Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?
Vitamin C as a cancer therapy has a controversial history. Much of the controversy arises from the lack of predictive biomarkers for stratification of patients, as well as a clear understanding of the mechanism of action and its multiple targets underlying the anticancer effect. Our review expands the analysis of cancer vulnerabilities for high-dose vitamin C, based on several facts, illustrating the cytotoxic potential of the ascorbyl free radical (AFR) via impairment of mitochondrial respiration and the mechanisms of its elimination in mammals by the membrane-bound NADH:cytochrome b5 oxidoreductase 3 (Cyb5R3). This enzyme catalyzes rapid conversion of AFR to ascorbate, as well as reduction of other redox-active compounds, using NADH as an electron donor. We propose that vitamin C can function in "protective mode" or "destructive mode" affecting cellular homeostasis, depending on the intracellular "steady-state" concentration of AFR and differential expression/activity of Cyb5R3 in cancerous and normal cells. Thus, a specific anticancer effect can be achieved at high doses of vitamin C therapy. The review is intended for a wide audience of readers-from students to specialists in the field.


The Kimberley Hospital Rule (KHR) for urgent computed tomography of the brain in a resource-limited environment.
The indications for urgent computed tomography of the brain (CTB) in the acute setting are controversial. While guidelines have been proposed for CTB in well-resourced countries, these are not always appropriate for resource-limited environments. Furthermore, no unifying guideline exists for trauma-related and non-trauma-related acute intracranial pathology. Adoption by resource-limited countries of more conservative scanning protocols, with outcomes comparable to well-resourced countries, would have significant benefit. A multidisciplinary team from Kimberley Hospital in the Northern Cape Province of South Africa adopted the principles defined in the National Institute for Health and Care Excellence (NICE) guideline for the early management of head injury and drafted the Kimberley Hospital Rule (KHR), a proposed unifying guideline for the imaging of acute intracranial pathology in a resource-limited environment. To evaluate the sensitivity and specificity of the KHR. A prospective cohort study was conducted in the Northern Cape Province between 1 May 2010 and 30 April 2011. All patients older than 16 years presenting to emergency departments with acute intracranial symptoms were triaged according to the KHR into three groups, as follows: group 1 - immediate scan (within 1 hour); group 2 - urgent scan (within 8 hours); and group 3 - no scan required. Patients in groups 1 and 2 were studied. The primary outcome was CTB findings of clinically significant intracranial pathology requiring acute change in management. Seven hundred and three patients were included. The KHR achieved 90.3% sensitivity and 45.5% specificity, while reducing the number of immediate CTBs by 36.0%. The KHR is an accurate, unifying clinical guideline that appears to optimise the utilisation of CTB in a resource-limited environment.


Recombinant Production, Characterization, and Fiber Spinning of an Engineered Short Major Ampullate Spidroin (MaSp1s).
Spider dragline silk exhibits an extraordinary toughness and is typically composed of two types of major ampullate spidroins (MaSp1 and MaSp2), differing in their proline content and hydrophobicity. In this paper, we recombinantly produced an unusual but naturally occurring short major ampullate spidroin (MaSp1s) as a fusion construct between established Latrodectus hesperus terminal domains and the novel Cyrtophora moluccensis core domain. The sequence of the recombinant spidroin was engineered to guarantee high yields upon recombinant production and was named eMaSp1s. Its solution structure as well as the mechanical properties of wet-spun eMaSp1s fibers were examined. Structural characterization using CD- and FTIR spectroscopy showed a predominantly α-helical solution structure and a high ß-sheet content within fibers. Surprisingly, eMaSp1s fibers show similar mechanical properties as wet-spun fibers of other engineered spider silk proteins, albeit eMaSp1s has a lower molecular weight and not the typical sequence repeats in its core domain. Therefore, the findings provide insights into the molecular interplay necessary to obtain the typical silk fiber mechanics.


Microleakage study of flowable composite resin systems.
The purpose of this in vitro microleakage study was to evaluate four low-viscosity composite resin systems. Each resin system included the corresponding bonding agent for each respective flowable composite. A hybrid material was used as a control. A total of 75 noncarious, freshly extracted human teeth were prepared with a Class 5 occlusal preparation and a gingival preparation at the cementoenamel junction. The materials were inserted according to the manufacturers' recommendations using the single-component bonding agent for each system. Teeth were thermocycled 800 times between 5 degrees C and 55 degrees C with 30-second dwell times. The teeth were then coated with nail polish 1 mm short of the restoration, placed in a basic fuchsin dye for 24 hours, and sectioned with a diamond wheel. Enamel and dentin/cementum margins were analyzed for microleakage on a scale of 0 (no leakage) to 3 (axial wall). Results were evaluated with the Fisher's exact test. The results of the study indicate that there was no leakage at the enamel margin of any restorations. No statistically significant differences in microleakage were found in dentin/cementum margins among the samples in the experimental group or between the experimental group and control group. The results indicate flowable composites demonstrate resistance to microleakage in both enamel and cementum/dentin margins similar to TPH hybrid composite.


Ketorolac suppresses postoperative bladder spasms after pediatric ureteral reimplantation.
We evaluated the efficacy of ketorolac in suppressing postoperative bladder spasms after ureteroneocystostomy (ureteral reimplantation). Twenty-four pediatric patients undergoing intravesical ureteroneocystostomy were enrolled prospectively to receive either ketorolac or placebo via double-blinded randomization. Twelve patients in each group shared similar preoperative characteristics. All were maintained on an epidural infusion of bupivacaine (0.1%) with fentanyl (2 microg/mL) throughout the study. Patients were given either ketorolac (0.5 mg. kg(-1). dose(-1)) or placebo (equivalent volume saline) IV after surgery and every 6 h thereafter for 48 h. Parents were instructed to record bladder spasm episodes prospectively by using a standardized time-flow diary. Three patients (25%) in the ketorolac group experienced bladder spasms, compared with 10 patients (83%) in the placebo group (two-sided P < 0.05). The median severity score for the ketorolac group was 1.2 (mild = 1.0, severe = 3.0), compared with 2.6 for the placebo group (P = 0.003). We conclude that IV ketorolac reduces the frequency and severity of postoperative bladder spasms after intravesical ureteroneocystostomy. We studied the efficacy of ketorolac, a prostaglandin synthesis inhibitor, in the treatment of bladder spasm after ureteroneocystostomy (antireflux operation). Patients were randomized in a double-blinded manner to receive either ketorolac or placebo after the surgery. We demonstrate that ketorolac reduces the frequency and severity of postoperative bladder spasm.


Diffusion tensor imaging based network analysis detects alterations of neuroconnectivity in patients with clinically early relapsing-remitting multiple sclerosis.
Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of multiple sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We, therefore, attempted this pilot study for initial assessment of early relapsing-remitting MS (RRMS). Neuroconnectivity analysis was used for evaluation of 24 early RRMS patients within 2 years of presentation, and compared to the network measures of a group of 30 age-and-gender-matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length were computed and compared to characterize the network changes in efficiencies. Statistically significant (P < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25-foot Walk test with communicability measures in the left superior frontal (r = -0.71) as well as the left superior temporal gyrus (r = -0.43) and left postcentral gyrus (r = -0.41) were identified. Additionally identified were increased communicability between the deep gray matter structures (left thalamus and putamen) with the major interhemispheric and intrahemispheric white matter tracts, the corpus callosum, and cingulum, respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI-based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early RRMS and paves the way for longitudinal studies in larger patient groups.


Non-cellulosic polysaccharides from cotton fibre are differently impacted by textile processing.
Cotton fibre is mainly composed of cellulose, although non-cellulosic polysaccharides play key roles during fibre development and are still present in the harvested fibre. This study aimed at determining the fate of non-cellulosic polysaccharides during cotton textile processing. We analyzed non-cellulosic cotton fibre polysaccharides during different steps of cotton textile processing using GC-MS, HPLC and comprehensive microarray polymer profiling to obtain monosaccharide and polysaccharide amounts and linkage compositions. Additionally, in situ detection was used to obtain information on polysaccharide localization and accessibility. We show that pectic and hemicellulosic polysaccharide levels decrease during cotton textile processing and that some processing steps have more impact than others. Pectins and arabinose-containing polysaccharides are strongly impacted by the chemical treatments, with most being removed during bleaching and scouring. However, some forms of pectin are more resistant than others. Xylan and xyloglucan are affected in later processing steps and to a lesser extent, whereas callose showed a strong resistance to the chemical processing steps. This study shows that non-cellulosic polysaccharides are differently impacted by the treatments used in cotton textile processing with some hemicelluloses and callose being resistant to these harsh treatments.


Microshape and rough-surface analysis by fringe projection.
A fringe-projection system for microscopic applications, fringe-projecting microscopy, is developed and analyzed. Projection of the grating and imaging of the fringe system, modulated by the surface, are accomplished by the same high-aperture objective. The spectrum of the grating is spatially filtered and projected into the aperture with a lateral shift, which leads to a telecentric projection under oblique incidence and telecentric imaging. Topographies of specularly as well as diffusely reflecting surfaces can be obtained. The measurement of highly rough surfaces is described together with preprocessing steps. The resulting intensity distribution of the fringes is analyzed. Formulas for vertical and lateral resolution, measuring range, and dynamic range, based on noise considerations, are presented and verified by topographies of technical surfaces.


