Outside the Safe Operating Space of the Planetary Boundary for Novel Entities.
We submit that the safe operating space of the planetary boundary of novel entities is exceeded since annual production and releases are increasing at a pace that outstrips the global capacity for assessment and monitoring. The novel entities boundary in the planetary boundaries framework refers to entities that are novel in a geological sense and that could have large-scale impacts that threaten the integrity of Earth system processes. We review the scientific literature relevant to quantifying the boundary for novel entities and highlight plastic pollution as a particular aspect of high concern. An impact pathway from production of novel entities to impacts on Earth system processes is presented. We define and apply three criteria for assessment of the suitability of control variables for the boundary: feasibility, relevance, and comprehensiveness. We propose several complementary control variables to capture the complexity of this boundary, while acknowledging major data limitations. We conclude that humanity is currently operating outside the planetary boundary based on the weight-of-evidence for several of these control variables. The increasing rate of production and releases of larger volumes and higher numbers of novel entities with diverse risk potentials exceed societies' ability to conduct safety related assessments and monitoring. We recommend taking urgent action to reduce the harm associated with exceeding the boundary by reducing the production and releases of novel entities, noting that even so, the persistence of many novel entities and/or their associated effects will continue to pose a threat.


Sexual Dysfunction in Females after Cancer Treatment: an Unresolved Issue
Cancer besides being a leading cause of mortality also creates a myriad of morbidities in survivors whether treated or untreated. Among women surviving after gynecological malignancies sexual dysfunction is a morbidity unexplored in Indian context because of cultural barriers. With the increasing proportion of women surviving carcinoma of the cervix, quality of life has become an important clinical issue. Despite the immense distress it causes in patients, sexual dysfunction is neither screened nor treated in Indian scenario. Despite this recognition, the area is not well researched and there is a paucity of information on the impact of cancer treatment on sexual health in Indian Context. Research has shown that up to 50% of women treated for cervix cancers have sexual dysfunction as they recover and become cancer survivors. This article aims to review the phases of sexual response and how each may be affected by the physical and emotional stress of cancer diagnosis and treatment. We will then discuss existing tools for assessment of sexual function and approaches to their treatment. Finally, we will conclude with advice to health care professionals based on current research and suggest questions for future study.


What is status epilepticus and what do we know about its epidemiology?
Epidemiological studies across medical conditions share many similar difficulties relating, for instance, to selection bias, defining a population frame, statistical power and adequate documentation. However, in the case of status epilepticus there are, in addition to these, a variety of specific issues that pose significant hurdles to accurate investigation - not least defining status epilepticus itself and determining whether it is simply a severe manifestation of epilepsy or should be considered a distinct entity in its own right. In this paper, we present a historical overview of how opinions about status epilepticus have changed with time, outline some of the issues unique to the study of status epilepticus and provide personal perspectives on certain controversies within this important area of epileptology. This article focuses on adult status epilepticus as paediatric status epilepticus has been covered in a separate Seizure special edition. With a focus on status epilepticus in adults, we review salient population based studies, exploring their advantages and limitations. While it can be difficult to draw conclusions from these studies, it does seem that status epilepticus is more common in African-Americans, males and in either young children or older adults. Given demographic changes resulting in an ageing population, the incidence of status epilepticus is therefore likely to rise. We illustrate how the majority of work performed to date has been in convulsive status epilepticus and demonstrate that more needs to be done to better understand nonconvulsive status epilepticus as well as to further refine the boundaries of status epilepticus as a whole. Despite status epilepticus being common and associated with significant morbidity, our knowledge of the true epidemiology of this condition remains far from complete.


Modeling the effects of dispersion and pulsatility of blood flow in pulsed arterial spin labeling.
Arterial spin labeling (ASL) is a method of using MRI to image cerebral perfusion. For the measurement to be calibrated, a model is required describing the kinetics of the flow of the inverted blood from the labeling region to the imaging region. It is common to assume plug-flow, but alternatives such as a Gaussian distribution of arrival times have also been suggested. In this study a physiologically based model for dispersion is developed and compared to existing models when fit to experimental data. The model is based on the assumption of parabolic flow in the major arteries, and also allows inclusion of cardiac pulsatility. It was found that fitting using the proposed model leads to higher perfusion estimates, with the difference becoming more pronounced in regions where the dispersion is greater. This suggests that current models may underestimate perfusion in these areas. However, fitting using the proposed model also leads to high uncertainties in parameter estimates due to non-orthogonality of the parameters. Effects due to pulsatility are expected to be observable, but when no cardiac-gating is used the mean curve over several cardiac cycles is predicted to closely match the curve which assumes constant flow.


Disruption of vascular Ca2+-activated chloride currents lowers blood pressure.
High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction-inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension.


Intravenous metoprolol versus diltiazem for rate control in noncardiac, nonthoracic postoperative atrial fibrillation.
Little guidance exists on effective management of postoperative atrial fibrillation (POAF) following noncardiac, nonthoracic (NCNT) surgery. The purpose of this study was to identify whether a difference exists between intravenous (IV) metoprolol and diltiazem when used to achieve hemodynamically stable rate control in POAF following NCNT surgery. This retrospective cohort study examined critically ill adult surgical patients experiencing POAF with rapid ventricular response. Inclusion in the metoprolol or diltiazem treatment group was determined by the initial rate control agent chosen by the prescriber. The primary end point was hemodynamically stable rate control, defined by heart rate (HR) <110 beats/min and blood pressure >90 mm Hg, maintained for 6 hours. Patients on metoprolol (n = 66) and diltiazem (n = 55) were similar in age, comorbidities, surgical procedure distribution, acuity of illness, and home rate and rhythm control medications continued during hospitalization; 76% of diltiazem-treated patients achieved hemodynamically stable rate control, compared with only 53% of those receiving metoprolol (P = .005). Safety end points were similar between groups, including the portion requiring a new vasopressor or fluid bolus for hemodynamic support. In NCNT surgery, patients with POAF, IV diltiazem more effectively controlled HR and hemodynamics compared with metoprolol. Results warrant further research into optimal medical management of POAF in this population using these 2 agents.


Longitudinal Associations Between Metabolic Syndrome Components and Telomere Shortening.
Deterioration of metabolic syndrome (MetS) has been associated with short telomere length (TL). Large-scale longitudinal studies with repeated measures of MetS and TL are lacking. We examined whether baseline MetS components predict TL over time, and whether deteriorations in MetS parallel telomere attrition. Participants were part of The Netherlands Study of Depression and Anxiety, an ongoing prospective cohort study. This study included 1808 participants age 18-65 years. Leukocyte TL (using qPCR) and MetS components (waist circumference, triglycerides, high-density lipoprotein [HDL] cholesterol, systolic blood pressure, and fasting glucose) were determined at baseline and after 6 years. Generalized estimated equation models were used to examine the associations between baseline MetS and TL over time, and linear regressions were used to associate 6-year changes in both MetS components and TL, while adjusting for sociodemographic and lifestyle factors. Higher baseline waist circumference (B = -29.7; P = .006) and glucose (B = -26.4; P = .02), and lower HDL (B = 25.5; P = .03) were consistently associated with shorter TL over followup. Greater 6-year increase in waist circumference was associated with larger telomere attrition (B = -41.8; P = .01), and similar but nonsignificant associations were observed for larger increase in triglycerides and glucose levels. Metabolic dysregulations are associated with shorter telomeres over two time points. In particular, increasing abdominal adiposity is accompanied by accelerated telomere attrition. Future studies should elucidate underlying mechanisms of this bidirectional relationship and investigate whether targeting obesity may reduce telomere attrition to prevent further deterioration toward cardiovascular and aging-related complications.


Task-induced deactivation from rest extends beyond the default mode brain network.
Activity decreases, or deactivations, of midline and parietal cortical brain regions are routinely observed in human functional neuroimaging studies that compare periods of task-based cognitive performance with passive states, such as rest. It is now widely held that such task-induced deactivations index a highly organized 'default-mode network' (DMN): a large-scale brain system whose discovery has had broad implications in the study of human brain function and behavior. In this work, we show that common task-induced deactivations from rest also occur outside of the DMN as a function of increased task demand. Fifty healthy adult subjects performed two distinct functional magnetic resonance imaging tasks that were designed to reliably map deactivations from a resting baseline. As primary findings, increases in task demand consistently modulated the regional anatomy of DMN deactivation. At high levels of task demand, robust deactivation was observed in non-DMN regions, most notably, the posterior insular cortex. Deactivation of this region was directly implicated in a performance-based analysis of experienced task difficulty. Together, these findings suggest that task-induced deactivations from rest are not limited to the DMN and extend to brain regions typically associated with integrative sensory and interoceptive processes.


