National injury prevention measures in team sports should focus on knee, head, and severe upper limb injuries.
To examine acute injuries in licensed floorball, football, handball, and ice hockey players in all ages nationwide in Sweden, and to identify the most common and severe injuries in each body location and recommend injury prevention measures. Using national sport insurance data from years 2006-2015 was the incidence and proportion of acute injuries, and injuries leading to permanent medical impairment (PMI), calculated in the four team sports. The most common injury type and injured body part was identified, with a particular focus of the severe injuries. Comparison between sexes was made. In total, there were 92,162 registered injuries in all sports together. Knee injuries were most common, and also had the highest incidence of PMI, in all ball sports and in female ice hockey players. In male ice hockey, the most common injury was a dental and face injury, and PMI injuries were mostly in the shoulder. The most severe PMI injuries were rare and most often a face/eye injury in male floorball and ice hockey, a concussion in female ice hockey, and a knee injury in female floorball, and in both sexes in football and handball. To achieve the greatest impact in reducing the adverse effects of acute sport injuries nationwide in Sweden, preventive measures should focus on knee injuries in all the investigated team sports. The severe head/face and upper limb injuries also need attention. Protective equipment, neuromuscular training programs, rules enforcements, and fair-play interventions may reduce the incidence of injuries.


Brain Network Mechanisms Underlying Motor Enhancement by Transcranial Entrainment of Gamma Oscillations.
Gamma and beta oscillations are routinely observed in motor-related brain circuits during movement preparation and execution. Entrainment of gamma or beta oscillations via transcranial alternating current stimulation (tACS) over primary motor cortex (M1) has opposite effects on motor performance, suggesting a causal role of these brain rhythms for motor control. However, it is largely unknown which brain mechanisms characterize these changes in motor performance brought about by tACS. In particular, it is unclear whether these effects result from brain activity changes only in the targeted areas or within functionally connected brain circuits. Here we investigated this issue by applying gamma-band and beta-band tACS over M1 in healthy humans during a visuomotor task and concurrent functional magnetic resonance imaging (fMRI). Gamma tACS indeed improved both the velocity and acceleration of visually triggered movements, compared with both beta tACS and sham stimulation. Beta tACS induced a numerical decrease in velocity compared with sham stimulation, but this was not statistically significant. Crucially, gamma tACS induced motor performance enhancements correlated with changed BOLD activity in the stimulated M1. Moreover, we found frequency- and task-specific neural compensatory activity modulations in the dorsomedial prefrontal cortex (dmPFC), suggesting a key regulatory role of this region in motor performance. Connectivity analyses revealed that the dmPFC interacted functionally with M1 and with regions within the executive motor system. These results suggest a role of the dmPFC for motor control and show that tACS-induced behavioral changes not only result from activity modulations underneath the stimulation electrode but also reflect compensatory modulation within connected and functionally related brain networks. More generally, our results illustrate how combined tACS-fMRI can be used to resolve the causal link between cortical rhythms, brain systems, and behavior. Recent research has suggested a causal role for gamma oscillations during movement preparation and execution. Here we combine transcranial alternating current stimulation (tACS) with functional magnetic resonance imaging (fMRI) to identify the neural mechanisms that accompany motor performance enhancements triggered by gamma tACS over the primary motor cortex. We show that the tACS-induced motor performance enhancements correlate with changed neural activity in the stimulated area and modulate, in a frequency- and task-specific manner, the neural activity in the dorsomedial prefrontal cortex. This suggests a regulatory role of this region for motor control. More generally, we show that combined tACS-fMRI can elucidate the causal link between brain oscillations, neural systems, and behavior.


Imaging Findings Associated with Space-Occupying Edema in Patients with Large Middle Cerebral Artery Infarcts.
Prominent space-occupying cerebral edema is a devastating complication occurring in some but not all patients with large MCA infarcts. It is unclear why differences in the extent of edema exist. Better knowledge of factors related to prominent edema formation could aid treatment strategies. This study aimed to identify variables associated with the development of prominent edema in patients with large MCA infarcts. From the Dutch Acute Stroke Study (DUST), 137 patients were selected with large MCA infarcts on follow-up NCCT (3 ± 2 days after stroke onset), defined as ASPECTS ≤4. Prominent edema was defined as a midline shift of ≥5 mm on follow-up. Admission patient and treatment characteristics were collected. Admission CT parameters used were ASPECTS on NCCT and CBV and MTT maps, and occlusion site, clot burden, and collaterals on CTA. Permeability on admission CTP, and day 3 recanalization and reperfusion statuses were obtained if available. Unadjusted and adjusted (age and NIHSS) odds ratios were calculated for all variables in relation to prominent edema. Prominent edema developed in 51 patients (37%). Adjusted odds ratios for prominent edema were higher with lower ASPECTS on NCCT (adjusted odds ratio, 1.32; 95% CI, 1.13-1.55) and CBV (adjusted odds ratio, 1.26; 95% CI, 1.07-1.49), higher permeability (adjusted odds ratio, 2.35; 95% CI, 1.30-4.24), more proximal thrombus location (adjusted odds ratio, 3.40; 95% CI, 1.57-7.37), higher clot burden (adjusted odds ratio, 2.88; 95% CI, 1.11-7.45), and poor collaterals (adjusted odds ratio, 3.93; 95% CI, 1.78-8.69). Extensive proximal occlusion, poor collaterals, and larger ischemic deficits with higher permeability play a role in the development of prominent edema in large MCA infarcts.


Inter-rater Reliability of Sustained Aberrant Movement Patterns as a Clinical Assessment of Muscular Fatigue.
The assessment of clinical manifestation of muscle fatigue is an effective procedure in establishing therapeutic exercise dose. Few studies have evaluated physical therapist reliability in establishing muscle fatigue through detection of changes in quality of movement patterns in a live setting. The purpose of this study is to evaluate the inter-rater reliability of physical therapists' ability to detect altered movement patterns due to muscle fatigue. A reliability study in a live setting with multiple raters. Forty-four healthy individuals (ages 19-35) were evaluated by six physical therapists in a live setting. Participants were evaluated by physical therapists for altered movement patterns during resisted shoulder rotation. Each participant completed a total of four tests: right shoulder internal rotation, right shoulder external rotation, left shoulder internal rotation and left shoulder external rotation. For all tests combined, the inter-rater reliability for a single rater scoring ICC (2,1) was .65 (95%, .60, .71) This corresponds to moderate inter-rater reliability between physical therapists. The results of this study apply only to healthy participants and therefore cannot be generalized to a symptomatic population. Moderate inter-rater reliability was found between physical therapists in establishing muscle fatigue through the observation of sustained altered movement patterns during dynamic resistive shoulder internal and external rotation.


Comparison of lignin derivatives as substrates for laccase-catalyzed scavenging of oxygen in coatings and films.
Lignin derivatives are phenylpropanoid biopolymers derived from pulping and biorefinery processes. The possibility to utilize lignin derivatives from different types of processes in advanced enzyme-catalyzed oxygen-scavenging systems intended for active packaging was explored. Laccase-catalyzed oxidation of alkali lignin (LA), hydrolytic lignin (LH), organosolv lignin (LO), and lignosulfonates (LS) was compared using oxygen-scavenging coatings and films in liquid and gas phase systems. When coatings containing lignin derivatives and laccase were immersed in a buffered aqueous solution, the oxygen-scavenging capability increased in the order LO < LH < LA < LS. Experiments with coatings containing laccase and LO, LH or LA incubated in oxygen-containing gas in air-tight chambers and at a relative humidity (RH) of 100% showed that paperboard coated with LO and laccase reduced the oxygen content from 1.0% to 0.4% during a four-day period, which was far better than the results obtained with LA or LH. LO-containing coatings incubated at 92% RH also displayed activity, with a decrease in oxygen from 1.0% to 0.7% during a four-day period. The oxygen scavenging was not related to the content of free phenolic hydroxyl groups, which increased in the order LO < LS < LH < LA. LO and LS were selected for further studies and films containing starch, clay, glycerol, laccase and LO or LS were characterized using gel permeation chromatograpy, dynamic mechanical analysis, and wet stability. The investigation shows that different lignin derivatives exhibit widely different properties as a part of active coatings and films. Results indicate that LS and LO were most suitable for the application studied and differences between them were attributed to a higher degree of laccase-catalyzed cross-linking of LS than of LO. Inclusion in active-packaging systems offers a new way to utilize some types of lignin derivatives from biorefining processes.