Evaluation of stream chemistry trends in US Geological Survey reference watersheds, 1970-2010.
The Hydrologic Benchmark Network (HBN) is a long-term monitoring program established by the US Geological Survey in the 1960s to track changes in the streamflow and stream chemistry in undeveloped watersheds across the USA. Trends in stream chemistry were tested at 15 HBN stations over two periods (1970-2010 and 1990-2010) using the parametric Load Estimator (LOADEST) model and the nonparametric seasonal Kendall test. Trends in annual streamflow and precipitation chemistry also were tested to help identify likely drivers of changes in stream chemistry. At stations in the northeastern USA, there were significant declines in stream sulfate, which were consistent with declines in sulfate deposition resulting from the reductions in SO₂ emissions mandated under the Clean Air Act Amendments. Sulfate declines in stream water were smaller than declines in deposition suggesting sulfate may be accumulating in watershed soils and thereby delaying the stream response to improvements in deposition. Trends in stream chemistry at stations in other part of the country generally were attributed to climate variability or land disturbance. Despite declines in sulfate deposition, increasing stream sulfate was observed at several stations and appeared to be linked to periods of drought or declining streamflow. Falling water tables might have enhanced oxidation of organic matter in wetlands or pyrite in mineralized bedrock thereby increasing sulfate export in surface water. Increasing sulfate and nitrate at a station in the western USA were attributed to release of soluble salts and nutrients from soils following a large wildfire in the watershed.


Supporting Pacific Island countries to strengthen their resistance to tobacco industry interference in tobacco control: a case study of Papua New Guinea and Solomon Islands.
Tobacco use is the biggest single preventable cause of non-communicable diseases (NCDs) in the Western Pacific region. Currently, 14 Pacific Island countries have ratified the WHO Framework Convention on Tobacco Control (FCTC) and, in having done so, are committed to implementing tobacco control measures aligned with the FCTC. Progressing strong and effective tobacco control legislation is essential to achieving long term gains in public health in small island countries. However, survey evidence suggests that pervasive tobacco industry interference serves to undermine tobacco control and public policy in several Pacific countries. An initiative was developed to provide dedicated, in-country technical support for developing legislation and policy to support implementation of Article 5.3 of the FCTC in the Solomon Islands and Papua New Guinea. This paper examines the factors that have assisted the two Pacific countries to make progress in implementing Article 5.3 and what this might mean for supporting progress in other Pacific settings. A document analysis was undertaken to identify the process and outcome of the intervention. Two significant outputs from the project including having identified and documented specific examples of TII and the development of draft legislation for Article 5.3 and other key resources for public servants both within and outside the health sector. Key determinants of progress included a motivated and engaged Ministry of Health, active civil society group or champion and access to media to prepare tobacco industry related material to stimulate public and policy sector debate.


Loss of HLTF function promotes intestinal carcinogenesis.
HLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown. To address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apcmin/+ mutant background, Hltf- deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf-/-/Apcmin/+ mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apcmin/+ mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased. Taken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer.


R-spondin-3 is an oncogenic driver of poorly differentiated invasive breast cancer.
R-spondins (RSPOs) are influential signaling molecules that promote the Wnt/β-catenin pathway and self-renewal of stem cells. Currently, RSPOs are emerging as clinically relevant oncogenes, being linked to cancer development in multiple organs. Although this has instigated the rapid development and testing of therapeutic antibodies targeting RSPOs, functional evidence that RSPO causally drives cancer has focused primarily on the intestinal tract. Here, we assess the oncogenic capacity of RSPO in breast cancer in a direct fashion by generating and characterizing a novel mouse model with conditional Rspo3 expression in the mammary gland. We also address the prevalence of RSPO gene alterations in breast cancer patients. We found that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number amplifications, which are associated with lack of steroid hormone receptor expression and reduced patient survival. Foremost, we demonstrate the causal oncogenic capacity of RSPO3 in the breast, as conditional Rspo3 overexpression consistently drives the development of mammary adenocarcinomas in our novel Rspo3 breast cancer model. RSPO3-driven mammary tumors typically show poor differentiation, areas of epithelial-to-mesenchymal transition, and metastatic potential. Given the reported interplay in the Wnt/β-catenin pathway, we comparatively analyzed RSPO3-driven mouse mammary tumors versus classical WNT1-driven analogues. This revealed that RSPO3-driven tumors are distinct, as the poorly differentiated tumor morphology and metastatic potential were observed in RSPO3-driven tumorigenesis exclusively, further substantiated by differentiating gene expression profiles. Co-expression of Rspo3 and Wnt1 transduced mammary tumors with a mixed phenotype harboring morphological features characteristic of both transgenes. In summary, we report that a quarter of breast cancer patients harbor RSPO2/RSPO3 copy number gains, and these patients have a worse prognosis, whilst providing in vivo evidence that RSPO3 drives poorly differentiated invasive breast cancer in mice. Herewith, we establish RSPO3 as a driver of breast cancer with clinical relevance, proposing RSPO3 as a novel candidate target for therapy in breast cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Detection of the Entomopathogenic Fungus Beauveria bassiana in the Rhizosphere of Wound-Stressed Zea mays Plants.
Entomopathogenic fungi from the genus Beauveria (Vuillemin) play an important role in controlling insect populations and have been increasingly utilized for the biological control of insect pests. Various studies have reported that Beauveria bassiana (Bals.), Vuill. also has the ability to colonize a broad range of plant hosts as endophytes without causing disease but while still maintaining the capacity to infect insects. Beauveria is often applied as an inundative spore application, but little research has considered how plant colonization may alter the ability to persist in the environment. The aim of this study was to investigate potential interactions between B. bassiana and Zea mays L. (maize) in the rhizosphere following inoculation, in order to understand the factors that may affect environmental persistence of the fungi. The hypothesis was that different isolates of B. bassiana have the ability to colonize maize roots and/or rhizosphere soil, resulting in effects to the plant microbiome. To test this hypothesis, a two-step nested PCR protocol was developed to find and amplify Beauveria in planta or in soil; based on the translation elongation factor 1-alpha (ef1α) gene. The nested protocol was also designed to enable Beauveria species differentiation by sequence analysis. The impact of three selected B. bassiana isolates applied topically to roots on the rhizosphere soil community structure and function were consequently assessed using denaturing gradient gel electrophoresis (DGGE) and MicroRespTM techniques. The microbial community structure and function were not significantly affected by the presence of the isolates, however, retention of the inocula in the rhizosphere at 30 days after inoculation was enhanced when plants were subjected to intensive wounding of foliage to crudely simulate herbivory. The plant defense response likely changed under wound stress resulting in the apparent recruitment of Beauveria in the rhizosphere, which may be an indirect defensive strategy against herbivory and/or the result of induced systemic susceptibility in maize enabling plant colonization.


The use of classroom training and simulation in the training of medical responders for airport disaster.
There is a dire need to have complementary form of disaster training which is cost effective, relatively easy to conduct, comprehensive, effective and acceptable. This will complement field drills training. A classroom-based training and simulation module was built by combining multiple tools: Powerpoint lectures, simulations utilising the Kuala Lumpur International Airport (KLIA) schematic module into 'floortop' model and video show of previous disaster drill. 76 participants made up of medical responders, categorised as Level 1 (specialists and doctors), Level 2 (paramedics), Level 3 (assistant paramedics) and Level 4 (health attendants and drivers) were trained using this module. A pre-test with validated questions on current airport disaster plans was carried out before the training. At the end of training, participants answered similar questions as post-test. Participants also answered questionnaire for assessment of training's acceptance. There was a mean rise from 47.3 (18.8%) to 84.0 (18.7%) in post-test (p<0.05). For Levels 1, 2, 3 and 4 the scores were 94.8 (6.3)%, 90.1 (11)%, 80.3 (20.1)% and 65 (23.4)% respectively. Nevertheless Level 4 group gained most increase in knowledge rise from baseline pre-test score (51.4%). Feedback from the questionnaire showed that the training module was highly acceptable. A classroom-based training can be enhanced with favourable results. The use of classroom training and simulation effectively improves the knowledge of disaster plan significantly on the back of its low cost, relatively-easy to conduct, fun and holistic nature. All Levels of participants (from specialists to drivers) can be grouped together for training. Classroom training and simulation can overcome the problem of "dead-document" phenomenon or "paper-plan syndrome".


Additional hepatic 166Ho-radioembolization in patients with neuroendocrine tumours treated with 177Lu-DOTATATE; a single center, interventional, non-randomized, non-comparative, open label, phase II study (HEPAR PLUS trial).
Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE. The HEPAR PLUS trial ("Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-DOTATATE in Salvage NET patients") is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30-48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry. This is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects. Clinicaltrials.gov NCT02067988 , 13 February 2014. Protocol version: 6, 30 november 2016.


SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis.
Mechanisms underlying global changes in gene expression during tumour progression are poorly understood. SATB1 is a genome organizer that tethers multiple genomic loci and recruits chromatin-remodelling enzymes to regulate chromatin structure and gene expression. Here we show that SATB1 is expressed by aggressive breast cancer cells and its expression level has high prognostic significance (P < 0.0001), independent of lymph-node status. RNA-interference-mediated knockdown of SATB1 in highly aggressive (MDA-MB-231) cancer cells altered the expression of >1,000 genes, reversing tumorigenesis by restoring breast-like acinar polarity and inhibiting tumour growth and metastasis in vivo. Conversely, ectopic SATB1 expression in non-aggressive (SKBR3) cells led to gene expression patterns consistent with aggressive-tumour phenotypes, acquiring metastatic activity in vivo. SATB1 delineates specific epigenetic modifications at target gene loci, directly upregulating metastasis-associated genes while downregulating tumour-suppressor genes. SATB1 reprogrammes chromatin organization and the transcription profiles of breast tumours to promote growth and metastasis; this is a new mechanism of tumour progression.


An Immune-Responsive Cytoskeletal-Plasma Membrane Feedback Loop in Plants.
Cell wall appositions (CWAs) are produced reactively by the plant immune system to arrest microbial invasion through the local inversion of plant cell growth. This process requires the controlled invagination of the plasma membrane (PM) in coordination with the export of barrier material to the volume between the plant PM and cell wall. Plant actin dynamics are essential to this response, but it remains unclear how exocytosis and the cytoskeleton are linked in space and time to form functional CWAs. Here, we show that actin-dependent trafficking to immune response sites of Arabidopsis thaliana delivers membrane-integrated FORMIN4, which in turn contributes to local cytoskeletal dynamics. Total internal reflection fluorescence (TIRF) microscopy combined with controlled induction of FORMIN4-GFP expression reveals a dynamic population of vesicular bodies that accumulate to form clusters at the PM through an actin-dependent process. Deactivation of FORMIN4 and its close homologs partially compromises subsequent defense and alters filamentous actin (F-actin) distribution at mature CWAs. The localization of FORMIN4 is stable and segregated from the dynamic traffic of the endosomal network. Moreover, the tessellation of FORMIN4 at the PM with meso-domains of PEN3 reveals a fine spatial segregation of destinations for actin-dependent immunity cargo. Together, our data suggest a model where FORMIN4 is a spatial feedback element in a multi-layered, temporally defined sequence of cytoskeletal response. This positional feedback makes a significant contribution to the distribution of actin filaments at the dynamic CWA boundary and to the outcomes of pre-invasion defense.


Role of vitamin D in insulin resistance.
Vitamin D is characterized as a regulator of homeostasis of bone and mineral metabolism, but it can also provide nonskeletal actions because vitamin D receptors have been found in various tissues including the brain, prostate, breast, colon, pancreas, and immune cells. Bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation are all biological functions of vitamin D. Vitamin D may play an important role in modifying the risk of cardiometabolic outcomes, including diabetes mellitus (DM), hypertension, and cardiovascular disease. The incidence of type 2 DM is increasing worldwide and results from a lack of insulin or inadequate insulin secretion following increases in insulin resistance. Therefore, it has been proposed that vitamin D deficiency plays an important role in insulin resistance resulting in diabetes. The potential role of vitamin D deficiency in insulin resistance has been proposed to be associated with inherited gene polymorphisms including vitamin D-binding protein, vitamin D receptor, and vitamin D 1 alpha-hydroxylase gene. Other roles have been proposed to involve immunoregulatory function by activating innate and adaptive immunity and cytokine release, activating inflammation by upregulation of nuclear factor κB and inducing tumor necrosis factor α, and other molecular actions to maintain glucose homeostasis and mediate insulin sensitivity by a low calcium status, obesity, or by elevating serum levels of parathyroid hormone. These effects of vitamin D deficiency, either acting in concert or alone, all serve to increase insulin resistance. Although there is evidence to support a relationship between vitamin D status and insulin resistance, the underlying mechanism requires further exploration. The purpose of this paper was to review the current information available concerning the role of vitamin D in insulin resistance.


Database management using optical array logic.
Database management is considered as an application of optical array logic. To generalize the problem, a systematic procedure for massively parallel data processing that consists of pattern expansion, template matching, magnitude comparison, and sorting is presented. With this procedure, a method for implementing basic operations for relational database models is developed. Basic operations are described by parallel programs in optical array logic. Developed programs are evaluated by their performance. To improve the performance, the development of specialized optical functional modules is needed.


Postnatal development of the primate hippocampal formation.
The hippocampal formation is a multicomponent region of the medial temporal lobe preferentially involved in declarative and relational memory processing. Behavioral studies have suggested a protracted functional maturation of these structures in primates, and postnatal developmental abnormalities in the hippocampal formation are thought to contribute to neurodevelopmental disorders, such as autism, schizophrenia, epilepsy and Down syndrome. Despite all that we know about the functional organization of the adult hippocampal formation, notably absent is a systematic study of its postnatal maturation in primates. In this article, we review current knowledge of the structural development of the primate hippocampal formation and present new data on its postnatal neuroanatomical development. We summarize what is known about the neurobiological processes, such as the addition of new neurons, the establishment and elaboration of connectivity, and the neurochemical changes, that underlie the structural development and functional maturation of the primate hippocampal formation. We conclude that there is yet insufficient information to identify distinct developmental windows during which different hippocampal regions undergo specific maturational processes. For this reason, it is currently impossible to determine the ages at which specific hippocampal circuits become structurally mature and potentially capable of supporting defined, age-specific functional processes. Together with work in rodents, systematic studies of the structural development and functional maturation of the monkey hippocampal formation will be necessary to gain insight not only into the types of information processing that it subserves, but also into the specific maturational processes that might be affected in human neurodevelopmental disorders.


[Molecular tests of mitochondrial genome].
Mitochondria are considered to have originated from the symbiotic invasion of bacteria with aerobic ATP production into pro-eukaryotic cells about two billion years ago. For this evolutionary reason, mitochondria have maintained their own genome. Mitochondrial DNA is circular and is inherited maternally. Thus, mitochondrial DNA has characteristics different from nuclear DNA. Human mitochondrial DNA is small, about 16.5kbp in length, and encodes only two rRNAs, 22 tRNAs, and 13 proteins. However, the mitochondrial genome is essential for normal integrity of the mitochondrial electron transfer system (or respiratory chain). The electron transfer system is not only responsible for about 90% of cellular ATP production but is also closely linked to the metabolism of fatty acids, amino acids, and nucleic acids. In addition, its lack of integrity can cause overproduction of reactive oxygen species. Therefore, mutations of the mitochondrial genome are currently believed to be involved in many common diseases as well as classical mitochondrial neuromyopathies. Accordingly, more researchers have begun to take an interest in the association of mitochondrial DNA polymorphisms with aging and common diseases such as cancer, diabetes, neurodegeneration, and so on.


Nipple reconstruction using the C-V flap technique: a long-term evaluation.
Numerous procedures are available for nipple reconstruction with no true universal favorite. This study presents long-term follow-up data for nipple reconstruction using the C-V flap technique. Patients were identified by searching the Breast Reconstruction Database, and they were asked to return for a follow-up visit. All those who underwent nipple reconstruction using the C-V flap technique between January of 1992 and December of 1996 were reviewed in an attempt to conduct a long-term follow-up evaluation. The response was poor, and 11 patients participated in the study and returned for follow-up. They all completed a questionnaire, which focused on patient satisfaction using a visual analogue scale. Nipple measurements were taken with a caliper and compared with the opposite breast for symmetry. Fourteen nipple reconstructions were evaluated in 11 patients with an average follow-up of 5.3 years. All patients had undergone transverse rectus abdominis musculocutaneous (TRAM) flap reconstructions. Patient satisfaction was 42 percent with nipple projection, 62 percent with pigmentation, and 26 percent with sensation. Overall patient satisfaction with the procedure was 81 percent. Average nipple projection of the reconstructed nipple was 3.77 mm and was not statistically different when compared with the opposite nipple. Long-term subjective evaluation of the C-V flap technique does report a loss in nipple projection; however, overall patient satisfaction at 5.3 years is good, as is the ability to restore symmetry with the opposite breast.


Deficiency of immunity to poliovirus type 3: a lurking danger?
Europe was certified to be polio-free in 2002 by the WHO. However, wild polioviruses remain endemic in India, Pakistan, Afghanistan, and Nigeria, occasionally causing polio outbreaks, as in Tajikistan in 2010. Therefore, effective surveillance measures and vaccination campaigns remain important. To determine the poliovirus immune status of a German study population, we retrospectively evaluated the seroprevalence of neutralizing antibodies (NA) to the poliovirus types 1, 2 and 3 (PV1, 2, 3) in serum samples collected from 1,632 patients admitted the University Hospital of Frankfurt am Main, Germany, in 2001, 2005 and 2010. Testing was done by using a standardized microneutralization assay. Level of immunity to PV1 ranged between 84.2% (95%CI: 80.3-87.5), 90.4% (88.3-92.3) and 87.5% (85.4-88.8) in 2001, 2005 and 2010. For PV2, we found 90.8% (87.5-90.6), 91.3% (89.3-93.1) and 89.8% (88.7-90.9), in the same period. Seroprevalence to PV3 was 76.6% (72.2-80.6), 69.8% (66.6-72.8) and 72.9% (67.8-77.5) in 2001 and 2005 and 2010, respectively. In 2005 and 2010 significant lower levels of immunity to PV3 in comparison to PV1 and 2 were observed. Since 2001, immunity to PV3 is gradually, but not significantly decreasing. Immunity to PV3 is insufficient in our cohort. Due to increasing globalization and worldwide tourism, the danger of polio-outbreaks is not averted - even not in developed countries, such as Germany. Therefore, vaccination remains necessary.


