Genome-wide mapping of large deletions and their population-genetic properties in dairy cattle.
Large genomic deletions are potential candidate for loss-of-function, which could be lethal as homozygote. Analysing whole genome data of 175 cattle, we report 8,480 large deletions (199 bp-773 KB) with an overall false discovery rate of 8.8%; 82% of which are novel compared with deletions in the dbVar database. Breakpoint sequence analyses revealed that majority (24 of 29 tested) of the deletions contain microhomology/homology at breakpoint, and therefore, most likely generated by microhomology-mediated end joining. We observed higher differentiation among breeds for deletions in some genic-regions, such as ABCA12, TTC1, VWA3B, TSHR, DST/BPAG1, and CD1D. The genes overlapping deletions are on average evolutionarily less conserved compared with known mouse lethal genes (P-value = 2.3 × 10-6). We report 167 natural gene knockouts in cattle that are apparently nonessential as live homozygote individuals are observed. These genes are functionally enriched for immunoglobulin domains, olfactory receptors, and MHC classes (FDR = 2.06 × 10-22, 2.06 × 10-22, 7.01 × 10-6, respectively). We also demonstrate that deletions are enriched for health and fertility related quantitative trait loci (2-and 1.5-fold enrichment, Fisher's P-value = 8.91 × 10-10 and 7.4 × 10-11, respectively). Finally, we identified and confirmed the breakpoint of a ∼525 KB deletion on Chr23:12,291,761-12,817,087 (overlapping BTBD9, GLO1 and DNAH8), causing stillbirth in Nordic Red Cattle.


Rewiring-induced chaos in pulse-coupled neural networks.
The dependence of the dynamics of pulse-coupled neural networks on random rewiring of excitatory and inhibitory connections is examined. When both excitatory and inhibitory connections are rewired, periodic synchronization emerges with a Hopf-like bifurcation and a subsequent period-doubling bifurcation; chaotic synchronization is also observed. When only excitatory connections are rewired, periodic synchronization emerges with a saddle node-like bifurcation, and chaotic synchronization is also observed. This result suggests that randomness in the system does not necessarily contaminate the system, and sometimes it even introduces rich dynamics to the system such as chaos.


Rapid evolution of the human mutation spectrum.
DNA is a remarkably precise medium for copying and storing biological information. This high fidelity results from the action of hundreds of genes involved in replication, proofreading, and damage repair. Evolutionary theory suggests that in such a system, selection has limited ability to remove genetic variants that change mutation rates by small amounts or in specific sequence contexts. Consistent with this, using SNV variation as a proxy for mutational input, we report here that mutational spectra differ substantially among species, human continental groups and even some closely related populations. Close examination of one signal, an increased TCC→TTC mutation rate in Europeans, indicates a burst of mutations from about 15,000 to 2000 years ago, perhaps due to the appearance, drift, and ultimate elimination of a genetic modifier of mutation rate. Our results suggest that mutation rates can evolve markedly over short evolutionary timescales and suggest the possibility of mapping mutational modifiers.


Renal denervation: a potential new treatment modality for polycystic ovary syndrome?
Polycystic ovary syndrome (PCOS) is associated with sympathetic nervous system activation, insulin resistance, and blood pressure elevation. Renal nerve ablation has been demonstrated to reduce sympathetic outflow and improve blood pressure control. Here we report on the effects of renal denervation on hemodynamic, metabolic, and renal parameters in two obese PCOS patients with hypertension. Sympathetic nerve activity was assessed at baseline using microneurography and norepinephrine spillover measurements. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Measurements of cystatin-C, creatinine clearance, and urinary albumin-creatinine ratio were also obtained. All measurements were repeated 3 months after bilateral renal denervation achieved via percutaneous endovascular radiofrequency ablation. Muscle sympathetic nerve activity and whole body norepinephrine spillover were substantially elevated at baseline in both patients by approximately 2.5-3-fold. Bilateral renal nerve ablation reduced both indices of sympathetic nerve activity. This was associated with moderate reductions in blood pressure and a substantial improvement in insulin sensitivity by approximately 17.5% in the absence of weight changes at 3-month follow-up. Glomerular hyperfiltration and urinary albumin excretion were also reduced. These findings corroborate the relevance of sympathetic activation in PCOS and suggest that renal denervation exerts beneficial effects not only on blood pressure control but also on insulin sensitivity, renal, and endocrine abnormalities characteristic of PCOS.


Infant mortality in three population-based cohorts in Southern Brazil: trends and differentials.
We studied time trends in infant mortality and associated factors between three cohort studies carried out in Pelotas, Rio Grande do Sul State, Brazil, in 1982, 1993, and 2004. All hospital births and deaths were determined by means of regular visits to hospitals, registrar's offices, and cemeteries. This data was used to calculate neonatal, post-neonatal, and infant mortality rates per thousand live births. Rates were also calculated according to cause of death, sex, birth weight, gestational age, and family income. The infant mortality rate fell from 36.4 per 1,000 live births in 1982 to 21.1 in 1993 and 19.4 in 2004. Major causes of infant mortality in 2004 were perinatal causes and respiratory infections. Mortality among low birth weight children from poor families fell 16% between 1993 and 2004; however, this rate increased by more than 100% among high-income families due to the increase in the number of preterm deliveries in this group. The stabilization of infant mortality in the last decade is likely to be due to excess medical interventions relating to pregnancies and delivery care.


The unfolded protein response: An emerging therapeutic target for pancreatitis and pancreatic ductal adenocarcinoma.
Pancreatitis is a debilitating disease involving inflammation and fibrosis of the exocrine pancreas. Recurrent or chronic forms of pancreatitis are a significant risk factor for pancreatic ductal adenocarcinoma. While genetic factors have been identified for both pathologies, environmental stresses play a large role in their etiology. All cells have adapted mechanisms to handle acute environmental stress that alters energy demands. A common pathway involved in the stress response involves endoplasmic reticulum stress and the unfolded protein response (UPR). While rapidly activated by many external stressors, in the pancreas the UPR plays a fundamental biological role, likely due to the high protein demands in acinar cells. Despite this, increased UPR activity is observed in response to acute injury or following exposure to risk factors associated with pancreatitis and pancreatic cancer. Studies in animal and cell cultures models show the importance of affecting the UPR in the context of both diseases, and inhibitors have been developed for several specific mediators of the UPR. Given the importance of the UPR to normal acinar cell function, efforts to affect the UPR in the context of disease must be able to specifically target pathology vs. physiology. In this review, we highlight the importance of the UPR to normal and pathological conditions of the exocrine pancreas. We discuss recent studies suggesting the UPR may be involved in the initiation and progression of pancreatitis and PDAC, as well as contributing to chemoresistance that occurs in pancreatic cancer. Finally, we discuss the potential of targeting the UPR for treatment.


The impact of the sequence-dependent physical properties of DNA on chromatin dynamics.
The local mechanical properties of DNA depend on local sequence. Here we review recent genomic, structural, and computational efforts at deciphering the "mechanical code", i.e., the mapping between sequence and mechanics. We then discuss works that suggest how evolution has exploited the mechanical code to control the energetics of DNA-deforming biological processes such as nucleosome organization, transcription factor binding, DNA supercoiling, gene regulation, and 3D chromatin organization. As a whole, these recent works suggest that DNA sequence in diverse organisms can encode regulatory information governing diverse processes via the mechanical code.


Cancer anxiety and attitudes toward mammography among screening attenders, nonattenders, and women never invited.
A mailed questionnaire survey was conducted among the following groups: 179 women who screened false positive at a free mammography screening; a random sample of 250 women who screened negative; 670 nonattenders of the screening; and a random population sample of 250 women who lived in another city and were not invited, but were otherwise comparable. The most frequently reported reason for nonattendance was not having the opportunity. Furthermore, only 18% of the nonattenders reported anxiety about breast cancer compared with 33% of the population sample (P less than .05). Ninety-nine percent of the women who attended indicated a positive attitude toward mammography that had not been adversely affected by screening experiences.


Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors.
Sustained stimulation of G-protein-coupled receptors (GPCRs) typically causes receptor desensitisation, which is mediated by phosphorylation, often within the C-terminal tail of the receptor. The consequent binding of beta-arrestin not only prevents the receptor from activating its G protein (causing desensitisation), but can also target it for internalisation via clathrin-coated vesicles and can mediate signalling to proteins regulating endocytosis and mitogen-activated protein kinase (MAPK) cascades. GnRH acts via phospholipase C (PLC)-coupled GPCRs on pituitary gonadotrophs to stimulate a Ca(2+)-mediated increase in gonadotrophin secretion. The type I GnRH receptors (GnRH-Rs), found only in mammals, are unique in that they lack C-terminal tails and apparently do not undergo agonist-induced phosphorylation or bind beta-arrestin; they are therefore resistant to receptor desensitisation and internalise slowly. In contrast, the type II GnRH-Rs, found in numerous vertebrates, possess such tails and show rapid desensitisation and internalisation, with concomitant receptor phosphorylation (within the C-terminal tails) or binding of beta-arrestin, or both. The association with beta-arrestin may also be important for regulation of dynamin, a GTPase that controls separation of endosomes from the plasma membrane. Using recombinant adenovirus to express GnRH-Rs in Hela cells conditionally expressing a dominant negative mutant of dynamin (K44A), we have found that blockade of dynamin-dependent endocytosis inhibits internalisation of type II (xenopus) GnRH-Rs but not type I (human) GnRH-Rs. In these cells, blockade of dynamin-dependent internalisation also inhibited GnRH-R-mediated MAPK activation, but this effect was not receptor specific and therefore not dependent upon dynamin-regulated GnRH-R internalisation. Although type I GnRH-Rs do not desensitise, sustained activation of GnRH-Rs causes desensitisation of gonadotrophin secretion, and we have found that GnRH can cause down-regulation of inositol (1,4,5) trisphosphate receptors and desensitisation of Ca(2+) mobilisation in pituitary cells. The atypical resistance of the GnRH-R to desensitisation may underlie its atypical efficiency at provoking this downstream adaptive response. GnRH-Rs are also expressed in several extrapituitary sites, and these may mediate direct inhibition of proliferation of hormone-dependent cancer cells. Infection with type I GnRH-R-expressing adenovirus facilitated expression of high-affinity, PLC-coupled GnRH-R in mammary and prostate cancer cells, and these mediated pronounced antiproliferative effects of receptor agonists. No such effect was seen in cells transfected with a type II GnRH-R, implying that it is mediated most efficiently by a non-desensitising receptor. Thus it appears that the mammalian GnRH-Rs have undergone a period of rapidly accelerated molecular evolution that is of functional relevance to GnRH-Rs in pituitary and extrapituitary sites.


