The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis.
Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of </=1nmol/L and inhibited activation of downstream signaling molecules. Additionally, cediranib blocked VEGF-C156S-induced and VEGF-E-induced proliferation, survival, and migration of lymphatic and blood vascular endothelial cells. In vivo, cediranib (6 mg/kg/d) prevented angiogenesis and lymphangiogenesis induced by VEGF-E-expressing and VEGF-C156S-expressing adenoviruses, respectively. Cediranib (6 mg/kg/day) also blocked angiogenesis and lymphangiogenesis induced by adenoviruses expressing VEGF-A or VEGF-C and compromised the blood and lymphatic vasculatures of VEGF-C-expressing tumors. Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis.


PET/CT in the evaluation of anti-NMDA-receptor encephalitis: What we need to know as a NM physician.
Anti N-methyl-D-aspartate receptor encephalitis (ANMDARE), also known as limbic encephalitis (LE), is a treatable rare disorder characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia. It is classified under paraneoplastic syndrome (PNS) and produces antibodies against NR1 and NR2 subunits of glutamate aspartate receptor. It is thought to be closely related with malignancies like small cell lung cancer, ovarian teratoma and Hodgkin's lymphoma, apart from testis, breast and rarely gastric malignancies. Non-paraneoplastic encephalitis cases are the ones with no detectable malignancy and may be triggered by severe infection. As nuclear medicine physicians, we must be aware of the diverse presentation of ANMDARE or LE and should include a whole body positron emission tomography / computed tomography (PET/CT) and not just brain PETCT during imaging. We describe the first case of PET/CT in an idiopathic ANMDARE Indian adolescent girl.


The Plausibility of Sampling as an Algorithmic Theory of Sentence Processing.
Words that are more surprising given context take longer to process. However, no incremental parsing algorithm has been shown to directly predict this phenomenon. In this work, we focus on a class of algorithms whose runtime does naturally scale in surprisal-those that involve repeatedly sampling from the prior. Our first contribution is to show that simple examples of such algorithms predict runtime to increase superlinearly with surprisal, and also predict variance in runtime to increase. These two predictions stand in contrast with literature on surprisal theory (Hale, 2001; Levy, 2008a) which assumes that the expected processing cost increases linearly with surprisal, and makes no prediction about variance. In the second part of this paper, we conduct an empirical study of the relationship between surprisal and reading time, using a collection of modern language models to estimate surprisal. We find that with better language models, reading time increases superlinearly in surprisal, and also that variance increases. These results are consistent with the predictions of sampling-based algorithms.


Impact of intravitreal pharmacotherapies including antivascular endothelial growth factor and corticosteroid agents on diabetic retinopathy.
Diabetic retinopathy is common and increasing in prevalence. Pharmacologic management of diabetic macular edema (DME) has improved tremendously over the last decade with the use of two families of intravitreally administered medications: antivascular endothelial growth factor-specific agents and corticosteroids. Clinical evaluation of these pharmaceuticals has demonstrated that they can have a substantial impact on diabetic retinopathy severity levels and the underlying retinal vasculature itself. Phase 3 trials employing ranibizumab, aflibercept, and fluocinolone acetonide enrolling eyes with center-involving DME causing visual acuity loss have demonstrated impressive alteration of the natural history of progressive diabetic retinopathy worsening over time through blunted progression to proliferative diabetic retinopathy, improving diabetic retinopathy severity levels, and slowing progressive retinal nonperfusion, the underlying disease process central to diabetic retinopathy itself. Accumulating data indicate that the threshold to initiate ocular-specific pharmacologic treatment for diabetic retinopathy, previously predominately limited to eyes with visual loss because of center-involved DME or proliferative diabetic retinopathy, is being lowered to earlier stages of diabetic retinopathy. Ongoing clinical trials and secondary analyses continue to further explore the impact and durability of vascular endothelial growth factor blockade and corticosteroids on modification of diabetic retinopathy and the underlying retinal vasculature itself.


The role of neighborhood social cohesion in the association between seeing people walk and leisure-time walking among Latino adults.
Few studies have investigated the association between seeing people walk and leisure-time walking, and the role of neighborhood social cohesion among Latinos/Latinx. We examined the association between frequency of seeing people walk within sight of home and leisure-time walking, and whether neighborhood social cohesion explained this association. We utilized cross-sectional data from the 2015 National Health Interview Survey from Latinos aged 18+ years (n=4,669). A structural equation model was used to estimate the association between seeing people walk and leisure-time walking, and to test the extent to which neighborhood social cohesion accounted for the association. Findings indicate that there is a strong association between seeing people walk and leisure-time walking, and neighborhood social cohesion partially explains this association among Latinos/Latinx. Neighborhood social cohesion may strengthen efforts focused on neighborhood-level behavioral norms that promote walking.


Egress of non-enveloped enteric RNA viruses.
A long-standing paradigm in virology was that non-enveloped viruses induce cell lysis to release progeny virions. However, emerging evidence indicates that some non-enveloped viruses exit cells without inducing cell lysis, while others engage both lytic and non-lytic egress mechanisms. Enteric viruses are transmitted via the faecal-oral route and are important causes of a wide range of human infections, both gastrointestinal and extra-intestinal. Virus cellular egress, when fully understood, may be a relevant target for antiviral therapies, which could minimize the public health impact of these infections. In this review, we outline lytic and non-lytic cell egress mechanisms of non-enveloped enteric RNA viruses belonging to five families: Picornaviridae, Reoviridae, Caliciviridae, Astroviridae and Hepeviridae. We discuss factors that contribute to egress mechanisms and the relevance of these mechanisms to virion stability, infectivity and transmission. Since most data were obtained in traditional two-dimensional cell cultures, we will further attempt to place them into the context of polarized cultures and in vivo pathogenesis. Throughout the review, we highlight numerous knowledge gaps to stimulate future research into the egress mechanisms of these highly prevalent but largely understudied viruses.


Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal.
The dual function of stem cells requires them not only to form new stem cells through self-renewal but also to form lineage-committed cells through differentiation. Embryonic stem cells (ESC), which are derived from the blastocyst inner cell mass, retain properties of self-renewal and the potential for lineage commitment. To balance self-renewal and differentiation, ESC must carefully control the levels of several transcription factors, including Nanog, Sox2, and Oct4. While molecular mechanisms promoting transcription of these genes have been described, mechanisms preventing excessive levels in self-renewing ESC remain unknown. By examining the function of the TCF family of transcription factors in ESC, we have found that Tcf3 is necessary to limit the steady-state levels of Nanog mRNA, protein, and promoter activity in self-renewing ESC. Chromatin immunoprecipitation and promoter reporter assays showed that Tcf3 bound to a promoter regulatory region of the Nanog gene and repressed its transcriptional activity in ESC through a Groucho interaction domain-dependent process. The absence of Tcf3 caused delayed differentiation of ESC in vitro as elevated Nanog levels persisted through 5 days of embryoid body formation. These new data support a model wherein Tcf3-mediated control of Nanog levels allows stem cells to balance the creation of lineage-committed and undifferentiated cells.


Management of hypertension in patients with acute stroke.
Lowering systemic blood pressure (BP) in patients with acute cerebral infarction may produce clinical deterioration. Because of impaired cerebral autoregulation and the spontaneous fluctuations in BP following stroke, antihypertensive medication should be avoided in patients with acute cerebral infarction unless vital organs such as the heart or kidney are compromised, the diastolic BP rises to 130 mm Hg or greater, or the patient has hypertensive encephalopathy. Brief remarks about BP control in intracerebral hematoma and subarachnoid hemorrhage are also included.


Study product adherence measurement in the iPrEx placebo-controlled trial: concordance with drug detection.
To evaluate the concordance between adherence estimated by self-report (in-person interview or computer-assisted self-interview), in-clinic pill counts, and pharmacy dispensation records and drug detection among participants in a placebo-controlled pre-exposure prophylaxis HIV prevention trial (iPrEx). Cross-sectional evaluation of 510 participants who had drug concentration data and matched adherence assessments from their week-24 study visit. Self-reported adherence collected through (1) interview and (2) computer-assisted self-interview surveys, (3) adherence estimated by pill count, and (4) medication possession ratio was contrasted to having a detectable level of drug concentrations [either tenofovir diphosphate (TFV-DP) or emtricitabine triphosphate (FTC-TP)], as well as to having evidence of consistent dosing (tenofovir diphosphate ≥ 16 fmol/10⁶ cells), focusing on positive predictive values, overall and by research site. Overall, self-report and pharmacy records suggested high rates of product use (over 90% adherence); however, large discrepancies between these measures and drug detection were noted, which varied considerably between sites (positive predictive values from 34% to 62%). Measures of adherence performed generally well in the US sites but had poor accuracy in other research locations. Medication possession ratio outperformed other measures but still had relatively low discrimination. The sizable discrepancy between adherence measures and drug detection in certain regions highlights the potential contribution of factors that may have incentivized efforts to seem adherent. Understanding the processes driving adherence reporting in some settings, but not others, is essential for finding effective ways to increase accuracy in measurement of product use and may generalize to promotion efforts for open-label pre-exposure prophylaxis.


Upstream induction sequence, the cis-acting element required for response to the allantoin pathway inducer and enhancement of operation of the nitrogen-regulated upstream activation sequence in Saccharomyces cerevisiae.
Expression of the DAL2, DAL4, DAL7, DUR1,2, and DUR3 genes in Saccharomyces cerevisiae is induced by the presence of allophanate, the last intermediate of the allantoin degradative pathway. Analysis of the DAL7 5'-flanking region identified an element, designated the DAL upstream induction sequence (DAL UIS), required for response to inducer. The operation of this cis-acting element requires functional DAL81 and DAL82 gene products. We determined the DAL UIS structure by using saturation mutagenesis. A specific dodecanucleotide sequence is the minimum required for response of reporter gene transcription to inducer. There are two copies of the sequence in the 5'-flanking region of the DAL7 gene. There are one or more copies of the sequence upstream of each allantoin pathway gene that responds to inducer. The sequence is also found 5' of the allophanate-inducible CAR2 gene as well. No such sequences were detected upstream of allantoin pathway genes that do not respond to the presence of inducer. We also demonstrated that the presence of a UIS element adjacent to the nitrogen-regulated upstream activation sequence significantly enhances its operation.