ERG rearrangement in small cell prostatic and lung cancer.
Small cell prostatic cancer is a rare but aggressive disease. Currently, its histogenetic origin is unclear and its distinction from metastatic small cell lung cancer is challenging. The aim of our study was to determine whether the ERG rearrangement commonly observed in acinar prostatic cancer can distinguish small cell prostatic cancer from small cell lung cancer samples. We assessed 15 small cell prostatic cancers and 22 small cell lung cancers for ERG rearrangement using fluorescence in situ hybridization. Commonly used and novel immunohistochemical markers (i.e. androgen receptor, calcium activated nucleotidase 1, Golgi phosphoprotein 2, prostate-specific antigen, prostate-specific membrane antigen, CD56, epithelial membrane antigen, thyroid transcription factor 1, chromogranin A, synaptophysin and Ki67) were further studied. ERG rearrangement occurred in 86% of small cell prostatic cancers but in none of the small cell lung cancers and was the best marker to differentiate between both tumours (P < 0.0001). The ERG rearrangement is commonly observed in small cell prostatic cancer, supporting the hypothesis that ERG rearrangement occurs in aggressive prostatic cancers. Furthermore, the ERG rearrangement is the most significant marker to differentiate between small cell prostatic cancer and small cell lung cancer. Moreover, our data suggest that small cell prostatic cancer is not a tumour entity on its own, but a dedifferentiated variant of common acinar prostatic cancer.


Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.
Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.


Extending inter-professional learning through the use of a multi-disciplinary Wiki.
This paper reports our experiences of a student learning activity which employed a Wiki for student radiographers and nurses to build on an inter-professional learning event. The aim of the Wiki was to facilitate inter-professional learning for students who, having met face-to-face once for a classroom based activity, would not be timetabled to meet again. It was designed to allow students from differing disciplines to: construct knowledge together, learn from and about one another, and collaboratively produce a textual learning resource. 150 nursing and radiography undergraduates were provided with a PBL trigger related to the acute presentation of stroke. The students met once (5 mixed-discipline groups) to discuss the role of the professions and the outcomes for the trigger scenario. Further learning was enabled through the provision of a Wiki for each group. At week 4, all Wikis were made visible for group peer assessment. Wiki editing skills were provided by student 'Wiki champions', who cascaded training to their peers. We report and reflect on the students' evaluations of both the Wiki as process and outcome and discuss the value of Wikis for inter-professional learning. Findings show that, in addition to being an enjoyable and flexible learning experience, the Wiki satisfied its intended aims. There was a variation in the level and quality of student participation the causes of which are discussed. Ground rules for effective Wiki use are proposed.


Non-invasive metabolomic analysis using a commercial NIR instrument for embryo selection.
Metabolomics was introduced in human in vitro fertilization (IVF) for noninvasive identification of viable embryos with the highest developmental competence. To determine whether embryo selection using a commercial version of metabolomic analysis leads to increased implantation rates (IRs) with fetal cardiac activity (FCA) compared with morphology evaluation alone. Randomized controlled trial from April to December 2010 at a private IVF unit. The study was terminated prematurely due to the market withdrawal of the instrument. IVF patients ≥18 and ≤43 years with ≥4 × 2PN were randomly allocated to metabolomic analysis combined with embryo morphology (ViaMetrics-E; metabolomics + morphology group) or embryo morphology alone (morphology group). Cycles with frozen embryos, oocyte donations, or testicular biopsy were excluded. Categorical and continuous data were analyzed for statistical significance using 2-tailed Fisher's exact test and t-test, respectively. Statistical significance was accepted when P > 0.05. A total of 125 patients were included in the study; 39 patients were allocated to metabolomics + morphology group and 86 patients to morphology group. Patients were stratified according to the day of embryo transfer (Days 2, 3, or 5). IRs with FCA were similar for Days 2 and 3 transfers in both groups. For Day 5 transfers, IRs with FCA were significantly higher in the metabolomics + morphology group (46.8% vs. 28.9%; P = 0.041; 95% confidence intervalp [CI]: 1.09-34.18). Pregnancy and live births rates were similar for Days 2, 3, and 5 in both groups. The study was terminated early following the voluntary market withdrawal of ViaMetrics-E in December 2010. Metabolomic analysis using the commercial near-infrared (NIR) instrument does not appear to have a beneficial effect on pregnancy and live births, with improvement in IR with FCA for Day 5 transfers. However, no solid conclusions can be reached due to the lack of adequate study power.ClinicalTrials.gov Identifier: NCT01490515.


The survival of Burkholderia pseudomallei in liquid media.
We studied the effect of environmental parameters on the survival of Burkholderia pseudomallei. There was a small increase in bacterial count for up to 28 days in sterilized distilled water or rain water, in water at 20 degrees C or 40 degrees C, and in buffered solutions of pH 4 or higher. Counts of culturable B. pseudomallei declined at pH 3, in the presence of seawater or water with concentrations of 4% salt or higher, and under refrigeration. The morphological appearances of B. pseudomallei changed under conditions that maintained culturable numbers from bacilli to coccoid cells and spiral forms under pH or salt stress. These observations indicate that B. pseudomallei can endure nutrient-depleted environments as well as a wide range of pH, salt concentrations, and temperatures for periods of up to 28 days. The relative stability of B. pseudomallei under these conditions underlines the tenacity of this species and its potential for natural dispersal in water: in surface water collections, in managed water distribution systems, and through rainfall. These survival properties help explain the recent expansion of the known melioidosis endemic zone in Australia and may have played a part in recent melioidosis outbreaks.


Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.


The viral and cellular microRNA targetome in lymphoblastoid cell lines.
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus linked to a number of B cell cancers and lymphoproliferative disorders. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. To date, only a limited number of EBV miRNA targets have been identified; thus, the role of EBV miRNAs in viral pathogenesis and/or lymphomagenesis is not well defined. Here, we used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined with deep sequencing and computational analysis to comprehensively examine the viral and cellular miRNA targetome in EBV strain B95-8-infected lymphoblastoid cell lines (LCLs). We identified 7,827 miRNA-interaction sites in 3,492 cellular 3'UTRs. 531 of these sites contained seed matches to viral miRNAs. 24 PAR-CLIP-identified miRNA:3'UTR interactions were confirmed by reporter assays. Our results reveal that EBV miRNAs predominantly target cellular transcripts during latent infection, thereby manipulating the host environment. Furthermore, targets of EBV miRNAs are involved in multiple cellular processes that are directly relevant to viral infection, including innate immunity, cell survival, and cell proliferation. Finally, we present evidence that myc-regulated host miRNAs from the miR-17/92 cluster can regulate latent viral gene expression. This comprehensive survey of the miRNA targetome in EBV-infected B cells represents a key step towards defining the functions of EBV-encoded miRNAs, and potentially, identifying novel therapeutic targets for EBV-associated malignancies.


Contrast enhanced ultrasound in mixed hepatocellular cholangiocarcinoma: Case series and review of the literature.
Mixed hepatocellular cholangiocarcinoma is a rare form of primary liver cancer. The aim of this study is to report the results of the use of contrast enhanced ultrasound in a series of patients with confirmed mixed hepatocellular cholangiocarcinoma and to provide an updated literature review. Between January 2012 and October 2016, 25 Asian patients with confirmed mixed hepatocellular cholangiocarcinoma were included in this bicentric retrospective analysis. Clinical data as well recorded images of a standardized conventional B-mode ultrasound and contrast-enhanced ultrasound examination were interpreted by two blinded, independent, experienced radiologists in consensus. All mixed hepatocellular cholangiocarcinoma lesions were heteroechoic on B-mode ultrasound, with ill-defined margins and irregular shapes. Arterial phase hyperenhancement was present in all 25 patients. Late-phase washout and hypoenhancement was present in 24/25 (96%) patients. However, rim-enhancement and early wash-out (which are common in cholangiocellular carcinoma) were found in over 60% of the cases. Contrast-enhanced ultrasound demonstrated findings not typical for HCC in a large proportion of patients with confirmed mixed hepatocellular cholangiocarcinoma. Therefore, histological confirmation is crucial, especially in lesions with atypical findings.


Mechanism of osteoporosis in adolescent idiopathic scoliosis: experimental scoliosis in pinealectomized chickens.
To clarify the mechanism of osteoporosis in adolescent idiopathic scoliosis (AIS), we investigated radiological and histological changes in the cervical vertebrae of a chicken thoracic scoliosis model. Forty newly hatched broiler chicks were randomly divided into four equal groups: sham-operated chickens serving as control (CON), pinealectomized chickens (PNX), sham-operated (CON + MLT) and pinealectomized chickens (PNX + MLT) that received intraperitoneal administration of melatonin. Pinealectomy was performed at the age of 3 days, and the chickens were killed at 2 months of age. Postmortem X-rays were examined for the presence of scoliosis, and micro-computed tomography (micro-CT) images were taken to evaluate the microstructure of the cervical vertebrae. Histological specimens of the scanned cervical vertebra were prepared, and a midsagittal section was stained with hematoxylin and eosin and tartrate-resistant acid phosphatase to evaluate the numbers of osteoblasts and osteoclasts, respectively. Scoliosis developed at the thoracic spine in all chickens of the PNX and in two of the PNX + MLT group. Micro-CT data revealed that chickens in the PNX group had a greater degree of generalized osteoporosis compared with the other birds. The number of osteoblasts was significantly decreased in the PNX group, while no significant difference was observed among chickens in the numbers of osteoclasts. Our results suggest that melatonin deficiency reduces osteoblast proliferation and leads to the development of scoliosis and osteoporosis. The restoration of melatonin prevented the development of scoliosis and osteoporosis, indicating that melatonin levels may be crucial to the development of deformity and osteoporosis in AIS.