Research Themes and Hotspots in Nursing Informatics Education Based Co-Word Analysis.
The purpose of the study is to identify research topics and hotspots in nursing informatics education during the period of 2009-2018. The relevant literature of nursing informatics education was retrieved from the Web of Science Core Collection (WoSCC). This study identified three research themes and hotspots in nursing informatics education using co-word analysis. The themes are curriculum, technology, and nursing informatics. The results provide useful information for researchers to research topic choices and in-depth research.


Deformation of crowns during cementation.
Deformation of crowns during cementation was investigated by a simple loading system of defined crowns with silicone fluids as cements. Deformation of the crowns was measured by long stain gauges that encircled the cervical margins. Die spacing was simulated by etching the die. Venting was simulated by removing a small screw. Deformation of the crowns was decreased by decreasing the viscosity of fluid, increasing the thickness of the crowns, and venting. Etching the die decreased the seating times of the crowns, but did not alter the level of deformation. Terminal cementation with zinc phosphate cement confirmed the presence of crown deformation during cementation. The results have consequences for bonded and all-ceramic crowns, and explain several clinical phenomena. It is suggested that low viscosity cements, low seating forces, and die spacing be used to decrease the deformation of crowns during seating. The importance of passive fitting of the crown to the tooth is stressed.


Pseudomonas Aeruginosa Lung Infection Subverts Lymphocytic Responses through IL-23 and IL-22 Post-Transcriptional Regulation.
Pseudomonas aeruginosa (P.a) is a pathogen causing significant morbidity and mortality, particularly in hospital patients undergoing ventilation and in individuals with cystic fibrosis. Although we and others have investigated mechanisms used by P.a to subvert innate immunity, relatively less is known about the potential strategies used by this bacterium to fight the adaptive immune system and, in particular, T cells. Here, using RAG KO (devoid of 'classical' αβ and γδ TCR T lymphocytes) and double RAG γC KO mice (devoid of T, NK and ILC cells), we demonstrate that the lymphocytic compartment is important to combat P.a (PAO1 strain). Indeed, we show that PAO1 load was increased in double RAG γC KO mice. In addition, we show that PAO1 down-regulates IL-23 and IL-22 protein accumulation in the lungs of infected mice while up-regulating their RNA production, thereby pointing towards a specific post-transcriptional regulatory mechanism not affecting other inflammatory mediators. Finally, we demonstrate that an adenovirus-mediated over-expression of IL-1, IL-23 and IL-7 induced lung neutrophil and lymphocytic influx and rescued mice against P.a-induced lethality in all WT, RAG γC KO and RAG γC KO RAG-deficient mice, suggesting that this regimen might be of value in 'locally immunosuppressed' individuals such as cystic fibrosis patients.


Evaluation of the in vitro ⍺-amylase inhibitory, antiglycation, and antioxidant properties of Punica granatum L. (pomegranate) fruit peel acetone extract and its effect on glucose uptake and oxidative stress in hepatocytes.
Punica granatum L. (pomegranate) is a widely eaten fruit. The antidiabetic, antioxidative, and antilipidemic properties of the hydroalcoholic extracts of the different plant's parts have been extensively studied, with scarce information on the acetone extract (ACE). This study investigated antidiabetic, antioxidative, and antiobesogenic properties of ACE of the fruit peel. Preliminary data showed that ACE showed stronger antioxidant (radical-scavenging IC50 = 1.56 μg/ml) and ⍺-amylase inhibitory (IC50 = 10.6 μg/ml) properties than the hydroalcoholic extracts and Acarbose. The ACE inhibited protein glycation and lipase activity. In hepatocytes, ACE impaired oxidative stress-induced lipid peroxidation and reduced glutathione depletion but increased glucose uptake without decreasing the cell viability. HPLC analysis showed predominant presence of bioactive phenolic acids (ferulic, caffeic, and gallic acids) in this extract. This study suggests that ACE of P. granatum fruit peel may be an understudied extract that contains potent antidiabetic and antioxidative bioactive principles with minimal toxicity. PRACTICAL APPLICATIONS: Plant derived medicines have been an affordable and effective alternative therapy for many metabolic diseases, including diabetes. The fruit juice and fruits of pomegranate is widely consumed for the palatable taste and cardiovascular benefits. This study provides preliminary experimental evidences confirming that of the acetone extracts of pomegranate fruit peel, which has been sparsely studied, may possess more potent antidiabetic and antioxidative property than to the routinely studied hydroalcoholic counterparts. Additionally, the acetone extract is rich in bioactive phenolic acids, suggesting that the acetone extract of pomegranate fruit peel may be a promising candidate for further antidiabetic study and a source of bioactive principles for the management of diabetes and oxidative complications.


Anatomy of the olfactory mucosa.
The classic notion that humans are microsmatic animals was born from comparative anatomy studies showing the reduction in the size of both the olfactory bulbs and the limbic brain relative to the whole brain. However, the human olfactory system contains a number of neurons comparable to that of most other mammals, and humans have exquisite olfactory abilities. Major advances in molecular and genetic research have resulted in the identification of extremely large gene families that express receptors for sensing odors. Such advances have led to a renaissance of studies focused on both human and nonhuman aspects of olfactory physiology and function. Evidence that olfactory dysfunction is among the earliest signs of a number of neurodegenerative and neuropsychiatric disorders has led to considerable interest in the use of olfactory epithelial biopsies for potentially identifying such disorders. Moreover, the unique features of the olfactory ensheathing cells have made the olfactory mucosa a promising and unexpected source of cells for treating spinal cord injuries and other neural injuries in which cell guidance is critical. The olfactory system of humans and other primates differs in many ways from that of other species. In this chapter we provide an overview of the anatomy of not only the human olfactory mucosa but of mucosae from a range of mammals from which more detailed information is available. Basic information regarding the general organization of the olfactory mucosa, including its receptor cells and the large number of other cell types critical for their maintenance and function, is provided. Cross-species comparisons are made when appropriate. The polemic issue of the human vomeronasal organ in both the adult and fetus is discussed, along with recent findings regarding olfactory subsystems within the nose of a number of mammals (e.g., the septal organ and Grüneberg ganglion).


Facilitators and barriers to clinical practice guideline-consistent supportive care at pediatric oncology institutions: a Children's Oncology Group study.
Clinical practice guideline (CPG)-consistent care improves patient outcomes, but CPG implementation is poor. Little is known about CPG implementation in pediatric oncology. This study aimed to understand supportive care CPG implementation facilitators and barriers at pediatric oncology National Cancer Institute (NCI) Community Oncology Research Program (NCORP) institutions. Healthcare professionals at 26 pediatric, Children's Oncology Group-member, NCORP institutions were invited to participate in face-to-face focus groups. Serial focus groups were held until saturation of ideas was reached. Supportive care CPG implementation facilitators and barriers were solicited using nominal group technique (NGT), and implementation of specific supportive care CPG recommendations was discussed. Notes from each focus group were analyzed using a directed content analysis. The top five themes arising from an analysis of NGT items were identified, first from each focus group and then across all focus groups. Saturation of ideas was reached after seven focus groups involving 35 participants from 18 institutions. The top five facilitators of CPG implementation identified across all focus groups were organizational factors including charging teams with CPG implementation, individual factors including willingness to standardize care, user needs and values including mentorship, system factors including implementation structure, and implementation strategies including a basis in science. The top five barriers of CPG implementation identified were organizational factors including tolerance for inconsistencies, individual factors including lack of trust, system factors including administrative hurdles, user needs and values including lack of inclusivity, and professional including knowledge gaps. Healthcare professionals at pediatric NCORP institutions believe that organizational factors are the most important determinants of supportive care CPG implementation. They believe that CPG-consistent supportive care is most likely to be delivered in organizations that prioritize evidence-based care, provide structure and resources to implement CPGs, and eliminate implementation barriers. ClinicalTrials.gov Identifier: NCT02847130. Date of registration: July 28, 2016.


Apoptosis in severe, compensated pressure overload predominates in nonmyocytes and is related to the hypertrophy but not function.
It is widely held that myocyte apoptosis in left ventricular hypertrophy (LVH) contributes to left ventricle (LV) dysfunction and heart failure. The main goal of this investigation was to determine if there is a statistical relationship among LV hypertrophy, apoptosis and LV function, and importantly whether the apoptosis occurs in myocytes or nonmyocytes in the heart. We used both rat and canine models of severe LVH induced by chronic thoracic aortic banding with resultant LV-aortic pressure gradients 145-155 mmHg and increases in LV/body weight of 58 and 70%. These models also provided the ability to examine transmural apoptosis in LVH. In both models, the overwhelming majority (88%) of apoptotic cells were nonmyocytes. The regressions for apoptosis vs. LVH were stronger for nonmyocytes than myocytes and also stronger in the subendocardium than the subepicardium. Importantly, LV systolic and diastolic wall stresses were normal, indicating that the apoptosis could not be attributed to LV stretch or heart failure. In addition, there was no relationship between the extent of apoptosis and LV ejection fraction, which actually increased (P < 0.05), in the face of elevated LV systolic pressure, indicating that greater apoptosis did not result in a decrease in LV function. Thus, in response to chronic, severe pressure overload, LVH in the absence of LV dilation, and elevated LV wall stress, apoptosis occurred predominantly in nonmyocytes in the myocardial interstitium, more in the subendocardium than the subepicardium. The extent of apoptosis was linearly related to the amount of LV hypertrophy, but not to LV function.