Antagonistic roles for the ubiquitin ligase Asr1 and the ubiquitin-specific protease Ubp3 in subtelomeric gene silencing.
Ubiquitin, and components of the ubiquitin-proteasome system, feature extensively in the regulation of gene transcription. Although there are many examples of how ubiquitin controls the activity of transcriptional regulators and coregulators, there are few examples of core components of the transcriptional machinery that are directly controlled by ubiquitin-dependent processes. The budding yeast protein Asr1 is the prototypical member of the RPC (RING, PHD, CBD) family of ubiquitin-ligases, characterized by the presence of amino-terminal RING (really interesting new gene) and PHD (plant homeo domain) fingers and a carboxyl-terminal domain that directly binds the largest subunit of RNA polymerase II (pol II), Rpb1, in response to phosphorylation events tied to the initiation of transcription. Asr1-mediated oligo-ubiquitylation of pol II leads to ejection of two core subunits of the enzyme and is associated with inhibition of polymerase function. Here, we present evidence that Asr1-mediated ubiquitylation of pol II is required for silencing of subtelomeric gene transcription. We show that Asr1 associates with telomere-proximal chromatin and that disruption of the ubiquitin-ligase activity of Asr1--or mutation of ubiquitylation sites within Rpb1--induces transcription of silenced gene sequences. In addition, we report that Asr1 associates with the Ubp3 deubiquitylase and that Asr1 and Ubp3 play antagonistic roles in setting transcription levels from silenced genes. We suggest that control of pol II by nonproteolytic ubiquitylation provides a mechanism to enforce silencing by transient and reversible inhibition of pol II activity at subtelomeric chromatin.


The potential cytotoxic effects of urban particle matter on olfaction.
Urban particulate matter (UPM) in ambient air is implicated in a variety of human health issues worldwide, however, few studies exist on the effect of UPM on the olfactory system. This study aimed to identify the factors affecting the destruction of the olfactory system in a mouse model following UPM exposure. Mice were divided into: control and four UPM-exposed groups (200 μg UPM at 1 and 2 weeks, and 400 μg UPM at 1 and 2 weeks [standard reference material 1649b; average particle diameter 10.5 μm]). The olfactory neuroepithelium was harvested for histologic examination, gene ontology, quantitative real-time polymerase chain reaction, and western blotting. Compared to the control group, olfactory marker protein, Olfr1507, ADCY3, and GNAL mRNA levels were lower, and S-100, CNPase, NGFRAP1, BDNF, and TACR3 mRNA levels were higher in the olfactory neuroepithelium of the UPM groups. Moderately positive correlation was present between the 1- and 2-week groups. After analyzing the 200 and 400 UPM groups separately, the strength of the association between the 200 UPM 1- and 2-week groups was moderately positive. No differences was present in the neuroepithelial inflammatory marker levels between the UPM and control groups. UPM could have cytotoxic effects on the olfactory epithelium. The exposure time and particular concentration of UPM exposure could affect the degree of destruction of the olfactory neuroepithelium. The olfactory regeneration mechanism could be related to the neurotrophic factors, olfactory ensheathing cell stimulation, and trigeminal nerve support.


Sudden unexpected cardio-respiratory arrest after venipuncture in children.
This study aimed to investigate the clinical and socioenvironmental characteristics of sudden cardiorespiratory arrest after venipuncture in children. We conducted a retrospective email-based survey of all members of the Korean Pediatric Society. The questionnaire included items on patient demographics, socioenvironmental circumstances of the venipuncture, type of cardiorespiratory arrest, symptoms and signs, treatment, prognosis, and presumed cause of the arrest. Fourteen patients were identified. Of these, 13 were young children (<2 years old), and 1 was 14 years old. All patients had been previously healthy and had no specific risk factors for sudden cardiorespiratory arrest. Most cases (n=11, 79%) were defined as cardiac or cardiorespiratory arrest, while the remaining cases (n=3, 21%) were defined as respiratory arrest. Aspiration (n=3), acute myocarditis (n=2), and laryngeal chemoreflex (n=1) were presumed as the causes; however, the exact causes were unclear. The overall prognosis was poor (death, n=7; morbidity, n=5; full recovery, n=2). The medical institutions faced severe backlash because of these incidents (out-of-court settlement, n=5; medical lawsuit, n=5; continuous harassment, n=3). Cardiorespiratory arrest after venipuncture is unpredictable and the probable cause of most cases is a vasovagal reaction. Medical personnel must be aware of the risk of unexpected cardiorespiratory arrest during routine intravenous procedures.


Multisystemic engagement and nephrology based educational intervention: a randomized controlled trial protocol on the KidneyTteam At Home study.
Living donor kidney transplantation (LDKT) is the most successful form of renal replacement therapy in terms of wait time and survival rates. However, we observed a significant inequality in the number of LDKT performed between the Dutch and the non-Dutch patients. The objective of this study is to adapt, implement and test an educational home-based intervention to contribute to the reduction of this inequality. Our aim is to establish this through guided communication together with the social network of the patients in an attempt that well-informed decisions regarding renal replacement therapy can be made: Multisystemic Engagement & Nephrology. This manuscript is a detailed description of the Kidney Team At Home-study protocol. All patients (>18 yrs) that are referred to the pre-transplantation outpatient clinic are eligible to participate in the study. Patients will be randomly assigned to either an experimental or a control group. The control group will continue to receive standard care. The experimental group will receive standard care plus a home-based educational intervention. The intervention consists of two sessions at the patient's home, an initial session with the patient and a second session for which individuals from their social network are invited to take part. Based on the literature and behavioural change theories we hypothesize that reducing hurdles in knowledge, risk perception, subjective norm, self-efficacy, and communication contribute to well-informed decision making and reducing inequality in accessing LDKT programs. A change in these factors is consequently our primary outcome-measure. Based on power calculations, we aim to include 160 patients over a period of two years. If we are able to show that this home-based group educational intervention contributes to 1) achieving well-informed decision regarding treatment and 2) reducing the inequality in LDKT, the quality of life of patients will be improved while healthcare costs are reduced. As the intervention is investigated in a random heterogeneous patient group in daily practice, the transfer to clinical practice in other kidney transplant centers should be relatively easy. Netherlands Trial Register, NTR2730.


Synchrony dynamics during initiation, failure, and rescue of the segmentation clock.
The "segmentation clock" is thought to coordinate sequential segmentation of the body axis in vertebrate embryos. This clock comprises a multicellular genetic network of synchronized oscillators, coupled by intercellular Delta-Notch signaling. How this synchrony is established and how its loss determines the position of segmentation defects in Delta and Notch mutants are unknown. We analyzed the clock's synchrony dynamics by varying strength and timing of Notch coupling in zebra-fish embryos with techniques for quantitative perturbation of gene function. We developed a physical theory based on coupled phase oscillators explaining the observed onset and rescue of segmentation defects, the clock's robustness against developmental noise, and a critical point beyond which synchrony decays. We conclude that synchrony among these genetic oscillators can be established by simultaneous initiation and self-organization and that the segmentation defect position is determined by the difference between coupling strength and noise.


Unexpected multiplicity of QRFP receptors in early vertebrate evolution.
The neuropeptide QRFP, also called 26RFa, and its G protein-coupled receptor GPR103 have been identified in all vertebrates investigated. In mammals, this peptide-receptor pair has been found to have several effects including stimulation of appetite. Recently, we reported that a QRFP peptide is present in amphioxus, Branchiostoma floridae, and we also identified a QRFP receptor (QRFPR) that mediates a functional response to sub-nanomolar concentrations of the amphioxus peptide as well as short and long human QRFP (Xu et al., submitted). Because the ancestral vertebrate underwent two tetraploidizations, it might be expected that duplicates of the QRFP gene and its receptor gene may exist. Indeed, we report here the identification of multiple vertebrate QRFPR genes. Three QRFPR genes are present in the coelacanth Latimeria chalumnae, representing an early diverging sarcopterygian lineage. Three QRFPR genes are present in the basal actinopterygian fish, the spotted gar. Phylogenetic and chromosomal analyses show that only two of these receptor genes are orthologous between the two species, thus demonstrating a total of four distinct vertebrate genes. Three of the QRFPR genes resulted from the early vertebrate tetraploidizations and were copied along with syntenic neuropeptide Y receptor genes. The fourth QRFPR gene may be an even older and distinct lineage. Because mammals and birds have only a single QRFPR gene, this means that three genes have been lost in these lineages, and at least one of these was lost independently in mammals and birds because it is still present in a turtle. In conclusion, these results show that the QRFP system gained considerable complexity in the early stages of vertebrate evolution and still maintains much of this in some lineages, and that it has been secondarily reduced in mammals.


Differential language network functional connectivity alterations in Alzheimer's disease and the semantic variant of primary progressive aphasia.
Patients with Alzheimer's disease (AD) and semantic variant primary progressive aphasia (svPPA) can present with similar language impairments, mainly in naming. It has been hypothesized that these deficits are associated with different brain mechanisms in each disease, but no previous study has used a network approach to explore this hypothesis. The aim of this study was to compare resting-state functional magnetic resonance imaging (rs-fMRI) language network in AD, svPPA patients, and cognitively unimpaired elderly adults (CTRL). Therefore, 10 AD patients, 12 svPPA patients and 11 CTRL underwent rs-fMRI. Seed-based functional connectivity analyses were conducted using regions of interest in the left anterior temporal lobe (ATL), left posterior middle temporal gyrus (pMTG) and left inferior frontal gyrus (IFG), applying a voxelwise correction for gray matter volume. In AD patients, the left pMTG was the only key language region showing functional connectivity changes, mainly a reduced interhemispheric functional connectivity with its right-hemisphere counterpart, in comparison to CTRL. In svPPA patients, we observed a functional isolation of the left ATL, both decreases and increases in functional connectivity from the left pMTG and increased functional connectivity form the left IFG. Post-hoc analyses showed that naming impairments were overall associated with the functional disconnections observed across the language network. In conclusion, AD and svPPA patients present distinct language network functional connectivity profiles. In AD patients, functional connectivity changes were restricted to the left pMTG and were overall less severe in comparison to svPPA patients. Results in svPPA patients suggest decreased functional connectivity along the ventral language pathway and increased functional connectivity along the dorsal language pathway. Finally, the observed connectivity patterns are overall consistent with previously reported structural connectivity and language profiles in these patients.