Membrane traffic and control of proximal tubular sodium phosphate (Na/Pi)-cotransport.
Phosphate (P(i)) is freely filtered at the glomerular capillaries and largely reabsorbed in the proximal tubule by a Na-dependent, secondary active transport mechanism. Two different brush border membrane Na/P(i)-cotransporters have recently been "cloned" (type I and type II). Only the type II transporter undergoes physiological regulation (e.g., diet, acid/base, parathyroid hormone); it is also involved in pathophysiological alterations of renal Pi-handling (e.g., X-linked hypophosphatemia). In recent experiments on rats and on tissue culture cells (Opossum kidney cells, OK cells) id was documented that manoeuvres leading to increased uptake involve membrane insertion (fast changes) and new synthesis of type II transporters (slow changes), whereas decreased Na/Pi-cotransport activity is associated with their specific membrane retrieval (fast changes) and lysosomal degradation (slow changes).


Nerve-sparing dissection as alternative to anesthesia of carotid sinus nerve in preparation for carotid endarterectomy.
This prospective randomized study was undertaken to determine intraoperatively the hemodynamic effects of local anesthesia of the carotid sinus nerve during carotid dissection in preparation for endarterectomy. Twenty carotid endarterectomy patients were divided into 2 groups: a control group of 10 patients, in whom ordinary saline solution was infiltrated into the carotid bifurcation; and a study group of 10 patients, in whom 5 mL of 2% lidocaine hydrochloride was infiltrated. To determine whether a nerve-sparing dissection might in itself be adequate to prevent the perioperative hemodynamic instability associated with carotid endarterectomy, we took scrupulous care in all patients to avoid injuring the carotid sinus nerve. After we had established baseline values for heart rate and blood pressure in each patient, we recorded heart rate and blood pressure again intraoperatively, every 2 minutes during a 10-minute period. Because the series was small, an analysis of variance showed no statistically significant changes in these values during carotid dissection in either group. However, intraoperative increases in systolic pressure (p < 0.0064) and mean pressure (p < 0.0028) were greater in the lidocaine group. Neither group experienced any deaths, or any neurologic or hemodynamic sequelae during 48 hours of postoperative observation. We conclude that local anesthetic injection of the carotid sinus nerve before carotid dissection and endarterectomy is unnecessary when nerve-sparing dissection is performed; and we conclude further that such injection might actually be deleterious to intraoperative systolic and mean blood pressures.


Does cost-effectiveness of influenza vaccine choice vary across the U.S.? An agent-based modeling study.
In a prior agent-based modeling study, offering a choice of influenza vaccine type was shown to be cost-effective when the simulated population represented the large, Washington DC metropolitan area. This study calculated the public health impact and cost-effectiveness of the same four strategies: No Choice, Pediatric Choice, Adult Choice, or Choice for Both Age Groups in five United States (U.S.) counties selected to represent extremes in population age distribution. The choice offered was either inactivated influenza vaccine delivered intramuscularly with a needle (IIV-IM) or an age-appropriate needle-sparing vaccine, specifically, the nasal spray (LAIV) or intradermal (IIV-ID) delivery system. Using agent-based modeling, individuals were simulated as they interacted with others, and influenza was tracked as it spread through each population. Influenza vaccination coverage derived from Centers for Disease Control and Prevention (CDC) data, was increased by 6.5% (range 3.25%-11.25%) to reflect the effects of vaccine choice. Assuming moderate influenza infectivity, the number of averted cases was highest for the Choice for Both Age Groups in all five counties despite differing demographic profiles. In a cost-effectiveness analysis, Choice for Both Age Groups was the dominant strategy. Sensitivity analyses varying influenza infectivity, costs, and degrees of vaccine coverage increase due to choice, supported the base case findings. Offering a choice to receive a needle-sparing influenza vaccine has the potential to significantly reduce influenza disease burden and to be cost saving. Consistent findings across diverse populations confirmed these findings.


Structure and self-assembly of the calcium binding matrix protein of human metapneumovirus.
The matrix protein (M) of paramyxoviruses plays a key role in determining virion morphology by directing viral assembly and budding. Here, we report the crystal structure of the human metapneumovirus M at 2.8 Å resolution in its native dimeric state. The structure reveals the presence of a high-affinity Ca²⁺ binding site. Molecular dynamics simulations (MDS) predict a secondary lower-affinity site that correlates well with data from fluorescence-based thermal shift assays. By combining small-angle X-ray scattering with MDS and ensemble analysis, we captured the structure and dynamics of M in solution. Our analysis reveals a large positively charged patch on the protein surface that is involved in membrane interaction. Structural analysis of DOPC-induced polymerization of M into helical filaments using electron microscopy leads to a model of M self-assembly. The conservation of the Ca²⁺ binding sites suggests a role for calcium in the replication and morphogenesis of pneumoviruses.


A cooperative pathway for water activation using a bimetallic Pt0-CuI system.
A mixture of the platinum(0) complex [Pt(PtBu3)2] and tetrakis(acetonitrile)copper(i) hexafluorophosphate in acetone activated a water molecule and gave the hydride platinum(ii) complex [PtH(CH3CN)(PtBu3)2]PF6, 1, and the hydroxide Cu(i) species. The crystal structure of complex 1 was determined by X-ray crystallography, indicating a distorted square planar geometry around the platinum center. Although three possible mechanisms are proposed for this transformation, monitoring of the reaction using NMR spectroscopy at low temperature reveals that a cooperative pathway involving formation of a Pt0-CuI dative bond complex is the most probable pathway. The hydride platinum complex 1 is stable in acidic and neutral conditions but undergoes intramolecular C-H activation in the presence of pyridine. Monitoring of the reaction using 1H and 31P NMR spectroscopy shows that a cyclometalation reaction of one of the phosphine ligands is followed by displacement of a second phosphine ligand by pyridine to give the cyclometalated platinum(ii) complex, [Pt(κ2PC-PtBu2CMe2CH2)(py)2], 4. The structure of 4 in solution and solid state phases was determined using NMR spectroscopy and X-ray crystallography, respectively.


[Hospitalisation associated with Rotavirus gastroenteritis in Italy, 2001-2003, evaluated by means of ICD9-CM diagnostic codes].
Rotaviruses (RV) are the most common etiological agents in acute gastroenteritis (GE) in children in the first years of life. Data from the national scientific literature show that RV is responsible of 26% of all cases of hospitalisation for diarrea in children, resulting the most frequently identified agent. The Italian database of hospital discharge, freely available from the web site of the national Ministry of Health, was searched to investigate the epidemiology of RV gastroenteritis. The mean number of hospitalisation for RV enteritis in children in the first 4 years of live was 4.758 in the years 2001, 2002 and 2003, representing 84% of viral enteritis. RV was identified as agent in 17% of all intestinal infectious diseases in this age group. This percentage shows the important role of RV in severe gastrointestinal infections; it is however much lower than the value expected from specifically performed surveys. This underestimation may be attributed to the high number of undefined gastroenteritis found in the database (54%), to the scarce sensitivity of the hospital discharge code, and to the fact that the analysis was performed using only the principal diagnosis. A specific immunisation strategy, safe, effective, cost-effective and easy to perform, could have a great impact on the incidence of the disease and on the associated costs.


Antioxidant Effects of Bone Marrow Mesenchymal Stem Cell against Carbon Tetrachloride-Induced Oxidative Damage in Rat Livers.
Liver fibrosis results from excessive accumulation of extracellular matrix, which affects liver function over time and leads to its failure. In the past, liver transplant was thought to be the only treatment for end-stage liver disease, but due to the shortage of proper donors other medical treatments have been taken into consideration. To evaluate the therapeutic effects of bone marrow derived mesenchymal stem cells (BM-MSC) in CCl4 damaged rats. Liver damage in adult male Wistar rats was induced with carbon tetrachloride (CCl4). The rats were divided into normal control group, receiving CCl4, and those receiving CCl4 + marrow derived-MSC. Human BM-MSC was isolated, cultured, and characterized. The rats were injected with xenograft MSCs into the hepatic lobes of the liver. In the eighth week, blood samples were taken from all groups. Histological examination and biochemical analyses were used to compare the morphological and functional liver regeneration among different groups. Measurement of lipid peroxidation and glutathione transferase activity was also performed. Histopathology and biochemical analyses indicated that local injection of human BM-MSCs was effective in treating liver failure in the rat model. Furthermore, oxidative stress was attenuated by increased level of GSH content after MSC transplantation. Evidence of this animal model approach showed that bone marrow-derived MSCs promote an antioxidant response and support the potential of using MSCs transplantation as an effective treatment modality for liver disease.