An active current-sensing constant-frequency HCC buck converter using phase-frequency-locked techniques.
A hysteresis-current-controlled (HCC) buck converter with active current-sensing and phase-frequencylocked techniques is presented in this paper. The proposed active current-sensing technique can not only consume less power than previous techniques, but also fully sense the inductor current. Although the buck converter is HCC, the switching frequency can be constant due to the devised phase-frequency-locked technique. The proposed converter has been designed and implemented with TSMC 0.35 microm DPQM CMOS processes. It is shown in the experimental results that the HCC buck converter features the following characteristics: 1) up to 800 mA of load current, 2) wide input and output voltage range, 3) high power efficiency, and 4) constant-frequency operation.


In situ activity of suspended and immobilized microbial communities as measured by fluorescence lifetime imaging.
In this study, the feasibility of fluorescence lifetime imaging (FLIM) for measurement of RNA:DNA ratios in microorganisms was assessed. The fluorescence lifetime of a nucleic acid-specific probe (SYTO 13) was used to directly measure the RNA:DNA ratio inside living bacterial cells. In vitro, SYTO 13 showed shorter fluorescence lifetimes in DNA solutions than in RNA solutions. Growth experiments with bacterial monocultures were performed in liquid media. The results demonstrated the suitability of SYTO 13 for measuring the growth-phase-dependent RNA:DNA ratio in Escherichia coli cells. The fluorescence lifetime of SYTO 13 reflected the known changes of the RNA:DNA ratio in microbial cells during different growth phases. As a result, the growth rate of E. coli cells strongly correlated with the fluorescence lifetime. Finally, the fluorescence lifetimes of SYTO 13 in slow- and fast-growing biofilms were compared. For this purpose, biofilms developed from activated sludge were grown as autotrophic and heterotrophic communities. The FLIM data clearly showed a longer fluorescence lifetime for the fast-growing heterotrophic biofilms and a shorter fluorescence lifetime for the slow-growing autotrophic biofilms. Furthermore, starved biofilms showed shorter lifetimes than biofilms supplied with glucose, indicating a lower RNA:DNA ratio in starved biofilms. It is suggested that FLIM in combination with SYTO 13 represents a useful tool for the in situ differentiation of active and inactive bacteria. The technique does not require radioactive chemicals and may be applied to a broad range of sample types, including suspended and immobilized microorganisms.


Platelet-derived growth factor-BB inhibits rat alpha1D-adrenergic receptor gene expression in vascular smooth muscle cells by inducing AP-2-like protein binding to alpha1D proximal promoter region.
We have previously found that, in addition to mediating contraction of vascular smooth muscle, activation of alpha1D-adrenergic receptors (AR) induces smooth muscle cell (SMC) hypertrophy. Despite their importance, little is known about how alpha1D-AR expression is regulated. Recently, we demonstrated that platelet-derived growth factor (PDGF)-beta receptor stimulation, but not various other growth factors, inhibits transcription of alpha1D-, but not alpha1A- or alpha1B-ARs, resulting in reduced norepinephrine-mediated SMC growth. To investigate this inhibitory mechanism, herein we cloned and characterized 1.6 kb of the 5'-flanking region of the rat alpha1D-AR gene. Reporter gene transfection assays in rat aorta and vena cava SMCs showed that this 5'-flanking region, which lacks a TATA-box, possesses strong promoter activity. Two transcription initiation sites and their flanking promotor regions were identified, wherein the proximal promotor mediated PDGF-BB inhibition of transcription. Gel mobility shift assays suggested that Sp1 binds constitutively at two consensus sites within the -399 base pair (bp)/-349-bp region of the proximal promotor. This constitutive binding was unaffected by PDGF-BB. In contrast, a flanking motif (-384 bp/-349 bp), possessing putative Sp1/activator protein-2 (AP-2) overlapping binding sites and located upstream of the proximal transcription initiation site, was required for PDGF-BB inhibition of alpha1D transcription. PDGF-BB increased AP-2 binding to the distal AP-2 site in this region in the context of SMCs. Furthermore, overexpression of AP-2 protein, by transgene transfection, dose-dependently inhibited alpha1D-AR activity driven by this motif. Thus, PDGF-BB may increase AP-2 binding within the proximal promoter to cause down-regulation of alpha1D-AR expression in SMCs when PDGF is elevated, such as in the postnatal growing vascular wall and in vascular hypertrophic diseases.


Problems in identifying predictors and correlates of weight loss and maintenance: implications for weight control therapies based on behaviour change.
Weight management is a dynamic process, with a pre-treatment phase, a treatment (including process) phase and post-treatment maintenance, and where relapse is possible during both the treatment and maintenance. Variability in the statistical power of the studies concerned, heterogeneity in the definitions, the complexity of obesity and treatment success, the constructs and measures used to predict weight loss and maintenance, and an appreciation of who and how many people achieve it, make prediction difficult. In models of weight loss or maintenance: (i) predictors explain up to 20-30% of the variance; (ii) many predictors are the sum of several small constituent variables, each accounting for a smaller proportion of the variance; (iii) correlational or predictive relationships differ across study populations; (iv) inter-individual variability in predictors and correlates of outcomes is high and (v) most of the variance remains unexplained. Greater standardization of predictive constructs and outcome measures, in more clearly defined study populations, tracked longitudinally, is needed to better predict who sustains weight loss. Treatments need to develop a more individualized approach that is sensitive to patients' needs and individual differences, which requires measuring and predicting patterns of intra-individual behaviour variations associated weight loss and its maintenance. This information will help people shape behaviour change solutions to their own lifestyle needs.


Simplifying the Forehead Flap for Nasal Reconstruction: A Review of 420 Consecutive Cases.
The forehead flap is an important tool in nasal reconstruction. The authors present objective data and recommendations based on over a decade of consecutive forehead flap nasal reconstructions performed by the senior author (J.F.T.). In addition, the authors separate the technique into its individual steps and provide details of the senior author's approach to each. The authors performed a retrospective analysis of patients who underwent nasal reconstruction with the forehead flap over a 10-year period performed by the senior author (J.F.T.). Each case was evaluated for defect location, pedicle design, time of division, number of stages, use of cartilage grafts, lining reconstruction, donor-site closure, and complications. Four hundred twenty patients underwent forehead flap nasal reconstruction. Average time to pedicle division was 32 days. Three-fourths of patients completed reconstruction in two stages. Defects most commonly involved the nasal ala and tip. Approximately half of patients received cartilage grafts and half underwent lining reconstruction. There were 16 complications, ranging from partial flap loss to postoperative death (n = 1). Confidently grasping the nuances of forehead flap nasal reconstruction arms the reconstructive surgeon with a reliable tool that can effectively treat a variety of defects. It is safe to use in an outpatient setting even in elderly patients. Recommendations include ipsilateral flap design and turn-in component as the first choice for lining replacement. Therapeutic, IV.


Moving Beyond the Gym: A Content Analysis of YouTube as an Information Resource for Physical Literacy.
The Internet, and particularly YouTube, has been found to be and continues to develop as a resourceful educational space for health-related information. Understanding physical literacy as a lifelong health-related outcome and facilitator of an active lifestyle, we sought to assess the content, exposure, engagement, and information quality of uploaded physical literacy videos on YouTube. Two researchers collected 300 YouTube videos on physical literacy and independently coded each video's: title, media source of upload, content topics related to physical literacy, content delivery style, and adherence to adapted Health on the Net Foundation Code of Conduct (HONcode) principles of information quality. Physical literacy videos that focused on physical activity and behaviors were the strongest predictor of high quality ratings, followed closely by videos covering affective domains (motivation, confidence, and self-esteem) of physical literacy. The content delivery method was also important, with videos utilizing presentations and testimonials containing high quality information about physical activity. Thus, providers of physical literacy and health-related online video content should be aware of and adhere to the expected quality standards. As health information expectations and ethical standards increase, the Internet, and specifically YouTube, has the potential to enhance video resources, virtual networking opportunities, as well as the sharing, dissemination, accumulation, and enrichment of physical literacy information for all.


Aortic valve disease in Turner syndrome.
Our goal was to determine the prevalence and characteristics of aortic valve disease in girls and women with monosomy for the X chromosome, or Turner syndrome (TS). Complications from congenital aortic valve disease are a major source of premature mortality in TS, but accurate data on the prevalence of aortic valve abnormalities and their association with aortic root dilation are not available. This prospective study characterized the aortic valve and proximal aorta in 253 individuals with TS age 7 to 67 years using transthoracic echocardiography as our primary screening tool, supplemented with magnetic resonance imaging. Transthoracic echocardiography revealed a normal tricuspid aortic valve (TAV) in 172 and a bicuspid aortic valve (BAV) in 66 subjects. Transthoracic echocardiography could not visualize the aortic valve in 15 of 253 or 6%. Magnetic resonance imaging diagnosed 12 of 15 of these cases (8 BAV and 4 TAV), so that only 3 of 253 (1.2%) could not be visualized by either modality. The aortic valve was bicuspid in 74 of 250 (30%) adequately imaged subjects. The prevalence was equal in pediatric (<18 years, n = 89) and adult populations. Over 95% of abnormal aortic valves in TS resulted from fusion of the right and left coronary leaflets. Ascending aortic diameters were significantly greater at the annulus, sinuses, sinotubular junction, and ascending aorta in the BAV group, with aortic root dilation in 25% of subjects with BAV versus 5% of those with TAV. Girls and women with TS need focused screening of the aortic valve and root to identify the many asymptomatic individuals with abnormal valvular structure and/or aortic root dilation.


