (1) cost-related medication nonadherence and (2) drug-shopping behaviors, not directly impacting medication compliance. The two factors were moderately correlated (r=0.55), highlighting the presence of a 2 distinct but related constructs for cost-related medication burden. An item assessing the use of mail or internet pharmacies did not load well on either factor and may not necessarily measure medication-related cost burden. An item assessing reduced spending on basic needs loaded strongly on the same factor with the cost-related medication nonadherence items, suggesting they together may represent extreme compensatory behaviors that may adversely affect health outcomes. Two distinct constructs were derived from these items examining cost-related medication burden. Although cost-related medication burden is often associated with nonadherence, drug-shopping behaviors that do not directly impact adherence are also important measure of this burden.


Subacute Arsenic Neuropathy: Clinical and Electrophysiological Observations.
We report a patient who developed subacute peripheral neuropathy following ingestion of a traditional medicine for obesity. A 9-year-old girl who had a residual equinus varus deformity and sphincter disturbance due to pelvic ganglioneuroma presented with subacute sensorimotor peripheral neuropathy of 2 weeks duration. Her symptoms started 3 weeks after she started taking a locally made traditional medicine for obesity. She had no other systemic features of arsenic toxicity. She had Mee's lines on her nails and high serum arsenic levels and 24-hour urine levels confirmed the diagnosis of arsenic neuropathy. Nerve conduction study on admission demonstrated axonal sensorimotor neuropathy with slowed conduction velocity. She was not given any specific treatment and recovery was slow. At 18 months, she showed complete recovery and electrodiagnostic parameters returned to normal values. Arsenic is a known ingredient of many Indian ethnic remedies and possibility of arsenic neuropathy should be thought of in patients presenting with acute or sub-acute peripheral neuropathy of unknown etiology.


[DIAGNOSTIC SIGNIFICANCE OF PLASMA TROPONIN AND CARDIOMYOCYTE FATTY ACID-BINDING PROTEIN LEVELS IN ACUTE CORONARY SYNDROME].
Blood serum content of fatty acid-binding (FABP) protein increases within 2-3 h after the onset of acute coronary syndrome and myocardial infarction (MI) and reaches the maximum 8.5 h after the initiation of cardiomyocyte death. FABP content considerably decreases by the end of at 24-h period due to excretion with urine, remaining elevated for subsequent 24 h. High clinical sensitivity and relatively high organ specificity are typical of FABP for 12 h after ACS. Within the early period of MI clinical specificity of FABP prevails over troponin in terms of concentration. Troponins display higher clinical sensitivity and diagnostic specificity during a 12-h period after ACS, prevailing for several days after MI. Simultaneous measuring of FABP and troponins (Tr) within the first 12 h increases the sensitivity of biochemical diagnostics by 30%. At later periods, simultaneous determination of FABP and Tr becomes unnecessary: FABP is excreted with urine and Tr level acquires predominant diagnostic significance. No relationship has been revealed between blood content of FABP and reperfusion according to electrocardiography data, probably due to rare measurements of this highly dynamic parameter. FABP test cannot be used in patients with circulatory disorders since its results are not adequate. The best option for differential diagnostics of ACS within the first 24 h would be a combined express immunochromatographic test which allows to measure blood FABP and Tr levels pending objective evaluation.


Life With HIV: Insights from HIV-infected Women in Cameroon, Central Africa.
Women in Cameroon are disproportionately burdened by HIV illness. Understanding the impact HIV has on women is essential for developing interventions to enhance their quality of life. Our aim was to explore and provide an in-depth understanding of the daily experiences of a sample of women living with HIV in Cameroon. Qualitative semi-structured in-depth interviews were conducted with women (N = 30) from the northwest region of Cameroon who self-reported being infected with HIV. Participants shared that they had multiple challenges in their daily experiences living with HIV. The themes that emerged included: (a) receiving an HIV diagnosis is traumatic, (b) living with HIV is a constant struggle, (c) limited resources and support cause problems, and (d) stigma and powerlessness exacerbate the impact of HIV. We provide insight into the daily experiences of HIV-infected women in Cameroon. Implications for improving health care and social services to women living with HIV in Cameroon are suggested.