Shear-induced hemolysis with commercial and glow discharge silicones.
The hemolytic characteristics of 14 different polydimethyl-siloxane materials were studied, using a rotating disk device to shear whole human blood for 6000 sec. Disk surfaces included commercial Silastic products with and without silica filler, coatings formed from hexa-methyl and tetra-methyl disiloxane monomer vapors by glow discharge, and heparinized silicones. Results are presented in the form of kinetic hemolysis curves (KHC)--plots of plasma hemoglobin vs. time--and analyzed in terms of the slopes of these curves in the 1500-6000 sec region where the KHC is nearly linear. It was found that most silicone products are low-hemolysis materials, comparable to polyethylene (PE) but often about 20% less ehmolytic; one product was superior by about 40%. The only consistent exceptions to this were the glow discharge surfaces from HEXA-methyl disiloxane (15-80% poorer than PE) and heparinized surfaces (70-280% more hemolytic than PE).


Fish communities on the world's warmest reefs: what can they tell us about the effects of climate change in the future?
To examine the role of climatic extremes in structuring reef fish communities in the Arabian region, reef fish communities were visually surveyed at four sites within the southern Persian Gulf (also known as the Arabian Gulf and The Gulf), where sea-surface temperatures are extreme (range: 12-35° C annually), and these were compared with communities at four latitudinally similar sites in the biogeographically connected Gulf of Oman, where conditions are more moderate (range: 22-31° C annually). Although sites were relatively similar in the cover and composition of coral communities, substantial differences in the structure and composition of associated fish assemblages were apparent. Fish assemblages in the southern Persian Gulf held significantly lower estimates of abundance, richness and biomass, with significantly higher abundances of smaller sized individuals than Gulf of Oman assemblages. Functionally, southern Persian Gulf sites held significantly lower abundances of nearly all the common fish trophic guilds found on Gulf of Oman sites, although higher abundances of herbivorous grazers were apparent. These results suggest the potential for substantial changes in the structure of reef-associated fish communities, independent of changes in habitat within an environment of increasing fluctuations in oceanic climate.


Near-field imaging of graphene triangles patterned by helium ion lithography.
Plasmon nanoresonators in graphene have many applications in biosensing, photodetectors and modulators. As a result, an efficient and precise patterning technique for graphene is required. Helium ion lithography (HIL) emerges as a promising tool for direct writing fabrication because it owns improved fabrication precision compared to electron beam lithography and conventional gallium focused ion beam technique. In this paper, utilizing HIL, a set of graphene triangles are patterned and excellent plasmon response is detected. Particularly, the evolution of breathing mode in these structures is unveiled by scattering-type scanning near-field optical microscopy. Besides, the plasmon response of graphene structures can be efficiently tuned by adjusting the irradiated ion dose during the etching process, which can be explained by the phenomenal simulation model. Our work demonstrates that HIL is a feasible way for precise plasmonic nanostructure fabrication, and can be applied to graphene plasmon control at the nanoscale as well.


Rostral migratory stream neuroblasts turn and change directions in stereotypic patterns.
Neuroblasts generated in the adult subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB). Previous work uncovered motility ranging from straight to complex, but it was unclear if directional changes were stochastic or exhibited stereotypical patterns. Here, we provide the first in-depth two-photon time-lapse microscopy study of morphological and dynamic features that accompany turning and direction reversals in the RMS. We identified three specific kinds of turning (30-90 degrees): bending of the leading process proximal to the cell body (P-bending 47% of cases), bending of the distal leading process (D-bending 30%) or branching of the leading process or lamellipodium (23%). Bending and branching angles were remarkably constrained and were significantly different from one another. Cells reversed direction (> 90 degrees) through D-bendings (54%), branching (11%) or de novo growth of processes from the soma (23%), but not P-bending. Direction reversal was often composed of several iterations of D-bending or branching as opposed to novel modalities. Individual neuroblasts could turn or change direction in multiple patterns suggesting that the patterns are not specific for different lineages. These findings show that neuroblasts in the RMS use a limited number of distinct and constrained modalities to turn or reverse direction.


OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.


Genetic factors underlie the association between anxiety, attitudes and performance in mathematics.
Students struggling with mathematics anxiety (MA) tend to show lower levels of mathematics self-efficacy and interest as well as lower performance. The current study addresses: (1) how MA relates to different aspects of mathematics attitudes (self-efficacy and interest), ability (understanding numbers, problem-solving ability, and approximate number sense) and achievement (exam scores); (2) to what extent these observed relations are explained by overlapping genetic and environmental factors; and (3) the role of general anxiety in accounting for these associations. The sample comprised 3410 twin pairs aged 16-21 years, from the Twins Early Development Study. Negative associations of comparable strength emerged between MA and the two measures of mathematics attitudes, phenotypically (~ -0.45) and genetically (~ -0.70). Moderate negative phenotypic (~ -0.35) and strong genetic (~ -0.70) associations were observed between MA and measures of mathematics performance. The only exception was approximate number sense whose phenotypic (-0.10) and genetic (-0.31) relation with MA was weaker. Multivariate quantitative genetic analyses indicated that all mathematics-related measures combined accounted for ~75% of the genetic variance in MA and ~20% of its environmental variance. Genetic effects were largely shared across all measures of mathematics anxiety, attitudes, abilities and achievement, with the exception of approximate number sense. This genetic overlap was not accounted for by general anxiety. These results have important implications for future genetic research concerned with identifying the genetic underpinnings of individual variation in mathematics-related traits, as well as for developmental research into how children select and modify their mathematics-related experiences partly based on their genetic predispositions.


Development of and Selected Performance Characteristics of CANJEM, a General Population Job-Exposure Matrix Based on Past Expert Assessments of Exposure.
We developed a job-exposure matrix called CANJEM using data generated in population-based case-control studies of cancer. This article describes some of the decisions in developing CANJEM, and some of its performance characteristics. CANJEM is built from exposure information from 31673 jobs held by study subjects included in our past case-control studies. For each job, experts had evaluated the intensity, frequency, and likelihood of exposure to a predefined list of agents based on jobs histories and descriptions of tasks and workplaces. The creation of CANJEM involved a host of decisions regarding the structure of CANJEM, and operational decisions regarding which parameters to present. The goal was to produce an instrument that would provide great flexibility to the user. In addition to describing these decisions, we conducted analyses to assess how well CANJEM covered the range of occupations found in Canada. Even at quite a high level of resolution of the occupation classifications and time periods, over 90% of the recent Canadian working population would be covered by CANJEM. Prevalence of exposure of specific agents in specific occupations ranges from 0% to nearly 100%, thereby providing the user with basic information to discriminate exposed from unexposed workers. Furthermore, among exposed workers there is information that can be used to discriminate those with high exposure from those with low exposure. CANJEM provides good coverage of the Canadian working population and possibly that of several other countries. Available in several occupation classification systems and including 258 agents, CANJEM can be used to support exposure assessment efforts in epidemiology and prevention of occupational diseases.


Association between tissue gamma-glutamyl-transferase and clinical markers of adjuvant arthritis in Lewis rats.
To assess glucomannan and pyridoindole derivatives for possible antioxidant therapy of rheumatoid arthritis (RA) by using the model of adjuvant arthritis (AA). We evaluated the association between clinical markers of the adjuvant arthritis model used - increase of hind paw volume (HPV), changes of body mass (CBM), and tissue gamma-glutamyl transferase (GGT) activity assessed in the spleen and the joint. AA was induced in Lewis rats by a single intradermal injection of Mycobacterium butyricum. The two independent experiments included healthy animals as reference, arthritic animals without any drug administration and arthritic animals with pyridoindole administration in one dose tested or glucomannan administration in two different doses. The pyridoindoles (PI) studied were stobadine dipalmitate and its derivatives SMe1.2HCl and SMe1EC2.HCl. We monitored CBM and HPV twice a week. Parameter of inflammation - GGT in the spleen and the joint from the hind paw (cartilage and soft tissue without bone) was determined on day 28. The correlation coefficient of GGT activity with CBM and with HPV was calculated. The antioxidants tested were effective in slowing down the progress of adjuvant arhritis. The association between tissue GGT activity and the clinical marker of adjuvant arthritis - CBM was higher in the spleen than in the joint. The other clinical marker assessed - HPV, gave a better association with GGT activity measured in the joint than in the spleen. It may be concluded that GGT activity in tissues as the spleen and the joint could provide a simple and inexpensive marker for AA and RA development at systemic as well as local level; all the antioxidants studied were effective in slowing down the progress of adjuvant arhritis.


International overview of high-level simulation education initiatives in relation to critical care.
The use of simulation in health care education has become very topical across all professions and specialties in order to improve patient safety and quality of care. In the last decade, the adoption of more realistic simulation-based teaching methodologies, which serves as a bridge between the acquisition and application of clinical skills, knowledge, and attributes, has been accompanied by the development of a multitude of international and national simulation societies. These serve as important exchange fora for educators, clinicians, researchers, and engineers who desire to learn and share their experience and knowledge around simulation-based education. Several countries have derived their own strategy in order to promote the use of such training methodology. Current key national strategies will be presented in this paper alongside a discussion of their expected impact. Various approaches have been adopted and each has their own place and the potential to be adopted by other nations depending on their political, economic or even geographic context. Within the critical care arena, simulation has generated considerable interest and there is a growing evidence base for its use as a learning and teaching strategy within this environment. A number of critical care-related associations and societies are now recognizing simulation as an appropriate pedagogical approach and acknowledging its potential to improve patient care and clinical outcomes. Its implementation should be carefully considered to ensure that developments are based on current best educational practice to maximize the efficiency of these educational interventions.