Atrazine Exposure and Reproductive Dysfunction through the Hypothalamus-Pituitary-Gonadal (HPG) Axis.
Endocrine disrupting chemicals (EDC) are exogenous agents that alter endogenous hormone signaling pathways. These chemicals target the neuroendocrine system which is composed of organs throughout the body that work alongside the central nervous system to regulate biological processes. Of primary importance is the hypothalamic-pituitary-gonadal (HPG) axis which is vital for maintaining proper reproductive function. Atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) is a pre-emergent herbicide used to prevent the growth of weeds on various crops. This herbicide is reported to widely contaminate potable water supplies everywhere it is applied. As such, the European Union banned the use of atrazine in 2004. Currently the United States Environmental Protection Agency regulates atrazine at 3 parts per billion (ppb; μg/L) in drinking water, while the World Health Organization recently changed their drinking water guideline to 100 ppb. Atrazine is implicated to be an EDC that alters reproductive dysfunction by targeting the HPG axis. However, questions remain as to the human health risks associated with atrazine exposure with studies reporting mixed results on the ability of atrazine to alter the HPG axis. In this review, the current findings for atrazine's effects on the HPG axis are examined in mammalian, anuran, and fish models and in epidemiological studies.


A photoelectron spectroscopy and ab initio study of the structures and chemical bonding of the B25(-) cluster.
Photoelectron spectroscopy and ab initio calculations are used to investigate the structures and chemical bonding of the B25(-) cluster. Global minimum searches reveal a dense potential energy landscape with 13 quasi-planar structures within 10 kcal/mol at the CCSD(T)/6-311+G(d) level of theory. Three quasi-planar isomers (I, II, and III) are lowest in energy and nearly degenerate at the CCSD(T) level of theory, with II and III being 0.8 and 0.9 kcal/mol higher, respectively, whereas at two density functional levels of theory isomer III is the lowest in energy (8.4 kcal/mol more stable than I at PBE0/6-311+G(2df) level). Comparison with experimental photoelectron spectroscopic data shows isomer II to be the major contributor while isomers I and III cannot be ruled out as minor contributors to the observed spectrum. Theoretical analyses reveal similar chemical bonding in I and II, both involving peripheral 2c-2e B-B σ-bonding and delocalized interior σ- and π-bonding. Isomer III has an interesting elongated ribbon-like structure with a π-bonding pattern analogous to those of dibenzopentalene. The high density of low-lying isomers indicates the complexity of the medium-sized boron clusters; the method dependency of predicting relative energies of the low-lying structures for B25(-) suggests the importance of comparison with experiment in determining the global minima of boron clusters at this size range. The appearance of many low-lying quasi-planar structures containing a hexagonal hole in B25(-) suggests the importance of this structural feature in maintaining planarity of larger boron clusters.


Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures.
By 27 February 2020, the outbreak of coronavirus disease 2019 (COVID-19) caused 82 623 confirmed cases and 2858 deaths globally, more than severe acute respiratory syndrome (SARS) (8273 cases, 775 deaths) and Middle East respiratory syndrome (MERS) (1139 cases, 431 deaths) caused in 2003 and 2013, respectively. COVID-19 has spread to 46 countries internationally. Total fatality rate of COVID-19 is estimated at 3.46% by far based on published data from the Chinese Center for Disease Control and Prevention (China CDC). Average incubation period of COVID-19 is around 6.4 days, ranges from 0 to 24 days. The basic reproductive number (R0 ) of COVID-19 ranges from 2 to 3.5 at the early phase regardless of different prediction models, which is higher than SARS and MERS. A study from China CDC showed majority of patients (80.9%) were considered asymptomatic or mild pneumonia but released large amounts of viruses at the early phase of infection, which posed enormous challenges for containing the spread of COVID-19. Nosocomial transmission was another severe problem. A total of 3019 health workers were infected by 12 February 2020, which accounted for 3.83% of total number of infections, and extremely burdened the health system, especially in Wuhan. Limited epidemiological and clinical data suggest that the disease spectrum of COVID-19 may differ from SARS or MERS. We summarize latest literatures on genetic, epidemiological, and clinical features of COVID-19 in comparison to SARS and MERS and emphasize special measures on diagnosis and potential interventions. This review will improve our understanding of the unique features of COVID-19 and enhance our control measures in the future.


[Yield of ultrasound-guided transrectal biopsy in the diagnosis of prostatic cancer in symptomatic patients].
The aim of this retrospective study was to evaluate the utility of US-guided transrectal biopsy of the prostate in the diagnosis of prostatic cancer in symptomatic patients and its correlation with the digital rectal examination (DRE), PSA levels and ultrasound findings. From 1994 to 1995, 427 patients with prostatic symptomatology underwent prostatic biopsy. The mean age was 69.1 +/- 8.3 years (range 44 - 89). The criteria for biopsy were abnormal DRE, PSA > 10 ng/ml, abnormal US findings and/or PSA density > 0.15. Prostate cancer was confirmed in 42% of the patients. The incidence of cancer when DRE was abnormal was 73%, 46% when PSA was > 10 ng/ml and 55% when the US findings were abnormal; 82% for abnormal DRE and PSA > 10 ng/ml, and 84% when the criterion of abnormal US was included. The incidence of cancer when DRE was normal was 16%, 18% when combined with PSA > 10 ng/ml and remained unchanged when combined with the US findings. In patients with normal DRE and PSA between 10 - 30 ng/ml, the incidence of cancer was 14% and 41% for those with PSA > 30 ng/ml. DRE was the best independent predictor of prostate cancer and the combination of abnormal DRE, PSA > 10 ng/ml and abnormal US findings gave the highest detection rate. The incidence of prostate cancer was very low in patients with normal DRE and PSA between 10 - 30 ng/ml, which may be due to the fact that the PSA levels are raised by the non neoplastic changes in the transitional zone in symptomatic patients.


Giant suprasellar Rathke's cleft cyst mimicking craniopharyngioma: implications for a spectrum of cystic epithelial lesions of ectodermal origin.
Cystic epithelial lesions such as Rathke's cleft cysts (RCCs) and craniopharyngiomas may be difficult to distinguish on a clinical, radiographic, and sometimes histopathological basis. We describe a case of a giant 6.5 cm suprasellar cystic lesion that was presumed to be a craniopharyngioma based on the neuroimaging findings. The lesion extended from the anterior skull base and sella turcica to the lateral ventricle and sylvian fissure resulting in obstructive hydrocephalus. Complete surgical removal of the suprasellar lesion was achieved using an extended frontotemporal transbasal skull base approach. Intraoperatively, the cyst wall was thickened and partially calcified, resembling a craniopharyngioma. However, the histopathological examination revealed findings most consistent with a RCC with additional features of extensive squamous metaplasia, metaplastic bone formation, and chronic inflammation. The case raises the issue of whether there is a pathologic continuum of parasellar ectodermal lesions which may account for the overlap of features and transitional states. In this report, we discuss the possible spectrum between RCCs and craniopharyngiomas, and also emphasize the importance of complete resection of the cyst wall in RCCs that exhibit squamous metaplasia, inflammation, or ossification to minimize the probability of recurrence.


Magnetic resonance imaging in viral and prion diseases of the central nervous system.
The early detection and specific diagnosis of viral infections of the central nervous system are important because many of these diseases are potentially treatable. However, clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some, but not all, viruses. Neuroimaging, in conjunction with clinical history and laboratory tests, plays an important role in narrowing the differential diagnoses. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections and prions that involve the central nervous system.


[Comparative effectiveness of the basic drugs used in rheumatoid arthritis (long-term randomized study)].
Study of the comparative efficacy of the basic slow-acting drugs for the treatment of rheumatoid arthritis permits considering randomization as necessary for obtaining objective data. It has been established that gold salts (chrisanol and myochrysin) are the most efficacious drugs for the treatment of RA. D-Penicillamine and delagil, in particular, are less efficacious. Administration of levamisole is rather dangerous because of the frequency and intensity of side effects.


A pre-Hispanic head.
This report on a male head revealed biologic rhythms, as gleaned from hydrogen isotope ratios in hair, consistent with a South-American origin and Atomic Mass Spectrometry radiocarbon dating (AMS) compatible with the last pre-Hispanic period (1418-1491 AD, 95.4% probability). Biopsies showed exceptionally well-preserved tissues. The hair contained high levels of toxic elements (lead, arsenic and mercury) incompatible with life. There was no evidence for lead deposition in bone consistent with post-mortem accumulation of this toxic element in the hair. We propose that the high content of metals in hair was the result of metabolic activity of bacteria leading to metal complexation in extra cellular polymeric substances (EPS). This is a recognized protective mechanism for bacteria that thrive in toxic environments. This mechanism may account for the tissues preservation and gives a hint at soil composition where the head was presumably buried. Our results have implications for forensic toxicology which has, hitherto, relied on hair analyses as one means to reconstruct pre-mortem metabolism and for detecting toxic elements accumulated during life. Our finding also has implications for other archaeological specimens where similar circumstances may distort the results of toxicological studies.


Functional analysis of tenocytes gene expression in tendon fascicles subjected to cyclic tensile strain.
Tenocytes are known to be mechanoresponsive and the present study tests the hypothesis that distinct mechanical stimulation regimes, associated with the short-term and extended application of cyclic tensile strain, alters the balance between anabolic and catabolic processes. Microarray technology has been used to provide a comprehensive analysis of alterations in gene expression within isolated tendon fascicles in response to cyclic tensile strain using a well-established model system. Isolated rat tail tendon fascicles were subjected to cyclic tensile strain (3% amplitude superimposed on a 2% static strain) for 1 or 24 hr. Messenger RNA expression level was assessed using Illumina microarray. The number of genes significantly altered in strained fascicles from the level of unstrained control fascicles was greater at 24 hr than 1 hr. The expression levels of many extracellular matrix components remained unchanged at both time points; however, a number of members of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with a thrombospondin (ADAMTS) families were significantly downregulated at 24 hr. Functional annotation revealed that upregulated genes were significantly associated with the regulation of transcription at 1 hr and translation at 24 hr. Downregulated genes were associated with inflammatory responses at 1 hr, and genes inhibited at 24 hr were significantly associated with cell apoptosis and a variety of metabolic functions. The present results suggest that the metabolic balance was shifted in favor of catabolism by the application of a small number of tensile strain cycles, whereas an extended number stimulates strong anti-catabolic effects.