Prediction of pharmacokinetics and drug-drug interactions when hepatic transporters are involved.
Hepatobiliary transport mechanisms have been identified to play a significant role in determining the systemic clearance for a number of widely prescribed drugs and an increasing number of new molecular entities (NMEs). While determining the pharmacokinetics, drug transporters also regulate the target tissue exposure and play a key role in regulating the pharmacological and/or toxicological responses. Consequently, it is of great relevance in drug discovery and development to assess hepatic transporter activity in regard to pharmacokinetic and dose predictions and to evaluate pharmacokinetic variability associated with drug-drug interactions (DDIs) and genetic variants. Mechanistic predictions utilizing physiological-based pharmacokinetic modeling are increasingly used to evaluate transporter contribution and delineate the transporter-enzyme interplay on the basis of hypothesis-driven functional in vitro findings. Significant strides were made in the development of in vitro techniques to facilitate characterization of hepatobiliary transport. However, challenges exist in the quantitative in vitro-in vivo extrapolation of transporter kinetics due to the lack of information on absolute abundance of the transporter in both in vitro and in vivo situations, and/or differential function in the holistic in vitro reagents such as suspended and plated hepatocytes systems, and lack of complete mechanistic understanding of liver model structure. On the other hand, models to predict transporter-mediated DDIs range from basic models to mechanistic static and dynamic models. While basic models provide conservative estimates and are useful upfront in avoiding false negative predictions, mechanistic models integrate multiple victim and perpetrator drugs parameters and are expected to provide quantitative predictions. The aim of this paper is to review the current state of the model-based approaches to predict clinical pharmacokinetics and DDIs of drugs or NMEs that are substrates of hepatic transporters.


Dental erosion in children : an increasing clinical problem.
Epidemiological studies carried out on dental erosion have established that the prevalence is high in young people and adolescents. The objective of this study was to look at the prevalence and etiology of dental erosion, particularly in children, and its practical management for its possible control. The children between 5-6 yrs were examined and findings recorded, and this study has shown that approximately 1/3rd of 5-6 yrs old children have appreciable tooth wear and dental erosion.


Health behaviour and lifestyle of Pacific youth surveys: a resource for capacity building.
The changing global socio-economic environment over the last two decades has had significant ramifications for the health and development of youth in lower- and middle-income countries. In the Pacific region, young people are exposed to similar causes of ill-health as their peers in developed countries. This paper describes the development, implementation and major findings of the Health Behaviour and Lifestyle of Pacific Youth (HBLPY) surveys, a regional initiative to obtain representative data about health-related behaviour and needs of adolescents in Vanuatu, Tonga and the Federated States of Micronesia. The Pacific HBLPY is modelled on the WHO Europe Health Behaviour in School-aged Children (HBSC) surveys. The surveys, undertaken in 2000-2001, were built upon strong local partnerships and were undertaken with youth participation to ensure survey ownership. A regional technical group was formed to provide training and support to strengthen health survey capacity of youth and their agencies. The findings showed that tobacco was most commonly used substance, with 29.7% of 15-year-old boys and 15.7% of girls smoking weekly. Over half of the students did not engage in physical activity for at least 2 h per week; these rates are substantially lower than those usually found in Europe. Dietary habits among this group are also of concern, reflecting international trends away from highly nutritious traditional diets. The HBLPY surveys have shown that it is possible to collect population-based data in lower- and middle-income countries so that appropriate youth health programmes and policies can be developed. Implementation of an ongoing surveillance system similar to the HBLPY model in these countries warrants further investigation. Such initiatives should be supported at the regional and global level.


The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver.
As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called "neoGATA3," associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning of ER-dependent gene expression. This has opposite outputs in distinct hormonal context, having pro- or anti-proliferative effects, depending on the estrogen/progesterone ratio. Our data call for functional analyses of putative cancer drivers to guide clinical application.


C-GRApH: A Validated Scoring System for Early Stratification of Neurologic Outcome After Out-of-Hospital Cardiac Arrest Treated With Targeted Temperature Management.
Out-of-hospital cardiac arrest (OHCA) results in significant morbidity and mortality, primarily from neurologic injury. Predicting neurologic outcome early post-OHCA remains difficult in patients receiving targeted temperature management. Retrospective analysis was performed on consecutive OHCA patients receiving targeted temperature management (32-34°C) for 24 hours at a tertiary-care center from 2008 to 2012 (development cohort, n=122). The primary outcome was favorable neurologic outcome at hospital discharge, defined as cerebral performance category 1 to 2 (poor 3-5). Patient demographics, pre-OHCA diagnoses, and initial laboratory studies post-resuscitation were compared between favorable and poor neurologic outcomes with multivariable logistic regression used to develop a simple scoring system (C-GRApH). The C-GRApH score ranges 0 to 5 using equally weighted variables: (C): coronary artery disease, known pre-OHCA; (G): glucose ≥200 mg/dL; (R): rhythm of arrest not ventricular tachycardia/fibrillation; (A): age >45; (pH): arterial pH ≤7.0. A validation cohort (n=344) included subsequent patients from the initial site (n=72) and an external quaternary-care health system (n=272) from 2012 to 2014. The c-statistic for predicting neurologic outcome was 0.82 (0.74-0.90, P<0.001) in the development cohort and 0.81 (0.76-0.87, P<0.001) in the validation cohort. When subdivided by C-GRApH score, similar rates of favorable neurologic outcome were seen in both cohorts, 70% each for low (0-1, n=60), 22% versus 19% for medium (2-3, n=307), and 0% versus 2% for high (4-5, n=99) C-GRApH scores in the development and validation cohorts, respectively. C-GRApH stratifies neurologic outcomes following OHCA in patients receiving targeted temperature management (32-34°C) using objective data available at hospital presentation, identifying patient subsets with disproportionally favorable (C-GRApH ≤1) and poor (C-GRApH ≥4) prognoses.


Concordant induction of cyclin E and p21cip1 in differentiated keratinocytes by the human papillomavirus E7 protein inhibits cellular and viral DNA synthesis.
Productive infections by human papillomaviruses (HPVs) occur only in differentiated keratinocytes in squamous epithelia in which the HPV E7 protein reactivates the host DNA replication machinery to support viral DNA replication. In a fraction of the differentiated keratinocytes, E7 also posttranscriptionally induces p21Cip1, which is distributed in a mutually exclusive manner with unscheduled cellular DNA synthesis. In this study, double immunofluorescence labeling unexpectedly revealed that E7 caused a concordant accumulation of both cyclin E and p21Cip1 to high levels in patient papillomas and in organotypic cultures of primary human keratinocytes. The induction of cyclin E is mutually exclusive with unscheduled cellular DNA synthesis or abundant viral DNA. These novel virus-host interactions in differentiated keratinocytes are in contrast to previous observations made in submerged proliferating cultures, in which HPV E7 induces cyclin E and overcomes p21Cip1 inhibition of S-phase entry. We propose that an appropriately timed induction of cyclin E/cyclin-dependent kinase 2 by HPV E7 in postmitotic cells enables S-phase reentry and HPV DNA amplification, whereas prematurely induced cyclin E stabilizes p21Cip1 protein, which then inhibits cyclin E/cyclin-dependent kinase 2. Consequently, cyclin E and p21Cip1 both fail to turn over, and DNA synthesis does not occur.


Multilevel effective surgical workflow recognition in robotic left lateral sectionectomy with deep learning: experimental research.
Automated surgical workflow recognition is the foundation for computational models of medical knowledge to interpret surgical procedures. The fine-grained segmentation of the surgical process and the improvement of the accuracy of surgical workflow recognition facilitate the realization of autonomous robotic surgery. This study aimed to construct a multigranularity temporal annotation dataset of the standardized robotic left lateral sectionectomy (RLLS) and develop a deep learning-based automated model for multilevel overall and effective surgical workflow recognition. From December 2016 to May 2019, 45 cases of RLLS videos were enrolled in our dataset. All frames of RLLS videos in this study are labeled with temporal annotations. The authors defined those activities that truly contribute to the surgery as effective frames, while other activities are labeled as under-effective frames. Effective frames of all RLLS videos are annotated with three hierarchical levels of 4 steps, 12 tasks, and 26 activities. A hybrid deep learning model were used for surgical workflow recognition of steps, tasks, activities, and under-effective frames. Moreover, the authors also carried out multilevel effective surgical workflow recognition after removing under-effective frames. The dataset comprises 4 383 516 annotated RLLS video frames with multilevel annotation, of which 2 418 468 frames are effective. The overall accuracies of automated recognition for Steps, Tasks, Activities, and under-effective frames are 0.82, 0.80, 0.79, and 0.85, respectively, with corresponding precision values of 0.81, 0.76, 0.60, and 0.85. In multilevel effective surgical workflow recognition, the overall accuracies were increased to 0.96, 0.88, and 0.82 for Steps, Tasks, and Activities, respectively, while the precision values were increased to 0.95, 0.80, and 0.68. In this study, the authors created a dataset of 45 RLLS cases with multilevel annotations and developed a hybrid deep learning model for surgical workflow recognition. The authors demonstrated a fairly higher accuracy in multilevel effective surgical workflow recognition when under-effective frames were removed. Our research could be helpful in the development of autonomous robotic surgery.