The analgesic potential of cannabinoids.
Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as antiemetic, appetite modulating, and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. As opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis-based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.


Why do patients not keep their appointments? Prospective study in a gastroenterology outpatient clinic.
Unkept outpatient appointments are a drain on resources. In a prospective study we asked non-attenders at a gastroenterology clinic why they had missed their appointment. 103 patients missed their appointment (14% of the total invited); 3 had died. The remaining 100 were asked to complete questionnaires, 68 by mail (43 returned) and 32 by telephone (30 successful); the response rate was thus 73%. 49 of the respondents were new patients, 6 of them with urgent referrals. The explanations for non-attendance by the 73 patients were: forgot to attend or to cancel (30%); no reason (26%); clerical errors (10%); felt better (8%), fearful of being seen by junior doctor (3%); inpatient in another hospital (3%); miscellaneous other (20%). 13 (27%) of the review patients had not kept one or more previous appointments. The non-attendance rates for different clinics ranged from 10% to 25% (average 14%). A substantial number of non-attenders claimed to have forgotten their appointment or to cancel it. If, as we surmise, this reflects apathy, no strategy to improve attendance is likely to have great impact. Since the non-attendance rate is reasonably constant, it can be taken into account when patients are booked.


Increasing training load without risking the female athlete triad: menstrual cycle based periodized training may be an answer?
An improved muscle strength are of great importance in many sports, hence an increased understanding on how to generate optimal strength training programs in women without negative side effects that may lead to the female athlete triad are essential. The purpose of this study was to investigate potential negative effects of high frequency periodized menstrual/oral contraceptives (OC) cycle based leg resistance training on components in the female athlete triad. Fifty-nine women, with experience of resistance training and with regular menstrual/OC cycles were included in the analyses. The participants were randomly assigned a training program consisted of high frequency leg resistance training, periodized to the first two weeks (group 1) or the last two weeks (group 2) of each cycle, or to a control group performing regular training, during four consecutive menstrual/OC cycles. The main analysis was the pre-to-post change of sex and growth hormones, cortisol, total body fat mass, bone mineral density in the spine. We further examined the participants' own experience of the training programs. No significant negative impact on sex and growth hormones, cortisol, total body fat mass and bone mineral density in the spine, was detected in any of the groups. Moreover, the women in group 1 experienced their training program as positive. The high frequency periodized leg resistance training was not associated with exercise-related negative consequences on components in the female athlete triad. Moreover, the training was well accepted when performed during the first two weeks of each cycle.


Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex.
The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [1-5]. Although these evolutionary changes most likely contributed to the origin of distinctively human cognitive faculties, their genetic basis remains almost entirely unknown. Highly conserved non-coding regions showing rapid sequence changes along the human lineage are candidate loci for the development and evolution of uniquely human traits. Several studies have identified human-accelerated enhancers [6-14], but none have linked an expression difference to a specific organismal trait. Here we report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size [15, 16]. Using transgenic mice, we demonstrate dramatic differences in human and chimpanzee HARE5 activity, with human HARE5 driving early and robust expression at the onset of corticogenesis. Similar to HARE5 activity, FZD8 is expressed in neural progenitors of the developing neocortex [17-19]. Chromosome conformation capture assays reveal that HARE5 physically and specifically contacts the core Fzd8 promoter in the mouse embryonic neocortex. To assess the phenotypic consequences of HARE5 activity, we generated transgenic mice in which Fzd8 expression is under control of orthologous enhancers (Pt-HARE5::Fzd8 and Hs-HARE5::Fzd8). In comparison to Pt-HARE5::Fzd8, Hs-HARE5::Fzd8 mice showed marked acceleration of neural progenitor cell cycle and increased brain size. Changes in HARE5 function unique to humans thus alter the cell-cycle dynamics of a critical population of stem cells during corticogenesis and may underlie some distinctive anatomical features of the human brain.


Self-Burns in Fars Province, Southern Iran.
The alarming incidence of self- burning provoked to set up a multidisciplinary preventive program to decrease the incidence and complications of this harmful issue. This study investigated the incidence and the preventive measures in self-burn in Fars Province, southern Iran. This study was a longitudinal prospective design on trend of self-inflicted burn injuries in Fars province after setting up a regional multidisciplinary preventive plan (2009-2012). From 18862 admitted patients, 388 (2%) committed self-burning. While the incidence showed a constant decrease in proportion of suicidal cases among all admitted patients (2.5% to 1.6%). The mean age of self-burning victims ranged from 28.3±10.8 to 30.3±11.7 years. The female victims comprised 67.4% of all suicidal burn patients (Female to male ratio: 2.18). The leading causes of suicide commitment were familial conflicts (75.6%) and psychological problems (16.7%). It is crucial to continue the regional preventive programs and pave the way to set up national, and even international collaborations to alleviate relevant financial, social, cultural and infrastructural difficulties in order to have lower incidence for this dramatic issue.


Association between adult and childhood socioeconomic status and prevalence of the metabolic syndrome in African Americans: the Pitt County Study.
We evaluated the association between socioeconomic status (SES) during childhood and adulthood and prevalence of the metabolic syndrome in African Americans. Higher adult educational status and adult skilled occupation were protective against the metabolic syndrome, but no associations were found between the metabolic syndrome and other SES variables. Differences by gender were observed. Improving access to education among African Americans could reduce risk for the metabolic syndrome, but more research is needed in minority populations.


Minimum Information about an Uncultivated Virus Genome (MIUViG).
We present an extension of the Minimum Information about any (x) Sequence (MIxS) standard for reporting sequences of uncultivated virus genomes. Minimum Information about an Uncultivated Virus Genome (MIUViG) standards were developed within the Genomic Standards Consortium framework and include virus origin, genome quality, genome annotation, taxonomic classification, biogeographic distribution and in silico host prediction. Community-wide adoption of MIUViG standards, which complement the Minimum Information about a Single Amplified Genome (MISAG) and Metagenome-Assembled Genome (MIMAG) standards for uncultivated bacteria and archaea, will improve the reporting of uncultivated virus genomes in public databases. In turn, this should enable more robust comparative studies and a systematic exploration of the global virosphere.


Cost-effectiveness of Denosumab for the treatment of postmenopausal osteoporosis.
Denosumab is an injectable drug that reduces the risk of fractures. The objective was to estimate the cost-effectiveness of denosumab in a Swedish setting, also accounting for poor adherence to treatment. Denosumab is cost-effective, particularly for patients at high risk of fracture and low adherence to oral treatments. Denosumab is a novel biologic agent developed for the treatment of osteoporosis and osteoporotic fractures that has been shown to reduce the risk of fractures in a phase III trial. The objective of this study was to estimate the cost-effectiveness of denosumab from a societal perspective compared with generic alendronate, branded risedronate, strontium ranelate, and no treatment in a Swedish setting. A Markov cohort model was used to estimate the cost-effectiveness of denosumab given for up to 5 years to a typical Swedish patient population (women aged 71 years, T-score ≤ -2.5 SD and a prevalence of morphometric vertebral fractures of 34%). The model included treatment persistence and residual effect after discontinuation assumed to be equal to the time on treatment. Persistence with the comparator treatments and with denosumab was derived from prescription data and a persistence study, respectively. The base-case incremental cost-effectiveness ratios were estimated at €27,000, €12,000, €5,000, and €14,000, for denosumab compared with generic alendronate, risedronate, strontium ranelate, and no treatment, respectively. Sub-optimal persistence had the greatest impact in the comparison with generic alendronate, where the difference in drug cost was large. Improving persistence with osteoporosis treatment impacts positively on cost-effectiveness with a larger number of fractures avoided in the population targeted for treatment. Denosumab is a cost-effective alternative to oral osteoporosis treatments, particularly for patients at high risk of fracture and low expected adherence to oral treatments.


Prospective, Randomized Comparison of Cervical Total Disk Replacement Versus Anterior Cervical Fusion: Results at 48 Months Follow-up.
This was a prospective, randomized, controlled multicenter trial. The purpose of this study was to compare clinical outcomes at 4-year follow-up of patients receiving cervical total disk replacement (TDR) with those receiving anterior cervical discectomy and fusion (ACDF). ACDF has been the traditional treatment for symptomatic disk degeneration. Several studies found single-level TDR to be as safe and effective as ACDF at ≥2 years follow-up. Patients from 23 centers were randomized in a 2:1 ratio with 164 receiving the investigational device (Mobi-C Cervical Disc Prosthesis) and 81 receiving ACDF using an anterior plate and allograft. Patients were evaluated preoperatively and 6 weeks, 3, 6, 12, 18, 24, 36, and 48 months postoperatively. Outcome assessments included a composite success score, Neck Disability Index, visual analog scales assessing neck and arm pain, patient satisfaction, major complications, subsequent surgery, segmental range of motion, and adjacent-segment degeneration. The composite success rate was similar in the 2 groups at 48-month follow-up. Mean Neck Disability Index, visual analog scale, and SF-12 scores were significantly improved in early follow-up in both groups with improvements maintained throughout 48 months. On some measures, TDR had significantly greater improvement during early follow-up. At no follow-up were TDR scores significantly worse than ACDF scores. Subsequent surgery rate was significantly higher for ACDF compared with TDR (9.9% vs. 3.0%, P<0.05). Range of motion was maintained with TDR having a mean baseline value of 8 degrees compared with 10 degrees at 48 months. The incidence of adjacent-segment degeneration was significantly higher with ACDF at inferior and superior segments compared with TDR (inferior: 50% vs. 30%, P<0.025; superior: 53% vs. 34%, P<0.025). Significant improvements were observed in pain and function. TDR patients maintained motion and had significantly lower rates of reoperation and adjacent-segment degeneration compared with ACDF. This study supports the safety and efficacy of TDR in appropriately selected patients.