Telomere length shortening in gastric mucosa is a field effect associated with increased risk of gastric cancer.
Telomere shortening occurs in many organs and tissues and is accelerated by oxidative injury and rapid cell turnover. Short telomeres initiate chromosomal instability and may eventually contribute to tumorigenesis. To evaluate telomere length as potential biomarker for gastric cancer (GC) risk, we measured average telomere length using quantitative real-time PCR in GC tissues and in non-neoplastic mucosa from patients with GC and without GC. We obtained of 217 GC patients matched biopsies from the GC and adjacent tissues as well as gastric biopsies of 102 subjects without GC. Relative telomere length was measured in genomic DNA by real-time PCR. Relative telomere length decreased gradually in Helicobacter pylori (H. pylori) negative and positive gastric mucosa of GC free subjects compared with adjacent mucosa and cancer tissue from GC patients (4.03 ± 0.3 vs. 2.82 ± 0.19 vs. 0.82 ± 0.07 vs. 0.29 ± 0.09, P < 0.0001). In non-neoplastic mucosa of GC patients, shorter telomeres were found significantly more often than in that of GC free subjects (age, sex, and H. pylori adjusted odds ratio = 7.81, 95 % confidence interval = 4.71-12.9, P < 0.0001). Telomere shortening in non-neoplastic mucosa was associated with chronic inflammation (P = 0.0018) and intestinal metaplasia (P < 0.0001). No significant associations were found between relative telomere length and clinicopathological features of GC and overall survival. Telomere shortening in gastric mucosa reflects a field effect in an early stage of carcinogenesis and is associated with an increased risk of GC. Telomere length in GC is not associated with clinicopathological features or prognosis.


Copper(II) complexes supported by click generated mixed NN, NO, and NS 1,2,3-triazole based ligands and their catalytic activity in azide-alkyne cycloaddition.
The preparation and characterization of four new copper(ii) complexes supported by click generated mixed NN, NO, and NS 1,2,3-triazoles are reported. The four complexes display a 1 : 2 copper/ligand ratio and give monomeric units in the solid state. Crystal structures demonstrate that depending on the flexibility of the ligand NX (X = O, N, S) pendant arm, the coordination environment around the metal center can feature square planar or octahedral geometries. All four complexes are catalytically active at room temperature in a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction using sodium ascorbate as a reducing agent and water-ethanol as a solvent mixture. Complex 8 supported by the NS ligand displayed the best catalytic performance of the series allowing for the easy and high yielding preparation of a variety of mono-, bis- and tris-1,2,3-triazoles under low catalyst loadings.


[Outcomes of carotid endarterectomy and stenting in patients with carotid artery stenosis].
Analysed in the article are the outcomes of treating a total of 156 patients diagnosed with carotid artery stenosis. Of these, carotid endarterectomy was performed in 82 patients and stenting of carotid arteries was carried out in the remaining 74 patients. The incidence rate of perioperative stroke in the carotid endarterectomy group amounted to 3.6%, being in the stenting group 4.8%, P = 0.57. Multifactorial analysis was used to reveal risk factors for each method. Thus, in the carotid endarterectomy group, the risk factors for cerebrovascular complications appeared to be contralateral occlusion in patients with a history of stroke endured within less than six previous months (P<0.05), as well as the age over 75 years amongst the patients requiring placement of a temporary intraluminal bypass graft (P<0.05). For carotid stenting, risk factors of cerebrovascular complications included a hypoechogenic heterogeneous type of an atherosclerotic plaque (P<0.05) and ulceration of its surface (P<0.05). The presence of the patient's baseline functional class III angina of effort appeared to be a risk factor for the development of cardiovascular complications for carotid endarterectomy (P<0.05). No cardiovascular risk factors for carotid stenting were revealed. Based on the assessment of the risk factors thus detected, the authors worked out an algorithm of choosing an optimal treatment policy for patients presenting with carotid artery stenosis.


An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis.
In Multiple Sclerosis (MS), detection of T2-hyperintense white matter (WM) lesions on magnetic resonance imaging (MRI) has become a crucial criterion for diagnosis and predicting prognosis in early disease. Automated lesion detection is not only desirable with regard to time and cost effectiveness but also constitutes a prerequisite to minimize user bias. Here, we developed and evaluated an algorithm for automated lesion detection requiring a three-dimensional (3D) gradient echo (GRE) T1-weighted and a FLAIR image at 3 Tesla (T). Our tool determines the three tissue classes of gray matter (GM) and WM as well as cerebrospinal fluid (CSF) from the T1-weighted image, and, then, the FLAIR intensity distribution of each tissue class in order to detect outliers, which are interpreted as lesion beliefs. Next, a conservative lesion belief is expanded toward a liberal lesion belief. To this end, neighboring voxels are analyzed and assigned to lesions under certain conditions. This is done iteratively until no further voxels are assigned to lesions. Herein, the likelihood of belonging to WM or GM is weighed against the likelihood of belonging to lesions. We evaluated our algorithm in 53 MS patients with different lesion volumes, in 10 patients with posterior fossa lesions, and 18 control subjects that were all scanned at the same 3T scanner (Achieva, Philips, Netherlands). We found good agreement with lesions determined by manual tracing (R2 values of over 0.93 independent of FLAIR slice thickness up to 6mm). These results require validation with data from other protocols based on a conventional FLAIR sequence and a 3D GRE T1-weighted sequence. Yet, we believe that our tool allows fast and reliable segmentation of FLAIR-hyperintense lesions, which might simplify the quantification of lesions in basic research and even clinical trials.


The topography of intimal thickening and associated remodeling pattern of early transplant coronary disease: influence of pre-existent donor atherosclerosis.
With native coronary disease, intimal plaque initially accumulates at focal areas in the artery, often accompanied by compensatory vessel enlargement. With transplant coronary disease, the topography of intimal thickening and associated remodeling pattern are less studied. We studied 72 prospectively recruited transplant patients with serial intravascular ultrasound using 4.3F catheters at baseline and at 1-year follow up. We considered 175 ultrasound-recorded segments (mean, 2.4 +/- 1.1 segments per patient) exactly matched on the serial studies by both angiographic criteria and ultrasound criteria, using arterial and venous branch points, pericardium, and sinuses as anatomic landmarks. Eighty-eight segments had no donor disease, and 87 had donor disease (80 eccentric and 7 concentric intimal thickening). Progressive intimal thickening occurred in 48 segments without (55%) and 43 segments with donor disease (48%, p = NS). Thickening from segments without donor disease was mainly eccentric (81%). Thickening from segments with donor eccentric plaque was also mainly eccentric (67%, p = NS compared with segments without donor disease), with further thickening superimposed on the original plaque. Concentric intimal thickening was uncommon. Of the 58 patients who had >1 segment matched, intimal changes were discordant in 34 (59%), with progression in some and lack of progression in other segments. Total vessel area change correlated with intimal area change (r = 0.37 with a slope of 0.79, p < 0.001), including segments with (r = 0.39; slope, 0.69) and segments without (r = 0.37; slope, 1.16) donor disease. The intimal thickening of early transplant coronary disease is mainly eccentric and often discordant within each individual patient. Donor eccentric plaque often serves as a nidus for further intimal growth. The topography of intimal thickening in transplant coronary disease resembles that of native coronary disease, but the presence of a pre-existent donor plaque may impede compensatory remodeling as further intimal thickening occurs after transplantation.


Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging.
Naive T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ≥ 70% of Ag-specific CD8 T cell precursors and that many of the remaining precursors acquire a virtual (central) memory (VM; CD44(hi)CD62L(hi)) phenotype. In this study, we demonstrate that unimmunized TCR transgenic (TCRTg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended on replacement of the original TCRTg specificity by endogenous TCRα rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild-type and old TCRTg mice; that is, old VM, but not old true naive, T cells exhibited blunted TCR-mediated, but not IL-15-mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 and IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and they demonstrate that two separate age-related defects--drastic reduction in true naive T cell precursors and impaired proliferative capacity of their VM cousins--combine to reduce naive T cell responses with aging.


Chytridiomycosis causes catastrophic organism-wide metabolic dysregulation including profound failure of cellular energy pathways.
Chytridiomycosis is among several recently emerged fungal diseases of wildlife that have caused decline or extinction of naïve populations. Despite recent advances in understanding pathogenesis, host response to infection remains poorly understood. Here we modelled a total of 162 metabolites across skin and liver tissues of 61 frogs from four populations (three long-exposed and one naïve to the fungus) of the Australian alpine tree frog (Litoria verreauxii alpina) throughout a longitudinal exposure experiment involving both infected and negative control individuals. We found that chytridiomycosis dramatically altered the organism-wide metabolism of clinically diseased frogs. Chytridiomycosis caused catastrophic failure of normal homeostatic mechanisms (interruption of biosynthetic and degradation metabolic pathways), and pronounced dysregulation of cellular energy metabolism. Key intermediates of the tricarboxylic acid cycle were markedly depleted, including in particular α-ketoglutarate and glutamate that together constitute a key nutrient pathway for immune processes. This study was the first to apply a non-targeted metabolomics approach to a fungal wildlife disease and specifically to dissect the host-pathogen interface of Bd-infected frogs. The patterns of metabolite accumulation we have identified reveal whole-body metabolic dysfunction induced by a fungal skin infection, and these findings have broad relevance for other fungal diseases.


