SCD1 is required for cytokinesis and polarized cell expansion in Arabidopsis thaliana [corrected].
In the leaf epidermis, guard mother cells undergo a stereotyped symmetric division to form the guard cells of stomata. We have identified a temperature-sensitive Arabidopsis mutant, stomatal cytokinesis-defective 1-1 (scd1-1), which affects this specialized division. At the non-permissive temperature, 22 degrees C, defective scd1-1 guard cells are binucleate, and the formation of their ventral cell walls is incomplete. Cytokinesis was also disrupted in other types of epidermal cells such as pavement cells. Further phenotypic analysis of scd1-1 indicated a role for SCD1 in seedling growth, root elongation and flower morphogenesis. More severe scd1 T-DNA insertion alleles (scd1-2 and scd1-3) markedly affect polar cell expansion, most notably in trichomes and root hairs. SCD1 is a unique gene in Arabidopsis that encodes a protein related to animal proteins that regulate intracellular protein transport and/or mitogen-activated protein kinase signaling pathways. Consistent with a role for SCD1 in membrane trafficking, secretory vesicles were found to accumulate in cytokinesis-defective scd1 cells. In addition the scd1 mutant phenotype was enhanced by low doses of inhibitors of cell plate consolidation and vesicle secretion. We propose that SCD1 functions in polarized vesicle trafficking during plant cytokinesis and cell expansion.


The medaka novel immune-type receptor (NITR) gene clusters reveal an extraordinary degree of divergence in variable domains.
Novel immune-type receptor (NITR) genes are members of diversified multigene families that are found in bony fish and encode type I transmembrane proteins containing one or two extracellular immunoglobulin (Ig) domains. The majority of NITRs can be classified as inhibitory receptors that possess cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). A much smaller number of NITRs can be classified as activating receptors by the lack of cytoplasmic ITIMs and presence of a positively charged residue within their transmembrane domain, which permits partnering with an activating adaptor protein. Forty-four NITR genes in medaka (Oryzias latipes) are located in three gene clusters on chromosomes 10, 18 and 21 and can be organized into 24 families including inhibitory and activating forms. The particularly large dataset acquired in medaka makes direct comparison possible to another complete dataset acquired in zebrafish in which NITRs are localized in two clusters on different chromosomes. The two largest medaka NITR gene clusters share conserved synteny with the two zebrafish NITR gene clusters. Shared synteny between NITRs and CD8A/CD8B is limited but consistent with a potential common ancestry. Comprehensive phylogenetic analyses between the complete datasets of NITRs from medaka and zebrafish indicate multiple species-specific expansions of different families of NITRs. The patterns of sequence variation among gene family members are consistent with recent birth-and-death events. Similar effects have been observed with mammalian immunoglobulin (Ig), T cell antigen receptor (TCR) and killer cell immunoglobulin-like receptor (KIR) genes. NITRs likely diverged along an independent pathway from that of the somatically rearranging antigen binding receptors but have undergone parallel evolution of V family diversity.


Early Numeracy and Literacy Skills Among Monolingual and Bilingual Kindergarten Children.
Early numeracy and literacy skills are all the knowledge that children acquire spontaneously and independently before entering school and beginning formal learning. This knowledge is essential and forms the basis for the acquisition of reading and arithmetic in school. A bilingual child is a child who is fluent in two languages, as opposed to a monolingual child who is exposed to only one language. Bilingualism has been found to affect verbal and mathematical abilities in children, but only a few studies have focused on the early numeracy and literacy skills of preschoolers. This study examined the connection between early numeracy and literacy skills and among monolingual children as compared to bilingual children in preschool. Three hundred and two children aged 5-6years old were recruited from 74 kindergartens. Participants were divided into two groups: 151 monolingual children who spoke and were exposed to only one language (Hebrew) and 151 bilingual children who spoke and were exposed to two languages (the bilingual children spoke different languages). Monolingual children performed better than the bilingual children in most of the literacy tasks, except for phonological awareness, in which no differences were found between the groups. In addition, in the early numeracy tasks, a difference was found only in the task, which included linguistic knowledge, number knowledge, and counting tasks, in which the monolingual children performed better. Furthermore, stronger correlations were found between the early numeracy and literacy skills among the monolingual group compared to the bilingual group. The study findings stress the importance of strengthening linguistic abilities, such as vocabulary expansion in kindergarten among populations in which more than one language is spoken. Supporting these abilities can reduce the gap between bilingual children and their monolingual classmates before entering school.


IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2.
Destruction of the transcriptional inhibitor IkappaB by the ubiquitin (Ub) system is required for signal-dependent activation of the multifunctional transcriptional factor NF-kappaB, but details of this ubiquitination are largely unknown. We report here that the IkappaBalpha-ubiquitin ligase (IkappaBalpha-E3) is an SCF-like complex containing Skp1, cullin-1, and two homologous F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2. Intriguingly, all these components are cooperatively recruited to bind to a phosphorylated IkappaBalpha (pIkappaBalpha) produced by tumor necrosis factor-alpha (TNF-alpha) stimulation. IkappaBalpha-E3 bound to pIkappaBalpha catalyzed in vitro ubiquitination of pIkappaBalpha in the presence of ATP, Ub, and E1-activating and E2-conjugating enzymes. Forced expression of betaTrCP1 and betaTrCP2 resulted in dramatic augmentation of the in vitro polyubiquitination activity of IkappaBalpha-E3. These results indicate that the long-sought IkappaBalpha-E3 is an SCF-like complex consisting of multiple proteins which are coordinately assembled during phosphorylation of IkappaBalpha in response to external signals.


[Dental ethics, esthetics and cosmetics].
By means of adhesive dentistry sound teeth can be made more beautiful without damaging tooth structure. This is called cosmetic dentistry. Within the dental profession there is a discussion about the following questions: is cosmetic dentistry real dentistry? Is it ethical to render cosmetic services to patients? In this article arguments are displayed to answer this question in a positive manner.


The relief of mitral stenosis. An historic step in cardiac surgery.
Significant progress has been achieved in cardiac surgery in the last 50 years. Mitral valve surgery (especially for the relief of mitral stenosis) has paralleled the innovations and trends of cardiac surgery and often has served as the benchmark of the latest procedures and techniques. A chronological survey of mitral valve surgery is presented, with emphasis on parallels to cardiac surgery in general and with highlights of key figures and events that have conclusively altered the surgeon's approach to and success with cardiac dysfunction. A few surgeons promulgated the idea of cardiac surgery in the late 19th century, but mitral valve surgeries were not performed in earnest until Souttar's and Cutler's initial attempts in the 1920s and were not successful on large groups of patients until Bailey and Harken made independent breakthroughs in the 1940s, finally laying to rest the idea of the "inviolable heart." Cardiopulmonary bypass provided cardiac surgeons with the time to implant mechanical and bioprosthetic valves for palliative benefit to patients. The "perfect" valve has yet to be found, but the Starr-Edwards mechanical valve since its inception in 1961 has been one of the most successful and widely used prosthetic valves. Gradual improvement in surgical technique and growing knowledge of valve function enabled the re-emergence of mitral valve repair in the 1980s as the preferred surgical method of treating mitral stenosis. In the last 10 years, mitral valve balloon dilation has provided a nonsurgical technique for relief of stenosis and represents the broader trend towards interventional techniques.


Stress hormones predict a host superspreader phenotype in the West Nile virus system.
Glucocorticoid stress hormones, such as corticosterone (CORT), have profound effects on the behaviour and physiology of organisms, and thus have the potential to alter host competence and the contributions of individuals to population- and community-level pathogen dynamics. For example, CORT could alter the rate of contacts among hosts, pathogens and vectors through its widespread effects on host metabolism and activity levels. CORT could also affect the intensity and duration of pathogen shedding and risk of host mortality during infection. We experimentally manipulated songbird CORT, asking how CORT affected behavioural and physiological responses to a standardized West Nile virus (WNV) challenge. Although all birds became infected after exposure to the virus, only birds with elevated CORT had viral loads at or above the infectious threshold. Moreover, though the rate of mortality was faster in birds with elevated CORT compared with controls, most hosts with elevated CORT survived past the day of peak infectiousness. CORT concentrations just prior to inoculation with WNV and anti-inflammatory cytokine concentrations following viral exposure were predictive of individual duration of infectiousness and the ability to maintain physical performance during infection (i.e. tolerance), revealing putative biomarkers of competence. Collectively, our results suggest that glucocorticoid stress hormones could directly and indirectly mediate the spread of pathogens.