Papillomas of the nasal and paranasal cavities.
Intranasal papilloma is an uncommon, benign tumor of the nasal cavity and, by extension, the paranasal sinuses. It occurs only once for every 25 cases of ordinary nasal polyps. A recent case is reported, followed by a summary of the cases treated at the Emory University Hospitals in the last ten years. The histologic classification is reviewed, as well as current treatment, with an emphasis on wide surgical excision through the lateral rhinotomy approach. Because about 10% of these tumors will have associated malignancy, guidelines are given to insure that this malignant transformation is not missed.


Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development.
Tissue regeneration is an orchestrated progression of cells from an immature state to a mature one, conventionally represented as distinctive cell subsets. A continuum of transitional cell states exists between these discrete stages. We combine the depth of single-cell mass cytometry and an algorithm developed to leverage this continuum by aligning single cells of a given lineage onto a unified trajectory that accurately predicts the developmental path de novo. Applied to human B cell lymphopoiesis, the algorithm (termed Wanderlust) constructed trajectories spanning from hematopoietic stem cells through to naive B cells. This trajectory revealed nascent fractions of B cell progenitors and aligned them with developmentally cued regulatory signaling including IL-7/STAT5 and cellular events such as immunoglobulin rearrangement, highlighting checkpoints across which regulatory signals are rewired paralleling changes in cellular state. This study provides a comprehensive analysis of human B lymphopoiesis, laying a foundation to apply this approach to other tissues and "corrupted" developmental processes including cancer.


Electrophysiological Assessment of Serotonin and GABA Neuron Function in the Dorsal Raphe during the Third Trimester Equivalent Developmental Period in Mice.
Alterations in the development of the serotonin system can have prolonged effects, including depression and anxiety disorders later in life. Serotonin axonal projections from the dorsal raphe undergo extensive refinement during the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy). However, little is known about the functional properties of serotonin and GABA neurons in the dorsal raphe during this critical developmental period. We assessed the functional properties and synaptic connectivity of putative serotoninergic neurons and GABAergic neurons in the dorsal raphe during early [postnatal day (P) P5-P7] and late (P15-P17) stages of the third trimester equivalent period using electrophysiology. Our studies demonstrate that GABAergic neurons are hyperexcitable at P5-P7 relative to P15-P17. Furthermore, putative serotonin neurons exhibit an increase in both excitatory and GABAA receptor-mediated spontaneous postsynaptic currents during this developmental period. Our data suggest that GABAergic neurons and putative serotonin neurons undergo significant electrophysiological changes during neonatal development.


Informing child welfare policy and practice: using knowledge discovery and data mining technology via a dynamic Web site.
Proper management and implementation of an effective child welfare agency requires the constant use of information about the experiences and outcomes of children involved in the system, emphasizing the need for comprehensive, timely, and accurate data. In the past 20 years, there have been many advances in technology that can maximize the potential of administrative data to promote better evaluation and management in the field of child welfare. Specifically, this article discusses the use of knowledge discovery and data mining (KDD), which makes it possible to create longitudinal data files from administrative data sources, extract valuable knowledge, and make the information available via a user-friendly public Web site. This article demonstrates a successful project in North Carolina where knowledge discovery and data mining technology was used to develop a comprehensive set of child welfare outcomes available through a public Web site to facilitate information sharing of child welfare data to improve policy and practice.


Can formulation affect tryptophan depletion results? Hints from studies in experimental panic.
Acute Tryptophan Depletion (ATD) is a specific serotonergic challenge tool. Central serotonergic effects of different ATD procedures are possibly not those that are usually assumed. In this paper we review data of ATD in an experimental fear model to investigate whether and how methodological differences may affect fear outcomes. Next we point to discrepancies of studies in our laboratory in order to test the hypotheses formulated in the review. Literature was searched in PubMed and MEDLINE and studies of our laboratory were compared. Eight studies were included in the review: five in patients with panic disorder, three in healthy individuals. Methodologically the studies in our laboratory were quite similar except for the applied ATD mixtures. ATD exerts fear-enhancing effects in patients with panic disorders, more than in healthy individuals. However, our findings are inconclusive. The discrepant findings of studies in our laboratory can possibly be explained by differences in the ATD mixtures used. We suggest mechanisms as to how these might have affected the central availability of tryptophan and hence serotonin.


Risk factors for venous thromboembolism.
Risk factors for venous thromboembolism (VTE) are often modifiable and overlap with risk factors for coronary artery disease. Encouraging our patients to adopt a heart-healthy lifestyle by abstaining from cigarettes, maintaining lean weight, limiting red meat intake, and controlling hypertension might lower the risk of pulmonary embolism and deep vein thrombosis (DVT), although a cause-effect relationship has not been firmly established. For hospitalized patients, guidelines have provided evidence-based strategies to identify patients at risk, such as elderly persons and those with cancer, congestive heart failure, or chronic obstructive pulmonary disease or undergoing major surgery. Most should receive pharmacological prophylaxis, which will minimize the risk of VTE. Because approximately 3 of every 4 pulmonary embolism and DVT events occur outside the hospital setting, patients should also be assessed for persistent high-risk of VTE at the time of hospital discharge.


Characterization of rotavirus P genotypes circulating among paediatric inpatients in northern brazil
Between November 1992 and August 1993, twenty-eight rotavirus-positive stool samples obtained from paediatric inpatients in Belem, Brazil, aged less than four years, were tested by RT-PCR to determine the P genotype specificities. With the exception of 7 non-diarrhoeic children, all patients were either diarrhoeic at admission or developed diarrhoea while in hospital. Rotavirus strains with the gene 4 alleles corresponding to P1B[4] and P1A[8] types (both of which bearing G2 specificity) predominated, accounting for 78.6% of the strains. While only one P2A[6] type strain - with (mixed) G1 and 4 type specificities - was detected, the gene 4 allele could not be identified in 4 (14.3%) of the strains. Most (81%) of the specimens were obtained from children during their first 18 months of life. Rotavirus strains bearing single P1B[4] type-specificity were identified in both diarrhoeic (either nosocomial, 28.6% or community-acquired diarrhoea, 28.6%) and non-diarrhoeic (42.8%) children. P1A[8] gene 4 allele, on the other hand, was detected only among diarrhoeic children, at rates of 57.1% and 42.9% for nosocomial- and- community acquired diarrhoea, respectively. Mixed P1A[8],1B[4] type infection was identified in only one case of community-acquired diarrhoea.


Thirty-Day Mortality After Infection Among Persons With Severe Mental Illness: A Population-Based Cohort Study in Denmark.
Persons with severe mental illness die 15-20 years earlier on average than persons without severe mental illness. Although infection is one of the leading overall causes of death, no studies have evaluated whether persons with severe mental illness have a higher mortality after infection than those without. The authors studied mortality rate ratios and cumulative mortality proportions after an admission for infection for persons with severe mental illness compared with persons without severe mental illness by linking data from Danish national registries. The cohort consisted of all persons hospitalized for infection during the period 1995-2011 in Denmark (N=806,835), of whom 11,343 persons had severe mental illness. Within 30 days after an infection, 1,052 (9.3%) persons with a history of severe mental illness and 58,683 (7.4%) persons without a history of severe mental illness died. Thirty-day mortality after any infection was 52% higher in persons with severe mental illness than in persons without (mortality rate ratio=1.52, 95% CI=1.43-1.61). Mortality was increased for all infections, and the mortality rate ratios ranged from 1.27 (95% CI=1.15-1.39) for persons hospitalized for sepsis to 2.61 (95% CI=1.69-4.02) for persons hospitalized for CNS infections. Depending on age, 1.7 (95% CI=1.2-2.2) to 2.9 (95% CI=2.0-3.7) more deaths were observed within 30 days after an infection per 100 persons with a history of severe mental illness compared with 100 persons without such a history. Persons with severe mental illness have a markedly elevated 30-day mortality after infection. Some of these excess deaths may be prevented by offering individualized and targeted interventions.


Quantification of myocardial viability distribution with Gd(DTPA) bolus-enhanced, signal intensity-based percent infarct mapping.
A substantial, common shortcoming of the currently used semiautomated techniques for the quantification of myocardial infarct with delayed enhancement magnetic resonance imaging is the assumption that the whole myocardial slab that corresponds to the hyperenhanced tomographic area is 100% nonviable. This assumption is, however, incorrect. To resolve this conflict, we have recently proposed the signal intensity percent-infarct mapping method and validated it in an ex vivo, canine experiment. The purpose of the current study has been the validation of the signal intensity percent-infarct mapping method in vivo, using a porcine model of reperfused myocardial infarct. In swines (n=6), reperfused myocardial infarct was generated occluding for 90 min by an angioplasty balloon either the left anterior descending or the left circumflex coronary artery. To obtain DE images, Gd(DTPA) enhanced inversion-recovery fast gradient-echo acquisitions were carried out on day 28 after myocardial infarction. Scanning started 15 min after intravenous injection of 0.2 mmol/kg Gd(DTPA). At the end of the MRI session, the animal was sacrificed and 2,3,5-triphenyltetrazolium chloride staining was used to validate the existence and to determine the accurate size of the myocardial infarct. Tissue samples were taken and stained with hematoxylin-eosin and Masson's trichrome for histological assessment of the infarct and the periinfarct zone. The signal intensity percent-infarct mapping data were compared with corresponding data from the delayed enhancement images analyzed with SI(remote+2S.D.) thresholding, and with corresponding triphenyltetrazolium-chloride staining data using Friedman's repeated measure analysis of variance on ranks. The infarct volume determined by the triphenyltetrazolium chloride, SI(remote+2S.D.) and signal intensity percent-infarct mapping methods was 3.04 ml [2.74, 3.45], 13.62 ml [9.06, 18.45] and 4.27 ml [3.45, 6.33], respectively. Median infarct volume determined by SI(remote+2S.D.) significantly differed from that determined by triphenyltetrazolium chloride (P<.05). The Bland-Altman overall bias was 12.49% of the volume of the left ventricle. Median infarct volume determined by signal intensity percent-infarct mapping, however, did not differ significantly (NS) from that obtained by triphenyltetrazolium chloride. Signal intensity percent-infarct mapping yielded only a 1.99% Bland-Altman overall bias of the left ventricular volume. This in vivo study in the porcine reperfused myocardial infarct model demonstrates that signal intensity percent-infarct mapping is a highly accurate method for the determination of the extent of myocardial infarct. MRI images for signal intensity percent-infarct mapping are obtained with the pulse sequence of conventional delayed enhancement imaging and are acquired within clinically acceptable scanning time. This makes signal intensity percent-infarct mapping a practical method for clinical implementation.