Acute myocardial infarction during regadenoson myocardial perfusion imaging.
Pharmacologic stress testing uses vasodilators to provide objective evidence of myocardial ischemia. Adenosine and dipyridamole are nonselective adenosine receptor agonists that have been associated with myocardial infarction (MI) during intravenous infusion. Mechanisms postulated for this effect include coronary steal, transmural steal, global hypotension, and direct vasoconstriction. Regadenoson, a direct A2A agonist, was approved for use in stress testing in 2008. We describe a 68-year-old man who presented to our institution with typical angina, relieved by nitroglycerin. He did not have electrocardiogram (ECG) changes suggestive of myocardial pathology, and laboratory testing did not reveal a significant rise in troponin-I levels. To further assess the etiology of his symptoms, he underwent a pharmacologic stress test with regadenoson followed by technetium 99 m sestamibi. Six minutes after regadenoson infusion, the patient developed severe retrosternal chest pain accompanied by ST elevations on ECG. Sublingual nitroglycerin was administered that resolved both the pain and ECG changes. The patient subsequently underwent urgent coronary angiography and was found to have a 95% critical stenosis involving the left anterior descending artery. We conclude this case represents a MI secondary to coronary steal phenomenon induced by regadenoson infusion. Clinicians should be aware this adverse effect can occur despite the improved side-effect profile of regadenoson. Continuous monitoring of vital signs and the ECG with regular assessment of symptoms is imperative to identify this rare but potentially devastating adverse event.


Situations and reasons for missed nursing care in medical and surgical clinic units.
To evaluate the frequency and reasons for missed nursing care and to verify whether the reasons for omission differ between professional categories. A quantitative and cross-sectional study carried out in the adult hospitalization units of a public hospital of a teaching institution. Data collection was performed from February to April 2017, through a personal and professional characterization form and the MISSCARE-BRASIL instrument. Fifty-eight (58) nursing professionals responsible for direct patient care participated in the study, of which 74.1% reported at least one missed nursing care activity during the work shift. The main reasons attributed to missed care situations were an inadequate amount of professionals, urgent situations with the patients during the work shift, and the non-availability of medicine, materials or equipment when necessary. Most care was "always" or "often" performed, and the reasons given for missed care are related to work resources, materials, and management style. Nurses differ from the technicians as to the reasons for not performing care.


Effect of statin therapy on mortality in patients with peripheral arterial disease and comparison of those with versus without associated chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) and peripheral arterial disease (PAD) are both inflammatory conditions. Statins are commonly used in patients with PAD and have anti-inflammatory properties, which may have beneficial effects in patients with COPD. The relation between statin use and mortality was investigated in patients with PAD with and without COPD. From 1990 to 2006, we studied 3,371 vascular surgery patients. Statin use was noted at baseline and, if prescribed, converted to <25% (low dose) and > or =25% (intensified dose) of the maximum recommended therapeutic dose. The diagnosis of COPD was based on the Global Initiative for Chronic Obstructive Lung Disease guidelines using pulmonary function test. End points were short- (30-day) and long-term (10-year) mortality. A total of 330 patients with COPD (25%) used statins, and 480 patients (23%) without COPD. Statin use was independently associated with improved short- and long-term survival in patients with COPD (odds ratio 0.48, 95% confidence interval [CI] 0.23 to 1.00; hazard ratio 0.67, 95% CI 0.52 to 0.86, respectively). In patients without COPD, statins were also associated with improved short- and long-term survival (odds ratio 0.42, 95% CI 0.20 to 0.87; hazard ratio 0.76, 95% CI 0.60 to 0.95, respectively). In patients with COPD, only an intensified dose of statins was associated with improved short-term survival. However, for the long term, both low-dose and intensive statin therapy were beneficial. In conclusion, statin use was associated with improved short- and long-term survival in patients with PAD with and without COPD. Patients with COPD should be treated with an intensified dose of statins to achieve an optimal effect on both the short and long term.


Compact piezoelectric stacked actuators for high power applications.
Small, hollow, multilayer actuators with a diameter of 3 mm were fabricated by the stacking method from piezoelectric hard lead zirconate titanate (PZT) ceramics. Langevin vibrators were also constructed with the hollow multilayer actuators. The performance capabilities of the actuator and Langevin vibrator samples were examined under high-power conditions. The high-power vibration level at a given sinusoidal drive voltage was significantly enhanced by using a multilayer structure under either a nonresonance or resonance condition. A maximum vibration velocity of 0.17 m/sec was obtained for the 9-layer actuator sample under nonresonance conditions. The vibration velocity was further improved with the Langevin vibrator driven at the resonance frequency. The temperature rise due to heat generation under high-power conditions was the immediate limitation on the maximum accessible vibration velocity for the stacked actuators.


Decline of caries prevalence after the cessation of water fluoridation in the former East Germany.
In contrast to the anticipated increase in dental caries following the cessation of water fluoridation in the cities Chemnitz (formerly Karl-Marx-Stadt) and Plauen, a significant fall in caries prevalence was observed. This trend corresponded to the national caries decline and appeared to be a new population-wide phenomenon. Additional surveys (N=1017) carried out in the formerly-fluoridated towns of Spremberg (N=9042) and Zittau (N=6232) were carried out in order to support this unexpected epidemiological finding. Pupils from these towns, aged 8/9-, 12/13- and 15/16-years, have been examined repeatedly over the last 20 years using standardised caries-methodological procedures. While the data provided additional support for the established fact of a caries reduction brought about by the fluoridation of drinking water (48% on average), it has also provided further support for the contention that caries prevalence may continue to fall after the reduction of fluoride concentration in the water supply from about 1 ppm to below 0.2 ppm F. Caries levels for the 12-year-olds of both towns significantly decreased during the years 1993-96, following the cessation of water fluoridation. In Spremberg, DMFT fell from 2.36 to 1.45 (38.5%) and in Zittau from 2.47 to 1.96 (20.6%). These findings have therefore supported the previously observed change in the caries trend of Chemnitz and Plauen. The mean of 1.81 DMFT for the 12-year-olds, computed from data of the four towns, is the lowest observed in East Germany during the past 40 years. The causes for the changed caries trend were seen on the one hand in improvements in attitudes towards oral health behaviour and, on the other hand, to the broader availability and application of preventive measures (F-salt, F-toothpastes, fissure sealants etc.). There is, however, still no definitive explanation for the current pattern and further analysis of future caries trends in the formerly fluoridated towns would therefore seem to be necessary.


Aerosol transmission of SARS-CoV-2? Evidence, prevention and control.
As public health teams respond to the pandemic of coronavirus disease 2019 (COVID-19), containment and understanding of the modes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is of utmost importance for policy making. During this time, governmental agencies have been instructing the community on handwashing and physical distancing measures. However, there is no agreement on the role of aerosol transmission for SARS-CoV-2. To this end, we aimed to review the evidence of aerosol transmission of SARS-CoV-2. Several studies support that aerosol transmission of SARS-CoV-2 is plausible, and the plausibility score (weight of combined evidence) is 8 out of 9. Precautionary control strategies should consider aerosol transmission for effective mitigation of SARS-CoV-2.


Worker honeybee brain proteome.
A large-scale mapping of the worker honeybee brain proteome was achieved by MudPIT. We identified 2742 proteins from forager and nurse honeybee brain samples; 17% of the total proteins were found to be differentially expressed by spectral count sampling statistics and a G-test. Sequences were compared with the EuKaryotic Orthologous Groups (KOG) catalog set using BLASTX and then categorized into the major KOG categories of most similar sequences. According to this categorization, nurse brain showed increased expression of proteins implicated in translation, ribosomal structure, and biogenesis (14.5%) compared with forager (1.8%). Experienced foragers overexpressed proteins involved in energy production and conversion, showing an extensive difference in this set of proteins (17%) in relation to the nurse subcaste (0.6%). Examples of proteins selectively expressed in each subcaste were analyzed. A comparison between these MudPIT experiments and previous 2-DE experiments revealed nine coincident proteins differentially expressed in both methodologies.


Safety and immunogenicity of a diphtheria, tetanus, and acellular pertussis-inactivated poliovirus vaccine/Haemophilus influenzae type B combination vaccine administered to Taiwanese infants at 2, 4, and 6 months of age.
Combined vaccines are urgently needed to ensure compliance with the increasing number of recommended vaccines for children. We evaluated the safety and antibody response to a diphtheria, tetanus, and acellular pertussis-inactivated poliovirus vaccine/Haemophilus influenzae type b (DTaP-IPV/Hib) combination vaccine administrated to infants at 2, 4, and 6 months of age. Sixty healthy infants between 6 and 12 weeks of age were enrolled. One group of vaccines received the DTaP-IPV/Hib in a single injection, while another group concurrently received DTaP-IPV and Hib at separate injection sites. Solicited adverse events were monitored by parental observation and were recorded on a diary card. Levels of serum antibodies to DTaP and polyribosyl-ribitolphosphate-tetanus (PRP-T) antigens were collected before the first vaccine dose and 1 month after the third vaccine dose. The combined-injection group tended to have lower local reactions, and there was no increase in reactogenicity when compared with the separate-injection group. Seroconversion rates were 100% in both groups for all antigens, except for the anti-polio 2 antibody in the combined-injection group (96.4%). The combined-injection group had lower antibody levels of PRP (8.45 microg/ml) than did the separate-injection group (20.61 microg/ml). However, the percentage of vaccines achieving protective levels of antibody to PRP (> or = 0.15 microg/ml or > or = 1.0 microg/ml) was similar in both groups. DTaP-IPV/Hib may be safely and effectively administered to healthy infants, using a 2-, 4-, and 6-month vaccination schedule. This combined vaccine is cost-effective, more acceptable to parents and physicians, and minimizes distress to infants.