Mechanism of in vitro percutaneous absorption enhancement of carvedilol by penetration enhancers.
The effect of penetration enhancers like tulsi (basil) oil, eucalyptus oil, clove oil, black cumin oil, oleic acid and Tween 80 on the percutaneous absorption of model lipophilic drug-carvedilol was investigated using excised rat abdominal skin. Transdermal flux, permeability coefficient and enhancement factor were calculated for each penetration enhancer. Black cumin oil (5% v/v) was selected on the basis of its highest enhancement in permeation and was evaluated further for its mode of action using DSC, FTIR and histological studies. The results indicated that the oil shows its action by extraction of lipids from stratum corneum as well as by loosening the hydrogen bonds between ceramides subsequently leading to fluidization of the lipid bilayer.


Clinical Characteristics of Necrotizing Enterocolitis in Preterm Patients With and Without Persistent Ductus Arteriosus and in Patients With Congenital Heart Disease.
Background: Diagnosis and management of NEC is based on clinical, radiological, and laboratory findings. Discrimination of pathogens for an improved understanding of NEC in preterm infants and NEC in infants with congenital heart disease has been previously discussed and enables evaluation of further NEC biomarkers. Patients and Methods: Within a study period of 11 years (2008-2019), we identified 107 patients with a diagnosis of NEC at our primary care center. Thirty-six out of 54 patients suffering from NEC in high Bell stages who underwent surgery met inclusion criteria. These patients were classified according to their cardiac status, and analyses of clinical factors influencing NEC were conducted. Additionally, clinical factors associated with a fulminant course of NEC were examined. Univariable and multivariable analyses were performed. Results: The study populations consisted of 12 preterm infants with NEC but without patent ductus arteriosus (PT-NEC), seven preterm infants with NEC and patent ductus arteriosus (PDA-NEC), and 17 infants with NEC and congenital heart disease (CHD-NEC). Blood flow in intestinal vessels was impaired in infants with PDA-NEC and CDH-NEC. Therefore, we used logistic regression to compare PDA-NEC and CDH-NEC infants with PT-NEC infants: positive bacterial culture of intraoperative swabs (p = 0.0199; odds ratio: 21.9) and macroscopic intestinal necrosis (p = 0.0033; odds ratio: 43.5) were observed more frequently in the first group. Furthermore, multiple regression analysis determined the NEC localization (p = 0.0243) as a significant factor correlated with a fulminant course. Compared to a NEC exclusively localized in the colon, there is a 5.8-fold increased risk of a fulminant course when the small intestine is affected and a 42-fold increase of risk when both small intestine and colon were affected. Conclusion: An early diagnosis and timely surgical intervention of NEC, especially in infants with PDA and CDH may be considered to avoid major bowel necrosis (resulting in loss of intestinal tissue) and multiple operations.


Methods for providing probe position and temperature information on MR images during interventional procedures.
Interventional magnetic resonance imaging (MRI) can be defined as the use of MR images for guiding and monitoring interventional procedures (e.g., biopsy, drainage) or minimally invasive therapy (e.g., thermal ablation). This work describes the development of a prototype graphical user interface and the appropriate software methods to accurately overlay a representation of a rigid interventional device [e.g., biopsy needle, radio-frequency (RF) probe] onto an MR image given only the probe's spatial position and orientation as determined from a three-dimensional (3-D) localizer used for interactive scan plane definition. This permits 1) "virtual tip tracking," where the probe tip location is displayed on the image without the use of separate receiver coils or a "road map" image data set, and, 2) "extending" the probe to predict its path if it were directly moved forward toward the target tissue. Further, this paper describes the design and implementation of a method to facilitate the monitoring of thermal ablation procedures by displaying and overlaying temperature maps from temperature sensitive MR acquisitions. These methods provide rapid graphical updates of probe position and temperature changes to aid the physician during the actual interventional MRI procedures without altering the usual operation of the MR imager.


[Abnormal calcium metabolism in the remote period after bariatric surgery].
Calcium metabolism in the long-term period after bariatric surgery is reviewed in the present article. The study of calcium metabolism parameters and vitamin D status was performed in The Endocrinology Research Center. Morbidly obese patients (BMI > 40) were included in the 1st group (n = 22), patients who underwent biliopancreatic diversion for morbid obesity (n = 23) were included in the 2nd group, healthy normal weight controls (n = 22) were included in the 3rd group. 25 (OH) D level was different in the 3 groups (p < 0.001). Vitamin D deficiency prevailed in morbidly obese patients compared to healthy controls (p = 0.007). Elevated parathyroid hormone (PTH) level was found in 4 (18%) morbidly obese patients, in 12 (52%) operated patients. Not a single case of PTH over reference interval was found in the controls. The frequency of secondary hyperparathyroidism was significantly higher in the operated patients.