Tyrosine kinases and gastric cancer.
Carcinoma of the stomach is one of the most prevalent cancer types in the world today. Two major forms of gastric cancer are distinguished according to their morphological and clinicopathological classifications (well differentiated/intestinal type and poorly differentiated/diffuse type), characteristics that could also be attributed to the altered expression of different types of oncogenes or tumor suppressor genes. Significant differences exist for gastric cancer incidence comparing people of different ethnic origins, implicating various genetic and epigenetic factors for gastric oncogenesis. There are only a limited number of molecular markers available for gastric cancer detection and prognostic evaluation, among which are tyrosine kinases. There is convincing evidence that tyrosine kinases are involved in oncogenesis and disease progression for many human cancers. Amplifications of certain tyrosine kinases (c-met, k-sam and erbB2/neu) have been associated with human gastric cancer progression. Alternatively spliced transcripts and enhanced protein-expression levels for some of these tyrosine kinases are correlated with clinical outcomes for gastric cancer patients. With advent of high throughput techniques, it is now possible to detect nearly all expressed tyrosine kinases in a single screen. This increases the chance to identify additional tyrosine kinases as predictive markers for gastric cancers. In this article, we will first review the literature data concerning certain tyrosine kinases implicated in gastric carcinogenesis and then summarize more recent work which provide comprehensive tyrosine kinase profiles for gastric cancer specimens and cell lines. Two new gastric cancer molecular markers (tie-1 and mkk4) have been identified through the use of these profiles and demonstrated effective as clinical prognostic indicators.


Financial conflicts of interest in science.
This Article proposes a new direction for addressing financial conflicts of interest, which plague biomedical research and threaten scientific integrity. This Article descriptively states the controversy surrounding financial conflicts of interest by explaining how these conflicts arise and the damage that can be created as a result. By describing the scientific process, the Article explains that changes to the academic environment may allow the public-private interaction to proceed, without creating the problems associated with financial conflicts of interest. Financial conflicts of interest are created when the profit-seeking motive of a private funding source unduly influences an academic scientist's primary responsibilities. The problem with financial conflicts of interest has grown since the passage of the Bayh-Dole Act in 1980. The cornerstone of current policies to address financial conflicts of interest is disclosure, which is inadequate and unsatisfying. The analysis herein changes the trajectory of current approaches in this area by proposing that an analysis of the underlying environment and behavior leading to conflicts of interest must be considered. This Article proposes the use of behavioral economics to craft a policy that effectively addresses conflicts of interest. To this end, this Article applies research from the field of psychology to understand both the environment of academic scientists as well as to begin to understand how academic scientists make decisions. Drawing on psychology literature, this article proposes that academic scientists may experience cognitive dissonance when faced with a situation in which a conflict of interest may arise. This helps to understand why an academic scientist may make a decision that creates a conflict of interest. In addition, this Article utilizes the results of an empirical study conducted by myself and a colleague. In this study, we asked faculty at five medical schools to respond to an anonymous survey containing hypothetical situations in which a conflict may arise. The combination of the psychology literature and our empirical study can provide support to the creation of new policies. Policy proposals include implementation of default rules, education, and changes to academic requirements. Furthermore, this Article considers ways to incentivize medical centers to implement effective policies as well as changes to intellectual property law.


Prevalence of the newly described human circovirus, TTV, in United States blood donors.
A novel nonenveloped single-stranded circular DNA virus (TTV) was recently identified. The prevalence of TTV in blood donors in the United States is, however, still unclear. Viral DNA was detected in US blood donors from five cities by using two sets of TTV primers: NG059/NG061/NG063 primers, which amplified the conserved region of strains 1 and 2, and T801/T935 primers, which amplified the 5' end region of the TTV sequence. A TTV antibody assay system was based on the detection of the truncated open reading frame (ORF)-1 (amino acids 1-411) from type 1b. The truncated ORF-1 was expressed as a fusion protein in Escherichia coli, and the fusion protein was used as the antigen in the antibody assay system. Viremia was detected in 21 (8. 4%) of 250 donors by use of NG059/NG061/NG063 primers and 104 (41. 6%) of 250 by use of T801/T935 primers. There was little correlation among the assays, which suggests the preferential detection of different strains with the different primers. TTV antibody was detected in 38 of 100 donors: 32 (84%) of 38 with concurrent TTV viremia and 6 (16%) of 38 without TTV viremia. TTV viremia and/or TTV antibody-positive samples were detected in 52 (52%) of 100 of US blood donors. Evidence of infection or exposure to TTV appears to be common among blood donors in United States.


Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.
The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)


RNA-seq analysis of the response of the halophyte, Mesembryanthemum crystallinum (ice plant) to high salinity.
Understanding the molecular mechanisms that convey salt tolerance in plants is a crucial issue for increasing crop yield. The ice plant (Mesembryanthemum crystallinum) is a halophyte that is capable of growing under high salt conditions. For example, the roots of ice plant seedlings continue to grow in 140 mM NaCl, a salt concentration that completely inhibits Arabidopsis thaliana root growth. Identifying the molecular mechanisms responsible for this high level of salt tolerance in a halophyte has the potential of revealing tolerance mechanisms that have been evolutionarily successful. In the present study, deep sequencing (RNAseq) was used to examine gene expression in ice plant roots treated with various concentrations of NaCl. Sequencing resulted in the identification of 53,516 contigs, 10,818 of which were orthologs of Arabidopsis genes. In addition to the expression analysis, a web-based ice plant database was constructed that allows broad public access to the data. The results obtained from an analysis of the RNAseq data were confirmed by RT-qPCR. Novel patterns of gene expression in response to high salinity within 24 hours were identified in the ice plant when the RNAseq data from the ice plant was compared to gene expression data obtained from Arabidopsis plants exposed to high salt. Although ABA responsive genes and a sodium transporter protein (HKT1), are up-regulated and down-regulated respectively in both Arabidopsis and the ice plant; peroxidase genes exhibit opposite responses. The results of this study provide an important first step towards analyzing environmental tolerance mechanisms in a non-model organism and provide a useful dataset for predicting novel gene functions.


Manipulating interfacial polymer structures through mixed surfactant adsorption and complexation.
The effects of a nonionic alcohol ethoxylate surfactant, C(13)E(7), on the interactions between PVP and SDS both in the bulk and at the silica nanoparticle interface are studied by photon correlation spectroscopy, solvent relaxation NMR, SANS, and optical reflectometry. Our results confirmed that, in the absence of SDS, C(13)E(7) and PVP are noninteracting, while SDS interacts strongly both with PVP and C(13)E(7) . Studying interfacial interactions showed that the interfacial interactions of PVP with silica can be manipulated by varying the amounts of SDS and C(13)E(7) present. Upon SDS addition, the adsorbed layer thickness of PVP on silica increases due to Coulombic repulsion between micelles in the polymer layer. When C(13)E(7) is progressively added to the system, it forms mixed micelles with the complexed SDS, reducing the total charge per micelle and thus reducing the repulsion between micelle and the silica surface that would otherwise cause the PVP to desorb. This causes the amount of adsorbed polymer to increase with C(13)E(7) addition for the systems containing SDS, demonstrating that addition of C(13)E(7) hinders the SDS-mediated desorption of an adsorbed PVP layer.


Estimation of visual maps with a robot network equipped with vision sensors.
In this paper we present an approach to the Simultaneous Localization and Mapping (SLAM) problem using a team of autonomous vehicles equipped with vision sensors. The SLAM problem considers the case in which a mobile robot is equipped with a particular sensor, moves along the environment, obtains measurements with its sensors and uses them to construct a model of the space where it evolves. In this paper we focus on the case where several robots, each equipped with its own sensor, are distributed in a network and view the space from different vantage points. In particular, each robot is equipped with a stereo camera that allow the robots to extract visual landmarks and obtain relative measurements to them. We propose an algorithm that uses the measurements obtained by the robots to build a single accurate map of the environment. The map is represented by the three-dimensional position of the visual landmarks. In addition, we consider that each landmark is accompanied by a visual descriptor that encodes its visual appearance. The solution is based on a Rao-Blackwellized particle filter that estimates the paths of the robots and the position of the visual landmarks. The validity of our proposal is demonstrated by means of experiments with a team of real robots in a office-like indoor environment.