A gender difference in the association between salt sensitivity and family history of hypertension.
We examined 174 subjects (82 men and 92 women) with essential hypertension to determine whether gender played an important role in the association of blood pressure (BP) familial disposition, and hypertension. To evaluate the salt sensitivity of BP, we measured changes in blood pressure after restricting salt intake from about 15 g/day to less than 3 g/day. The familial disposition to hypertension was categorized into four groups according to the presence or absence of hypertension in the father, mother, and siblings. If none, one, two, or three family members had hypertension, they were assigned the FH(-), FH(+), FH(++), and FH( ) groups, respectively. Only in women did the FH(-) group show a significantly smaller blood pressure reduction than that of the other groups. The mean BP reduction in the four groups was 4.1 +/- 1.9, 8.5 +/- 1.1, 10.1 +/- 1.5, and 11.2 +/- 2.8 mm Hg (mean +/- SEM), respectively. This difference in BP reduction was not observed in men. Multiple regression analysis, using percent changes in mean BP as the dependent variable and other factors as independent variables, also showed a significant partial correlation coefficient for familial disposition to hypertension only in women. Thus, the relationship between salt sensitivity and familial disposition to hypertension differed according to gender. This difference may provide an important insight into the hereditary nature of hypertension.


Analysis of the cell adhesion molecule sticks-and-stones reveals multiple redundant functional domains, protein-interaction motifs and phosphorylated tyrosines that direct myoblast fusion in Drosophila melanogaster.
The larval body wall muscles of Drosophila melanogaster arise by fusion of founder myoblasts (FMs) and fusion-competent myoblasts (FCMs). Sticks-and-Stones (SNS) is expressed on the surface of all FCMs and mediates adhesion with FMs and developing syncytia. Intracellular components essential for myoblast fusion are then recruited to these adhesive contacts. In the studies herein, a functional analysis of the SNS cytodomain using the GAL4/UAS system identified sequences that direct myoblast fusion, presumably through recruitment of these intracellular components. An extensive series of deletion and site-directed mutations were evaluated for their ability to rescue the myoblast fusion defects of sns mutant embryos. Deletion studies revealed redundant functional domains within SNS. Surprisingly, highly conserved consensus sites for binding post-synaptic density-95/discs large/zonula occludens-1-domain-containing (PDZ) proteins and serines with a high probability of phosphorylation play no significant role in myoblast fusion. Biochemical studies establish that the SNS cytodomain is phosphorylated at multiple tyrosines and their site-directed mutagenesis compromises the ability of the corresponding transgenes to rescue myoblast fusion. Similar mutagenesis revealed a requirement for conserved proline-rich regions. This complexity and redundancy of multiple critical sequences within the SNS cytodomain suggest that it functions through a complex array of interactions that likely includes both phosphotyrosine-binding and SH3-domain-containing proteins.


Tripolyphosphate cross-linked macromolecular composites for the growth of shape- and size-controlled apatites.
Bioactive composites that enable the formation of calcium phosphates have received increased attention over the last decade, in the development of osteoconductive biomaterials for orthopaedic applications. In this work, tripolyphosphate (TPP)-cross-linked chitosan/gelatin composites (TPP-CG) were prepared for the growth of shape- and size-controlled calcium phosphates on/in the composites. The mineralization pattern of the composites, after soaking in the Ca(OH)(2) aqueous solution, clearly demonstrated oriented, needle-like nanocrystallites of calcium phosphates in the matrix with especially high Ca/P molar ratio (3.98) as detected by energy dispersive X-ray spectroscopy (EDX) analysis. Subsequent to mineralization in a simulated body fluid (SBF), the mineralized composites showed micro-scaled spherical aggregates deposited on the surface and granule-like nanocrystallites grew in the matrix. The Ca/P molar ratio (1.72) and X-ray diffraction pattern of the nanocrystallites grown in the composites were similar to those of hydroxyapatite (HAp). Osteoblastic differentiation of ROS cells cultured on the mineralized composites allowed an enhanced expression of the chosen osteogenic marker (alkaline phosphatase, ALPase). These results indicated that the composites mineralized with micro- and nano-scaled calcium phosphates with various structural features make them attractive for bone tissue engineering applications.


Mitral valve prolapse--a review.
Mitral valve prolapse is one of the more common cardiac conditions in our community. The prevalence is difficult to assess due to differences in diagnostic criteria and population selection. The prevalence in the community has been estimated to be from 5 to 15%. In females there is a decline in prevalence with increasing age which is not observed in males. 30% of subjects with mitral valve prolapse have relatives with the same condition. Strahan et al suggested that mitral valve prolapse was inherited as an autosomal dominant trend with its manifestations modified by age and other factors.


Single-incision versus conventional laparoscopic appendectomy in 688 patients: a retrospective comparative analysis.
Laparoscopic surgery has become the standard for treating appendicitis. The cosmetic benefits of using single-incision laparoscopy are well known, but its duration, complications and time to recovery have not been well documented. We compared 2 laparoscopic approaches for treating appendicitis and evaluated postoperative pain, complications and time to full recovery. We retrospectively reviewed the cases of consecutive patients with appendicitis and compared those who underwent conventional laparoscopic appendectomy (CLA) performed using 3 incisions and those who underwent single-incision laparoscopic appendectomy (SILA). During SILA, the single port was prepared to increase visibility of the operative site. Our analysis included 688 consecutive patients: 618 who underwent CLA and 70 who underwent SILA. Postsurgical complications occurred more frequently in the CLA than the SILA group (18.1% v. 7.1%, p = 0.018). Patients who underwent SILA returned to oral feeding sooner than those who underwent CLA (median 12 h v. 22 h, p < 0.001). These between-group differences remained significant after controlling for other factors. Direct comparison of only nonperforated cases, which was determined by pathological examination, revealed that SILA was significantly longer than CLA (60 min v. 50 min, p < 0.001). Patients who underwent SILA had longer in-hospital stays than those who underwent CLA (72 v. 55 h, p < 0.001); however, they had significantly fewer complications (3.0% v. 14.4%, p = 0.006). In addition to its cosmetic advantages, SILA led to rapid recovery and no increase in postsurgical pain or complications.


Using Martial Arts Training as Exercise Therapy Can Benefit All Ages.
Martial arts training focus on whole-body movement patterning, philosophy, interpersonal interactions, and functional self-defense. Such training has positive impacts on physical, psychological, and cognitive well-being in older adults and children with and without clinical conditions. We hypothesize that martial arts training can be delivered as a form of exercise therapy for people at all ages to enhance overall health.


Selective tyrosine kinase inhibition of insulin-like growth factor-1 receptor inhibits human and mouse breast cancer-induced bone cell activity, bone remodeling, and osteolysis.
Insulin-like growth factor 1 (IGF-1) plays an important role in both bone metabolism and breast cancer. In this study, we investigated the effects of the novel IGF-1 receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) on osteolytic bone disease associated with breast cancer. Human MDA-MB-231 and mouse 4T1 breast cancer cells enhanced osteoclast formation in receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulated bone marrow cultures, and these effects were significantly inhibited by PQIP. Functional studies in osteoclasts showed that PQIP inhibited both IGF-1 and conditioned medium-induced osteoclast formation by preventing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) activation without interfering with RANKL or M-CSF signaling. Treatment of osteoblasts with PQIP significantly inhibited the increase in RANKL/osteoprotegerin (OPG) ratio by IGF-1 and conditioned medium and totally prevented conditioned medium-induced osteoclast formation in osteoblast-bone marrow (BM) cell cocultures, thereby suggesting an inhibitory effect on osteoblast-osteoclast coupling. PQIP also inhibited IGF-1-induced osteoblast differentiation, spreading, migration, and bone nodule formation. Treatment with PQIP significantly reduced MDA-MB-231 conditioned medium-induced osteolytic bone loss in a mouse calvarial organ culture system ex vivo and in adult mice in vivo. Moreover, once daily oral administration of PQIP significantly decreased trabecular bone loss and reduced the size of osteolytic bone lesions following 4T1 intratibial injection in mice. Quantitative histomorphometry showed a significant reduction in bone resorption and formation indices, indicative of a reduced rate of cancer-associated bone turnover. We conclude that inhibition of IGF-1 receptor tyrosine kinase activity by PQIP suppresses breast cancer-induced bone turnover and osteolysis. Therefore, PQIP, and its novel derivatives that are currently in advanced clinical development for the treatment of a number of solid tumors, may be of value in the treatment of osteolytic bone disease associated with breast cancer.


[Infection caused by viridans streptococci in children with malignant hematologic diseases].
This is a review of the symptoms and signs of children with malignant diseases and septicemia due to viridans streptococci, treated during a 6-year-period (1990-1995) in the Departments of Pediatrics or Pediatric Surgery, University of Leipzig. All 11 children suffered from leukemia. Streptococcus mitis was the most frequently isolated streptococcal species. All patients had fever and malaise, in most cases we could find inflammatory signs of the respiratory tract. In two children we saw a severe course of the disease, one child had symptoms and signs of ARDS, the other died on septicemic shock. All 11 patients had neutropenia and a central venous line, 10 of them were treated by cytarabine before the streptococcal infection was diagnosed. Like others we could note during the last years an increase of systemic infections due to viridans streptococci in neutropenic patients with malignant diseases. Possibly there is an association between streptococcal infection and cytarabine therapy. The empiric antibiotic therapy in neutropenic patients with malignant diseases should cover also streptococcal infections.