Terminally ill African American elders' access to and use of hospice care.
The underuse of hospice care by terminally ill African American elders suggests they are suffering when hospice care could offer quality end of life care. Guided by the Behavioral Model for Vulnerable Populations, this study sought understanding of structural barriers faced when seeking access to hospice care and reasons for using it when access is possible. Data was collected through interviews with 28 African American hospice patients. Themes from directed content analysis provide insights into strategies used to overcome access barriers posed by income, health insurance and administrative procedure, as well as the role religion, family, information and health beliefs played in using it. Distributing educational materials and addressing spiritual/religious concerns in choosing hospice care are key in promoting African Americans' use of hospice care.


Mental- and physical-health effects of acute exposure to media images of the September 11, 2001, attacks and the Iraq War.
Millions of people witnessed early, repeated television coverage of the September 11 (9/11), 2001, terrorist attacks and were subsequently exposed to graphic media images of the Iraq War. In the present study, we examined psychological- and physical-health impacts of exposure to these collective traumas. A U.S. national sample (N = 2,189) completed Web-based surveys 1 to 3 weeks after 9/11; a subsample (n = 1,322) also completed surveys at the initiation of the Iraq War. These surveys measured media exposure and acute stress responses. Posttraumatic stress symptoms related to 9/11 and physician-diagnosed health ailments were assessed annually for 3 years. Early 9/11- and Iraq War-related television exposure and frequency of exposure to war images predicted increased posttraumatic stress symptoms 2 to 3 years after 9/11. Exposure to 4 or more hr daily of early 9/11-related television and cumulative acute stress predicted increased incidence of health ailments 2 to 3 years later. These findings suggest that exposure to graphic media images may result in physical and psychological effects previously assumed to require direct trauma exposure.


Geometry, charge distribution, and surface speciation of phosphate on goethite.
The surface speciation of phosphate has been evaluated with surface complexation modeling using an interfacial charge distribution (CD) approach based on ion adsorption and ordering of interfacial water. In the CD model, the charge of adsorbed ions is distributed over two electrostatic potentials in the double-layer profile. The CD is related to the structure of the surface complex. A new approach is followed in which the CD values of the various surface complexes have been calculated theoretically from the geometries of the surface complexes. Molecular orbital calculations based on density functional theory (MO/DFT) have been used to optimize the structure of a series of hydrated surface complexes of phosphate. These theoretical CD values are corrected for dipole orientation effects. Data analysis of the PO4 adsorption, applying the independently derived CD coefficients, resolves the presence of two dominant surface species. A nonprotonated bidentate (B) complex is dominant over a broad range of pH values at low loading (< or =1.5 micromol/m(2)). For low pH and high loading, a strong contribution of a singly protonated monodentate (MH or MH-Na) complex is found, which differs from earlier interpretations. For the conditions studied, the doubly protonated bidentate (BH2) and monodentate (MH2) surface complexes and the nonprotonated monodentate (M) complex are not significant contributors. These findings are discussed qualitatively and quantitatively in relation to published experimental in-situ CIR-FTIR data and theoretical MO/DFT-IR information. The relative variation in the peak intensities as a function of pH and loading approximately agrees with the surface speciation calculated with the CD model. The model correctly predicts the proton co-adsorption of phosphate binding on goethite and the shift of the IEP at low phosphate loading (< or =1.5 micromol/m(2)). At higher loading, it deviates.