Predictors of treatment outcome in individuals with eating disorders: A systematic review and meta-analysis.
Understanding the factors that predict a favourable outcome following specialist treatment for an eating disorder may assist in improving treatment efficacy, and in developing novel interventions. This review and meta-analysis examined predictors of treatment outcome and drop-out. A literature search was conducted to identify research investigating predictors of outcome in individuals treated for an eating disorder. We organized predictors first by statistical type (simple, meditational, and moderational), and then by category. Average weighted mean effect sizes (r) were calculated for each category of predictor. The most robust predictor of outcome at both end of treatment (EoT) and follow-up was the meditational mechanism of greater symptom change early during treatment. Simple baseline predictors associated with better outcomes at both EoT and follow-up included higher BMI, fewer binge/purge behaviors, greater motivation to recover, lower depression, lower shape/weight concern, fewer comorbidities, better interpersonal functioning and fewer familial problems. Drop-out was predicted by more binge/purge behaviors and lower motivation to recover. For most predictors, there was large interstudy variability in effect sizes, and outcomes were operationalized in different ways. There were generally insufficient studies to allow analysis of predictors by eating disorder subtype or treatment type. To ensure that this area continues to develop with robust and clinically relevant findings, future studies should adopt a consistent definition of outcome and continue to examine complex multivariate predictor models. Growth in this area will allow for stronger conclusions to be drawn about the prediction of outcome for specific diagnoses and treatment types.


Self-assembly and polymerization of diacetylene-containing peptide amphiphiles in aqueous solution.
A systematic study was performed of the fiber forming properties and polymerization characteristics of two peptide amphiphiles containing a diacetylene functionality in the alkyl tail comprising 23 and 25 C atoms, respectively. Both diyne containing peptide amphiphiles were able to form stable beta-sheet fibers of micrometers length in an aqueous solution. However, there was a large difference between the stability of the two amphiphiles. This was shown by a large difference in assembly and disassembly temperature and by different behavior during polymerization. Because the monomers were preorganized with a tight molecular packing, the polymerization could be carried out using wavelengths up to 532 nm. For both amphiphiles, the fiber structure did not change when the polymerization was carried out at an elevated temperature. The degree of polymerization, however, barely decreased for the longer amphiphile (2) but showed a gradual decline for the shorter one (1) when the temperature was raised from room temperature to the melting temperature of the fibers. Furthermore, the pH did not influence the fiber assembly for 2, but hampered it for 1 at alkaline pH. The fiber structure was, for both of the amphiphiles, not dependent on the pH. After polymerization, the molecular packing of the amphiphiles was only slightly influenced by an increase in temperature, as indicated by the small color change of polymerized fibers, which was also reversible. Additionally, pH had no influence on the assembly structure, as indicated by the color of the polymer which was the same at all pH values. Thus, both fibers increased in stability upon polymerization. The large difference in assembly and polymerization behavior of the two similar-looking amphiphiles 1 and 2, with a 23 or 25 carbon tail, is indicative of the subtlety of the assembly and disassembly processes in these fibrous architectures.


Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer.
Cancer of unknown primary site (CUP) is considered an aggressive metastatic disease but whether the prognosis differs from metastatic cancers of known primary site is not known. Such data may give insight into the biology of CUP and the metastatic process in general. 6,745 cancer patients, with primary metastatic cancer at diagnosis, were identified from the Swedish Cancer Registry, and were compared with 2,881 patients with CUP. Patients were diagnosed and died between 2002 and 2008. The influence of the primary site, known or unknown, on survival in patients with metastases at specific locations was investigated. Hazard ratios (HRs) of death were estimated for several sites of metastasis, where patients with known primary sites were compared with CUP patients. Overall, patients with metastatic cancers with known primary sites had decreased hazards of death compared to CUP patients (HR = 0.69 [95% CI = 0.66-0.72]). The exceptions were cancer of the pancreas (1.71 [1.54-1.90]), liver (1.58 [1.36-1.85]), and stomach (1.16 [1.02-1.31]). For individual metastatic sites, patients with liver or bone metastases of known origin had better survival than those with CUP of the liver and bone. Patients with liver metastases of pancreatic origin had an increased risk of death compared with patients with CUP of the liver (1.25 [1.06-1.46]). The median survival time of CUP patients was three months. Patients with CUP have poorer survival than patients with known primaries, except those with brain and respiratory system metastases. Of CUP sites, liver metastases had the worst prognosis. Survival in CUP was comparable to that in metastatic lung cancer. The aggressive behavior of CUP may be due to initial immunosuppression and immunoediting which may allow accumulation of mutations. Upon escape from the suppressed state an unstoppable tumor spread ensues. These novel data on the epidemiology of the metastatic process at the population level demonstrated large survival differences in organ defined metastases depending on the original cancer.


[The results of presbyopia correction with multifocal and accommodating intraocular lenses].
Clinical results of implantation of intraocular lenses (IOL) Restor +3D and Crystalens HD 500 for presbyopia correction were compared, indications for every IOL type were optimized. 40 patients were divided into 2 equal groups: the 1st included patients without concomitant ocular and somatic diseases, patients with these conditions were enrolled into the the 2nd group. Uncorrected visual acuity, optic phenomena and patient's satisfaction with the results of treatment were estimated in 6-12 months after surgery. Restor +3D and Crystalens implantation is effective in presbyopia correction. MIOLs provide high visual functions in all distances but reduce vision quality. In patients with concomitant diseases Crystalens HD implantation is preferable.


Analysis of Body Composition and Food Habits of Spanish Celiac Women.
The purpose of the present work was both to analyze composition of Spanish celiac women and to study the food habits and gluten-free diet of these celiac patients, in order to determine whether they achieve a balanced and healthy diet as well as to highlight nutritional qualitative and/or quantitative differences. 54 adult celiac women (34 ± 13 years) took part in the six-month study. Height, weight and body composition were measured. An analysis of energy consumption and of the macronutrient distribution of their diet was carried out. Their fulfillment of micronutrient intake recommendations was verified. Participants showed a Body Mass Index of 21.6 ± 2.4 kg/m2. Energy Intake was slightly lower than the Dietary Reference Intakes. Excessive protein apart from over-consumption of fat was observed. More than three quarters of participants consumed meat in excess. Carbohydrate consumption along with that of fiber was below recommended levels. Vitamin D, iron, and iodine had a low percentage of recommendation compliance. In general, participants followed the recommendations of dairy products and fruit intake whereas vegetable consumption was not enough for the vast majority. We conclude that although the diet of celiac women does not differ much from the diet of general population, some considerations, such as reducing fat and protein consumption and increasing fiber intake, must be taken into account.


[Prevalence and risk factors of urinary incontinence in young women].
Urinary incontinence is a very common disease among women but only few studies have been published in young adult and middle-aged population. We studied urinary incontinence prevalence and risk factors in this young and middle-aged population. We studied during the year 1998 the prevalence of global incontinence and stress, urge and mixed urinary incontinence in 1700 women working in a French academic hospital (n = 2800). Women received the questionnaire at the same time than their convocation for their yearly visit in occupational medicine. Usual risk factors of constitutional events (increasing âge, obesity defined by a Body Mass Index > or = 25); obstetric events (pregnancy, previous caesarean delivery, previous vaginal delivery, post-partum incontinence) and gynaecological event (hysterectomy) were evaluated. 177 women (mean âge 40.0 years) returned the questionnaire. 467 women (27.5% 95% CI = 25.4-29.7) reported urinary incontinence, 210 (12.4% 95% CI = 10.8-14.0) stress urinary incontinence, 28 (1.6% 95% CI = 1.1-2.4) urge urinary incontinence and 229 (13.5% 995% CI = 11.9-15.2) mixed urinary incontinence. 38 women (8.1%) suffered from frequent urinary leakage corresponding to 1 (0.5%), 4 (14.3%) and 33 (14.4%) stress, urge and mixed urinary incontinence. The prevalence of urinary incontinence increased significantly with âge > or = 40 years (RR = 2.16 95% CI = 1.86-2.57) pregnancy (RR = 2.22 95% CI = 1.71-2.87), previous vaginal delivery (RR = 2.15 95% CI = 1.72-2.69), post-partum incontinence (RR = 2.57 95% CI = 2.22-2.97, hysterectomy (RR = 1.52 95% CI = 1.11-2.08). Obesity (RR = 1.14 95% CI = 0.99-1.32) and previous caesarean delivery (RR = 2.15 95% CI = 1.72-2.69) did not increase the risk of urinary incontinence. The risk factors for stress urinary incontinence were âge > or = 40 years (RR = 2.18 95% CI = 1.66-2.87), pregnancy (RR = 2.36 95% CI = 1.55-3.58), previous vaginal delivery (RR = 2.47 95% CI = 1.70-3.59), post-partum incontinence (RR = 2.78 95% CI = 2.14-3.61) and hysterectomy (RR = 2.83 95% CI = 1.93-4.15). No relationship was found between stress urinary incontinence and obesity (RR = 1.25 95% CI = 0.96-1.64) and previous caesarean delivery (RR = 1.02 95% CI = 0.45-2.32). A high prevalence of urinary incontinence was observed among young adult and middle-aged female hospital workers with an easy access to medical resources. Gynaecological and obstetric event (pregnancy particularly previous vaginal delivery and hysterectomy) were the most prominent risk factors, especially for stress urinary incontinence.