Personal Therapy and Self-Care in the Making of Psychologists.
Psychologists are skilled in assessing, researching, and treating patients' distress, but frequently experience difficulty in applying these talents to themselves. The authors offer 13 research-supported and theoretically neutral self-care strategies catered to psychologists and those in training: valuing the person of the psychologist, refocusing on the rewards, recognizing the hazards, minding the body, nurturing relationships, setting boundaries, restructuring cognitions, sustaining healthy escapes, maintaining mindfulness, creating a flourishing environment, cultivating spirituality and mission, fostering creativity and growth, and profiting from personal therapy. The latter deserves special emphasis in the making of health care psychologists. These strategies are recommended both during training and throughout the career span. Recommendations are offered for enhancing and publicizing systems of self-care throughout the profession.


Host Genetic Variants Potentially Associated With SARS-CoV-2: A Multi-Population Analysis.
Clinical outcomes of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showed enormous inter-individual and inter-population differences, possibly due to host genetics differences. Earlier studies identified single nucleotide polymorphisms (SNPs) associated with SARS-CoV-1 in Eastern Asian (EAS) populations. In this report, we aimed at exploring the frequency of a set of genetic polymorphisms that could affect SARS-CoV-2 susceptibility or severity, including those that were previously associated with SARS-CoV-1. We extracted the list of SNPs that could potentially modulate SARS-CoV-2 from the genome wide association studies (GWAS) on SARS-CoV-1 and other viruses. We also collected the expression data of these SNPs from the expression quantitative trait loci (eQTLs) databases. Sequences from Qatar Genome Programme (QGP, n = 6,054) and 1000Genome project were used to calculate and compare allelic frequencies (AF). A total of 74 SNPs, located in 10 genes: ICAM3, IFN-γ, CCL2, CCL5, AHSG, MBL, Furin, TMPRSS2, IL4, and CD209 promoter, were identified. Analysis of Qatari genomes revealed significantly lower AF of risk variants linked to SARS-CoV-1 severity (CCL2, MBL, CCL5, AHSG, and IL4) compared to that of 1000Genome and/or the EAS population (up to 25-fold change). Conversely, SNPs in TMPRSS2, IFN-γ, ICAM3, and Furin were more common among Qataris (average 2-fold change). Inter-population analysis showed that the distribution of risk alleles among Europeans differs substantially from Africans and EASs. Remarkably, Africans seem to carry extremely lower frequencies of SARS-CoV-1 susceptibility alleles, reaching to 32-fold decrease compared to other populations. Multiple genetic variants, which could potentially modulate SARS-CoV-2 infection, are significantly variable between populations, with the lowest frequency observed among Africans. Our results highlight the importance of exploring population genetics to understand and predict COVID-19 outcomes. Indeed, further studies are needed to validate these findings as well as to identify new genetic determinants linked to SARS-CoV-2.


Reinforcement learning in children with FASD.
It is often said that children with Fetal Alcohol Spectrum Disorder (FASD) have difficulty learning from reinforcement. However, there is little empirical evidence to support or deny this claim. To examine reinforcement learning in children with FASD, specifically: (1) the rate of learning from reinforcement; and (2) the impact of concreteness of the reinforcer. Participants included 18 children with FASD (IQ ≥ 70), ages 11-17, and 18 age- and sex-matched controls. Participants each completed a novel reinforcement learning discrimination task that involved visual probabilistic learning (70% contingent feedback). The task was completed twice, once with tokens, and once with points (counterbalanced). The control group demonstrated significantly stronger overall reinforcement learning, although rates of improvement and effect of concreteness of the reinforcer (tokens vs. points) were not different between groups. The FASD group's responses were more likely to be guided by the most recent information, rather than based on integration of reward status over multiple trials. Reinforcement learning does not appear to occur in a functionally different manner in children with FASD, but does take longer, and is more impacted by recent reward than an integration of overall reinforcement information. Children with FASD without an intellectual disability may be able to learn from reinforcement given sufficient consistent repetition. However, other failures associated with learning difficulties such as the complexity of the material, transfer of learning, or impulsivity were not addressed in this study.


Renal trauma in a Trauma Intensive Care Unit population.
For the majority of renal injuries, non-operative management is the standard of care with nephrectomy reserved for those with severe trauma. This study in a dedicated Trauma Intensive Care Unit (TICU) population aimed to assess the outcomes of renal injuries and identify factors that predict the need for nephrectomy. Patients, older than 18 years, admitted to TICU from January 2007 to December 2014 who sustained renal injuries had data extracted from the prospectively collected Class Approved Trauma Registry (BCA207-09). Patients who underwent surgical intervention for the renal injury or received non-operative management were compared. The key variables analysed were: patient demographics, mechanism of injury, grade of renal injury, presenting haemoglobin, initial systolic blood pressure, Injury Severity Score and Renal Injury AAST Grade on CT scan in patients who did not necessarily require immediate surgery, or at surgery in those patients who needed emergency laparotomy. There were 74 confirmed renal injuries. There were 42 low grade injuries (grade I-III) and 32 high grade injuries (5 grade IV and 27 grade V). Twenty-six (35%) had a nephrectomy: 24 with grade V injuries and 2 with grade IV injuries required nephrectomy. Six patients in the high injury grade arm had non-operative management. A low haemoglobin, low systolic blood pressure, higher injury severity score, and a high-grade renal injury, as well as increasing age were positive predictors for nephrectomy in trauma patients with renal injury. Non-operative management is a viable option with favourable survival rates in lower grade injury; however, complications should be anticipated and managed accordingly. High grade injuries predict the need for surgery.


The production of species-specific highly unsaturated fatty acyl-containing LCOs from Rhizobium leguminosarum bv. trifolii is stringently regulated by nodD and involves the nodRL genes.
A proportion of the Nod factors of some Rhizobium leguminosarum bv. trifolii strains is characterized by the presence of highly unsaturated fatty acyl chains containing trans double bonds in conjugation with the carbonyl group of the glycan oligosaccharide backbone. These fatty acyl chains are C18:3, C20:3, C18:4, or C20:4 and have UV-absorption maxima at 303 and 330 nm. These Nod factors are presumed to be important for host-specific nodulation on clover species. However, in wild-type R. leguminosarum bv. trifolii ANU843, Nod factors with these characteristic acyl chains were not observed using standard growth conditions. They were observed only when nod genes were present in multiple copies or when transcription was artificially increased to higher levels by introduction of extra copies of the transcriptional regulator gene nodD. In a screen for the genetic requirements for production of the Nod factors with these characteristic structures, it was found that the region downstream of nodF and nodE is essential for the presence of highly unsaturated fatty acyl moieties. Mu-lacZ insertion in this region produced a mutant that did not produce detectable levels of the highly unsaturated fatty acyl-bearing Nod factors. The Mu-lacZ insertion was translationally fused to a putative new gene, designated nodR, in the nodE-nodL intergenic region; however, no predicted function for the putative NodR protein has been obtained from database homology searches. In a set of 12 wild-type strains of R. leguminosarum by. trifolii originating from various geographical regions that were analyzed for the presence of a nodR-like gene, it was found that seven strains carry a homologous NodR open reading frame. Taken together, our results suggest a tightly controlled regulation of nod genes, in which we propose that it is the balance of transcriptional levels of nodFE and the nodRL genes that is critical for determining the presence of highly unsaturated fatty acyl moieties in the Nod factors produced by R. leguminosarum bv. trifolii.


Tea and coffee consumption and pathophysiology related to kidney stone formation: a systematic review.
To explore the mechanisms behind the potential protective effect of coffee and tea consumption, regarding urinary stone formation, previously demonstrated in large epidemiological studies. A systematic review was performed using the Medline, Cochrane library (CENTRAL) and Scopus databases, in concordance with the PRISMA statement. English, French and Spanish language studies, regarding the consumption of caffeinated and decaffeinated coffee and tea, and the relationship to urinary stone formation were reviewed. Meta-analyses, systematic reviews, case reports and letters, unpublished studies, posters and comments abstracts were excluded. As per the inclusion criteria, 13 studies were included in the final review. The major findings show that caffeine increases urinary excretion of calcium, sodium and magnesium, in addition to a diuretic action with consumption > 300-360 mg (approximately four cups of coffee). Together with other components of coffee, this beverage might have potential protective effects against the formation of urinary stones. Tea exerts many protective effects against stone formation, through the accompanying water intake, the action of caffeine and the effects of components with antioxidant properties. Caffeine has a hypercalciuric effect, balanced partially by a diuretic effect which appears after consumption of large quantities of caffeine. The current available literature supports in general, a potentially protective role for tea against stone formation, mainly for green tea. Additional standardization in this field of research, through specification of tea and coffee types studied, and their respective compositions, is needed for further clarification of the relation between coffee, tea and urinary stones.