Incidence, event rates, and early outcome of stroke in Dublin, Ireland: the North Dublin population stroke study.
The World Health Organization has emphasized the importance of international population-based data for unbiased surveillance of stroke incidence and outcome. To date, few such studies have been conducted using recommended gold-standard ascertainment methods. We conducted a large, population-based stroke study in Dublin, Ireland. Using gold-standard ascertainment methods, individuals with stroke and transient ischemic attack occurring over a 12-month period (December 1, 2005-November 30, 2006) in North Dublin were identified. Disability was assessed using the modified Rankin score and stroke severity (<72 hours) by the National Institutes of Health Stroke Scale. Stroke-related deaths were confirmed by review of medical files, death certificates, pathology, and coroner's records. Crude and standardized (to European and World Health Organization standard populations) rates of incidence, risk factors, severity, and early outcome (mortality, case-fatality, disability) were calculated, assuming a Poisson distribution for the number of events. Seven hundred one patients with new stroke or transient ischemic attack were ascertained (485 first-ever stroke patients, 83 recurrent stroke patients, 133 first-ever transient ischemic attack patients). Crude frequency rates (all rates per 1000 person-years) were: 1.65 (95% CI, 1.5-1.79; first-ever stroke), 0.28 (95% CI, 0.22-0.35; recurrent stroke), and 0.45 (95% CI, 0.37-0.53; first-ever transient ischemic attack). Age-adjusted stroke rates were higher than those in 9 other recent population-based samples from high-income countries. High rates of subtype-specific risk factors were observed (atrial fibrillation, 31.3% and smoking, 29.1% in ischemic stroke; warfarin use, 21.2% in primary intracerebral hemorrhage; smoking, 53.9% in subarachnoid hemorrhage; P<0.01 for all compared with other subtypes). Compared with recent studies, 28-day case-fatality rates for primary intracerebral hemorrhage (41%; 95% CI, 29.2%-54.1%) and subarachnoid hemorrhage (46%; 95% CI, 28.8%-64.5%) were greater in Dublin. Using gold-standard methods for case ascertainment, we found high incidence rates of stroke in Dublin compared with those in similar high-income countries; this is likely explained in part by high rates of subtype-specific risk factors.


A proposed life cycle for the Reiter treponeme.
Direct microscopical observations of single developing cysts in sealed slide microcultures prepared from 5-days-old tube cultures of the Reiter treponeme revealed two distinct phases in the life cycle. In one phase transverse fission was the main method of multiplication while in a second phase, occurring when conditions in the medium became unfavourable for propagation, cysts developed. These could release large numbers of actively motile treponemes when returned to optimum growth conditions. These observations, together with results of the dilution method for the calculation of the Most Probable Number and the absence of a response in treponemes killed by high temperature (45 degrees C) or abnormal pH (10), showed that the cysts were viable and a mode of propagation for the Reiter treponeme.


Linking Social Anxiety with Social Competence in Early Adolescence: Physiological and Coping Moderators.
Despite relatively universal feelings of discomfort in social situations, there is considerable evidence for diversity in the social behaviors and peer experiences of socially anxious youth. However, to date, very little research has been conducted with the aim of identifying factors that differentiate socially anxious youth who are more socially competent from those who are less socially competent. The present study addresses this gap in the literature by examining whether physiological and cognitive coping responses to social stress moderate the association between social anxiety and social competence. Participants were a community sample of 123 fifth and sixth graders (Mage = 12.03). Social anxiety was measured globally and in the context of a lab-based peer evaluation situation, and social competence was assessed via teacher-reports. Physiological (i.e., skin conductance level reactivity, SCLR, and respiratory sinus arrhythmia reactivity, RSAR) and coping (i.e., disengaged) responses to social stressors were also assessed. Results indicated that SCLR and disengaged coping with peer victimization moderated associations linking global and context-specific social anxiety with social competence, such that social anxiety was associated with lower social competence at lower levels of SCLR and higher levels of disengaged coping with peer victimization. Thus, whether socially anxious preadolescents exhibit more or less competent social behavior may depend, in part, on how they respond to peer-evaluative stress. Inflexible physiological responses and disengaged coping responses may undermine social competence, whereas engaged responses may counteract socially anxious preadolescents' tendency to withdraw from social interactions or focus primarily on threat cues.