New life for macrolides.
This article is an attempt to analyze and discuss the role and the purported mechanisms of azithromycin (AZM) in non-eosinophilic severe asthma, including antineutrophil activity, an effect on gastroesophageal reflux or antibacterial activity against an underlying chronic infection, such as Chlamydia pneumoniae. Macrolides have an expanding role in the therapy of chronic inflammatory diseases based on their additional anti-inflammatory and immunosuppressive properties. Many studies have been performed in lung transplantation field and maintenance treatment has been proved to be effective in cystic fibrosis, bronchiectasis, diffuse panbronchiolitis, and in bronchiolitis obliterans syndrome and in the prevention of exacerbations in patients with chronic obstructive pulmonary disease. Pathobiological studies of people with severe, refractory asthma focused on its heterogeneity encouraging more targeted and personalized approaches to asthma therapy. In neutrophilic asthma corticosteroids are not very effective, while the immunomodulatory action of macrolides is particularly relevant on neutrophils. Recently, The AZIthromycin in Severe ASThma (AZISAST) study, published on the April number of Thorax, provided evidences on the efficacy and safety of long-term add-on treatment with AZM in severe non-eosinophilic asthma. Despite concerns about an increased proportion of macrolide-resistant organism and about the effects of macrolides on cardiovascular events, there was no evidence of an increased risk of pneumonia or other adverse events. Because the AZISAST study was not able to demonstrate significant improvement in lung function and use of rescue medication, there is still a need for new data confirming the efficacy of AZM in severe non-eosinophilic asthma.


Uses of antimicrobials in plant agriculture.
Bacterial diseases of plants are less prevalent than diseases caused by fungi and viruses. Antimicrobials for prophylactic treatment of bacterial diseases of plants are limited in availability, use, and efficacy, and therapeutic use is largely ineffective. Most applications are by spray treatments in orchards. Monitoring and surveillance for drug resistance are not routinely done. In the United States, data on use of antimicrobials for treatment of bacterial diseases of plants are limited to streptomycin and oxytetracycline. Resistance to streptomycin has become widespread among bacterial phytopathogens; no resistance among these bacteria has yet been reported for oxytetracycline. No human health effects have been documented since inception of use of antimicrobials in plants in the 1950s. Transfer of antimicrobial resistance from marker genes in transgenic plants to bacteria has not been documented under natural conditions in field-grown plants. However, antimicrobial-resistance genes are being eliminated from use as marker genes because of concerns about possible transfer from plant genomes back to bacteria, with further horizontal transfer to the bacteria in the environment, or from plant genomes to animals by plant consumption. No new antimicrobials are expected to be used in plant agriculture because of high costs of development, regulatory constraints, and environmental and human health concerns. Alternatives to antimicrobials, such as biocontrol agents, transgenic plants, and novel chemicals, are being developed and marketed, although their efficacy remains to be determined.


Improving protein transfer efficiency and selectivity in affinity contact printing by using UV-modified surfaces.
Affinity contact printing (αCP) is a technique that allows the selective capture of a target protein from solutions to a polymeric stamp decorated with an antibody, and then the target protein is printed onto a solid surface. The success of αCP critically relies on the precise control of protein-surface interactions. Here, we report a study on the effect of UV on the protein-surface interactions between protein and polydimethylsiloxane stamps and between protein and glass slides decorated with N,N-dimethyl-n-octadecyl-3-aminopropyltrimethoxysilyl chloride (DMOAP). Our results show that UV-modified surfaces can be used to improve the transfer efficiency and selectivity of proteins during αCP. For example, the protein transfer efficiency of human IgG onto a DMOAP-coated slide increases from 7.2% to 45.1% after the UV treatment. On the basis of these results, UV-modified surfaces were employed to develop a αCP system for protein detection. The detection limit of anti-IgG in this system is around 10 ng/mL, and the dynamic range is 4 orders of magnitude.


Chemotherapy following estrogen-induced expansion of the growth fraction of human breast cancer.
We have evaluated the feasibility of a cytokinetically oriented regimen based on the induction of cell recruitment by diethylstilbestrol (DES) in locally advanced human breast cancer. Tumor proliferative activity was evaluated by the thymidine labeling index and the primer-dependent alpha-DNA polymerase labeling index, which gives an in vitro estimation of the growth fraction. Sixteen previously untreated patients received DES (1 mg daily for 3 days) followed by FAC [5-fluorouracil (600 mg/m2): Adriamycin (50 mg/m2): Cytoxan (600 mg/m2)] i.v. on day 4 every 21 days. Radical surgery was delayed to allow for three DES-FAC regimens in responsive patients. Proliferative activity on tumor biopsies was evaluated immediately before and after treatment with DES, 24 h after chemotherapy and, in nine patients, at the time of radical surgery. DES was able to induce a significant increase in thymidine labeling index in 8 of 16 patients, while the primer-dependent alpha-DNA polymerase labeling index was significantly increased in 13 of 16 tumors, independently of their estrogen receptor content. Subsequently administered chemotherapy induced an early decrease in tumor proliferation. In the nine patients submitted to surgery after three DES plus FAC courses, the average thymidine labeling index and primer-dependent alpha-DNA polymerase labeling index were 27.8 and 73% of the pretreatment values. Our preliminary results provide the rationale for the design of new therapeutic schemes in which antitumor drugs are given at the time of estrogen-induced tumor cell recruitment. Further extended studies are required to establish whether induction of tumor cell recruitment will actually translate into appreciable improvement of the clinical response to chemotherapy.


Tracking chronic disease and risk behavior prevalence as survey participation declines: statistics from the behavioral risk factor surveillance system and other national surveys.
Response rates for the Behavioral Risk Factor Surveillance System (BRFSS) have declined in recent years. The response rate in 1993 was approximately 72%; in 2006, the response rate was approximately 51%. To assess the impact of this decline on the quality of BRFSS estimates, we compared selected health and risk factor estimates from BRFSS with similar estimates from the National Health Interview Survey (NHIS) and the National Health and Nutrition Examination Survey (NHANES). We reviewed questionnaires from the 3 surveys and identified a set of comparable measures related to smoking prevalence, alcohol consumption, medical conditions, vaccination, health status, insurance coverage, cost barriers to medical care, testing for human immunodeficiency virus, and body measurements (height and weight). We compared weighted estimates for up to 15 outcome measures, including overall measures and measures for 12 population subgroups. We produced design-appropriate point estimates and carried out statistical tests of hypotheses on the equality of such estimates. We then calculated P values for comparisons of NHIS and NHANES estimates with their BRFSS counterparts. Although BRFSS and NHIS estimates were statistically similar for 5 of the 15 measures examined, BRFSS and NHANES estimates were statistically similar for only 1 of 6 measures. The observed differences for some of these comparisons were small, however. These surveys produced similar estimates for several outcome measures, although we observed significant differences as well. Many of the observed differences may have limited consequences for implementing related public health programs; other differences may require more detailed examination. In general, the range of BRFSS estimates examined here tends to parallel those from NHIS and NHANES, both of which have higher rates of participation.


Spanish version of the Coping Strategies Inventory.
The aim of the present study was to adapt the Coping Strategies Inventory (CSI) to the Spanish setting. This need is justified on the one hand by the shortage and limitations of the instruments available in our language and, on the other, by the excellent potentialities that the CSI offers. It was translated and applied to a sample of 337 adults, with diverse demographic characteristics, recruited from different teaching activities by the authors in the province of Seville (Spain). The results showed excellent psychometric properties surpassing those of the original study: eight factors accounted for 61 % of variance with only 40 items (as opposed to the 72 that accounted for 47% in the original study) and obtained Alpha coefficients between 0.63 and 0.89. The convergent validity was verified using intercorrelations between scales, correlations with personality dispositions (NEOFFI) and with the coping efficacy. The CSI was a valid and reliable measure of coping strategies used in many stressful situations.


Simultaneous demodulation and slow light of differential phase-shift keying signals using stimulated-Brillouin-scattering-based optical filtering in fiber.
For the first time to our knowledge, we demonstrate simultaneous demodulation and slow-light delay of differential phase-shift keying (DPSK) signals at flexible bit rates using the stimulated-Brillouin-scattering-based optical filtering effect in optical fiber. Both 10 and 2.5 Gbit/s DPSK signals have been demodulated and delayed with excellent performances. In the case of the 10 Gbit/s DPSK signal, after demodulation the tunable delay range with error-free operation is about 50 ps, which we believe is the best result obtained for 10 Gbit/s slow-light demonstrations. For the 2.5 Gbit/s DPSK signal, the optimal sensitivity after demodulation is -36.5 dBm, which is comparable with the back-to-back sensitivity of a 2.5 Gbit/s nonreturn-to-zero signal.


Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?
Current guidelines recommend initiating family screening for hypertrophic cardiomyopathy (HCM) after age 10 or 12 years unless early screening criteria are met. The aim was to evaluate if current screening guidelines miss early onset disease. Children who underwent family screening for HCM before age 18 years were analysed. Major cardiac events (MaCEs) were defined as death, sudden cardiac death (SCD), or need for major cardiac interventions (myectomy, implantable cardioverter-defibrillator insertion, transplantation). Of 524 children screened, 331 were under 10 years of age, 9.9% had echocardiographic evidence of HCM, and 1.1% were symptomatic at first screening. The median (interquartile range) age at HCM onset was 8.9 (4.7-13.4) years, and at MaCE was 10.9 (8.5-14.3) years with a median time to MaCE from HCM onset of 1.5 (0.5-4.1) years. About 52.5% phenotype-positive children and 41% with MaCEs were <10 years old. Only 69% children with early HCM met early screening criteria. Cox regression identified male gender, family history of SCD, and pathogenic variants in MYH7/MYBPC3 as a predictor of early onset HCM and MaCEs. A third of children not eligible for early screening by current guidelines had phenotype-positive HCM. MYH7 and MYBC3 mutation-positive patients were at highest risk for developing early HCM and experiencing an event or requiring a major intervention. Our findings suggest that younger family members should be considered for early clinical and genetic screening to identify the subset in need of closer monitoring and interventions.


Randomized comparison of carbon ion-implanted stent versus bare metal stent in coronary artery disease: the Asian Pacific Multicenter Arthos Stent Study (PASS) trial.
Heavy metal ions can cause allergic and inflammatory reactions that might be associated with in-stent restenosis. This randomized multicenter clinical study was designed to determine if carbon ion-implanted stents reduce luminal late loss by blocking heavy metal ion diffusion into the surrounding tissue. A total of 225 patients with 230 native coronary lesions were randomly assigned to receive either a carbon ion-implanted Arthos Inert stent (group 1, n = 113) or a bare metal Arthos stent (group 2, n = 117). The primary endpoint was in-stent luminal late loss at 6-month angiographic follow-up, and the secondary endpoints were the 6-month angiographic restenosis rate and the occurrence of the major adverse cardiac events (MACE) including death, nonfatal myocardial infarction, and target lesion revascularization at 12 months. The baseline characteristics were similar in the 2 groups. In-hospital events did not occur in any patients. Angiographic follow-up at 6 months was obtained in 184 lesions (80%). At follow-up, the luminal late loss was similar in the 2 groups (0.91 +/- 0.77 mm in group 1 vs 0.88 +/- 0.80 mm in group 2, P = .79), and the angiographic restenosis rates were 11.0% in group 1 and 16.1% in group 2 (P = .31). The occurrence rates of MACE at 12 months were 9.1% in group 1 and 10.4% in group 2 (P = .73). The initial and long-term outcomes of the carbon ion-implanted stent were excellent. However, it did not improve long-term outcomes vs the bare metal stent.


Optimization of a nanomedicine-based silicon phthalocyanine 4 photodynamic therapy (Pc 4-PDT) strategy for targeted treatment of EGFR-overexpressing cancers.
The current clinical mainstays for cancer treatment, namely, surgical resection, chemotherapy, and radiotherapy, can cause significant trauma, systemic toxicity, and functional/cosmetic debilitation of tissue, especially if repetitive treatment becomes necessary due to tumor recurrence. Hence there is significant clinical interest in alternate treatment strategies like photodynamic therapy (PDT) which can effectively and selectively eradicate tumors and can be safely repeated if needed. We have previously demonstrated that the second-generation photosensitizer Pc 4 (silicon phthalocyanine 4) can be formulated within polymeric micelles, and these micelles can be specifically targeted to EGFR-overexpressing cancer cells using GE11 peptide ligands, to enhance cell-specific Pc 4 delivery and internalization. In the current study, we report on the in vitro optimization of the EGFR-targeting, Pc 4 loading of the micellar nanoformulation, along with optimization of the corresponding photoirradiation conditions to maximize Pc 4 delivery, internalization, and subsequent PDT-induced cytotoxicity in EGFR-overexpressing cells in vitro. In our studies, absorption and fluorescence spectroscopy were used to monitor the cell-specific uptake of the GE11-decorated Pc 4-loaded micelles and the cytotoxic singlet oxygen production from the micelle-encapsulated Pc 4, to determine the optimum ligand density and Pc 4 loading. It was found that the micelle formulations bearing 10 mol % of GE11-modified polymer component resulted in the highest cellular uptake in EGFR-overexpressing A431 cells within the shortest incubation periods. Also, the loading of ∼ 50 μg of Pc 4 per mg of polymer in these micellar formulations resulted in the highest levels of singlet oxygen production. When formulations bearing these optimized parameters were tested in vitro on A431 cells for PDT effect, a formulation dose containing 400 nM Pc 4 and photoirradiation duration of 400 s at a fluence of 200 mJ/cm(2) yielded close to 100% cell death.


A randomized, double-blind and placebo-controlled study of a Ganoderma lucidum polysaccharide extract in neurasthenia.
Ganoderma lucidum has been widely used to treat various diseases, including cancer, diabetes, and neurasthenia in many Asian countries. This randomized, double-blind, placebo-controlled parallel study aimed to investigate the efficacy and safety of a polysaccharide extract of G. lucidum (Ganopoly) in Chinese patients with neurasthenia. One hundred thirty-two patients with neurasthenia according to the diagnosis criteria of the 10th International Classification of Diseases were included in this study. Written consents were obtained from the patients, and the study was conducted in accordance with Good Clinical Practice guidelines. Patients were randomized to receive Ganopoly or placebo orally at 1,800 mg three times a day for 8 weeks. Efficacy assessments comprised the Clinical Global Impression (CGI) improvement of severity scale and the Visual Analogues Scales for the sense of fatigue and well-being. In 123 assessable patients in two treatment groups at the end of the study, Ganopoly treatment for 8 weeks resulted in significantly lower scores after 8 weeks in the CGI severity score and sense of fatigue, with a respective reduction of 15.5% and 28.3% from baseline, whereas the reductions in the placebo group were 4.9% and 20.1%, respectively. The score at day 56 in the sense of well-being increased from baseline to 38.7% in the Ganopoly group compared with 29.7% in the placebo group. The distribution of the five possible outcomes from very much improved to minimally worse was significantly different (X (2) = 10.55; df = 4; P = .0322) after treatment with Ganopoly or placebo. There was a percentage of 51.6% (32 of 62) in the Ganopoly group rated as more than minimally improved compared with 24.6% (15 of 61) in the placebo group (X (2) = 9.51; df = 1; P = .002). Ganopoly was well tolerated in the study patients. These findings indicated that Ganopoly was significantly superior to placebo with respect to the clinical improvement of symptoms in neurasthenia.


Layers II/III of Prefrontal Cortex in Df(h22q11)/+ Mouse Model of the 22q11.2 Deletion Display Loss of Parvalbumin Interneurons and Modulation of Neuronal Morphology and Excitability.
The 22q11.2 deletion has been identified as a risk factor for multiple neurodevelopmental disorders. Behavioral and cognitive impairments are common among carriers of the 22q11.2 deletion. Parvalbumin expressing (PV+) interneurons provide perisomatic inhibition of excitatory neuronal circuits through GABAA receptors, and a deficit of PV+ inhibitory circuits may underlie a multitude of the behavioral and functional deficits in the 22q11.2 deletion syndrome. We investigated putative deficits of PV+ inhibitory circuits and the associated molecular, morphological, and functional alterations in the prefrontal cortex (PFC) of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. We detected a significant decrease in the number of PV+ interneurons in layers II/III of PFC in Df(h22q11)/+ mice together with a reduction in the mRNA and protein levels of GABAA (α3), a PV+ putative postsynaptic receptor subunit. Pyramidal neurons from the same layers further experienced morphological reorganizations of spines and dendrites. Accordingly, a decrease in the levels of the postsynaptic density protein 95 (PSD95) and a higher neuronal activity in response to the GABAA antagonist bicuculline were measured in these layers in PFC of Df(h22q11)/+ mice compared with their wild-type littermates. Our study shows that a hemizygotic deletion of the 22q11.2 locus leads to deficit in the GABAergic control of network activity and involves molecular and morphological changes in both the inhibitory and excitatory synapses of parvalbumin interneurons and pyramidal neurons specifically in layers II/III PFC.


A molecule in teleost fish, related with human MHC-encoded G6F, has a cytoplasmic tail with ITAM and marks the surface of thrombocytes and in some fishes also of erythrocytes.
In teleost fish, a novel gene G6F-like was identified, encoding a type I transmembrane molecule with four extracellular Ig-like domains and a cytoplasmic tail with putative tyrosine phosphorylation motifs including YxN and an immunoreceptor tyrosine-based activation motif (ITAM). G6F-like maps to a teleost genomic region where stretches corresponding to human chromosomes 6p (with the MHC), 12p (with CD4 and LAG-3), and 19q are tightly linked. This genomic organization resembles the ancestral "Ur-MHC" proposed for the jawed vertebrate ancestor. The deduced G6F-like molecule shows sequence similarity with members of the CD4/LAG-3 family and with the human major histocompatibility complex-encoded thrombocyte marker G6F. Despite some differences in molecular organization, teleost G6F-like and tetrapod G6F seem orthologous as they map to similar genomic location, share typical motifs in transmembrane and cytoplasmic regions, and are both expressed by thrombocytes/platelets. In the crucian carps goldfish (Carassius auratus auratus) and ginbuna (Carassius auratus langsdorfii), G6F-like was found expressed not only by thrombocytes but also by erythrocytes, supporting that erythroid and thromboid cells in teleost fish form a hematopoietic lineage like they do in mammals. The ITAM-bearing of G6F-like suggests that the molecule plays an important role in cell activation, and G6F-like expression by erythrocytes suggests that these cells have functional overlap potential with thrombocytes.