The experiences of self-care in community-dwelling older people: a meta-synthesis.
To identify, critically appraise and synthesize qualitative evidence of self-care experiences in health promotion for home-dwelling elders. A meta-synthesis was conducted following the Joanna Briggs Institute guidelines and using Qualitative Assessment and Review Instrument Software. The literature search was conducted on PubMed, CINHAL, Embase, PsycInfo, Eric and ILISI databases from inception up until March 2015. Other articles were searched on Scopus and Web of Knowledge. The reference list of all the identified articles was also searched for additional studies. Studies published in English, Italian, French, Portuguese, and Spanish were considered for inclusion in the review. Data from the selected qualitative articles were extracted independently by two reviewers using the data extraction tool of the Joanna Briggs Institute-Qualitative Assessment and Review Instrument. The meta-synthesis involved the following three steps: the production of a set of statements representing the aggregated data obtained by assembling the findings of qualitative studies; the categorization of findings on the basis of similarity in meaning; and the aggregation of these categories to produce a comprehensive set of synthesized findings. No studies were excluded due to methodological quality. Of the 4001 records identified, 11 articles met the inclusion criteria. Most articles were conducted in Scandinavian countries and used a phenomenological design. Most elders in the sample were middle-class, cognitively intact, independent, and in good health. The meta-synthesis revealed that older people living at home make decisions about their self-care activities on the basis of their attitudes toward their life and future. These self-care activities are directed toward holistic wellness, prevention and treatment of aging effects, obtaining a sense of satisfaction, and self-realization. Furthermore, self-care activities are settled in a social and relational network that allows old people to take care of themselves and of others or to be cared for by others. This meta-synthesis presents the perspectives of home-dwelling old people on health-promoting self-care experiences. Such information can help healthcare professionals to maintain long-term autonomy of elders in self-care and to promote healthy aging. Further qualitative research describing self-care experiences of home-dwelling elders from different cultures, education levels, and social backgrounds is needed.


Disturbances in morning cortisol secretion in association with maternal postnatal depression predict subsequent depressive symptomatology in adolescents.
We have previously reported higher and more variable salivary morning cortisol in 13-year-old adolescents whose mothers were depressed in the postnatal period, compared with control group adolescents whose mothers did not develop postnatal depression (PND). This observation suggested a biological mechanism by which intrafamilial risk for depressive disorder may be transmitted. In the current article, we examined whether the cortisol disturbances observed at 13 years could predict depressive symptomatology in adolescents at 16 years of age. We measured self-reported depressive symptoms in 16-year-old adolescents who had (n = 48) or had not (n = 39) been exposed to postnatal maternal depression and examined their prediction by morning and evening cortisol indices obtained via 10 days of salivary collections at 13 years. Elevated morning cortisol secretion at 13 years, and particularly the maximum level recorded over 10 days of collection, predicted elevated depressive symptoms at 16 years over and above 13-year depressive symptom levels and other possible confounding factors. Morning cortisol secretion mediated an association between maternal PND and symptomatology in 16-year-old offspring. Alterations in steroid secretion observed in association with maternal PND may provide a mechanism by which risk for depression is transmitted from mother to offspring.


Management and health issues in women with epilepsy - a review.
Although epilepsy affects men and women equally, there are special implications for women, especially during their childbearing years, and particularly when pregnancy is contemplated. This review summarisesthe complexity and multifaceted nature of health issues affecting women with epilepsy (WWE) in general and epilepsy in women beyond childbearing age. The female sex hormones and their cyclic as well as age-related variations certainly influence seizure activity and epilepsy in women. Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. There are special concerns for women of child bearing years with regard to contraception, pregnancy and teratogenicity that should be considered during counseling and selection of appropriate treatment.Although the majority of pregnant WWE experience normal pregnancies and deliveries, their children have a higher risk of birth defects. Individualised treatment coupling antiepileptic drug use (AED) and the specific phase of impact of the reproductive cycle must be considered in treatment selection. As the number of available treatment options for epilepsy increases, the optimal goal for the general practitioner is to work as a team with obstetricians and gynaecologists, and neurologists in an effort to ensure the best treatment of WWE


Controlling methanogenesis and improving power production of microbial fuel cell by lauric acid dosing.
Methanogens compete with anodophiles for substrate and thus reduce the power generation and coulombic efficiency (CE) of the microbial fuel cell (MFC). Performance of a baked clayware membrane MFC inoculated with mixed anaerobic sludge pretreated with lauric acid was investigated in order to enhance power recovery by controlling methanogenesis. In the presence of lauric acid pretreated inoculum, MFC produced maximum volumetric power density of 4.8 W/m(3) and the CE increased from 3.6% (for untreated inoculum) to 11.6%. Cyclic voltammetry (CV) and electro-kinetic evaluation indicated a higher bio-catalytic activity at the anode of the MFC inoculated with lauric acid pretreated sludge. With the lauric acid pretreated inoculum a higher catalytic current of 114 mA, exchange current density of 40.78 mA/m(2) and lower charge transfer resistance of 0.00016 Ωm(2) were observed during oxidation at the anode. Addition of lauric acid significantly achieved suppression of methanogenesis and enhanced the sustainable power generation of MFC by 3.9 times as compared with control MFC inoculated with sludge without any pretreatment.


Human Bocavirus as a Possible Contributor to Respiratory Disease in the Georgian Military Population.
The coronavirus disease 2019 (COVID-19) pandemic has demonstrated that new and devastating respiratory pathogens can emerge without warning. It is therefore imperative that Special Operations medical personnel be aware of the presence of emerging pathogens within their area of operation. Human bocavirus (HBoV) is a newly described member of a family of viruses known as the Parvovirinae that are often associated with acute respiratory illness. The presence of HBoV in the country of Georgia has not been previously reported. Nasal and throat swabs were collected from 95 symptomatic members of the Georgian military. HBoV was detected in 11 of them (12%). To our knowledge, this is the first report of HBoV infection in the country of Georgia. This finding may have a significant impact on members of the Special Operations community who train in Georgia as more data concerning the transmission, pathogenesis, and treatment of HBoV are accumulated and the role of HBoV in human disease is more clearly defined.


Structural insights into the Type II secretion nanomachine.
The Type II secretion nanomachine transports folded proteins across the outer membrane of Gram-negative bacteria. Recent X-ray crystallography, electron microscopy, and molecular modeling studies provide structural insights into three functionally and spatially connected units of this nanomachine: the cytoplasmic and inner membrane energy-harvesting complex, the periplasmic helical pseudopilus, and the outer membrane secretin. Key advances include cryo-EM reconstruction of the secretin and demonstration that it interacts with both secreted substrates and a crucial transmembrane clamp protein, plus a biochemical and structural explanation of the role of low-abundance pseudopilins in initiating pseudopilus growth. Combining structures and protein interactions, we synthesize a 3D view of the complete complex consistent with a stepwise pathway in which secretin oligomerization defines sites of nanomachine biogenesis.


Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.
Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-alpha and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-alpha and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.


20th-century industrial black carbon emissions altered Arctic climate forcing.
Black carbon (BC) from biomass and fossil fuel combustion alters chemical and physical properties of the atmosphere and snow albedo, yet little is known about its emission or deposition histories. Measurements of BC, vanillic acid, and non-sea-salt sulfur in ice cores indicate that sources and concentrations of BC in Greenland precipitation varied greatly since 1788 as a result of boreal forest fires and industrial activities. Beginning about 1850, industrial emissions resulted in a sevenfold increase in ice-core BC concentrations, with most change occurring in winter. BC concentrations after about 1951 were lower but increasing. At its maximum from 1906 to 1910, estimated surface climate forcing in early summer from BC in Arctic snow was about 3 watts per square meter, which is eight times the typical preindustrial forcing value.


Organotypic Spheroid Culture to Mimic Radiation-Induced Salivary Hypofunction.
Radiation treatment often leads to irreversible damage to normal salivary glands (SGs) because of their proximity to head and neck cancers. Optimization of the in vitro model of irradiation (IR)-induced SG damage is warranted to investigate pathophysiology and monitor treatment outcome. Here, we present an organotypic spheroid culture model to investigate the impact of IR on SGs and the mechanisms underlying IR-induced structural and functional changes. Human parotid epithelial cells were obtained from human parotid glands and plated on either plastic plates or Matrigel. A number of 3-dimensional (3D) spheroids were assembled on Matrigel. After IR at 10 and 20 Gy, morphologic changes in cells in 2D monolayers and 3D spheroids were observed. As the structural integrity of the 3D spheroids was destroyed by IR, the expression levels of salivary epithelial and structural proteins and genes decreased proportionally with radiation dosage. Furthermore, the spheroid culture allowed better measurement of functional alterations following IR relative to the monolayer culture, in which IR-inflicted spheroids exhibited a loss of acinar-specific cellular functions that enable Ca2+ influx or secretion of α-amylase in response to cholinergic or β-adrenergic agonists. p53-mediated apoptotic cell death was observed under both culture conditions, and its downstream signals increased, such as p53 upregulated modulator of apoptosis (PUMA), Bax, cytochrome c, caspase 9, and caspase 3. These results suggest that the organotypic spheroid culture could provide a useful alternative model for exploration of radiobiology and mode of action of new therapies for prevention of radiation-induced salivary hypofunction.