Sonochemically-Induced Reduction of Alkenes to Alkanes with Ammonia.
With the progressive defossilization of our industry, hydrogen (H2 ) has been identified as a central molecule to store renewable electricity. In this context, ammonia (NH3 ) is now rapidly emerging as a promising hydrogen carrier for the future. This game change indirectly impacts the field of fine chemistry where hydrogenation reactions are widely deployed. In particular, the possibility of performing hydrogenation reactions using ammonia directly instead of hydrogen has become highly desirable but it remains a very difficult scientific task, which we address in this communication. Here we show that the N-H bond of NH3 can be cleaved within cavitation bubbles, generated by ultrasonic irradiation at a high frequency, leading to the in situ formation of a diimide, which then induces the hydrogenation of alkenes. Advantageously, this work does not involve any transition metal and releases N2 as a sole co-product.


Checking stationarity of the incidence rate using prevalent cohort survival data.
When survival data are collected as part of a prevalent cohort study with follow-up, the recruited cases have already experienced their initiating event, say onset of a disease, and consequently the incidence process is only partially observed. Nevertheless, there are good reasons for interest in certain features of the underlying incidence process, for example whether or not it is stationary. Indeed, the well known relationship between incidence and prevalence, often used by epidemiologists, requires stationarity of the incidence rate for its validity. Also, the statistician can exploit stationarity of the incidence process by improving the efficiency of estimators in a prevalent cohort survival analysis. In addition, whether the incident rate is stationary is often in itself of central importance to medical and other researchers. We present here a necessary and sufficient condition for stationarity of the underlying incidence process, which uses only survival observations, possibly right censored, from a prevalent cohort study with follow-up. This leads to a simple graphical means of checking for the stationarity of the underlying incidence times by comparing the plots of two Kaplan-Meier estimates that are based on partially observed incidence times and follow-up survival data. We use our method to discuss the incidence rate of dementia in Canada between 1971 and 1991.


Nutrition label use is associated with lower longer-term diabetes risk in US adults.
Background: Regular nutrition label use may have important long-term health implications. To our knowledge, the role of nutrition label use in protecting against the development of chronic diseases was unexplored prospectively before this study.Objective: We tested the association between nutrition label use and risk of a future diabetes diagnosis in a multiethnic US cohort.Design: Data from the ongoing National Longitudinal Survey of Youth-1979 (NLSY79) were analyzed. From 2002 (baseline) to 5 follow-up time points (2004-2012), 7150 diabetes-free, multiethnic young adults were prospectively followed for a diagnosis of incident diabetes. Nutrition label use, diabetes diagnosis, time to diabetes diagnosis, and all covariates were self-reported.Results: Between January 2002 and September 2013, 430 participants (6.0%) were diagnosed with diabetes. A weighted, multivariable, extended Cox regression was conducted, which suggested that in nutrition label users, the HR of diabetes diagnosis risk decreased significantly with time (P-nutrition label use × time interaction < 0.05) compared with risk in nutrition label nonusers.Conclusions: There is an association between nutrition label use and diabetes risk in the longer term. However, additional longitudinal research with a robust dietary intake assessment is needed to test this hypothesis.