Acute post-traumatic stress symptoms and age predict outcome in military blast concussion.
High rates of adverse outcomes have been reported following blast-related concussive traumatic brain injury in US military personnel, but the extent to which such adverse outcomes can be predicted acutely after injury is unknown. We performed a prospective, observational study of US military personnel with blast-related concussive traumatic brain injury (n = 38) and controls (n = 34) enrolled between March and September 2012. Importantly all subjects returned to duty and did not require evacuation. Subjects were evaluated acutely 0-7 days after injury at two sites in Afghanistan and again 6-12 months later in the United States. Acute assessments revealed heightened post-concussive, post-traumatic stress, and depressive symptoms along with worse cognitive performance in subjects with traumatic brain injury. At 6-12 months follow-up, 63% of subjects with traumatic brain injury and 20% of controls had moderate overall disability. Subjects with traumatic brain injury showed more severe neurobehavioural, post-traumatic stress and depression symptoms along with more frequent cognitive performance deficits and more substantial headache impairment than control subjects. Logistic regression modelling using only acute measures identified that a diagnosis of traumatic brain injury, older age, and more severe post-traumatic stress symptoms provided a good prediction of later adverse global outcomes (area under the receiver-operating characteristic curve = 0.84). Thus, US military personnel with concussive blast-related traumatic brain injury in Afghanistan who returned to duty still fared quite poorly on many clinical outcome measures 6-12 months after injury. Poor global outcome seems to be largely driven by psychological health measures, age, and traumatic brain injury status. The effects of early interventions and longer term implications of these findings are unknown.


Beliefs of stop smoking practitioners in United Kingdom on the use of nicotine replacement therapy for smoking reduction.
This paper aimed to assess the current beliefs of stop smoking practitioners and managers about using nicotine replacement therapy (NRT) for smoking reduction (SR) and the factors related to these beliefs. An online survey was conducted of practitioners and managers working in the 152 English stop smoking services (SSSs). Questions were asked about their beliefs concerning the safety of using NRT for SR. Sixteen percent and 30% of the sample, respectively, believed that NRT use for a year or more and the concurrent use of NRT and cigarettes was harmful to health. The most commonly reported potential harms of the long-term use of NRT and the concurrent use of NRT and cigarettes were addiction, overdose and mouth cancer. Seventeen percent of the sample also believed that the use of NRT for SR could hinder smoking cessation. Reports differed as a function of the managers' relationship with their commissioner and influence on the commissioning process, while among practitioners as a function of the number of months worked, gender, frequency of update training and whether they advised reduction as a treatment option. A significant minority of stop smoking practitioners and stop smoking managers believe that NRT use for SR can be harmful to health and undermine smoking cessation. These beliefs should be addressed, especially if the use of NRT in these ways is provided as a route to quitting in SSSs.


Medial Malleolar Screw Length to Achieve Thread Purchase in the Dense Bone of the Tibial Epiphyseal Scar Location Based on CT Model.
Medial malleolar ankle fractures are one of the most common surgically treated fractures of the ankle joint. Current AO guidelines for medial malleolar fractures recommend 2 partially threaded cancellous screws across the fracture line. For these screws to cross the fracture line, the threads must purchase the distal tibial metaphysis, which is an area of decreased bone density especially in elderly osteoporotic bone. The epiphyseal scar of the tibia is the densest portion of distal metaphysis of the tibia, and it has been determined that bone density decreases significantly further proximal through the tibia. One hundred eighty-three individual weightbearing coronal CT scans were assessed to measure the location of the epiphyseal scar and propose an ideal screw length to purchase this area and remain within the distal most portion of the tibia. In following with this criteria it was determined that a 34 mm ⅓ thread pattern screw and a 38 mm ½ thread pattern screw would suffice for 92.6% and 75.3% of males, respectively. It was determined that a 30 mm ⅓ thread pattern screw and a 32 mm ½ thread pattern screw would suffice for 93.4% and 85.3% of females, respectively. This study proposes optimal screw lengths in a theoretical area of increased bone density that may decrease complications in patients with compromised bone quality.


Validation of a clinical trial composite endpoint for patients with necrotizing soft tissue infections.
Our objective was to develop and validate a composite endpoint for patients with necrotizing soft tissue infections that incorporates: local tissue injury, systemic organ dysfunction, and mortality. The Necrotizing Infection Clinical Composite Endpoint (NICCE) was defined as follows:(i) alive at day 28, (ii) three or less debridements before day 14, (iii) no amputation beyond first debridement, (iv) modified sequential organ failure assessment score score (mSOFA) at day 14 ≤ 1. To be considered a success, all individual criteria must be met. Several data sets were used to assess validity: (i) a retrospective data set of 198 patients treated during 2013 at 12 US trauma centers; (ii) a subset with high disease acuity, admission mSOFA score of 3 or higher (n = 69); and (iii) 40 patients from a multicenter, phase 2 randomized trial of a CD28 immunomodulator (AB103). Clinical success based on each parameter and the composite score was assessed. Using the retrospective data set for all patients and those with high disease severity (respectively), survival rates were 92% and 84%; day 14 mSOFA 1 or lower score was 69% and 51%; three or less debridements was 84% and 77%; and no subsequent amputations were 96% and 94%. Overall, the percent meeting all success criteria for NICCE was 58% (all patients) and 33% (mSOFA > 3). NICCE success was also associated with reduced utilization of health care resources, intensive care unit-free days were median (interquartile range) of 25.3 (21.9-28) and 19.6 (4.3-25.1) days (one-sided Wilcoxon p < 0.001) and ventilator-free days were 28 (26-28) versus 25 (14-28) (p < 0.001) for NICCE success versus failure, respectively. Using the phase 2 data set, the treated group (0.5 mg/kg, n = 15) demonstrated a NICCE success rate of 73.3% versus 40% for placebo (n = 10). These data demonstrate internal consistency of the components and face and criterion validity of the NICCE endpoint. NICCE offers an opportunity to demonstrate a clinically relevant treatment effect for patients enrolled in clinical trials for necrotizing soft tissue infection. Prognostic/Epidemiological, level III; Therapeutic, level IV.


A Robust Screen-Free Brain-Computer Interface for Robotic Object Selection.
Brain signals represent a communication modality that can allow users of assistive robots to specify high-level goals, such as the object to fetch and deliver. In this paper, we consider a screen-free Brain-Computer Interface (BCI), where the robot highlights candidate objects in the environment using a laser pointer, and the user goal is decoded from the evoked responses in the electroencephalogram (EEG). Having the robot present stimuli in the environment allows for more direct commands than traditional BCIs that require the use of graphical user interfaces. Yet bypassing a screen entails less control over stimulus appearances. In realistic environments, this leads to heterogeneous brain responses for dissimilar objects-posing a challenge for reliable EEG classification. We model object instances as subclasses to train specialized classifiers in the Riemannian tangent space, each of which is regularized by incorporating data from other objects. In multiple experiments with a total of 19 healthy participants, we show that our approach not only increases classification performance but is also robust to both heterogeneous and homogeneous objects. While especially useful in the case of a screen-free BCI, our approach can naturally be applied to other experimental paradigms with potential subclass structure.


Thermal avoidance in Caenorhabditis elegans: an approach to the study of nociception.
Upon perception of a noxious stimulus, an organism executes defense mechanisms, such as escape responses. The molecular basis of these mechanisms is poorly understood. In this paper we show that upon exposure to noxious temperature, Caenorhabditis elegans reacts by a withdrawal reflex. To analyze this thermal avoidance behavior, we developed a laser-based assay to quantify the response. The escape reflex can be observed in 98% of the adult animals, but is not executed in animals in diapause. The thermal avoidance response differs significantly from the thermotaxis behavior that is based on the perception of physiological temperature. It involves different neurons and is influenced by mutations in distinct genes. As in mammals, the strength of the thermal avoidance response is increased by application of capsaicin, the pungent ingredient in chili peppers. We find that thermal avoidance is strongly reduced in mutants affecting the neural transmission modulated by glutamate and neuropeptides as well as in mutants affecting the structure and function of sensory neurons. We suggest that the study of this nociceptive behavior in C. elegans can be used to understand the genetic and molecular basis of thermal nociception.


Real-Time Instance Segmentation of Traffic Videos for Embedded Devices.
The paper proposes a novel instance segmentation method for traffic videos devised for deployment on real-time embedded devices. A novel neural network architecture is proposed using a multi-resolution feature extraction backbone and improved network designs for the object detection and instance segmentation branches. A novel post-processing method is introduced to ensure a reduced rate of false detection by evaluating the quality of the output masks. An improved network training procedure is proposed based on a novel label assignment algorithm. An ablation study on speed-vs.-performance trade-off further modifies the two branches and replaces the conventional ResNet-based performance-oriented backbone with a lightweight speed-oriented design. The proposed architectural variations achieve real-time performance when deployed on embedded devices. The experimental results demonstrate that the proposed instance segmentation method for traffic videos outperforms the you only look at coefficients algorithm, the state-of-the-art real-time instance segmentation method. The proposed architecture achieves qualitative results with 31.57 average precision on the COCO dataset, while its speed-oriented variations achieve speeds of up to 66.25 frames per second on the Jetson AGX Xavier module.


Incidence, Prognostic Factors and Survival Outcome in Patients With Primary Hepatic Lymphoma.
Aim: The objective of our study was to investigate the epidemiologic characteristics, prognostic factors and survival in patients with primary hepatic lymphoma (PHL). Methods: PHL patients diagnosed between 1983 and 2015 were identified from the SEER database. The temporal trend in PHL incidence was assessed using joinpoint regression software. Overall survival(OS) and disease-specific survival (DSS) was evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analysis was performed to identify the independent prognostic factors for OS and DSS. Nomograms to predict survival possibilities were constructed based on the identified independent prognostic factors. Results: A total of 1,182 patients were identified with PHL. The mean age was 61.7 ± 17.1 years with a male to female of 1.6:1. Diffuse large B-cell lymphoma (59.8%) was the most common histological subtype. The incidence of PHL steadily increasing by an annual percentage change (APC) of 2.6% (95% CI 2.0-3.2, P < 0.05). The 1-, 5-, and 10-year OS rates were 50.85, 39.6, and 30.4%, respectively, and the corresponding DSS rates were 55.3, 47.9, and 43.3%, respectively. Multivariate Cox regression analysis revealed that age, sex, race, marital status, histological subtype, surgery, and chemotherapy were independent prognostic factors for survival. Nomograms specifically for DLBCL were constructed to predict 1-, 5-, and 10-year OS and DSS possibility, respectively. The concordance index (C-index) and calibration plots showed the established nomograms had robust and accurate performance. Conclusion: PHL were rare but the incidence has been steadily increasing over the past four decades. Survival has improved in recent years. Surgery or chemotherapy could provide better OS and DSS. The established nomograms specifically for DLBCL were robust and accurate in predicting 1-, 5-, and 10-year OS and DSS.