Soluble, high-affinity dimers of T-cell receptors and class II major histocompatibility complexes: biochemical probes for analysis and modulation of immune responses.
T cell receptors (TCR) and major histocompatibility complex (MHC) molecules are integral membrane proteins that have central roles in cell-mediated immune recognition. Therefore, soluble analogs of these molecules would be useful for analyzing and possibly modulating antigen-specific immune responses. However, due to the intrinsic low-affinity and inherent solubility problems, it has been difficult to produce soluble high-affinity analogs of TCR and class II MHC molecules. This report describes a general approach which solves this intrinsic low-affinity by constructing soluble divalent analogs using IgG as a molecular scaffold. The divalent nature of the complexes increases the avidity of the chimeric molecules for cognate ligands. The generality of this approach was studied by making soluble divalent analogs of two different classes of proteins, a TCR (2C TCR2Ig) and a class II MHC (MCCI-Ek2Ig) molecule. Direct flow cytometry assays demonstrate that the divalent 2C TCR2Ig chimera retained the specificity of the native 2C TCR, while displaying increased avidity for cognate peptide/MHC ligands, resulting in a high-affinity probe capable of detecting interactions that heretofore have only been detected using surface plasmon resonance. TCR2IgG was also used in immunofluorescence studies to show ER localization of intracellular peptide-MHC complexes after peptide feeding. MCCI-Ek2Ig chimeras were able to both stain and activate an MCC-specific T cell hybridoma. Construction and expression of these two diverse heterodimers demonstrate the generality of this approach. Furthermore, the increased avidity of these soluble divalent proteins makes these chimeric molecules potentially useful in clinical settings for probing and modulating in vivo cellular responses.


Razor hamstring curl and Nordic hamstring exercise architectural adaptations: Impact of exercise selection and intensity.
To investigate knee flexor strength and biceps femoris long head (BFlh) architectural adaptations following two different Nordic hamstring exercise (NHE) interventions and one razor hamstring curl (RHC) intervention. Thirty recreationally active males performed a total of 128 reps of NHEbodyweight (n = 10), NHEweighted (n = 10), or RHCweighted training (n = 10) across 6 weeks. Following the intervention, participants avoided any eccentric training for 4 weeks (detraining period). Strength results during the NHE and RHC were recorded pre- and post-intervention, as well as following detraining. Architectural characteristics of the BFlh were assessed weekly throughout the intervention and detraining periods. For the NHEweighted group, NHE strength increased (+81N, P = 0.044, d = 0.90) and BFlh fascicles lengthened (+1.57 cm, P < 0.001, d = 1.41) after 6 weeks of training. After 1 week of detraining, BFlh fascicle lengths shortened, with the largest reductions seen in the NHEweighted group (-0.96 cm, P = 0.021, d = -0.90). Comparatively, BFlh fascicle length and NHE strength responses were moderate in the NHEbodyweight group and negligible in the RHCweighted group. The greatest RHC strength changes (+82N, P = 0.038, d = 1.15) were seen in the RHCweighted group. NHEweighted interventions induce large BFlh fascicle lengthening responses and these adaptations decay after just 1 week of detraining. NHEbodyweight training has a moderate impact on BFlh architecture while the RHCweighted group has the least. Weighted NHE and RHC training promoted exercise-specific increases in strength. These findings suggest that exercise selection and intensity should be considered when prescribing exercises aiming to increase eccentric strength and BFlh fascicle length.


Mitophagy in Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive solid malignancies, is characterized by the presence of oncogenic KRAS mutations, poor response to current therapies, prone to metastasis, and a low 5-year overall survival rate. Macroautophagy (herein referred to as autophagy) is a lysosome-dependent degradation system that forms a series of dynamic membrane structures to engulf, degrade, and recycle various cargoes, such as unused proteins, damaged organelles, and invading pathogens. Autophagy is usually upregulated in established cancers, but it plays a dual role in the regulation of the initiation and progression of PDAC. As a type of selective autophagy, mitophagy is a mitochondrial quality control mechanism that uses ubiquitin-dependent (e.g., the PINK1-PRKN pathway) and -independent (e.g., BNIP3L/NIX, FUNDC1, and BNIP3) pathways to regulate mitochondrial turnover and participate in the modulation of metabolism and cell death. Genetically engineered mouse models indicate that the loss of PINK1 or PRKN promotes, whereas the depletion of BNIP3L inhibits oncogenic KRAS-driven pancreatic tumorigenesis. Mitophagy also play a dual role in the regulation of the anticancer activity of certain cytotoxic agents (e.g., rocaglamide A, dichloroacetate, fisetin, and P. suffruticosa extracts) in PDAC cells or xenograft models. In this min-review, we summarize the latest advances in understanding the complex role of mitophagy in the occurrence and treatment of PDAC.