Induction of cytolytic activity by anti-T3 monoclonal antibody. Activation of alloimmune memory cells and natural killer cells from normal and immunodeficient individuals.
The ability of the monoclonal antibody directed at the T3 antigen (anti-T3) to induce cytolytic activity was investigated since several agents that can activate T cells induce the acquisition of cytolytic activity in a variety of test systems. Pretreatment of human alloimmune memory cells, generated in primary long-term mixed lymphocyte cultures, with anti-T3 resulted in the induction of statistically significant specific secondary cytolytic activity and natural killer (NK) cell-like activity. No such augmentation or induction of cytolytic activity was found with anti-T3 pretreatment when syngeneic cells or inappropriate allogeneic cells (HLA-A, B antigens different from the original priming stimulus) were used as target cells and pretreatment of memory cells with anti-T4 or anti-T8 did not induce cytolytic activity to allogeneic or syngeneic target cells. Differential effects were observed when anti-T3 was added to the cytotoxicity assay in which anti-T3 pretreated alloimmune memory cells were effectors. The addition of anti-T3 to the assay prior to the introduction of target cells resulted in 39 +/- 8% inhibition of specific secondary cytolytic activity and only 5 +/- 8% inhibition of NK cell activity. NK cell activity mediated by large granular lymphocyte-enriched fraction of peripheral blood mononuclear cells (PBM) obtained from normal individuals was significantly augmented by anti-T3 when NK-sensitive cell lines MOLT-4 or K-562 were used as target cells. This augmentation in NK cell activity was not associated with nonspecific cytotoxicity to syngeneic or allogeneic PBM, and anti-T3 failed to activate the LGL fraction depleted of T cells. The monoclonal antibodies, anti-T4 or anti-T8, did not increase NK cell activity. NK cell activity mediated by PBM from eight immunodeficient individuals (four with acquired immunodeficiency syndrome and four with renal allografts) was also significantly augmented by anti-T3 pretreatment. Our findings, in addition to providing a rationale for the frequent occurrence of re-rejection episodes in renal graft recipients treated with anti-T3, suggest that anti-T3 might be utilized to enhance the cytotoxic armamentarium of immunodeficient patients.


Identification of a monoclonal antibody to abscission tissue that recognises xylose/fucose-containing N-linked oligosaccharides from higher plants.
Monoclonal antibodies raised against extracts of the rachis abscission zone of Sambucus nigra L. were selected for high reactivity towards abscission-zone proteins. One antibody (YZ1/2.23) has been shown to cross-react, by both indirect and competition enzyme-linked immunosorbent assay and by Western blotting, with a number of plant enzymes including horseradish peroxidase, rice α-glucosidase, almond β-glucosidase and the lectins from Phaseolus vulgaris and Erythrina cristagalli.The major N-linked oligosaccharide isolated from horseradish peroxidase has the sequence Manα 3(Manα6)(Xylβ2)Manβ4GlcNAcβ4(Fucα3) GlcNAc. This oligosaccharide was found to be a potent inhibitor of the binding of YZ1/2.23 to the intact glycoprotein. The common determinant is therefore contained within this structure.


Miniaturization of Mass Spectrometry Analysis Systems.
The key concepts and technologies developed in our laboratories in Purdue University for the miniaturization of mass spectrometry analysis systems are introduced. Mass analyzers of simple geometries with a novel atmospheric pressure interface were employed allowed reduction in the size of the ion trap mass spectrometer. Ambient ionization methods were developed and coupled to miniature mass spectrometers to allow direct MS analysis of complex samples without sample preparation and chemical separation. The performance of desorption electrospray ionization, low temperature plasma probe, paper spray as well as two handheld MS systems, Mini 10 and Mini 11, are described with demonstrations of capabilities for chemical analysis.


REST: a toolkit for resting-state functional magnetic resonance imaging data processing.
Resting-state fMRI (RS-fMRI) has been drawing more and more attention in recent years. However, a publicly available, systematically integrated and easy-to-use tool for RS-fMRI data processing is still lacking. We developed a toolkit for the analysis of RS-fMRI data, namely the RESting-state fMRI data analysis Toolkit (REST). REST was developed in MATLAB with graphical user interface (GUI). After data preprocessing with SPM or AFNI, a few analytic methods can be performed in REST, including functional connectivity analysis based on linear correlation, regional homogeneity, amplitude of low frequency fluctuation (ALFF), and fractional ALFF. A few additional functions were implemented in REST, including a DICOM sorter, linear trend removal, bandpass filtering, time course extraction, regression of covariates, image calculator, statistical analysis, and slice viewer (for result visualization, multiple comparison correction, etc.). REST is an open-source package and is freely available at http://www.restfmri.net.


Efficacy of three-dimensional visualization in mobile apps for patient education regarding orthognathic surgery.
'Sur-face' is an interactive mobile app illustrating different orthognathic surgeries and their potential complications. This study aimed to evaluate the efficacy of Sur-face by comparing two methods of delivering patient information on orthognathic surgeries and their related potential complications: a mobile app with interactive three-dimensional (3D) animations and a voice recording containing verbal instructions only. For each method, the participants' acquired knowledge was assessed using a custom-designed questionnaire. Participants in the 'app' group performed significantly better (P<0.0034) than those in the 'voice' group and retained more knowledge, suggesting that interactive visualizations play a key role in improving understanding of the orthognathic surgical procedure and its associated complications. This study emphasizes the impact of 3D visualizations in delivering information regarding orthognathic surgery and highlights the advantage of delivering validated patient information through mobile apps.


One lens optical correlation: application to face recognition.
Despite its extensive use, the traditional 4f Vander Lugt Correlator optical setup can be further simplified. We propose a lightweight correlation scheme where the decision is taken in the Fourier plane. For this purpose, the Fourier plane is adapted and used as a decision plane. Then, the offline phase and the decision metric are re-examined in order to keep a reasonable recognition rate. The benefits of the proposed approach are numerous: (1) it overcomes the constraints related to the use of a second lens; (2) the optical correlation setup is simplified; (3) the multiplication with the correlation filter can be done digitally, which offers a higher adaptability according to the application. Moreover, the digital counterpart of the correlation scheme is lightened since with the proposed scheme we get rid of the inverse Fourier transform (IFT) calculation (i.e., decision directly in the Fourier domain without resorting to IFT). To assess the performance of the proposed approach, an insight into digital hardware resources saving is provided. The proposed method involves nearly 100 times fewer arithmetic operators. Moreover, from experimental results in the context of face verification-based correlation, we demonstrate that the proposed scheme provides comparable or better accuracy than the traditional method. One interesting feature of the proposed scheme is that it could greatly outperform the traditional scheme for face identification application in terms of sensitivity to face orientation. The proposed method is found to be digital/optical implementation-friendly, which facilitates its integration on a very broad range of scenarios.


Treating tobacco dependence: guidance for primary care on life-saving interventions. Position statement of the IPCRG.
Tobacco smoking is the world's leading cause of premature death and disability. Global targets to reduce premature deaths by 25% by 2025 will require a substantial increase in the number of smokers making a quit attempt, and a significant improvement in the success rates of those attempts in low, middle and high income countries. In many countries the only place where the majority of smokers can access support to quit is primary care. There is strong evidence of cost-effective interventions in primary care yet many opportunities to put these into practice are missed. This paper revises the approach proposed by the International Primary Care Respiratory Group published in 2008 in this journal to reflect important new evidence and the global variation in primary-care experience and knowledge of smoking cessation. Specific for primary care, that advocates for a holistic, bio-psycho-social approach to most problems, the starting point is to approach tobacco dependence as an eminently treatable condition. We offer a hierarchy of interventions depending on time and available resources. We present an equitable approach to behavioural and drug interventions. This includes an update to the evidence on behaviour change, gender difference, comparative information on numbers needed to treat, drug safety and availability of drugs, including the relatively cheap drug cytisine, and a summary of new approaches such as harm reduction. This paper also extends the guidance on special populations such as people with long-term conditions including tuberculosis, human immunodeficiency virus, cardiovascular disease and respiratory disease, pregnant women, children and adolescents, and people with serious mental illness. We use expert clinical opinion where the research evidence is insufficient or inconclusive. The paper describes trends in the use of waterpipes and cannabis smoking and offers guidance to primary-care clinicians on what to do faced with uncertain evidence. Throughout, it recognises that clinical decisions should be tailored to the individual's circumstances and attitudes and be influenced by the availability and affordability of drugs and specialist services. Finally it argues that the role of the International Primary Care Respiratory Group is to improve the confidence as well as the competence of primary care and, therefore, makes recommendations about clinical education and evaluation. We also advocate for an update to the WHO Model List of Essential Medicines to optimise each primary-care intervention. This International Primary Care Respiratory Group statement has been endorsed by the Member Organisations of World Organization of Family Doctors Europe.