Incidence and characteristics of severe exercise-associated collapse at the world's largest half-marathon.
Whilst many health benefits are associated with regular exercise, medical complications may occur during higher-intensity activities, such as long distance running contests. The most common complication is collapse. However, the incidence and characteristics of these collapses are not very well studied. This is a retrospective study of severe collapse, defined as a patient in need of advanced medical care after a collapse, during the large Gothenburg's half marathon, Göteborgsvarvet. The study included 230,501 competitors during the study-period of 5 years (2013-2017) with data being collected from medical race tents and using ambulance data. Vital signs, treatment and blood gas samples were noted and analyzed. The incidence of severe collapse was 1.53 per 1000 starting runners. The average age for patients was 34 years old and no difference in incidence were seen between male and female runners. The typical collapsed runner presented with tachycardia, normal systolic blood pressure, elevated body temperature and metabolic acidosis. The most common medical encounter was exercise-associated collapse. The incidence of severe collapse was similar to findings in other studies, even though this study was set in different part of the world. Typical characteristics of a collapsed runner were identified providing new information which could be beneficial in the medical planning of larger running competitions and future preventative interventions. Importantly, life threatening conditions seem uncommon; no case of hyponatremia and only two cases of hypoglycemia were seen.


A strategy to reduce red marrow dose for intraperitoneal radioimmunotherapy.
The aim of this study was to determine whether shorter-lived radionuclides can reduce red marrow (RM) toxicity for i.p. radioimmunotherapy (RIT). The potential radionuclides, which included Lu-177, I-131, Y-90, Re-186, Re-188, and Ho-166, were attached to antibody CC49. Each radiopharmaceutical was assumed to have identical in vivo pharmacokinetics. Blood and whole body retention data acquired from 26 patients who received i.p. RIT with Lu-177 CC49 were used as input. The average biological half-time of Lu-177 CC49 in the whole body was 280 h, and the average Lu-177 concentration in plasma increased to a maximum at 2 days postinfusion, followed by steady clearance. The residence time and RM doses were calculated for each radionuclide. In the current model, Re-188 was found to deliver the lowest RM dose, primarily because it had the shortest half-life, whereas Y-90 delivers the highest dose. Re-188 delivers 60% of the RM dose as compared with Lu-177 and can increase the dose to metastatic sites in the i.p. space by a similar factor. Based on limiting the RM dose to 200 cGy, the maximum administered activity of each radionuclide is as follows: (a) 106 mCi, Lu-177; (b) 58 mCi, I-131; (c) 34 mCi, Y-90; (d) 70 mCi, Re-186; (e) 169 mCi, Re-188; and (f) 110 mCi, Ho-166. Because of the delayed steady leakage of radiopharmaceuticals from the i.p. cavity to the plasma, short-lived radionuclides may offer special advantages for i.p. RIT.


Chronic lung injury by constitutive expression of activation-induced cytidine deaminase leads to focal mucous cell metaplasia and cancer.
Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.


Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity.
Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase and observed their rapid extension in number and length upon genotoxic treatments, frequently taking contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork remodeling is linked to deregulated chromatin loading of PrimPol, which promotes unrestrained and discontinuous DNA synthesis and limits the recruitment of RAD51 and SMARCAL1 to nascent DNA. Moreover, defective nuclear actin polymerization upon mild replication interference induces chromosomal instability in a PRIMPOL-dependent manner. Hence, by limiting PrimPol activity, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.


An independent indicator of erectile dysfunction is C-reactive protein/albumin ratio.
Research has found that, instead of passive lipid-accumulated vascular damage, atherosclerosis which is the primary cause of erectile dysfunction (ED) can be seen as an active inflammatory cycle and that inflammation has a central role in the entire atherosclerotic process. As an inflammatory marker, serum C-reactive protein (CRP)/albumin ratio (CAR) may link to ED and ED severity. The CAR, demographic features and other criteria of 198 patients with ED who visited our outpatient clinic during March 2019-April 2020 were prospectively evaluated. The research also included healthy control subjects without systemic or infectious diseases. The mean difference of CAR between ED and no ED was statistically significant (0.55 ± 0.27 and 0.79 ± 0.49, p = .002 respectively). On the basis of the ROC analysis, CAR has a good ED diagnostic value with an area under the curve (AUC) of 0.63 (95% CI:0.541-0.714) and better diagnostic performance to distinguish ED severity (AUC:0.73, 95% CI:0.620-0.842). Additionally, mean CAR gradually increased with increasing severity of ED (for all p < .001). The CAR has been described as an independent ED indicator in the multivariate analysis (p = .001OR = 8.934; 95% CI:2.449-32.583). Increased CAR is associated with ED severity and increased ED risk. For CAR predicting ED and ED severity, a considerable cut-off point was identified.


Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect.
Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial. We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search. Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia. With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.


Unexpected organellar locations of ESCRT machinery in Giardia intestinalis and complex evolutionary dynamics spanning the transition to parasitism in the lineage Fornicata.
Comparing a parasitic lineage to its free-living relatives is a powerful way to understand how that evolutionary transition to parasitism occurred. Giardia intestinalis (Fornicata) is a leading cause of gastrointestinal disease world-wide and is famous for its unusual complement of cellular compartments, such as having peripheral vacuoles instead of typical endosomal compartments. Endocytosis plays an important role in Giardia's pathogenesis. Endosomal sorting complexes required for transport (ESCRT) are membrane-deforming proteins associated with the late endosome/multivesicular body (MVB). MVBs are ill-defined in G. intestinalis, and roles for identified ESCRT-related proteins are not fully understood in the context of its unique endocytic system. Furthermore, components thought to be required for full ESCRT functionality have not yet been documented in this species. We used genomic and transcriptomic data from several Fornicata species to clarify the evolutionary genome streamlining observed in Giardia, as well as to detect any divergent orthologs of the Fornicata ESCRT subunits. We observed differences in the ESCRT machinery complement between Giardia strains. Microscopy-based investigations of key components of ESCRT machinery such as GiVPS36 and GiVPS25 link them to peripheral vacuoles, highlighting these organelles as simplified MVB equivalents. Unexpectedly, we show ESCRT components associated with the endoplasmic reticulum and, for the first time, mitosomes. Finally, we identified the rare ESCRT component CHMP7 in several fornicate representatives, including Giardia and show that contrary to current understanding, CHMP7 evolved from a gene fusion of VPS25 and SNF7 domains, prior to the last eukaryotic common ancestor, over 1.5 billion years ago. Our findings show that ESCRT machinery in G. intestinalis is far more varied and complete than previously thought, associates to multiple cellular locations, and presents changes in ESCRT complement which pre-date adoption of a parasitic lifestyle.


Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.
Impaired mitochondrial dynamics causes aging-related or metabolic diseases. Yet, the molecular mechanism responsible for the impairment of mitochondrial dynamics is still not well understood. Here, we report that elevated blood insulin and/or glucagon levels downregulate mitochondrial fission through directly phosphorylating AMPKα at S496 by AKT or PKA, resulting in the impairment of AMPK-MFF-DRP1 signaling and mitochondrial dynamics and activity. Since there are significantly increased AMPKα1 phosphorylation at S496 in the liver of elderly mice, obese mice, and obese patients, we, therefore, designed AMPK-specific targeting peptides (Pa496m and Pa496h) to block AMPKα1S496 phosphorylation and found that these targeting peptides can increase AMPK kinase activity, augment mitochondrial fission and oxidation, and reduce ROS, leading to the rejuvenation of mitochondria. Furthermore, these AMPK targeting peptides robustly suppress liver glucose production in obese mice. Our data suggest these targeting peptides are promising therapeutic agents for improving mitochondrial dynamics and activity and alleviating hyperglycemia in elderly and obese patients.


Sources and Variations in Social Support and Risk for Elder Mistreatment in a US Chinese Population.
Research has examined the relationships between positive social support (PSS) and elder mistreatment (EM) but less is known regarding the negative aspect of social support (NSS), especially among minority groups in the United States. This study aimed to investigate the relationships between PSS/NSS from different sources and EM among US Chinese older adults. Population-based cross-sectional study. Greater Chicago, IL, area. A representative sample of Chinese older adults aged 60 years or older (N = 3157) from the Population Study of ChINese Elderly in Chicago in 2011 to 2013. We applied a 10-item widely used instrument to assess EM. PSS and NSS from spouse/family members/friends were measured by a 12-item scale. Multivariate logistic regression analyses were conducted to examine the relationships. After adjusting for confounders, higher levels of overall PSS from all three sources, including spouse, family members, and friends (odds ratio [OR] = 0.88 [95% confidence interval {CI} = 0.85-0.91]), were associated with lower risk of EM. But participants with a higher level of overall NSS from all three sources (OR = 1.51 [95% CI = 1.41-1.61]) were more likely to experience EM. The results on the relationships between PSS from spouse (OR = 0.70 [95% CI = 0.64-0.76]), PSS from family members (OR = 0.73 [95% CI = 0.68-0.79]), and EM were similar to overall PSS. But PSS from friends had a nonsignificant association with EM. Greater levels of NSS from spouse (OR = 1.84 [95% CI = 1.64-2.07]), family members (OR = 2.36 [95% CI = 2.03-2.75]), and friends (OR = 1.69 [95% CI = 1.32-2.17]) were associated with increased risks of EM. Higher levels of SS were not always associated with lower risks of EM among US Chinese older adults. NSS might have counter effects. Future qualitative or longitudinal research needs to explore detailed cultural explanations and casual relationships between SS and EM. J Am Geriatr Soc 67:S499-S505, 2019.


High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2.
Severe acute respiratory syndrome coronavirus 2 is the causative agent of the ongoing coronavirus disease pandemic. Initial estimates of the early dynamics of the outbreak in Wuhan, China, suggested a doubling time of the number of infected persons of 6-7 days and a basic reproductive number (R0) of 2.2-2.7. We collected extensive individual case reports across China and estimated key epidemiologic parameters, including the incubation period (4.2 days). We then designed 2 mathematical modeling approaches to infer the outbreak dynamics in Wuhan by using high-resolution domestic travel and infection data. Results show that the doubling time early in the epidemic in Wuhan was 2.3-3.3 days. Assuming a serial interval of 6-9 days, we calculated a median R0 value of 5.7 (95% CI 3.8-8.9). We further show that active surveillance, contact tracing, quarantine, and early strong social distancing efforts are needed to stop transmission of the virus.