Association between vitamin C intake and lung cancer: a dose-response meta-analysis.
Epidemiological studies evaluating the association between the intake of vitamin C and lung cancer risk have produced inconsistent results. We conducted a meta-analysis to assess the association between them. Pertinent studies were identified by a search of PubMed, Web of Knowledge and Wan Fang Med Online through December of 2013. Random-effect model was used to combine the data for analysis. Publication bias was estimated using Begg's funnel plot and Egger's regression asymmetry test. Eighteen articles reporting 21 studies involving 8938 lung cancer cases were included in this meta-analysis. Pooled results suggested that highest vitamin C intake level versus lowest level was significantly associated with the risk of lung cancer [summary relative risk (RR) = 0.829, 95%CI = 0.734-0.937, I(2) = 57.8%], especially in the United States and in prospective studies. A linear dose-response relationship was found, with the risk of lung cancer decreasing by 7% for every 100 mg/day increase in the intake of vitamin C [summary RR = 0.93, 95%CI = 0.88-0.98]. No publication bias was found. Our analysis suggested that the higher intake of vitamin C might have a protective effect against lung cancer, especially in the United States, although this conclusion needs to be confirmed.


Surface-enhanced Raman scattering detection and tracking of nanoprobes: enhanced uptake and nuclear targeting in single cells.
We describe the development and application of a co-functionalized nanoprobe and biodelivery platform combining a nuclear targeting peptide (NTP) for improved cellular uptake and intracellular targeting with p-mercaptobenzoic acid (pMBA) as a surface-enhanced Raman scattering (SERS) reporter for tracking and imaging. The nuclear targeting peptide, an HIV-1 protein-derived TAT sequence, has been previously shown to aid entry of cargo through the cell membrane via normal cellular processes, and furthermore, to localize small cargo to the nucleus of the cell. Previous work in our lab has verified cell uptake and distribution of the nanoprobes in clinically relevant mouse and human cell lines. In this work, two-dimensional SERS mapping was used to track the spatial and temporal progress of nanoparticle uptake in PC-3 human prostate cells and to characterize localization at various time points, demonstrating the potential for an intracellularly targeted multiplexed nanobiosensing system with excellent sensitivity and specificity. Silver nanoparticles co-functionalized with the TAT peptide showed greatly enhanced cellular uptake over the control nanoparticles lacking the targeting moiety. The ability to detect and monitor nanoprobe trafficking using SERS spectroscopy offers an improved alternative over previous tracking and detection methods such as light microscopy and fluorescence methods. The development of multifunctional nanoconstructs for intracellular delivery has potential clinical applications in early detection and selective treatment of disease in affected cells. Other applications include use in basic research aimed at understanding the inner workings of living cells and how they respond to chemical and biological stimuli.


A deterministic genetic model for sympatric speciation by sexual selection.
A deterministic haploid genetic model confirms and explores in more detail the results of our previous individual-based simulation model for sympatric speciation by sexual selection. With the deterministic model, we are able to elucidate parameter dependence by phase plane analysis. We clarify how and why sympatric speciation by sexual selection can happen in a number of ways: (1) Female preferences for or against particular types of males have different effects. Whereas the former affects how readily speciation is invoked, the latter changes the stability of speciation equilibrium. (2) When there is no cost on male ornamentations, speciation is triggered regardless of initial haplotype frequencies if sufficient female preference is provided. (3) There exists a threshold for female initial frequencies for speciation to be invoked, but male initial frequencies have little effect. (4) A small cost on female mate choice does not cancel speciation, but when large, it greatly reduces the possibility of speciation.


Lanthanum chloride induces neuron damage by activating the nuclear factor-kappa B signaling pathway in activated microglia.
Lanthanum is a rare earth element which can have adverse effects on the central nervous system (CNS). However, the mechanisms of these effects are not fully understood. The activated microglia plays an important role in the pathogenesis of neurodegenerative diseases and thus could be involved in mediating the toxic effects of lanthanum on the CNS. Nuclear factor-kappa B (NF-κB) is a critical nuclear factor which regulates the expression of inflammatory mediators in the activated microglia. This study investigated the effects of lanthanum chloride (LaCl3) on the NF-κB signaling pathway and explored the relationship between the microglia activation and neuron damage induced by La in vitro. The results showed that BV2 microglial cells treated with 0, 0.05, 0.1 or 0.2 mM LaCl3 could up-regulate the expression of Iba1 protein, a marker of microglia activation, and of p-IKKαβ and p-IκBα in a dose-dependent manner. La could also increase the translocation of the NF-κB p65 subunit from the cytosol into the nucleus, and then elevate the production of NO, TNF-α, IL-1β, IL-6 and MCP-1 by BV2 microglial cells. In a neuron-microglia co-culture system, BV2 microglia treated with LaCl3 resulted in a significant increase of the rates of neuron apoptosis. Conversely, the pre-treatment with PDTC (an inhibitor of the NF-κB signaling pathway) could inhibit the release of inflammatory cytokines and reduce the number of apoptotic neurons caused by La. These findings suggested that the neuron injury induced by LaCl3 might be related to the abnormal activation of microglia, which could remarkably increase the expression and release of pro-inflammatory cytokines via activating the NF-κB signaling pathway.


The phenomenology of suffering in medicine and bioethics.
This article develops a phenomenology of suffering with an emphasis on matters relevant to medical practice and bioethics. An attempt is made to explain how suffering can involve many different things-bodily pains, inability to carry out everyday actions, and failure to realize core life values-and yet be a distinct phenomenon. Proceeding from and expanding upon analyses found in the works of Eric Cassell and Elaine Scarry, suffering is found to be a potentially alienating mood overcoming the person and engaging her in a struggle to remain at home in the face of loss of meaning and purpose in life. Suffering involves painful experiences at different levels that are connected through the suffering-mood but are nevertheless distinguishable by being primarily about (1) my embodiment, (2) my engagements in the world together with others, and (3) my core life values. Suffering is in essence a feeling (a mood), but as such, it has implications for and involves the person's entire life: how she acts in the world, communicates with others, and understands and looks upon her priorities and goals in life. Suffering-moods are typically intense and painful in nature, but they may also display a rather subconscious quality in presenting things in the world and my life as a whole in an alienating way. In such situations, we are not focused directly upon the suffering-mood-as in the cases of pain and other bodily ailments-but rather, upon the things that the mood presents to us: not only our bodies, but also other things in the world that prevent us from having a good life and being the persons we want to be. Such suffering may in many cases be transformed or at least mitigated by a person's identifying and changing her core life values and in such a manner reinterpreting her life story to become an easier and more rewarding one to live under the present circumstances.


A cross-sectional study describing motivations and barriers to voluntary medical male circumcision in Lesotho.
In February 2012, the Lesotho Ministry of Health launched a national voluntary medical male circumcision (VMMC) program. To assess the motivations for seeking VMMC, a cross-sectional mixed methods study was conducted among clients aged 18 years and older at four sites. A total of 161 men participated in individual survey interviews and 35 participated in four focus group discussions. Men sought medical circumcision for the following main reasons: protection against HIV (73%), protection from other sexually transmitted infections (62%), and improved penile hygiene (47%). Forty percent learned about VMMC through friends who had already accessed services. According to these men, perceived concerns hindering service uptake include fear of pain (57%), a female provider (18%), and "compulsory" HIV testing (15%). The study provides important insights into the motivations of clients seeking VMMC services. Findings can be used by the national VMMC program to attract more clients and address barriers to uptake.


Prediction of mammalian microRNA targets.
MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.


Demirjian approach of dental age estimation: Abridged for operator ease.
Present times have seen an alarming increase in incidence of crimes by juveniles and of mass destruction that Highlight the preponderance of individual age estimation. Of the numerous techniques employed for age assessment, dental age estimation (DAE) and its correlation with chronological age (CA) have been of great significance in the recent past. Demirjian system, considered as gold standard in DAE is a simple and convenient method for DAE, though,, although, referring to multiple tables make it cumbersome and less eco friendly due to excessive paper load. The present study was aimed to develop a comprehensive chart (DAEcc) inclusive of all Demirjian tables and developmental stages of teeth and also to as well as to test the operator ease of 50 undergraduate dental students in performing DAE using this chart. The study was performed in two stages, wherein the first stage was aimed at formulation of the comprehensive chart (DAECC) which included pictorial representation of calcification stages, the Federation Dentaire Internationale notation of the teeth, and the corresponding scores for each stage with a concluding column at the end to enter the total score. The second stage assessed the applicability of the ease of DAE by DAECC, whereby fifty 2nd year BDS students were asked to trace the calcification stages of the seven permanent left mandibular teeth on a panorex, identify the correct stage, assign the corresponding score, and to calculate the total score for subsequent dental age assessment. showed that average time taken by the students for tracing seven mandibular teeth was 5 min and for assessment of dental age was 7 min. The total time taken for DAE was approximately 12 min, thus making the procedure less time consuming. Hence, this study proposes the use of DAEcc for age estimation due to ease in comprehension and execution of Demirjian system.