Regulation of large coronary arteries by beta-adrenergic mechanisms in the conscious dog.
We examined, in conscious dogs, the effects of beta-adrenergic stimulation on measurements of left circumflex coronary arterial diameter and blood flow and on calculations of late diastolic coronary resistance (LDCR) and left circumflex coronary internal cross-sectional area (CSA). Isoproterenol (0.1 microgram/kg) initially decreased mean arterial pressure by 25 +/- 2% (mean +/- SEM), and LDCR by 62 +/- 4%, and increased heart rate by 82 +/- 10%, left ventricular (LV) dP/dt by 79 +/- 12%, and mean coronary blood flow by 85 +/- 5%, while CSA rose slightly. The peak effects on CSA (24 +/- 2%) occurred later, along with decreases in mean arterial pressure (7.4 +/- 1.0%) and LDCR (25 +/-5.3%) and increases in coronary blood flow (14 +/- 2%), LV dP/dt (12 +/- 3%), and heart rate (24 +/- 4%). Pirbuterol (1.0 microgram/kg) induced changes that were qualitatively similar to those induced by isoproterenol. Prenalterol (20 micrograms/kg), a cardioselective beta 1-adrenergic receptor agonist, did not affect mean arterial pressure, but increased heart rate by 40 +/- 5%, LV dP/dt by 72 +/- 10%, mean coronary blood flow by 34 +/- 11%, and CSA by 26 +/- 3%, and decreased LDCR by 29 +/- 5+. Isoproterenol and pirbuterol, but not prenalterol, increased coronary sinus O2 content and decreased A-VO2 difference. After beta 1-adrenergic receptor blockade with atenolol (1 mg/kg), prenalterol no longer induced significant effects, whereas isoproterenol and pirbuterol decreased mean arterial pressure similarly to what was observed prior to blockade, but did not increase LV dP/dt, and induced attenuated increases in mean coronary blood flow, CSA, and decreases in LDCR. Thus, in the intact, conscious animal, large coronary arteries are regulated by beta-adrenergic mechanisms. Surprisingly, a major fraction of large coronary arterial dilation appeared to be either directly or indirectly due to beta 1-adrenergic receptor mechanisms, although beta 2-adrenergic effects were also significant.


Rare Case of Giant Pulmonary Hydatid Cyst in a Female Patient Living in Taiz Governorate.
Pulmonary hydatid cyst is a common disorder in many areas of the world. In Yemen, echinococcosis is an endemic disease, however, hydatid disease of the lung is uncommon and usually caused by Echinococcus granulosus. We present a case of a 23-year old female who complained of shortness of breath, dry cough and left-sided dull aching pain for the past few weeks. Chest X-ray revealed a large, well-demarcated mass involving the left mid and lower lung zones with mediastinal shift to the right. Computed tomographic scan revealed a giant, low attenuation fluid density mass with enhancing wall. The diagnosis of giant hydatid cyst was confirmed by surgery and histopathological examination. Pulmonary hydatid cyst can assume a very large size without causing any symptoms and can be discovered incidentally while performing chest X-ray for another reason.


Successful treatment of Listeria monocytogenes prosthetic valve endocarditis using rifampicin and benzylpenicillin in combination with valve replacement.
Introduction.Listeria monocytogenes is an uncommon cause of prosthetic valve endocarditis (PVE). Recommended antimicrobial therapy typically includes intravenous β-lactams with or without synergistic aminoglycosides. In vitro studies have previously identified antagonism when rifampicin has been used in combination with β-lactams. However, in vivo data of rifampicin use are limited despite its enhanced anti-biofilm activity. Case presentation. A 63-year-old male presented with fever and back pain. L. monocytogenes bacteraemia and bioprosthetic aortic valve endocarditis was confirmed, along with spinal discitis and osteomyelitis. He was successfully treated with benzylpenicillin and rifampicin, in conjunction with valve replacement. Conclusion. Rifampicin remains an alternate agent to use, when there are contraindications to traditional aminoglycoside therapy. Further data on rifampicin use in L. monocytogenes PVE are awaited.