Chemical studies of tissue polypeptide antigen (TPA). III. on the nature of the antigenic determinant(s) of TPA subfraction B1.
Tissue Polypeptide Antigen (TPA)*** which is a protein isolated from e.g. human carcinoma cells, has previously been separated into subfractions and studied with biochemical methods. Gel diffusion studies show that the antigenic determinants are retained through the isolation and purification procedures. Specific modifications of the amino acid residues lysine, tyrosine, trytophan and arginine in subfraction B1 have been related to the change in the capacity of the antigen to bind to horse anti-HeLa serum. Complete although reversible loss of binding capacity resulted from blocking of arginine and a minor loss was noted upon modification of tyrosine. No measurable influence was noted upon modification of lysine or tryptophan. No cysteine has been detected in subfraction B1. Circular dichroism measurements show that TPA subfraction B1 is largely alpha-helical in solution, and that no correlation could be detected between antigenic activity and conformation.


Diabetes care delivery in the community.
Specialist nurses and practice nurses were asked about the future care and management of Type 2 diabetes. Consensus was high on issues such as audit, evidence-based practice, experience and record keeping. There were differences in opinion about nurse prescribing, teamwork, professional responsibility and education/training.


Comparison of vascular cognitive impairment--no dementia by multiple classification methods.
To compare vascular cognitive impairment-no dementia (VCI-ND) using different classification methods. We recruited 56 patients with VCI-ND between April 2012 and March 2013. We used a battery of neuropsychological tests to classify patients with VCI-ND into different subtypes based on memory and executive function as follows: cognitive screening (Mini-Mental State Examination, MMSE), memory (Auditory Verbal Learning Test, AVLT), executive/attention (Shape Trails Test, STT; Stroop Color-Word Test, SCWT; Reading the Mind in the Eyes, RME; Digit Ordering Test-A, DOT-A; Symbol Digit Modalities Test, SDMT), language (Action Naming Test, ANT; Boston Naming Test, BNT; Famous Face Test, FFT; Similarity Test, ST; Verbal Fluency Test, VFT) and visuospatial function (Complex Figure Test, CFT). The two groups had comparable demographic information (P>0.05). Amnestic VCI-ND (aVCI-ND) patients obtained significantly lower scores compared with individuals with nonamnestic VCI-ND (naVCI-ND) on the AVLT memory test, VFT language test and VFT-alternating executive test (P<0.05). Additionally, executive VCI-ND (eVCI-ND) patients performed significantly longer than nonexecutive VCI-ND (neVCI-ND) patients on the SCWT-C timed executive test. Finally, eVCI-ND patients obtained significantly lower scores compared with neVCI-ND patients on the RME, DOT-A and SDMT-correct executive tests and the ANT, BNT and ST language tests (P<0.05). aVCI-ND patients performed poorly compared with naVCI-ND patients in terms of executive and language functions, while eVCI-ND patients performed poorly compared with neVCI-ND patients in terms of language function.


Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.
Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.


Indications of chlormethiazole as a protective agent in experimental endotoxemia.
Chlormethiazole, which is derived from the thiazole moiety of thiamine, possesses sedative, hypnotic and anticonvulsant properties. This anesthetic agent was compared with ketamine in a porcine model of endotoxemia to evaluate effects on cardiovascular and pulmonary function, oxygen delivery and survival. Continuous 6-hour intravenous infusion of Escherichia coli endotoxin caused pronounced pulmonary and cardiovascular derangement and decreases in oxygen delivery and pH in 13 pigs given ketamine anesthesia. Eight of thirteen pigs survived the observation period. Contrastingly, 10 pigs given chlormethiazole anesthesia and endotoxin showed a significantly attenuated response. Thus, the increases in mean pulmonary arterial pressure, venous admixture and extravascular lung water were significantly lower and the decreases in cardiac output, oxygen delivery and pH were significantly modified by chlormethiazole. All 10 pigs survived the observation period. Chlormethiazole may increase the clearance of endotoxin and thus ameliorate the endotoxin response. Although extrapolating from animal data requires great caution, these data may favor the use of chlormethiazole in septic states requiring surgical intervention and anesthesia and as sedation in critically ill septic patients in our intensive care units.