[A clinical study of voiding status in multiple sclerosis patients].
During a period of 4.5 years, neurological and urodynamic evaluation was done on 12 patients with multiple sclerosis between 20 and 67 years old with an average age of 47.6 years. Pyramidal dysfunction (100%), sensory disturbance (100%) and brain stem dysfunction (60%) were common neurological signs. All patients were assessed by the Kurtzke's rating of neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Of the 12 cases 6 were diagnosed as severe multiple sclerosis (EDSS greater than or equal to 4.5) and the remainders were diagnosed as relatively mild (EDSS less than 4.5). Neurourologic evaluation was performed by rapid filling carbon dioxide cystometry and sphincter electromyography. Cystometry revealed overactive bladder in 4 (33%), underactive bladder in 3 (25%) and normoactive bladder in 5 (42%) of the 12 cases. Of the 6 severe cases of multiple sclerosis, 3 (50%) showed overactive bladder, while only 1 of the 6 (17%) mild cases showed overactive bladder. Detrusor sphincter dyssynergia (DSD) was observed in 4 of the 9 (67%) severe cases and none of the 6 mild cases. The presence of overactive bladder or DSD seems to correlate with the severity of multiple sclerosis.


Partial performance degradation of a remote sensor in a space environment, and some probable causes.
The Multispectral Scanner (MSS) was launched on the Earth Resources Technology Satellite (ERTS-1) 23 July 1972. The MSS has two calibration systems, one internal and one external. Both calibration systems have shown strong, spectrally dependent performance degradation since launch. This paper presents details on the optical system of the MSS and data on the performance degradation as a function of both spectral interval and time in orbit. The history of the MSS during tests is traced, and it is shown that hydrocarbons from an external source may have been deposited on optical surfaces in the instrument. It is postulated that these contaminant coatings may have polymerized as a result of the exposure to uv light from the sun, increasing their blue absorbtion and accounting for the observed performance degradation. Arguments supporting this postulate are presented, and other possible sources of the performance degradation are discussed.


'Minipatch' penile skin graft urethroplasty in the era of buccal mucosal grafting.
To describe our experience with 'minipatch' penile skin graft (PSG) urethroplasty, as at our institution we prefer excision and primary anastomosis (EPA) urethroplasty whenever feasible, as it gives better outcomes than substitution urethroplasty. However, despite careful preoperative planning, the unanticipated need for a small graft is occasionally recognised intra-operatively, and in such cases we have found that harvesting a minipatch is an efficient alternative to harvesting a buccal mucosal graft. Bulbar urethroplasty using a <3 cm PSG was performed via either a ventral onlay or augmented anastomotic technique. In each case the PSG was required to repair an unanticipated urethral defect recognised intra-operatively during various scenarios of challenging urethroplasty. We retrospectively reviewed our experience with this technique. Among a total of 425 urethral reconstructions over a 4-year period at our institution, four patients (1%) underwent minipatch PSG urethroplasty to repair either urethral strictures that were discovered intra-operatively to be too complex for EPA (two patients) or for intra-operatively identified, unanticipated synchronous strictures (two patients). The mean (range) stricture length was 2.4 (2-3) cm and the mean graft length was 2.1 (1.5-2.5) cm. At a mean follow-up of 18 months all repairs were patent with no need for further procedures or instrumentation. Minipatch PSG urethroplasty is an efficient alternative to a buccal mucosal graft repair, especially when the unanticipated need for short-segment tissue transfer arises during complex urethral reconstruction.


Recreational drug use in men who have sex with men (MSM) attending UK sexual health services is significantly higher than in non-MSM.
The aim of this study was to investigate the pattern of recreational drug use in patients attending a genitourinary medicine clinic, and to determine whether drug use was greater among men who have sex with men (MSM) patients, when compared to non-MSM male patients. A questionnaire was given to all patients attending the genitourinary medicine clinics at two inner city teaching hospitals over 3 months (July to September 2011). The questionnaire was self-completed by patients while waiting to be seen by a clinician. Data were collected on age, gender, gender of sexual partner(s), and previous/current recreational drug use (type/frequency of drugs used). Only data from male respondents have been analysed in this paper. 1328 questionnaires were completed. Of the male respondents (n=729), 475 (65.2%) were identified as non-MSM and 254 (34.8%) were identified as MSM. The mean ± SD age of male respondents was 31 ± 9 years years. Lifetime and last month use of mephedrone, ketamine, volatile nitrites ('poppers'), sildenafil (Viagra), GHB, and GBL were all significantly higher in the MSM group compared to the non-MSM group. Lifetime use of cocaine powder, MDMA, amphetamine, and methamphetamine were also significantly higher in the MSM group; however, there was no significant difference in last month use of these drugs between MSM and non-MSM groups. Both lifetime and last month use of most recreational drugs was more common in MSM, when compared to non-MSM males. Sexual health clinics may provide an opportunistic encounter to identify patterns of recreational drug use, explore motivations for use, and implement strategies to reduce harms related to drug use. This will require a multidisciplinary approach to address the psychosocial aspects of drug taking behaviours, in combination with healthcare professionals experienced in the management of recreational drug use.


Structure and alternative promoters of the mouse glutamic acid decarboxylase 67 gene.
gamma-Aminobutyric acid is synthesized by glutamic acid decarboxylase (GAD), which has two forms, GAD65 and GAD67. Genomic clones coding mouse GAD67 (mGAD67) have been isolated. The restriction map of the overlapping clones covers a region of more than 45 kb of genomic DNA. The mGAD67 gene contains 16 translated exons in addition to an exon which is preferentially expressed in foetal brain. The rapid amplification of 5'-cDNA ends showed that mGAD67 gene transcripts have two different 5'-untranslated regions. Analysis of the genomic clones encompassing the 5'-exons revealed that the two transcripts arose from a single gene by alternative splicing using two different donor sites and a common acceptor. The exons were found 1.5 and 0.6 kb upstream of exon 1. The corresponding promoter regions of these exons have a number of putative regulatory elements, including Sp1- and Krox-24-binding sites. Analysis of mGAD67 transcripts demonstrated that each of the 5'-untranslated exons was expressed in mouse brain. In contrast, exon 0A, but not exon 0B, was expressed in mouse testis and pancreas. These results suggest that these transcripts may be regulated under the control of independent promoters.


Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin.
Limonene has demonstrated efficacy in preclinical models of breast and colon cancers. The principal sources of d-limonene are the oils of orange, grapefruit, and lemon. The present case-control study was designed to determine the usual citrus consumption patterns of an older Southwestern population and to then evaluate how this citrus consumption varied with history of squamous cell carcinoma (SCC) of the skin. In this Arizona population, 64.3% and 74.5% of the respondents reported weekly consumption of citrus fruits and citrus juices, respectively. Orange juice (78.5%), orange (74.3%), and grapefruit (65.3%) were the predominant varieties of citrus consumed. Peel consumption was not uncommon, with 34.7% of all subjects reporting citrus peel use. We found no association between the overall consumption of citrus fruits [odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.73-1.32] or citrus juices (OR = 0.97, 95% CI = 0.71-1.31) and skin SCC. However, the most striking feature was the protection purported by citrus peel consumption (OR = 0.66, 95% CI = 0.45-0.95). Moreover, there was a dose-response relationship between higher citrus peel in the diet and degree of risk lowering. This is the first study to explore the relationship between citrus peel consumption and human cancers. Our results show that peel consumption, the major source of dietary d-limonene, is not uncommon and may have a potential protective effect in relation to skin SCC. Further studies with large sample sizes are needed to more completely evaluate the interrelationships between peel intake, bioavailability of d-limonene, and other lifestyle factors.