Biochemical and genetic analysis of ANK in arthritis and bone disease.
Mutations in the progressive ankylosis gene (Ank/ANKH) cause surprisingly different skeletal phenotypes in mice and humans. In mice, recessive loss-of-function mutations cause arthritis, ectopic crystal formation, and joint fusion throughout the body. In humans, some dominant mutations cause chondrocalcinosis, an adult-onset disease characterized by the deposition of ectopic joint crystals. Other dominant mutations cause craniometaphyseal dysplasia, a childhood disease characterized by sclerosis of the skull and abnormal modeling of the long bones, with little or no joint pathology. Ank encodes a multiple-pass transmembrane protein that regulates pyrophosphate levels inside and outside tissue culture cells in vitro, but its mechanism of action is not yet clear, and conflicting models have been proposed to explain the effects of the human mutations. Here, we test wild-type and mutant forms of ANK for radiolabeled pyrophosphate-transport activity in frog oocytes. We also reconstruct two human mutations in a bacterial artificial chromosome and test them in transgenic mice for rescue of the Ank null phenotype and for induction of new skeletal phenotypes. Wild-type ANK stimulates saturable transport of pyrophosphate ions across the plasma membrane, with half maximal rates attained at physiological levels of pyrophosphate. Chondrocalcinosis mutations retain apparently wild-type transport activity and can rescue the joint-fusion phenotype of Ank null mice. Craniometaphyseal dysplasia mutations do not transport pyrophosphate and cannot rescue the defects of Ank null mice. Furthermore, microcomputed tomography revealed previously unappreciated phenotypes in Ank null mice that are reminiscent of craniometaphyseal dysplasia. The combination of biochemical and genetic analyses presented here provides insight into how mutations in ANKH cause human skeletal disease.


Lack of generalization between explicit and implicit visuomotor learning.
Visuomotor adaptation has been thought to occur implicitly, although recent findings suggest that it involves both explicit and implicit processes. Here, we investigated generalization between an explicit condition, in which subjects reached toward imaginary targets under a veridical visuomotor condition, and an implicit condition, in which subjects reached toward visual targets under a 30-degree counterclockwise rotation condition. In experiment 1, two groups of healthy young adults first experienced either the explicit or the implicit condition, then the other condition. The third group experienced the explicit, then the implicit condition with an instruction that the same cognitive strategy could be used in both conditions. Results showed that initial explicit learning did not facilitate subsequent implicit learning, or vice versa, in the first two groups. Subjects in the third group performed better at the beginning of the implicit condition, but still had to adapt to the rotation gradually. In experiment 2, three additional subject groups were tested. One group experienced the explicit, then an implicit condition in which the rotation direction was opposite (30-degree clockwise rotation). Generalization between the conditions was still minimal in that group. Two other groups experienced either the explicit or implicit condition, then performed reaching movements without visual feedback. Those who experienced the explicit condition did not demonstrate aftereffects, while those who experienced the implicit condition did. Collectively, these findings suggest that visuomotor adaptation primarily involves implicit processes, and that explicit processes can add up in a complementary fashion as individuals become increasingly aware of the perturbation.


Differential roles of Angiotensinogen and Angiotensin Receptor type 1 polymorphisms in breast cancer risk.
While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1-1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1-2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.


A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats.
Szechuan peppers contain hydroxy-α-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-α-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal.


Hydroxycinnamic acid ethyl esters as precursors to ethylphenols in wine.
A method for determining ethyl coumarate and ethyl ferulate in wine using GC-MS with deuterium-labeled analogues has been developed and used to measure the evolution of these two esters during the production of two commercial monovarietal red wines, cv. Grenache and Shiraz. During fermentation, the concentration of ethyl coumarate rose from low levels to 0.4 mg/L in Grenache and 1.6 mg/L in Shiraz wines. These concentrations then increased further during barrel aging to 1.4 and 3.6 mg/L, respectively. The concentration of ethyl ferulate was much lower, reaching a maximum of only 0.09 mg/L. Conversion of ethyl coumarate and ethyl ferulate to their corresponding ethylphenols was observed during fermentations of a synthetic medium with two strains of Dekkera bruxellensis (AWRI 1499 and AWRI 1608), while a third (strain AWRI 1613) produced no ethylphenols at all from these precursors. Strains AWRI 1499 and 1608 produced 4-ethylphenol from ethyl coumarate in 68% and 57% yields, respectively. The corresponding yields of 4-ethylguaiacol from ethyl ferulate were much lower, 7% and 3%. Monitoring of ethyl coumarate and ethyl ferulate concentration during the Dekkera fermentations showed that the selectivity for ethylphenol production according to yeast strain and the precursor was principally a result of variation in esterase activity. Consequently, ethyl coumarate can be considered to be a significant precursor to 4-ethylphenol in wines affected by these two strains of Brettanomyces/Dekkera yeast, while ethyl ferulate is not an important precursor to 4-ethylguaiacol.


Updated Reported Distribution of Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus (Diptera: Culicidae) in the United States, 1995-2016.
Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) are potential vectors of Zika, dengue, and chikungunya viruses in the United States. A Zika virus outbreak in Florida in the summer of 2016, driven by Ae. aegypti and resulting in > 200 locally acquired cases of human illness, underscored the need for up-to-date information on the geographic distribution of Ae. aegypti and Ae. albopictus in the United States. In early 2016, we conducted a survey and literature review to compile county records for presence of Ae. aegypti and Ae. albopictus in the United States from 1995 to 2016. Surveillance for these vectors was intensified across the United States during the summer and fall of 2016. At the end of 2016, we therefore conducted a follow-up survey of mosquito control agencies, university researchers, and state and local health departments to document new collection records for Ae. aegypti and Ae. albopictus. The repeated survey at the end of the year added Ae. aegypti collection records from 38 new counties and Ae. albopictus collection records from 127 new counties, representing a 21 and 10 percent increase, respectively, in the number of counties with reported presence of these mosquitoes compared with the previous report. Moreover, through our updated survey, 40 and 183 counties, respectively, added additional years of collection records for Ae. aegypti and Ae. albopictus from 1995 to 2016. Our findings underscore the continued need for systematic surveillance of Ae. aegypti and Ae. albopictus.


District nurses' perceptions of the concept of delegating administration of medication to home care aides working in the municipality: a discrepancy between legal regulations and practice.
To describe district nurses' perceptions of the concept of delegating medication management to unlicensed personnel working in municipal social care. The delegation of medical tasks involves responsibility and is regulated by law to avoid damage and injuries and to protect the patient. The delegation of the administration of medication is a multifaceted task. The delegating district nurse is responsible for the outcome and should also follow up the delegated task. A descriptive qualitative study, involving semi-structured interviews and content analysis. Twenty district nurses were interviewed. The interviews were audio taped. The data were collected from April 2009-August 2010 and analysed using content analysis. The findings revealed that the statutes of delegation appear to be incompatible with practice, however, mostly due to lack of time. Communication between district nurses and home care aides, as well as tutoring, was regarded as important. The district nurses found it imperative to be available to the home care aides and made an effort to create a trusting atmosphere. District nurses cannot manage their workload without delegating the administration of medication in the present organisational model of health care and social care. The statutes regarding delegating medicine tasks are also cumbersome and difficult to incorporate for district nurses who are responsible for the delegation. The findings elucidate the current situation as regards district nurses and the need to delegate the administration of medication. Health care and social care for home-dwelling older patients, as well as statutes, needs to be evaluated and updated to meet and be prepared for the increasing demands of care.


Economic impact of HIV and antiretroviral therapy on education supply in high prevalence regions.
We set out to estimate, for the three geographical regions with the highest HIV prevalence, (sub-Saharan Africa [SSA], the Caribbean and the Greater Mekong sub-region of East Asia), the human resource and economic impact of HIV on the supply of education from 2008 to 2015, the target date for the achievement of Education For All (EFA), contrasting the continuation of access to care, support and Antiretroviral therapy (ART) to the scenario of universal access. A costed mathematical model of the impact of HIV and ART on teacher recruitment, mortality and absenteeism (Ed-SIDA) was run using best available data for 58 countries, and results aggregated by region. It was estimated that (1) The impact of HIV on teacher supply is sufficient to derail efforts to achieve EFA in several countries and universal access can mitigate this. (2) In SSA, the 2008 costs to education of HIV were about half of those estimated in 2002. Providing universal access for teachers in SSA is cost-effective on education returns alone and provides a return of $3.99 on the dollar. (3) The impacts on education in the hyperendemic countries in Southern Africa will continue to increase to 2015 from its 2008 level, already the highest in the world. (4) If treatment roll-out is successful, numbers of HIV positive teachers are set to increase in all the regions studied. The return on investing in care and support is also greater in those areas with highest impact. SSA requires increased investment in teacher support, testing and particularly ART if it is to achieve EFA. The situation for teachers in the Caribbean and East Asia is similar but on a smaller scale proportionate to the lower levels of infection and greater existing access to care and support.


Cholangiocarcinoma: diagnosis and evaluation of resectability by CT and sonography as procedures complementary to cholangiography.
The purpose of this study was to evaluate the usefulness of CT and sonography as procedures complementary to cholangiography in the detection and staging of cholangiocarcinoma. The studies of 42 patients with pathologically proved cholangiocarcinoma and preoperative CT (26 patients), sonography (30 patients), and cholangiography (31 patients) were reviewed blindly and retrospectively. The tumor was shown by CT in 69%, by sonography in 47%, and by cholangiography in 97% of patients. Three radiographic types of cholangiocarcinoma were identified: infiltrating stenotic (69%), bulky exophytic (19%), and polypoid intraluminal (12%). CT correctly staged 54%, sonography 50%, and cholangiography 58% of tumors as resectable (40%) or unresectable (60%). The sensitivities in detecting unresectability with CT, sonography, and cholangiography were 44%, 19%, and 43%, respectively; specificities were 78%, 100%, and 100%, respectively. CT and sonography combined with cholangiography increased the sensitivities to 64% and 50%, respectively. CT and sonography were complementary to cholangiography because they helped determine the extrabiliary extent of these tumors and therefore provided information on resectability.


Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor.
The transforming protein of a primate sarcoma virus and a platelet-derived growth factor are derived from the same or closely related cellular genes. This conclusion is based on the demonstration of extensive sequence similarity between the transforming protein derived from the simian sarcoma virus onc gene, v-sis, and a human platelet-derived growth factor. The mechanism by which v-sis transforms cells could involve the constitutive expression of a protein with functions similar or identical to those of a factor active transiently during normal cell growth.


Genetic variation and phylogenetics of Lanyu and exotic pig breeds in Taiwan analyzed by nineteen microsatellite markers.
The Lanyu pig is an indigenous miniature pig breed on Lanyu Islet near Taiwan, with a mitochondrial DNA genetic lineage remote from Asian and European pig breeds. The unknown population genetic structure and increased inbreeding among the small population of conserved Lanyu pigs is now of great conservation concern. Additionally, the presence for more than a century of exotic pig breeds in Taiwan has made gene introgression from exotic pig breeds into Lanyu pigs very possible. The present study thus aimed to investigate nuclear genetic variation within the conserved Lanyu pigs and the phylogenetic relationship and possible genetic introgression between Lanyu and exotic pig breeds by determining the polymorphism of 19 microsatellite loci. In the neighbor-joining tree constructed from 7 pig breeds based on Cavalli-Sforza and Edward chord genetic distances, 3 major clades were recognized, in which the Asian and European breeds were separately clustered into 2 clades with a 93.0 and 99.9% bootstrap confidence value, respectively. All individuals of the Lanyu breed formed a unique subclade within the Asian clade based on the distance of the proportion of shared alleles, -ln(ps), suggesting that the Lanyu breed possesses a unique nuclear genetic structure and that no nuclear gene introgression from exotic breeds into the conserved Lanyu pigs has occurred in recent history. Fifteen of 19 microsatellite loci deviated from Hardy-Weinberg equilibrium (by Wright's statistic), suggesting a significant loss of heterozygosity in the conserved population. The valuable nuclear genetic structure and phylogenetic information should assist future conservation and population management of Lanyu pigs.


Compact terahertz wave polarizing beam splitter.
We designed a compact terahertz (THz) wave polarizing beam splitter based on a periodic bilayer structure, which operates over a wide THz wavelength range. Within a short length (about 1 mm), this polarizing beam splitter separates THz wave TE- and TM-polarized modes into orthogonal output waveguides. Results of simulations with the finite-element method show that 99.99% of the TE-polarized THz wave is deflected by the periodic bilayer structure (with 39.9 dB extinction ratio), whereas 99.58% of the TM-polarized THz wave propagates through the structure (with a 23.7 dB extinction ratio). Tolerance analysis reveals a large tolerance to fabrication errors.


Feature Selection for Ridge Regression with Provable Guarantees.
We introduce single-set spectral sparsification as a deterministic sampling-based feature selection technique for regularized least-squares classification, which is the classification analog to ridge regression. The method is unsupervised and gives worst-case guarantees of the generalization power of the classification function after feature selection with respect to the classification function obtained using all features. We also introduce leverage-score sampling as an unsupervised randomized feature selection method for ridge regression. We provide risk bounds for both single-set spectral sparsification and leverage-score sampling on ridge regression in the fixed design setting and show that the risk in the sampled space is comparable to the risk in the full-feature space. We perform experiments on synthetic and real-world data sets; a subset of TechTC-300 data sets, to support our theory. Experimental results indicate that the proposed methods perform better than the existing feature selection methods.


Social Media in the Dental School Environment, Part A: Benefits, Challenges, and Recommendations for Use.
Social media consist of powerful tools that impact not only communication but relationships among people, thus posing an inherent challenge to the traditional standards of who we are as dental educators and what we can expect of each other. This article examines how the world of social media has changed dental education. Its goal is to outline the complex issues that social media use presents for academic dental institutions and to examine these issues from personal, professional, and legal perspectives. After providing an update on social media, the article considers the advantages and risks associated with the use of social media at the interpersonal, professional, and institutional levels. Policies and legal issues of which academic dental institutions need to be aware from a compliance perspective are examined, along with considerations and resources needed to develop effective social media policies. The challenge facing dental educators is how to capitalize on the benefits that social media offer, while minimizing risks and complying with the various forms of legal constraint.


A new perceptual illusion reveals mechanisms of sensory decoding.
Perceptual illusions are usually thought to arise from the way sensory signals are encoded by the brain, and indeed are often used to infer the mechanisms of sensory encoding. But perceptual illusions might also result from the way the brain decodes sensory information, reflecting the strategies that optimize performance in particular tasks. In a fine discrimination task, the most accurate information comes from neurons tuned away from the discrimination boundary, and observers seem to use signals from these 'displaced' neurons to optimize their performance. We wondered whether using signals from these neurons might also bias perception. In a fine direction discrimination task using moving random-dot stimuli, we found that observers' perception of the direction of motion is indeed biased away from the boundary. This misperception can be accurately described by a decoding model that preferentially weights signals from neurons whose responses best discriminate those directions. In a coarse discrimination task, to which a different decoding rule applies, the same stimulus is not misperceived, suggesting that the illusion is a direct consequence of the decoding strategy that observers use to make fine perceptual judgments. The subjective experience of motion is therefore not mediated directly by the responses of sensory neurons, but is only developed after the responses of these neurons are decoded.


Intravenous ethanol can provide bronchodilatation in asthma.
1. The effect of intravenous infusions of saline, and 2, 4 and 8% (v/v in saline) ethanol in airflow were assessed in five normal male subjects and five male patients with asthma. 2. Normal subjects showed no response to intravenous ethanol at any dose. 3. In patients with asthma, specific airways conductance (sGaw) showed a sustained rise of approx. 32.8% from baseline with 8% ethanol which was not seen at lower doses. By contrast, salbutamol (400 micrograms by aerosol) caused a mean rise in sGaw of 84.4% from baseline. 4. Blood ethanol concentrations showed a sustained rise over the full duration of the study with 8% ethanol but not with lower doses. 5. Ethanol causes a sustained improvement in sGaw in patients with asthma (38.9% of the response to salbutamol) if blood ethanol levels are sufficiently elevated.


Structural and ultrastructural evaluation of the aortic wall after transplantation of bone marrow-derived cells (BMCs) in a model for atherosclerosis.
Stem cells are characterized by their ability to differentiate into multiple cell lineages and display the paracrine effect. The aim of this work was to evaluate the effect of therapy with bone marrow-derived cells (BMCs) on glucose, lipid metabolism, and aortic wall remodeling in mice through the administration of a high-fat diet and subsequent BMCs transplantation. C57BL/6 mice were fed a control diet (CO group) or an atherogenic diet (AT group). After 16 weeks, the AT group was divided into 4 subgroups: an AT 14 days group and AT 21 days group that were given an injection of vehicle and sacrificed after 14 and 21 days, respectively, and an AT-BMC 14 days group and AT-BMC 21 days group that were given an injection of BMCs and sacrificed after 14 and 21 days, respectively. The BMCs transplant had reduced blood glucose, triglycerides, and total cholesterol. There was no significant difference in relation to body mass between the transplanted groups and non-transplanted groups, and all were different than CO. There was no significant difference in the glycemic curve among AT 14 days, AT-BMC 14 days, and AT 21 days, and these were different than the CO and the AT-BMC 21 days groups. The increased thickness of the aortic wall was observed in all atherogenic groups, but was significantly smaller in group AT-BMC 21 days compared to AT 14 days and AT 21 days. Vacuoles in the media tunic, delamination and the thinning of the elastic lamellae were observed in AT 14 days and AT 21 days. The smallest number of these was displayed on the AT-BMC 14 days and AT-BMC 21 days. Marking to CD105, CD133, and CD68 were observed in AT 14 days and AT 21 days. These markings were not observed in AT-BMC 14 days or in AT-BMC 21 days. Electron micrographs show the beneficial remodeling in AT-BMC 14 days and AT-BMC 21 days, and the structural organization was similar to the CO group. Vesicles of pinocytosis, projection of smooth muscle cells, and delamination of the internal elastic lamina are seen in groups AT 14 days and AT 21 days. Endothelial cells were preserved, and regular and continuous contour in internal elastic lamelae were observed in the CO, the AT-BMC 14 days, and AT-BMC 21 days groups. In conclusion, in an atherosclerotic model using mice and atherogenic diet, the injection of BMCs improves glucose, lipid metabolism, and causes a beneficial remodeling of the aortic wall.