The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.
Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15-25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.


Correlation analysis of the beam angle dependence for elastography.
Signal decorrelation is a major source of error in the displacements estimated using correlation techniques for elastographic imaging. Previous papers have addressed the variation in the correlation coefficient as a function of the applied compression for a finite window size and an insonification angle of zero degrees. The recent use of angular beam-steered radio-frequency echo signals for spatial angular compounding and shear strain estimation have demonstrated the need for understanding signal decorrelation artifacts for data acquired at different beam angles. In this paper, we provide both numerical and closed form theoretical solutions of the correlation between pre- and post-compression radio-frequency echo signals acquired at a specified beam angle. The expression for the correlation coefficient obtained is a function of the beam angle and the applied compression for a finite duration window. Accuracy of the theoretical results is verified using tissue-mimicking phantom experiments on a uniformly elastic phantom using beam-steered data acquisitions on a linear array transducer. The theory predicts a faster decorrelation with changes in the beam or insonification angle for longer radio-frequency echo signal segments and at deeper locations in the medium. Theoretical results provide useful information for improving angular compounding and shear strain estimation techniques for elastography.


Irreversible activation of adenylate cyclase of toad erythrocyte plasma membrane by 5'-guanylylimidodiphosphate.
The irreversible activation of adenylate-cyclase by 5'guanylylimidodiphosphate, a phosphoramidate analog of 5'GTP, has been examined in toad (Bufus marinus) plasma membranes using the technique of preincubating the membranes with the nucleotide under various controlled conditions followed by washing and subsequent assay of enzyme activity. Activation of adenylate cyclase by Gpp(NH)p, but not GTP, is essentially permanent and persists following extensive washing, prolonged incubation at 30 degrees C in the absence of the nucleotide, and after dissolution of the membranes with Lubrol PX. (-)-Isoproterenol increases the activation observed with maximal concentrations of Gpp(NH)p from eight- to 10-fold (in the absence of hormone) to 50- to 100-fold; final activities as high as 10-15 nmoles of cyclic AMP per min per mg protein are achieved. The activated state obtained with isoproterenol and Gpp(NH)p is also permanent and is not inhibited by propranolol. The synergism between Gpp(NH)p and hormone requires the simultaneous presence of these compounds, and the time-dependent enhancement of activation with (-)-isoproterenol may be interrupted by addition of propranolol. The stimulation is slow, and may proceed for as long as 45 min at 30 degrees C in the presence of maximal concentrations of Gpp(NH)p and (-)-isoproterenol. Very little activation occurs at 0 degrees C. The time course of activation at 30 degrees C exhibits an accelerating phase lasting from 5 to 30 min when Gpp(NH)p is added directly during assay of cyclase activity or when the membranes are preincubated for various times and washed prior to assay for a fixed time. The lag period occurs in the presence and absence of (-)-isoproterenol, although the rate of increase in velocity is greater with hormone. The length of the accelerating phase decreases with increasing concentrations of Gpp(NH)p, although it is still evident with maximal levels of Gpp(NH)p and hormone. However, prewarming the membranes at 30 degrees C for 10 min in the absence of Gpp(NH)p or (-)-isoproterenol results in an immediate onset of linear activation at a rate which is achieved in untreated membranes only after about 10 min. The events occurring during prewarming at 30 degrees C are readily reversible since chilling the warmed membranes to 0 degrees C results in a time course of activation identical to that of membranes maintained at 0 degrees C until addition of Gpp(NH)p. Activation is proportional to the concentration of Gpp(NH)p within the range of 10(-8) to 10(-4) mM. The apparent affinity for Gpp(NH)p increases with increasing time of incubation. The primary effect of increasing the concentration of Gpp(NH)p is to decrease the time required to obtain a maximal rate of activation. The possible relevance of these findings to the mechanism of action of Gpp(NH)p, adenylate cyclase and hormones is discussed within the context of current views of biological membranes which recognize the lateral mobility of membrane molecules.


In vitro organogenesis from pluripotent stem cells.
Pluripotent stem cells (PSCs) have the ability to spontaneously generate structured tissues in vitro reminiscent of embryonic tissue development. Recently, complex organoids such as cortical tissues, cerebral brain organoids, optical cups, intestinal tissues, and liver buds have been generated from PSCs derived from healthy individuals and patients with genetic diseases, providing powerful tools to understand morphogenesis and disease pathology. This article highlights recent advances in the state-of-art generation of organoids from PSCs, possible signaling pathways and mechanisms involved in organogenesis, and the understanding of extracellular microenvironment. Challenges involved in the organoid generation such as increasing organoid size, enhancing the tissue complexity, and improving functional maturation are also discussed.


Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining.
SUMOylation is critical for numerous cellular signalling pathways, including the maintenance of genome integrity via the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Using systematic human proteome microarray screening combined with widely applicable carbene footprinting, genetic code expansion and high-resolution structural profiling, we define two non-conventional and topology-selective SUMO2-binding regions on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ). Mechanistically, the interaction of SUMO2 and XRCC4 is incompatible with XRCC4 binding to three other proteins important for NHEJ-mediated DSB repair. These findings are consistent with SUMO2 forming a redundant NHEJ layer with the potential to regulate different NHEJ complexes at distinct levels including, but not limited to, XRCC4 interactions with XLF, LIG4 and IFFO1. Regulation of NHEJ is not only relevant for carcinogenesis, but also for the design of precision anti-cancer medicines and the optimisation of CRISPR/Cas9-based gene editing. In addition to providing molecular insights into NHEJ, this work uncovers a conserved SUMO-binding module and provides a rich resource on direct SUMO binders exploitable towards uncovering SUMOylation pathways in a wide array of cellular processes.


Illness identity as an important component of candidacy: Contrasting experiences of help-seeking and access to care in cancer and heart disease.
How and when we use health services or healthcare provision has dominated exploration of and debates around healthcare access. Levels of utilisation are assumed as a proxy for access. Yet, focusing on utilisation conceals an important aspect of the access conundrum: the relationships that patients and potential patients have with the healthcare system and the professionals within those systems. Candidacy has been proposed as an antidote to traditional utilisation models. The Candidacy construct offers the ability to include patient-professional aspects alongside utilisation and thus promotes a deeper understanding of access. Originally applied to healthcare access for vulnerable populations, additional socio-demographic factors, including age and ethnicity, have also been shown to influence the Candidacy process. Here we propose a further extension of the Candidacy construct and illustrate the importance of illness identities when accessing healthcare. Drawing on a secondary data analysis of three data sets of qualitative interviews from colorectal cancer and heart failure patients we found that though similar access issues are apparent pre-diagnosis, diagnosis marks a critical juncture in the experience of access. Cancer patients describe a person-centred responsive healthcare system where their patienthood requires only modest assertion. Cancer speaks for itself. In marked contrast heart failure patients, describe struggling within a seemingly impermeable system to understand their illness, its implications and their own legitimacy as patients. Our work highlights the pressing need for healthcare professionals, systems and policies to promote a person centred approach, which is responsive and timely, regardless of illness category. To achieve this, attitudes regarding the importance or priority afforded to different categories of illness need to be tackled as they directly influence ideas of Candidacy and consequently access and experiences of care.


Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for nonrhabdomyosarcoma soft tissue sarcomas.
Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In people with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage. To assess the efficacy and safety of high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) for all stages of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults. For this update, we revised the search strategy to improve the precision and reduce the number of irrelevant hits. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8), PubMed from 2012 to 6 September 2016, and Embase from 2012 to 26 September 2016. We searched online trial registries and congress proceedings from 2012 to 26 September 2016. Terms representing STS and autologous HSCT were required in the title or abstract. We restricted the study design to RCTs. We included studies if at least 80% of participants had a diagnosis listed in any version of the World Health Organization (WHO) classification and classified as malignant. The search included children and adults with no age limits. We used standard methodologic procedures expected by Cochrane. The primary outcomes were overall survival and treatment-related mortality. We identified 1549 records; 85 items from electronic databases, 45 from study registries, and 1419 from congress proceedings. The revised search strategy did not identify any additional RCTs. In the previous version of the review, we identified one RCT comparing HDCT followed by autologous HSCT versus standard-dose chemotherapy (SDCT). The trial randomized 87 participants who were considerably heterogeneous with respect to 19 different tumor entities. The data from 83 participants were available for analysis.In the single included trial, overall survival at three years was 32.7% in the HDCT arm versus 49.4% in the SDCT arm and there was no difference between the treatment groups (hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.70 to 2.29, P = 0.44; 1 study, 83 participants; high quality evidence). In a subgroup of participants who had a complete response before HDCT, overall survival was higher in both treatment groups and overall survival at three years was 42.8% in the HDCT arm versus 83.9% in the SDCT arm and favored the SDCT group (HR 2.92, 95% CI 1.1 to 7.6, P = 0.028; 1 study, 39 participants).In the single included trial, the authors reported one treatment-related leukemia death two years after HDCT. They also evaluated severe adverse events WHO grade 3 to 4 in 22 participants in the HDCT arm and in 51 participants in the SDCT arm. The authors reported 11 events concerning digestive-, infection-, pain-, or asthenia-related toxicity in the HDCT arm and one event in the SDCT arm (moderate quality evidence). The development of secondary neoplasia was not addressed. We judged the study to have an overall unclear risk of bias as three of seven items had unclear and four items had low risk of bias. For GRADE, we judged three items as high quality and three items were not reported. The limited data of a single RCT with an unclear risk of bias and moderate to high quality evidence showed no survival advantage for HDCT. If this treatment is offered it should only be given after careful consideration on an individual person basis and possibly only as part of a well-designed RCT.