The caregiving role following percutaneous coronary intervention.
The aim of this study is to describe the experience of caregivers of individuals who have had a percutaneous coronary intervention (PCI). Decreased lengths of hospital stay and an increased emphasis on chronic disease self-management increase the importance of carers in assisting in recovery and lifestyle modification. Cross-sectional dual-moderated focus group design. Three focus groups using a dual facilitation approach were held in the cardiac rehabilitation setting of a tertiary referral hospital in metropolitan Sydney. All sessions were audio recorded, transcribed and thematically analysed. Four themes emerged from the data: (1) a gendered approach to health, illness and caring; (2) shock, disbelief and the process of adjustment following PCI; (3) challenges and changes of the carer-patient relationship and (4) the needs of the carer for support and information. Issues emerging from this study parallel other findings describing the experience, yet provide new insights into the issues surrounding PCI. These findings highlight the need for including carers in care planning and decision-making and providing them with support and resources. Emphasises the importance of preparing carers of the likely experience following a PCI. Demonstrates the degree to which vigilance, deferment of carer-health needs and role conflict impact on the carer's personal relationship. Demonstrates the need for formal support interventions for carers of patients who have had PCI.


Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study.
Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men < or =50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women >50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.


Molecular and neurodevelopmental benefits to children of closure of a coal burning power plant in China.
Polycyclic aromatic hydrocarbons (PAH) are major toxic air pollutants released during incomplete combustion of coal. PAH emissions are especially problematic in China because of their reliance on coal-powered energy. The prenatal period is a window of susceptibility to neurotoxicants. To determine the health benefits of reducing air pollution related to coal-burning, we compared molecular biomarkers of exposure and preclinical effects in umbilical cord blood to neurodevelopmental outcomes from two successive birth cohorts enrolled before and after a highly polluting, coal-fired power plant in Tongliang County, China had ceased operation. Women and their newborns in the two successive cohorts were enrolled at the time of delivery. We measured PAH-DNA adducts, a biomarker of PAH-exposure and DNA damage, and brain-derived neurotrophic factor (BDNF), a protein involved in neuronal growth, in umbilical cord blood. At age two, children were tested using the Gesell Developmental Schedules (GDS). The two cohorts were compared with respect to levels of both biomarkers in cord blood as well as developmental quotient (DQ) scores across 5 domains. Lower levels of PAH-DNA adducts, higher concentrations of the mature BDNF protein (mBDNF) and higher DQ scores were seen in the 2005 cohort enrolled after closure of the power plant. In the two cohorts combined, PAH-DNA adducts were inversely associated with mBDNF as well as scores for motor (p = 0.05), adaptive (p = 0.022), and average (p = 0.014) DQ. BDNF levels were positively associated with motor (p = 0.018), social (p = 0.001), and average (p = 0.017) DQ scores. The findings indicate that the closure of a coal-burning plant resulted in the reduction of PAH-DNA adducts in newborns and increased mBDNF levels that in turn, were positively associated with neurocognitive development. They provide further evidence of the direct benefits to children's health as a result of the coal plant shut down, supporting clean energy and environmental policies in China and elsewhere.


Expression of RCAS1 and its function in human squamous cell carcinoma of the oral cavity.
Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a recently discovered human tumor-associated antigen expressed in a wide variety of cancer tissues. It has been suggested that tumor cells evade from immune surveillance by expression of RCAS1. We investigated whether RCAS1 is expressed in human oral squamous cell carcinomas (HOSCCs) or HOSCC (HSC-2, -3, -4, Ca9-22 and KB) cells and whether tumor cells expressing RCAS1, induce apoptosis in its receptor-positive cells, peripheral blood lymphocytes (PBLs). RCAS1 transcripts and proteins were detected in five HOSCC cell types. Immunohistochemical examinations revealed that RCAS1 was slightly to moderately positive in 32 of 40 cases (80%) of HOSCCs. Furthermore, the frequency of RCAS1 expression in HOSCC increased with advancing tumor stage according to the pTNM system. Confocal laser microscopy and DNA fragmentation assay showed that PBLs, which were stimulated with IL-2, underwent apoptosis by co-culturing with KB cells. It was also confirmed by Western dot blotting that soluble RCAS1 is secreted into culture supernatants of KB cells. The apoptotic tumor-infiltrating lymphocytes (TILs) were detected around RCAS1-positive tumor cells in HOSCCs by TUNEL method. These results suggest that RCAS1 expression might be associated with progression of oral tumors and offer a possible mechanism for oral cancer immune escape.


Support Desired by Women Following Termination of Pregnancy for a Fetal Anomaly.
With the rapidly evolving field of prenatal testing, there is a growing need to provide support for women pursuing termination of pregnancy following the discovery of a fetal anomaly. Previous studies have documented that women in this situation often feel unsupported, but the type of resources desired by this population remains undetermined. We studied the awareness and utilization of support resources in 51 women at the time of the procedure, at 6 weeks, and at 3 months following the event. Though largely knowledgeable of existing resources at the time of the procedure, only 50 % admitted contemplating their individualized need for support. Most expected to rely on the support of family and friends. Additionally, 50 % expressed the desire to commemorate the pregnancy, though none wanted direct contact with their healthcare provider(s). Responses from the 6 weeks and 3 months assessments were consistent with previous literature as many women indicated not coping as expected and were unprepared for the psychological consequences following the procedure. Our findings indicate that women in these situations may not realize what their long-term support needs will be. They further indicate that guidelines for routine follow-up care should be established among healthcare providers that respect this population's initial desires to avoid reminders of the pregnancy and promote a flexible timeframe for support uptake. Additional support resources that promote flexible uptake as well as meet the desires of anonymity and ease of access need to be developed for this population.


Rehabilitation of the rotator cuff: an evaluation-based approach.
Rotator cuff disease of the shoulder, a common condition, is often incapacitating. Whether nonsurgical or surgical, successful management of rotator cuff disease is dependent on appropriate rehabilitation. Numerous rehabilitation protocols for the management of rotator cuff disease are based primarily on anecdotal clinical observation. The available literature on shoulder rehabilitation, in conjunction with clinical observation that takes into consideration the underlying tissue quality and structural integrity of the rotator cuff, can be compiled into a set of rehabilitation guidelines. The four phases of rehabilitation begin with maintaining and protecting the repair in the immediate postoperative period, followed by progression from early passive range of motion through return to preoperative levels of function.


Immunohistochemical and cytogenetic characterization of acantholytic squamous cell carcinoma of the breast.
Primary acantholytic squamous cell carcinoma (ASCC) of the breast is a rare and aggressive variant of invasive breast cancer. Here we report two new cases of ASCC and their immunohistochemical and cytogenetic characterization. One case was associated with systemic metastases and death and the other with local failure prior to loss of follow-up. Using comparative genomic hybridization (CGH), both tumors showed a high overall number of chromosomal imbalances with a similar pattern of gains and losses. Genetic aberrations common to both tumors included losses at 3p11-p25, 5q21-q31, 8p, 9, 13p13-q21, 16q12-q21, and 17p and gains at 1q31-qter, 7p, 18q12-qter, 19q, and 20. Immunohistochemically, the tumors were characterized by high proliferative activity, an uncommon cytokeratin expression profile, reduced E-cadherin staining, and overexpression of p53 and epithelial growth factor receptor (EGFR). The results of our analyses suggest that genetic alterations observed in ASCC of the breast include imbalances commonly observed in both mammary adenocarcinoma and squamous cell carcinoma of other locations. Furthermore, the overexpressed EGFR could be a possible therapeutic target for individual cases of this aggressive tumor type.


An assessment of scientific and technical aspects of closed investigations of canine forensics DNA--case series from the University of California, Davis, USA.
To describe and assess the scientific and technical aspects of animal forensic testing at the University of California, Davis. The findings and recommendations contained in this report are designed to assess the past, evaluate the present, and recommend reforms that will assist the animal forensic science community in providing the best possible services that comply with court standards and bear judicial scrutiny. A batch of 32 closed files of domestic dog DNA cases processed at the University of California, Davis, between August 2003 and July 2005 were reviewed in this study. The case files comprised copies of all original paperwork, copies of the cover letter or final report, laboratory notes, notes on analyses, submission forms, internal chains of custody, printed images and photocopies of evidence, as well as the administrative and technical reviews of those cases. While the fundamental aspects of animal DNA testing may be reliable and acceptable, the scientific basis for forensic testing animal DNA needs to be improved substantially. In addition to a lack of standardized and validated genetic testing protocols, improvements are needed in a wide range of topics including quality assurance and quality control measures, sample handling, evidence testing, statistical analysis, and reporting. This review implies that although a standardized panel of short tandem repeat and mitochondrial DNA markers and publicly accessible genetic databases for canine forensic DNA analysis are already available, the persistent lack of supporting resources, including standardized quality assurance and quality control programs, still plagues the animal forensic community. This report focuses on closed cases from the period 2003-2005, but extends its scope more widely to include other animal DNA forensic testing services.


E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma.
Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.


A direct approach to the evaluation of the variance of the wave aberration.
Maréchal's treatment of tolerance theory shows that in designing high quality systems one should aim at minimizing the variance E of the wave aberration. Since the value of E is essentially positive, a useful criterion for the whole field is the sum of the suitably weighted values of E for a typical set of image points. It is shown here that the variance E (for both the axial and extraaxial images) may be calculated very simply by means of a set of universal coefficients [P(i,j), Q(i,j), and R(i,j)] once the wave aberrations of selected rays are known. The values of these coefficients are uniquely determined by the form of polynomial assumed for the wave aberration and by the pattern of rays traced. Tables of P(i,j), Q(i,j), and R(i,j) are presented for the different cases that can arise in practice.