Expression of hybrid isomyosins in human skeletal muscle.
Myosin of human skeletal muscles was analyzed by means of several electrophoretic techniques. Myosin heavy chain (HC)-IIa-and HC-IIb-based isomyosins were identified by pyrophosphate-polyacrylamide gel electrophoresis (PP-PAGE). The electrophoretic mobilities of these fast-twitch muscle isomyosins differed in the order HC-IIa triplets < HC-IIb triplets. To determine the subunit composition of myosin molecules that function in intact muscle, two-dimensional electrophoresis in which the first and second dimensions were PP-PAGE and sodium dodecyl sulfate-PAGE, respectively, was also performed. Slow-twitch muscle isomyosin contained, in addition to slow-twitch light chain (LC) and HC-I isoforms, appreciable amounts of LC-2f, HC-IIa, and HC-IIb isoforms, and fast-twitch muscle isomyosin consisted of LC-2s and HC-I isoforms as well as fast-twitch LC and HC isoforms. Without consideration of HC- and slow-twitch alkali LC heterodimers, at least 31 possible isomyosins are derived from these findings on the subunit composition of isomyosins in human skeletal muscle.


Enovid-induced exacerbation of the propensity for stroke in low protein fish diet-fed stroke-prone/SHR.
Weanling, male and female, stroke-prone, spontaneously hypertensive rats (SP/SHR) were fed either a regular diet, a low protein diet derived from fish tissue + 1% saline drinking water, or the fish diet + 1% saline + daily injections of 0.1 mg Enovid/100 g bw/sc. After 48 days, the Enovid-treated animals developed acute and lethal strokes characterized by massive thrombonecrogenic lesions of the parietal lobe. The blood pressure of the Enovid-treated SP/SHR rose most acutely. The low protein fish diet was markedly catabolic and caused hyperlipidemia, hyperglycemia, elevated ACTH and beta-endorphin levels concomitant with reduced gonadotrophic function. Treatment with Enovid caused severe exacerbation of all of the foregoing changes. It is proposed that a low protein fish diet + 1% saline will accelerate the appearance of strokes in SP/SHR and that Enovid will enhance this effect through its anti-gonadotrophic activity and ability to stimulate increased pituitary-adrenal secretion.


A New Stopping Rule for Computerized Adaptive Testing.
The goal of the current study was to introduce a new stopping rule for computerized adaptive testing. The predicted standard error reduction stopping rule (PSER) uses the predictive posterior variance to determine the reduction in standard error that would result from the administration of additional items. The performance of the PSER was compared to that of the minimum standard error stopping rule and a modified version of the minimum information stopping rule in a series of simulated adaptive tests, drawn from a number of item pools. Results indicate that the PSER makes efficient use of CAT item pools, administering fewer items when predictive gains in information are small and increasing measurement precision when information is abundant.


Talking about Death with Children with Incurable Cancer: Perspectives from Parents.
To investigate the rationale and consequences associated with a parent's decision to discuss death with a child with incurable cancer. We present data from a larger retrospective study involving bereaved parents of a child who died of cancer. Parents were asked whether they had discussed the impending death with their child, whether they reflected on this discussion positively, their reasons for not discussing death with their child, and the manner in which the conversation regarding death occurred. The data were analyzed qualitatively using a framework approach. Of the 86 parents of 56 children who answered the questions regarding discussing death with their child, 55 parents of 35 children did not discuss the impending death with their child. The following themes were identified: the parents' inability to discuss the impending death; the parents' desire to protect their child; views regarding talking with children; parents' views of child characteristics; the child's unwillingness to discuss the subject; lack of opportunity to talk; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they had brief, direct conversations regarding death. The majority of parents felt positive regarding their decision about whether to talk with their child about his/her impending death. Most parents in this study cited several reasons for not discussing death with their child. Our findings highlight the sensitive and complex issues surrounding these conversations, indicating that there may be a role for clinicians in supporting parents.


Pharmaceutical options for triggering of final oocyte maturation in ART.
Since the pioneering days of in vitro fertilization, hCG has been the gold standard to induce final follicular maturation. We herein reviewed different pharmaceutical options for triggering of final oocyte maturation in ART. The new upcoming agent seems to be GnRHa with its potential advantages over hCG trigger. GnRHa triggering elicits a surge of gonadotropins resembling the natural midcycle surge of gonadotropins, without the prolonged action of hCG, resulting in the retrieval of more mature oocytes and a significant reduction in or elimination of OHSS as compared to hCG triggering. The induction of final follicular maturation using GnRHa represents a paradigm shift in the ovulation triggering concept in ART and, thus, a way to develop a safer IVF procedure. Kisspeptins are key central regulators of the neuroendocrine mechanisms of human reproduction, who have been shown to effectively elicit an LH surge and to induce final oocyte maturation in IVF cycles. This new trigger concept may, therefore, offer a completely new, "natural" pharmacological option for ovulation induction. Whether kisspeptins will be the future agent to trigger ovulation remains to be further explored.


Tamoxifen: important considerations of a multi-functional compound with organ-specific properties.
Tamoxifen remains a frontline treatment for hormone-responsive breast cancer despite its use being associated with a 2-7-fold elevated risk of developing endometrial carcinoma. Several groups have investigated whether tamoxifen induces DNA-damaging (genotoxic) versus non-genotoxic mechanisms. Some studies point to the presence of tamoxifen-DNA adducts while others suggest otherwise. In many of these studies, the histological sub-type has not been considered; as type 1 carcinomas are associated with PTEN and KRAS2 mutations whereas type 2 carcinomas exhibit TP53 and ERBB-2 mutations, the absence of this information makes comparisons between such independent investigations difficult. An examination of the sub-types of endometrial carcinoma points to histological and mechanistic distinctions between sporadic and tamoxifen-associated disease; this could suggest differing aetiologies. On this basis, we propose a dual mechanism of action highlighted by the different patterns of endometrial carcinoma sub-types. Tamoxifen may initially be pro-oestrogenic in the endometrium giving rise to elevated type 1 endometrioid carcinoma occurrence whereas after long-term use, there is an increase of type 2 disease or malignant mixed mullerian tumours associated with a hormone-independent mechanism of action. Despite these associated risk factors, and the introduction of new selective oestrogen receptor modulators (SERMs), we suggest that the organ-specific pleiotrophic effects of tamoxifen mean that this effective therapeutic agent for breast cancer will continue to have significant usage. The focus of future research should concentrate on the different aetiologies of tamoxifen-associated endometrial carcinomas while efforts continue to develop future SERMs.


Emergency Department Utilization related to dental conditions and distribution of Dentists, Nebraska 2011-2013.
This study aims to provide estimates of hospital-based emergency department (ED) visits due to dental conditions in Nebraska and to examine patient-related characteristics associated with ED charges. In addition, this study provides dental-related ED visits and distribution of dentists by county. For the study, we used the State Emergency Department Database for Nebraska for the years 2011 through 2013 and the Health Resources and Services Administration's Area Health Resource File. All ED visits with dental conditions in Nebraska were selected. The primary outcome variable was hospital-based ED charges. Multivariable linear regression model was used to examine the effects of patient-related factors on ED charges. During the study period, a total of 9943 dental-related ED visits occurred. Of these, 55.5% patients aged between 25 and 44 years. Thirty-nine percent of all dental ED visits had patients who were self-financed or uninsured. Twenty counties in Nebraska do not have a dentist, and nine counties had more than 50 ED visits per 10,000 population. Patients residing in urban areas paid significantly higher charges than those living in rural towns, small rural towns, or isolated rural areas. The mean and total ED charges attributed to dental conditions for the entire study period were $934 and $9.3 million, respectively. Patients who are uninsured, aged 25-44 years, covered by private insurance, and residing in urban areas are identified to be at high risk. There is a need to develop health policies and programs to improve access to dental care in rural states.


Applications of dewetting in micro and nanotechnology.
Dewetting is a spontaneous phenomenon where a thin film on a surface ruptures into an ensemble of separated objects, like droplets, stripes, and pillars. Spatial correlations with characteristic distance and object size emerge spontaneously across the whole dewetted area, leading to regular motifs with long-range order. Characteristic length scales depend on film thickness, which is a convenient and robust technological parameter. Dewetting is therefore an attractive paradigm for organizing a material into structures of well-defined micro- or nanometre-size, precisely positioned on a surface, thus avoiding lithographical processes. This tutorial review introduces the reader to the physical-chemical basis of dewetting, shows how the dewetting process can be applied to different functional materials with relevance in technological applications, and highlights the possible strategies to control the length scales of the dewetting process.


X-ray pumping of the 229Th nuclear clock isomer.
The metastable first excited state of thorium-229, 229mTh, is just a few electronvolts above the nuclear ground state1-4 and is accessible by vacuum ultraviolet lasers. The ability to manipulate the 229Th nuclear states with the precision of atomic laser spectroscopy5 opens up several prospects6, from studies of fundamental interactions in physics7,8 to applications such as a compact and robust nuclear clock5,9,10. However, direct optical excitation of the isomer and its radiative decay to the ground state have not yet been observed, and several key nuclear structure parameters-such as the exact energies and half-lives of the low-lying nuclear levels of 229Th-remain unknown11. Here we present active optical pumping into 229mTh, achieved using narrow-band 29-kiloelectronvolt synchrotron radiation to resonantly excite the second excited state of 229Th, which then decays predominantly into the isomer. We determine the resonance energy with an accuracy of 0.07 electronvolts, measure a half-life of 82.2 picoseconds and an excitation linewidth of 1.70 nanoelectronvolts, and extract the branching ratio of the second excited state into the ground and isomeric state. These measurements allow us to constrain the 229mTh isomer energy by combining them with γ-spectroscopy data collected over the past 40 years.