Length of red cell unit storage and risk for delirium after cardiac surgery.
The time that red cell units are stored before transfusion may be associated with postoperative complications, although the evidence is conflicting. However, the association between the length of red cell unit storage and postoperative delirium has not been explored. We hypothesized that the length of storage of transfused red cell units would be associated with delirium after cardiac surgery. We conducted a case-control study in which patients undergoing coronary artery bypass, valve, or ascending aorta surgery with cardiopulmonary bypass at Johns Hopkins from 2005 to 2011 were eligible for inclusion. Patients were excluded if they did not receive red cell units, received >4 red cell units during hospitalization, received any transfusion after the first postoperative day, or received red cell units that were not exclusively stored for ≤14 days or >14 days. Eighty-seven patients met transfusion-related inclusion criteria and developed postoperative delirium. Controls who did not develop delirium were selected from the same source population of eligible patients and were matched 1:1 based on age (± 5 years), 2- to 2.5-year band of date of surgery, and surgical procedure. For each patient, we calculated the average storage duration of all transfused red cell units. The primary outcome was odds of delirium in patients who were transfused red cell units with exclusive storage duration >14 days compared with that of ≤14 days. Secondary outcomes were odds of delirium with each increasing day of average red cell unit storage duration. We used conditional multivariable regression to test our hypotheses. In conditional multivariable analysis of 87 case-control pairs, there was no difference in the odds of patients developing delirium if they were transfused red cell units with an exclusive storage age >14 days compared with that ≤14 days (odds ratio [OR] 1.83; 95% confidence interval, 0.73-4.58, P = 0.20). Each additional day of average red cell unit storage beyond 14 days was associated with a 1.01- to 1.13-fold increase in the odds of postoperative delirium (OR, 1.07; P = 0.03). Each additional day of average storage beyond 21 days was associated with a 1.02- to 1.23-fold increase in the odds of postoperative delirium (OR, 1.12; P = 0.02). Transfusion of red cell units that have been stored for >14 days is not associated with increased odds of delirium. However, each additional day of storage >14 or 21 days may be associated with increased odds of postoperative delirium in patients undergoing cardiac surgery. More research is needed to further characterize the association between delirium and storage duration of transfused red cell units.


Accuracy of pediatric primary care providers' screening and referral for early childhood caries.
Tooth decay is one of the more common diseases of childhood. Slightly >40% of US children are already affected by the time they reach kindergarten. Primary care physicians can play an important role in prevention and control of this disease because of their ready access to this population. Unlike dentists, they see a large percentage of children during their infant and toddler years. However, few studies have been conducted on oral screenings and referrals by primary care physicians or the effectiveness of their oral health preventive activities. The purpose of this study was to determine the accuracy of pediatric primary care providers' screening and referral for Early Childhood Caries. We sought to compare independent, blinded oral screening results and referral recommendations made by primary care providers with those of a pediatric dentist, considered for purposes of the study to be the reference gold standard. The study was conducted at a private pediatric group practice in North Carolina. The practice was selected because it serves a large volume of Medicaid patients and includes a large number of pediatric primary care providers (11 pediatricians and 1 nurse practitioner). Study participants included Medicaid-eligible children younger than 36 months of age with erupted teeth. The pediatric primary care providers in this practice received 2 hours of training in infant oral health. The training consisted of a review of the study methods and clinical slides illustrating dental caries in various stages of progression. Specific instructions were given to the providers on how to recognize a cavitated carious lesion and how to determine when a dental referral is needed. Providers were instructed to refer any child with 1 or more cavitated carious lesions, soft tissue pathology, or evidence of trauma to the teeth or mouth. Before commencing the study, calibration and a comparative analysis were performed to establish reliability and validity of the examinations performed by the pediatric dentist. Both a pediatric dentist and a pediatric primary care provider conducted a dental screening on each child and recorded carious teeth and whether a dental referral was needed. Sensitivity and specificity were calculated to compare the pediatric primary care providers' screenings to the gold standard (pediatric dentist) in 3 categories: caries at the tooth level, caries at the patient level (1 or more affected teeth), and need for referral. The final study sample consisted of 258 preschool-aged children (122 males and 136 females) with a mean age of 21.2 months (standard deviation [SD]: 9.13). One hundred eighty-four (71.3%) of the participants were white, 58 (22.5%) were black, and 16 (6.2%) were Hispanic. Tooth-Level Analysis: The pediatric dentist reported an average of 0.30 (SD: 0.005) cavitated teeth per child, whereas the pediatric primary care providers reported a mean of 0.25 (SD: 0.004). This difference was not statistically significant (t test). The pediatric dentist identified 80 (2.4%) teeth with cavitated carious lesions, whereas the pediatric primary care providers identified 64 (1.9%), 25 of which were false-positives. Their screening results include 41 false-negative teeth. Thus, the primary care providers tended to under-count the number of teeth with carious lesions. They achieved a sensitivity of 0.49 (95% confidence interval [CI]: 0.47-0.51) and a specificity of 0.99 (95% CI: 0.99-1.0) when their screening results for individual teeth were compared with the gold standard. Patient-Level Analysis: At the patient level, the pediatric dentist identified 25 (9.7%) children with 1 or more teeth affected by cavitated lesions. The pediatric primary care providers collectively identified 30 (11.6%) children who had cavitated lesions. They achieved a sensitivity of 0.76 (95% CI: 0.71-0.81) and a specificity of 0.95 (95% CI: 0.93-0.98) in identifying those children with cavitated carious lesions. There were 6 false-negatives and 11 false-positives when the pediatric primary care providers' findings were compared with the gold standard. At the patient-level, the positive predictive value of the dental screening was 0.63 and the negative predictive value was 0.97. Dental Referral: The pediatric dentist referred a total of 27 (10.5%) children to a dentist. Two of these children were referred for trauma and the other 25 were referred for cavities. The pediatric primary care providers referred a total of 23 (8.9%) children to a dentist. Two referrals were made because the provider was concerned about stains on the teeth, whereas the remaining 21 were referred for cavities. The pediatric primary care providers achieved a sensitivity of 0.63 (95% CI: 0.57-0.69) and a specificity of 0.98 (95% CI: 0.96-0.99) when their recommendations for referral were compared with the gold standard. The number of children receiving a referral from a pediatric primary care provider for cavities (N = 21) was less than the number of children they identified as having cavities (N = 30). The providers as a whole tended to under-refer, and only 70% of children with evidence of dental disease received a referral. After 2 hours of training in infant oral health, the pediatric primary care providers in this study achieved an adequate level of accuracy in identifying children with cavitated carious lesions. Additional training and research would be needed to optimize pediatric primary care providers' identification of carious teeth if that were the goal of screening. However, the purpose of screening by nondental personnel generally is to accurately identify those in need of referral, which does not require a tooth-by-tooth identification of cavities. Additional research is also needed to determine how to improve dental referrals by pediatric primary care providers. Results of our study suggest that dental screenings can easily be incorporated into a busy pediatrics practice and that pediatric primary care providers can significantly contribute to the overall oral health of young children by the identification of those children who need to be seen by a dentist.