Pediatric Exercise Testing: Value and Implications of Peak Oxygen Uptake.
Peak oxygen uptake (peak V ˙ O 2 ) measured by clinical exercise testing is the benchmark for aerobic fitness. Aerobic fitness, estimated from maximal treadmill exercise, is a predictor of mortality in adults. Peak V ˙ O 2 was shown to predict longevity in patients aged 7-35 years with cystic fibrosis over 25 years ago. A surge of exercise studies in young adults with congenital heart disease over the past decade has revealed significant prognostic information. Three years ago, the first clinical trial in children with pulmonary arterial hypertension used peak V ˙ O 2 as an endpoint that likewise delivered clinically relevant data. Cardiopulmonary exercise testing provides clinicians with biomarkers and clinical outcomes, and researchers with novel insights into fundamental biological mechanisms reflecting an integrated physiological response hidden at rest. Momentum from these pioneering observations in multiple disease states should impel clinicians to employ similar methods in other patient populations; e.g., sickle cell disease. Advances in pediatric exercise science will elucidate new pathways that may identify novel biomarkers. Our initial aim of this essay is to highlight the clinical relevance of exercise testing to determine peak V ˙ O 2 , and thereby convince clinicians of its merit, stimulating future clinical investigators to broaden the application of exercise testing in pediatrics.


Cost-effectiveness of preventing first-episode psychosis in ultra-high-risk subjects: multi-centre randomized controlled trial.
Although there is evidence for the effectiveness of interventions for psychosis among ultra-high-risk (UHR) groups, health economic evaluations are lacking. This study aimed to determine the cost effectiveness and cost-utility of cognitive-behavioural therapy (CBT) to prevent first-episode psychosis. The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients with an 18-month follow-up. All participants were treated with routine care (RC) for non-psychotic disorders. The experimental group (n = 95) received add-on CBT to prevent first-episode psychosis. We report the intervention, medical and travel costs, as well as costs arising from loss of productivity. Treatment response was defined as psychosis-free survival and quality-adjusted life years (QALYs) gained. In the cost-effectiveness analysis, the proportion of averted psychoses was significantly higher in the CBT condition (89.5% v. 76.2%). CBT showed a 63.7% probability of being more cost effective, because it was less costly than RC by US$844 (£551) per prevented psychosis. In the cost-utility analysis, QALY health gains were slightly higher for CBT than for RC (0.60 v. 0.57) and the CBT intervention had a 52.3% probability of being the superior treatment because, for equal or better QALY gains, the costs of CBT were lower than those of RC. Add-on preventive CBT for UHR resulted in a significant reduction in the incidence of first psychosis. QALY gains show little difference between the two conditions. The CBT intervention proved to be cost saving.


Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery.
Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with the challenge being to deliver it in a sustained manner. The combination of mesoporous silica nanoparticles (MSNs) and polycations in the confined pore space allows for incorporation and controlled release of therapeutic siRNA payloads. We hereby constructed MSNs with expanded mesopores and pore-surface-hyperbranched poly(ethyleneimine) (PEI) tethered with redox-cleavable linkers that could carry a high payload of siRNA (120 mg·g-1). The developed nanocarriers were efficiently taken up by cancer cells and were subsequently able to escape to the cytoplasm from the endosomes, most likely owing to the integrated PEI. Triggered by the intracellular redox conditions, the siRNA was sustainably released inside the cells over a period of several days. Functionality of siRNAs was demonstrated by using cell-killing siRNA as cargo. Despite not being the aim of the developed system, in vitro experiments using cell-killing siRNAs showed that the efficacy of siRNA transfection was comparable to the commercial in vitro transfection agent Lipofectamine. Consequently, the developed MSN-based delivery system offers a potential approach to hybrid nanocarriers for more efficient and long-term siRNA delivery and, in a longer perspective, in vivo gene silencing for RNA interference (RNAi) therapy.


Faster R-CNN: Towards Real-Time Object Detection with Region Proposal Networks.
State-of-the-art object detection networks depend on region proposal algorithms to hypothesize object locations. Advances like SPPnet [1] and Fast R-CNN [2] have reduced the running time of these detection networks, exposing region proposal computation as a bottleneck. In this work, we introduce a Region Proposal Network (RPN) that shares full-image convolutional features with the detection network, thus enabling nearly cost-free region proposals. An RPN is a fully convolutional network that simultaneously predicts object bounds and objectness scores at each position. The RPN is trained end-to-end to generate high-quality region proposals, which are used by Fast R-CNN for detection. We further merge RPN and Fast R-CNN into a single network by sharing their convolutional features-using the recently popular terminology of neural networks with 'attention' mechanisms, the RPN component tells the unified network where to look. For the very deep VGG-16 model [3] , our detection system has a frame rate of 5 fps (including all steps) on a GPU, while achieving state-of-the-art object detection accuracy on PASCAL VOC 2007, 2012, and MS COCO datasets with only 300 proposals per image. In ILSVRC and COCO 2015 competitions, Faster R-CNN and RPN are the foundations of the 1st-place winning entries in several tracks. Code has been made publicly available.


Reliability and validity of selected measures associated with increased fall risk in females over the age of 45 years with distal radius fracture - A pilot study.
Clinical measurement. This study examined test-retest reliability and convergent/divergent construct validity of selected tests and measures that assess balance impairment, fear of falling (FOF), impaired physical activity (PA), and lower extremity muscle strength (LEMS) in females >45 years of age after the distal radius fracture (DRF) population. Twenty one female participants with DRF were assessed on two occasions. Timed Up and Go, Functional Reach, and One Leg Standing tests assessed balance impairment. Shortened Falls Efficacy Scale, Activity-specific Balance Confidence scale, and Fall Risk Perception Questionnaire assessed FOF. International Physical Activity Questionnaire and Rapid Assessment of Physical Activity were administered to assess PA level. Chair stand test and isometric muscle strength testing for hip and knee assessed LEMS. Intraclass correlation coefficients (ICC) examined the test-retest reliability of the measures. Pearson correlation coefficients (r) examined concurrent relationships between the measures. The results demonstrated fair to excellent test-retest reliability (ICC between 0.50 and 0.96) and low to moderate concordance between the measures (low if r ≤ 0.4; moderate if r = 0.4-0.7). The results provide preliminary estimates of test-retest reliability and convergent/divergent construct validity of selected measures associated with increased risk for falling in the females >45 years of age after DRF. Further research directions to advance knowledge regarding fall risk assessment in DRF population have been identified.


The voice of non-pregnant women on alcohol consumption during pregnancy: a focus group study among women in Sweden.
Consensus is that fetal exposure to alcohol is harmful. Abstinence while trying to conceive and throughout pregnancy is recommended. Despite this, there are many women who consume alcohol around conception and until pregnancy recognition. The aim of this study was to explore the voice of non-pregnant women concerning alcohol consumption and its relation to pregnancy. Data were collected through seven focus groups interviews with 34 women of fertile age, who were neither pregnant nor mothers. Semi-structured interviews were undertaken, recorded and transcribed verbatim and then analysed using thematic analysis. Three main themes were identified in the analysis: an issue that cannot be ignored; awareness and uncertainty concerning alcohol and pregnancy; and transition to parenthood. Alcohol was an integral part of the women's lives. A societal expectation to drink alcohol was prevalent and the women used different strategies to handle this expectation. Most women agreed not to drink alcohol during pregnancy although their knowledge on the specific consequences was scanty and they expressed a need for more information. Most of the participants found drinking alcohol during pregnancy to be irresponsible and saw pregnancy as a start of a new way of life. Social expectations concerning women's alcohol use change with pregnancy when women are suddenly expected to abstain. Although most study participants shared an opinion for zero tolerance during pregnancy, their knowledge regarding consequences of drinking during pregnancy were sparse. In order for prospective mothers to make informed choices, there is a need for public health initiatives providing information on the relationship between alcohol consumption and reproduction.


The role of parental language acculturation in the formation of social capital: differential effects on high-risk children.
This person-centered study examines the extent to which parents' language dominance influences the effects of an after school, multi-family group intervention, FAST, on low-income children's emotional and behavioral outcomes via parents' relations with other parents and with school staff. Social capital resides in relationships of trust and shared expectations, which are highly dependent on whether parents share the language of other parents and teachers. This study is based on a community epidemiologically-defined sample of Latino families (N = 3,091) in San Antonio, Texas and Phoenix, Arizona. Latent profile analyses revealed three language profiles of parents across the two cities: English-dominant, Spanish-dominant, and bilingual. Path models revealed that FAST did not have a direct or indirect effect on children's emotional and behavior functioning, although FAST increased parent-parent and parent-school social capital among Spanish-dominant parents in Arizona and these parent-parent relations were associated with better child outcomes. Implications for interventions are discussed.