Nerve stretching: a history of tension.
Stretch injuries are among the most devastating forms of peripheral nerve injury; unfortunately, the scientific understanding of nerve biomechanics is widely and impressively conflicting. Experimental models are unique and disparate, victim to different testing conditions, and thus yield gulfs between conclusions. The details of the divergent reports on nerve biomechanics are essential for critical appraisal as we try to understand clinical stretch injuries in light of research evidence. These conflicts preclude broad conclusion, but they highlight a duality in thought on nerve stretch and, within the details, some agreement exists. To synthesize trends in nerve stretch understanding, the author describes the literature since its introduction in the 19th century. Research has paralleled clinical inquiry, so nerve research can be divided into epochs based largely on clinical or scientific technique. The first epoch revolves around therapeutic nerve stretching-a procedure known as neurectasy-in the late 19th century. The second epoch involves studies of nerves repaired under tension in the early 20th century, often the result of war. The third epoch occurs later in the 20th century and is notable for increasing scientific refinement and disagreement. A fourth epoch of research from the 21st century is just dawning. More than 150 years of research has demonstrated a stable and inherent duality: the terribly destructive impact of stretch injuries, as well as the therapeutic benefits from nerve stretching. Yet, despite significant study, the precise border between safe and damaging stretch remains an enigma.


Beta 3-adrenergic receptors regulate retinal endothelial cell migration and proliferation.
Sympathetic nerves may play a role in vascular disorders of the eye. In the present study, we hypothesized that activation of beta3-adrenergic receptors on retinal endothelial cells would promote migration and proliferation of these cells, two markers of an angiogenic phenotype. We show, for the first time, expression of beta3-adrenergic receptors on cultured retinal endothelial cells. Activation of these receptors with BRL37344, a specific beta3-adrenergic receptor agonist, promoted migration that was blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K), the mitogen activated protein kinase component MEK, and matrix metalloproteinases (MMPs) 2 and 9. BRL37344 stimulated proliferation, which could be blocked by inhibitors of Src, PI3K, and MEK. These cells also express the beta1-adrenergic receptor with no beta2-adrenergic receptor expression observed. Stimulation of the beta1-adrenergic receptor with xamoterol, a specific partial agonist, did not promote proliferation or migration. These results support the hypothesis that beta3-adrenergic receptors play a role in proliferation and migration of cultured human retinal endothelial cells.


Insulin Dependence Increases the Risk of 30-Day Postoperative Complications Following Ankle Fracture Surgery in Patients With Diabetes Mellitus.
Patients with diabetes mellitus that undergo ankle fracture surgery have higher rates of postoperative complications compared to patients without diabetes mellitus. We evaluated the rate of complications in insulin-dependent diabetes mellitus patients, non-insulin-dependent diabetes mellitus patients, and patients without diabetes in the 30-day postoperative period following ankle fracture surgery. We also analyzed hospital length of stay, unplanned readmission, unplanned reoperation, and death. Patients who underwent operative management for ankle fractures between 2012 and 2016 were identified in the American College of Surgeons National Surgical Quality Improvement Program® database using Current Procedural Terminology codes. Multiple logistic regression was implemented. Adjusted odds ratios were calculated along with the 95% confidence interval. A total of 19,547 patients undergoing ankle surgery were identified from 2012 to 2016. Of these patients, 989 (5.06%) had insulin-dependent diabetes mellitus, 1256 (6.43%) had noninsulin-dependent diabetes mellitus, and 17,302 (88.51%) did not have diabetes mellitus. Compared to patients without diabetes, patients with insulin-dependent diabetes mellitus had significantly greater adjusted odds of superficial surgical site infections, deep surgical site infections, osteomyelitis, wound dehiscence, pneumonia, unplanned intubation, mechanical ventilation, urinary tract infection, cardiac arrest, bleeding requiring transfusion, sepsis, hospital length of stay, unplanned readmission, unplanned reoperation, and death following ankle fracture surgery. We demonstrate that insulin-dependent diabetes mellitus is a strong predictor of 30-day postoperative complications, unplanned readmission, unplanned reoperation, and death following ankle fracture surgery.


Bayesian Peptide Peak Detection for High Resolution TOF Mass Spectrometry.
In this paper, we address the issue of peptide ion peak detection for high resolution time-of-flight (TOF) mass spectrometry (MS) data. A novel Bayesian peptide ion peak detection method is proposed for TOF data with resolution of 10 000-15 000 full width at half-maximum (FWHW). MS spectra exhibit distinct characteristics at this resolution, which are captured in a novel parametric model. Based on the proposed parametric model, a Bayesian peak detection algorithm based on Markov chain Monte Carlo (MCMC) sampling is developed. The proposed algorithm is tested on both simulated and real datasets. The results show a significant improvement in detection performance over a commonly employed method. The results also agree with expert's visual inspection. Moreover, better detection consistency is achieved across MS datasets from patients with identical pathological condition.


Influence of early-life risk factors on socioeconomic inequalities in weight gain.
Previous research has examined the role of early-life risk factors on childhood weight gain.The extent to which these factors drive socioeconomic differences in weight is unclear. We aimed to quantify the influence of early-life risk factors on the development of socioeconomic inequalities in children's body mass index (BMI) z-score at 10-11 years. Overall, 2186 children from the Longitudinal Study of Australian Children were examined. Socioeconomic position (SEP) was measured as a continuous composite of parent's education, occupation and income. The Product of Coefficients mediation method was used to quantify the contribution of maternal smoking during pregnancy, gestational diabetes, prematurity, caesarean section, birthweight, not being breastfed, early introduction of solid food, maternal BMI and paternal BMI to the relationship between SEP and BMI z-score. Each increasing decile of SEP (higher SEP) was associated with a 0.05 unit lower (95% CI: -0.06, -0.03) BMI z-score at 10-11 years. In total, 83.5% of these differences in BMI z-score could be explained by socioeconomic differences in maternal smoking during pregnancy (26.9%), maternal BMI (39.6%) and paternal BMI (17.0%). Interventions to reduce socioeconomic inequalities in excess weight gain during childhood should support the attainment of a healthy parental weight and prevent smoking during pregnancy.


Does Campylobacter jejuni form biofilms in food-related environments?
Campylobacter jejuni is one of the most frequent causes of bacterial gastrointestinal food-borne infection worldwide. This species is part of the normal flora of the gastrointestinal tracts of animals used for food production, including poultry, which is regarded as the primary source of human Campylobacter infections. The survival and persistence of C. jejuni in food processing environments, especially in poultry processing plants, represent significant risk factors that contribute to the spread of this pathogen through the food chain. Compared to other food-borne pathogens, C. jejuni is more fastidious in its growth requirements and is very susceptible to various environmental stressors. Biofilm formation is suggested to play a significant role in the survival of C. jejuni in the food production and processing environment. The aims of this minireview were (i) to examine the evidence that C. jejuni forms biofilms and (ii) to establish the extent to which reported and largely laboratory-based studies of C. jejuni biofilms provide evidence for biofilm formation by this pathogen in food processing environments. Overall existing studies do not provide strong evidence for biofilm formation (as usually defined) by most C. jejuni strains in food-related environments under the combined conditions of atmosphere, temperature, and shear that they are likely to encounter. Simple attachment to and survival on surfaces and in existing biofilms of other species are far more likely to contribute to C. jejuni survival in food-related environments based on our current understanding of this species.


[Testing the usefulness of relaxation techniques in drug addicts. Proving its usefulness].
Experience in a hospital detoxification unit teaches that one of withdrawal symptoms which produces the greatest anxiety for a patient is sleeping disorders, whether insomnia or difficulty starting sleep. Both cause anxiety as bedtime approaches. This article stresses the importance of relaxation techniques for this type of patient when they are admitted in our detoxification unit. These techniques form part of accepted methods which our unit employs.


Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro.
Although the metabolism and disposition of diclofenac (DF) has been studied extensively, information regarding the plasma levels of its acyl-β-d-glucuronide (DF-AG), a major metabolite, in human subjects is limited. Therefore, DF-AG concentrations were determined in plasma (acidified blood derived) of six healthy volunteers following a single oral DF dose (50 mg). Levels of DF-AG in plasma were high, as reflected by a DF-AG/DF ratio of 0.62 ± 0.21 (Cmax mean ± S.D.) and 0.84 ± 0.21 (area under the concentration-time curve mean ± S.D.). Both DF and DF-AG were also studied as substrates of different human drug transporters in vitro. DF was identified as a substrate of organic anion transporter (OAT) 2 only (Km = 46.8 µM). In contrast, DF-AG was identified as a substrate of numerous OATs (Km = 8.6, 60.2, 103.9, and 112 µM for OAT2, OAT1, OAT4, and OAT3, respectively), two organic anion-transporting polypeptides (OATP1B1, Km = 34 µM; OATP2B1, Km = 105 µM), breast cancer resistance protein (Km = 152 µM), and two multidrug resistance proteins (MRP2, Km = 145 µM; MRP3, Km = 196 µM). It is concluded that the disposition of DF-AG, once formed, can be mediated by various candidate transporters known to be expressed in the kidney (basolateral, OAT1, OAT2, and OAT3; apical, MRP2, BCRP, and OAT4) and liver (canalicular, MRP2 and BCRP; basolateral, OATP1B1, OATP2B1, OAT2, and MRP3). DF-AG is unstable in plasma and undergoes conversion to parent DF. Therefore, caution is warranted when assessing renal and hepatic transporter-mediated drug-drug interactions with DF and DF-AG.