Pharmacology of pravadoline: a new analgesic agent.
Pravadoline is a new chemical entity with analgesic activity in humans. This report describes the pharmacology of pravadoline and compares the activity of pravadoline with that of two major classes of analgesics, the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Like the NSAIDs, pravadoline inhibited the synthesis of prostaglandins (PGs) in mouse brain both in vitro (IC50, 4.9 microM) and ex vivo (ED50, 20 mg/kg p.o.) and displayed antinociceptive activity in rodents subjected to a variety of chemical, thermal and mechanical nociceptive stimuli. Administration of pravadoline prevented the writhing response induced by i.p. administration of acetylcholine (ED50, 41 mg/kg p.o.) or PGE2 (ED50, 24 mg/kg p.o.) and prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees C (minimum effective dose, 100 mg/kg s.c.). In the rat, treatment with pravadoline prevented acetic acid-induced writhing (ED50, 15 mg/kg p.o.), brewer's yeast-induced hyperalgesia (Randall-Selitto test) (minimum effective dose, 1 mg/kg p.o.), the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50, 41 mg/kg p.o.) and bradykinin-induced head and forepaw flexion (ED50, 78 mg/kg, p.o.). The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg s.c.) and pravadoline did not bind to opioid receptors at concentrations up to 10 microM. However, like the opioid analgesics, pravadoline diminished the electrically induced twitch response of mouse vas deferens preparations, but, in contrast to opioids, this action of pravadoline was not attenuated by naloxone. The possibility is discussed that this effect of pravadoline upon isolated tissues may contribute to its antinociceptive activity. In contrast to NSAIDs, pravadoline was more potent ex vivo as an inhibitor of the formation of PGs in brain vs. stomach. In addition, pravadoline failed to produce gastrointestinal lesions when administered p.o. to rats or mice, and did not possess significant anti-inflammatory activity at antinociceptive doses. Also unlike NSAIDs, pravadoline inhibited rat gastrointestinal transit when administered at doses similar to those which were antinociceptive. The overall pharmacologic profile of pravadoline suggests that the compound may be capable of managing more diverse or more severe pain than is achieved by anti-inflammatory analgesics, without producing side effects commonly associated with either the opioid or the nonopioid analgesics.


Improving Medical Decision Making and Health Promotion through Culture-Sensitive Health Communication: An Agenda for Science and Practice.
This review introduces the concept of culture-sensitive health communication. The basic premise is that congruency between the recipient's cultural characteristics and the respective message will increase the communication's effectiveness. Culture-sensitive health communication is therefore defined as the deliberate and evidence-informed adaptation of health communication to the recipients' cultural background in order to increase knowledge and improve preparation for medical decision making and to enhance the persuasiveness of messages in health promotion. To achieve effective health communication in varying cultural contexts, an empirically and theoretically based understanding of culture will be indispensable. We therefore define culture, discuss which evolutionary and structural factors contribute to the development of cultural diversity, and examine how differences are conceptualized as scientific constructs in current models of cultural differences. In addition, we will explicate the implications of cultural differences for psychological theorizing, because common constructs of health behavior theories and decision making, such as attitudes or risk perception, are subject to cultural variation. In terms of communication, we will review both communication strategies and channels that are used to disseminate health messages, and we will discuss the implications of cultural differences for their effectiveness. Finally, we propose an agenda both for science and for practice to advance and apply the evidence base for culture-sensitive health communication. This calls for more interdisciplinary research between science and practice but also between scientific disciplines and between basic and applied research.


Endoscopic resection of advanced ampullary adenomas: a single-center 14-year retrospective cohort study.
Endoscopic ampullectomy has been recognized as a safe and reliable means to resect selective tumors of the ampulla of Vater and is associated with lower morbidity and mortality rates compared to surgical resection. Success rates range from 42 to 92%, with recurrences reported in up to 33%. Studies on endoscopic resection of advanced lesions such as those with intraductal extension of adenoma (IEA) and lateral spreading adenomas (LSA) are limited. We aimed to evaluate the technical success, complications, and recurrence of endoscopic resection of ampullary adenomas, including advanced lesions. All patients referred to the Erasmus Medical Center for endoscopic resection of an ampullary lesion were retrospectively identified between 2002 and 2016. Endoscopic success was defined as complete excision of the adenoma, irrespective of the number of attempts, in the absence of recurrence. We included 87 patients with a median age of 65 years. Of these, 56 patients (64%) had an adenoma confined to the ampulla (ACA), 20 patients (23%) had an LSA, and 11 patients (13%) were treated for an IEA. The median lesion sizes were 24.6 mm, 41.4 mm, and 16.3 mm, respectively (P < 0.001). Complications occurred in 22 patients (25.3%), of which hemorrhage was most prevalent (12.6%), followed by perforation (8.1%). Complications were equally divided (P = 0.874). The median follow-up duration was 21.1 months (12-45.9) for ACA, 14.7 months (4.2-34.5) for LSA, and 5.8 months (3.7-22.0) for IEA (P = 0.051). Endoscopic resection was curative in 87.5% of patients with an ACA, 85% in patients with an LSA, and in only one patient with an IEA (P < 0.001). Recurrence occurred in 10 patients (11.5%) (P = 0.733). Endoscopic ampullectomy is safe and highly successful in selected patients with an adenoma with or without lateral spreading. Outcomes of endoscopic treatment adenomas with an intraductal extension are less favorable and in these cases surgery should be considered.


Wi-Fi (2.45 GHz)- and mobile phone (900 and 1800 MHz)-induced risks on oxidative stress and elements in kidney and testis of rats during pregnancy and the development of offspring.
The present study was designed to determine the effects of both Wi-Fi (2.45 GHz)- and mobile phone (900 and 1800 MHz)-induced electromagnetic radiation (EMR) on oxidative stress and trace element levels in the kidney and testis of growing rats from pregnancy to 6 weeks of age. Thirty-two rats and their 96 newborn offspring were equally divided into four different groups, namely, control, 2.45 GHz, 900 MHz, and 1800 MHz groups. The 2.45 GHz, 900 MHz, and 1,800 MHz groups were exposed to EMR for 60 min/day during pregnancy and growth. During the fourth, fifth, and sixth weeks of the experiment, kidney and testis samples were taken from decapitated rats. Results from the fourth week showed that the level of lipid peroxidation in the kidney and testis and the copper, zinc, reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and total antioxidant status (TAS) values in the kidney decreased in the EMR groups, while iron concentrations in the kidney as well as vitamin A and vitamin E concentrations in the testis increased in the EMR groups. Results for fifth-week samples showed that iron, vitamin A, and β-carotene concentrations in the kidney increased in the EMR groups, while the GSH and TAS levels decreased. The sixth week results showed that iron concentrations in the kidney and the extent of lipid peroxidation in the kidney and testis increased in the EMR groups, while copper, TAS, and GSH concentrations decreased. There were no statistically significant differences in kidney chromium, magnesium, and manganese concentrations among the four groups. In conclusion, Wi-Fi- and mobile phone-induced EMR caused oxidative damage by increasing the extent of lipid peroxidation and the iron level, while decreasing total antioxidant status, copper, and GSH values. Wi-Fi- and mobile phone-induced EMR may cause precocious puberty and oxidative kidney and testis injury in growing rats.


Generation of transgenic maize with enhanced provitamin A content.
Vitamin A deficiency (VAD) affects over 250 million people worldwide and is one of the most prevalent nutritional deficiencies in developing countries, resulting in significant socio-economic losses. Provitamin A carotenoids such as beta-carotene, are derived from plant foods and are a major source of vitamin A for the majority of the world's population. Several years of intense research has resulted in the production of 'Golden Rice 2' which contains sufficiently high levels of provitamin A carotenoids to combat VAD. In this report, the focus is on the generation of transgenic maize with enhanced provitamin A content in their kernels. Overexpression of the bacterial genes crtB (for phytoene synthase) and crtI (for the four desaturation steps of the carotenoid pathway catalysed by phytoene desaturase and zeta-carotene desaturase in plants), under the control of a 'super gamma-zein promoter' for endosperm-specific expression, resulted in an increase of total carotenoids of up to 34-fold with a preferential accumulation of beta-carotene in the maize endosperm. The levels attained approach those estimated to have a significant impact on the nutritional status of target populations in developing countries. The high beta-carotene trait was found to be reproducible over at least four generations. Gene expression analyses suggest that increased accumulation of beta-carotene is due to an up-regulation of the endogenous lycopene beta-cylase. These experiments set the stage for the design of transgenic approaches to generate provitamin A-rich maize that will help alleviate VAD.


Cost of providing injectable contraceptives through a community-based social marketing program in Tigray, Ethiopia.
To provide a cost analysis of an injectable contraceptive program combining community-based distribution and social marketing in Tigray, Ethiopia. We conducted a cost analysis, modeling the costs and programmatic outcomes of the program's initial implementation in 3 districts of Tigray, Ethiopia. Costs were estimated from a review of program expense records, invoices, and interviews with health workers. Programmatic outcomes include number of injections and couple-year of protection (CYP) provided. We performed a sensitivity analysis on the average number of injections provided per month by community health workers (CHWs), the cost of the commodity, and the number of CHWs trained. The average programmatic CYP was US $17.91 for all districts with a substantial range from US $15.48-38.09 per CYP across districts. Direct service cost was estimated at US $2.96 per CYP. The cost per CYP was slightly sensitive to the commodity cost of the injectable contraceptives and the number of CHWs. The capacity of each CHW, measured by the number of injections sold, was a key input that drove the cost per CYP of this model. With a direct service cost of US $2.96 per CYP, this study demonstrates the potential cost of community-based social marketing programs of injectable contraceptives. The findings suggest that the cost of social marketing of contraceptives in rural communities is comparable to other delivery mechanisms with regards to CYP, but further research is needed to determine the full impact and cost-effectiveness for women and communities beyond what is measured in CYP.