Stimulation of chloride transport by HCO3-CO2 in rabbit cortical collecting tubule.
We examined both the role of HCO3-CO2 in Cl transport as well as the effect of in vivo acid-base status on Cl transport by the rabbit cortical collecting tubule. The lumen-to-bath 36Cl tracer flux, expressed as the rate coefficient KCl, was measured in either HEPES-buffered (CO2-free) or HCO3-CO2-containing solutions. Amiloride was added to the perfusate to minimize the transepithelial voltage and thus the electrical driving force for Cl diffusion. Because KCl fell spontaneously with time in HCO3-CO2 solutions in the absence but not the presence of cAMP, we used cAMP throughout to avoid time-dependent changes. Acute in vitro removal of bath HCO3-CO2 reduced KCl. Acetazolamide addition in HEPES-buffered solutions also lowered KCl; KCl could be restored to control values by adding exogenous HCO3-CO2 in the presence of acetazolamide. In vivo acid-base effects on Cl transport were determined by dissecting tubules from either NaHCO3-loaded or NH4Cl-loaded rabbits. Tubules from HCO3-loaded rabbits had higher rates of Cl self exchange. Acute in vitro addition of bath HCO3-CO2 increased KCl and did so to a greater degree in tubules from HCO3-loaded rabbits. Most of this effect of HCO3-CO2 addition on KCl could not be accounted for by Cl-HCO3 exchange; rather, it appeared due to stimulation of Cl self exchange. The data are consistent with 36Cl transport occurring via Cl-HCO3 exchange as well as Cl self exchange. Both processes are acutely stimulated by HCO3 and/or Co2, and both are chronically regulated by in vivo acid-base status.


Typographic influences on reading.
The research reported here comprises an empirical investigation of the phenomenon of typographic allusion. In a preliminary study, subjects rated the perceptual qualities possessed by different typefaces (e.g. heavy-light, fast-slow). The results indicated that subjects agreed as to typeface characteristics and that typefaces were distinguished by such qualities. In Expt 1, subjects undertook a speeded decision task in which they responded according to which one of four adjectives appeared tachistoscopically. Each word appeared in a typeface whose qualities were either consistent or inconsistent with its meaning. Reaction times for inconsistent stimuli were significantly slower than those for consistent trials. In preparation for Expt 2, the same rating procedure was used to elicit subjects' judgements of the attributes of different animals. Subjects agreed as to animals' qualities and such qualities reliably distinguished between the animals. The names of these animals were then used as targets in a binary decision task and each one appeared in a typeface possessing qualities which were either congruent or incongruent with those of the animal. Subjects responded according to whether they considered the animal presented on each trial to be heavy or light, or fast or slow moving. Responses on trials in which the animal and typeface possessed conflicting attributes were significantly slower than responses when animal and typeface qualities were congruent. These results are discussed in relation to current views regarding the processing of written English. We argue that typographic features of words are able to access a semantic code and that this code can interact with the derivation of a linguistic code specifying a word's meaning and/or with post-lexical access decision processes.


A Review of Cranberry Use for Preventing Urinary Tract Infections in Older Adults.
Urinary tract infections (UTIs) are one the of the most common types of infections in adults older than 65 years of age. Preventing UTIs with prophylactic antibiotics increases the risk of side effects and microbial resistance, and is costly. Cranberry fruit and juices contain the compound proanthrocyanidins (PACs), specifically proanthrocyanidin-A, which exerts antiadhesion characteristics against bacteria. Cranberry products therefore have been an attractive, nonantibiotic preventative option for UTIs; however, the current literature supporting cranberry use in older adults is controversial. This could be multifactorial owing to the heterogeneity of the older population as well as inconsistencies in the recommended dose of PAC in the current literature. Evidence supports that cranberry may be beneficial in preventing UTIs in specific populations such as catheterassociated UTI and postradiotherapy prostate cancer. The cost of daily capsules versus the cost of preventing a UTI in older adults is an important consideration for initiating therapy.


Histone-lysine methyltransferase EHMT2 is involved in proliferation, apoptosis, cell invasion, and DNA methylation of human neuroblastoma cells.
Neuroblastoma (NB), a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behaviors ranging from spontaneous remission to rapid tumor progression and death. In addition to genetic abnormalities, recent studies have indicated that epigenetic aberrations also contribute toward NB pathogenesis. However, the epigenetic mechanisms underlying the pathogenesis of NB are largely unknown. Inhibition of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) was evaluated through the measurement of H3K9Me2 levels. Cell proliferation was examined by cell counting in human NB cell lines (LA1-55n, IMR-5, and NMB). The RNA expression of EHMT2, MYCN, and p21 was measured by real-time PCR. The expression of PCNA, MYCN, p53, cyclinD1, H3, H3K27M2, and H3K9Me2 was examined by western blot analysis. In-vitro invasion and the effects of the EHMT2 inhibitor (BIX-01294) were assessed in the Transwell chamber assay. Caspase 3 and 8 activities were measured using a Caspase-Glo assay kit. The level of overall DNA methylation was measured by liquid chromatography-mass spectroscopy. BIX-01294, a specific inhibitor of EHMT2 (a key enzyme for histone H3 dimethylation at lysine-9), specifically decreases the overall H3K9Me2 level but not H3K27Me2. The inhibition of EHMT2 decreased the proliferation of NB cells and induced apoptosis by increasing caspase 8/caspase 3 activity. BIX-01294 inhibited NB cell mobility and invasion. This was accompanied by a decreased expression of the MYCN oncogene. Inhibition of EHMT2 enhanced a doxorubicin-induced inhibitory effect on cell proliferation. Finally, EHMT2 inhibition modulated overall DNA methylation levels in NB cells. Our results show that histone-lysine methylation is involved in cell proliferation, apoptosis, cell invasion, and overall DNA methylation in human NB cells. Further understanding of this mechanism may provide an insight into the pathogenesis of NB progression and lead to novel treatment strategies.


African-American mitochondrial DNAs often match mtDNAs found in multiple African ethnic groups.
Mitochondrial DNA (mtDNA) haplotypes have become popular tools for tracing maternal ancestry, and several companies offer this service to the general public. Numerous studies have demonstrated that human mtDNA haplotypes can be used with confidence to identify the continent where the haplotype originated. Ideally, mtDNA haplotypes could also be used to identify a particular country or ethnic group from which the maternal ancestor emanated. However, the geographic distribution of mtDNA haplotypes is greatly influenced by the movement of both individuals and population groups. Consequently, common mtDNA haplotypes are shared among multiple ethnic groups. We have studied the distribution of mtDNA haplotypes among West African ethnic groups to determine how often mtDNA haplotypes can be used to reconnect Americans of African descent to a country or ethnic group of a maternal African ancestor. The nucleotide sequence of the mtDNA hypervariable segment I (HVS-I) usually provides sufficient information to assign a particular mtDNA to the proper haplogroup, and it contains most of the variation that is available to distinguish a particular mtDNA haplotype from closely related haplotypes. In this study, samples of general African-American and specific Gullah/Geechee HVS-I haplotypes were compared with two databases of HVS-I haplotypes from sub-Saharan Africa, and the incidence of perfect matches recorded for each sample. When two independent African-American samples were analyzed, more than half of the sampled HVS-I mtDNA haplotypes exactly matched common haplotypes that were shared among multiple African ethnic groups. Another 40% did not match any sequence in the database, and fewer than 10% were an exact match to a sequence from a single African ethnic group. Differences in the regional distribution of haplotypes were observed in the African database, and the African-American haplotypes were more likely to match haplotypes found in ethnic groups from West or West Central Africa than those found in eastern or southern Africa. Fewer than 14% of the African-American mtDNA sequences matched sequences from only West Africa or only West Central Africa. Our database of sub-Saharan mtDNA sequences includes the most common haplotypes that are shared among ethnic groups from multiple regions of Africa. These common haplotypes have been found in half of all sub-Saharan Africans. More than 60% of the remaining haplotypes differ from the common haplotypes at a single nucleotide position in the HVS-I region, and they are likely to occur at varying frequencies within sub-Saharan Africa. However, the finding that 40% of the African-American mtDNAs analyzed had no match in the database indicates that only a small fraction of the total number of African haplotypes has been identified. In addition, the finding that fewer than 10% of African-American mtDNAs matched mtDNA sequences from a single African region suggests that few African Americans might be able to trace their mtDNA lineages to a particular region of Africa, and even fewer will be able to trace their mtDNA to a single ethnic group. However, no firm conclusions should be made until a much larger database is available. It is clear, however, that when identical mtDNA haplotypes are shared among many ethnic groups from different parts of Africa, it is impossible to determine which single ethnic group was the source of a particular maternal ancestor based on the mtDNA sequence.


Interactions between life stress factors and carrying the APOE4 allele adversely impact self-reported health in old adults.
Based on the multiple logistic regression analysis of data from a random sample of 1,023 old adults collected in Taiwan in 2000, we found that interactions between carrying the APOE4 allele and one of four life stress factors (relocated mainlander, living in a crowded household with six or more persons, living in an earthquake-damaged house, and monthly financial difficulty) significantly increased the odds ratio of poor self-reported health. Correlations between carrying the APOE4 allele and the life stress factors were ruled out by statistical tests. These life stress factors had a substantially larger adverse impact on self-reported health in APOE4 allele carriers than in noncarriers. This study provides evidence that interaction between carrying APOE4 allele and chronic life stressors has significant impacts on self-reported health while controlling for various sociodemographic and health behavior factors. Further studies with richer biomarkers are warranted for deeper understanding of the biological mechanisms.