[Construction of a fecal protein Luminex liquid chip detection system for early diagnosis of colorectal tumors].
To construct a stool-based human protein diagnostic system using the Luminex liquid chip system for early diagnosis of colorectal tumors. From January, 2021 to January, 2023, 70 patients with colorectal cancer (CRC), 42 patients with colorectal adenoma (CRA), and 38 healthy individuals were recruited from our hospital for detecting fecal protein levels of matrix metalloproteinase-9 (MMP-9), retinol-binding protein 4 (RBP4), chitinase-3-like protein 1 (CHI3L1), and complement component 3a (C3a) using Luminex liquid chip technology and serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) using chemiluminescence assay. Receiver-operating characteristic (ROC) curve analysis was used for assessing the diagnostic efficacy of the combination of MMP-9, RBP4, CHI3L1 and C3a and the combination of CEA and CA19-9 for colorectal tumors. The fecal contents of MMP-9, RBP4, CHI3L1, and C3a were significantly higher in CRC patients than in healthy individuals (P < 0.05). Fecal MMP-9 and CHI3L1 levels were significantly higher in CRC than in CRA patients (P < 0.05), but RBP4 and C3a levels did not differ significantly (P>0.05). CRC patients had significantly higher serum CEA and CA19-9 levels than healthy individuals and CRA patients (P < 0.05), but the differences were not significant between the latter two groups (P>0.05). ROC analysis showed that the sensitivity and specificity of the combination of MMP-9, RBP4, CHI3L1, and C3a was 91.4% and 100.0%, for diagnosing CRC, 81.0% and 89.5% for diagnosing CRA, and 83.9% and 97.4% for a combined diagnosis of CRC and CRA, respectively. Z-test analysis indicated that fecal MMP-9, RBP4, CHI3L1, and C3a contents had a greater diagnostic efficacy than serum tumor markers CEA and CA19-9 for a combined diagnosis of colorectal tumors (P < 0.05). The Luminex liquid chip detection system for detecting decal RBP4, MMP-9, CHI3L1, and C3a provides an effective means for early diagnosis of colorectal tumors with a greater diagnostic efficacy than serum CEA and CA19-9 levels.


Gene expression analysis reveals functional pathways of glatiramer acetate activation.
Glatiramer acetate (GA, Copaxone®), a mixture of polymers comprising four amino acids, is approved for treatment of relapsing-remitting multiple sclerosis and clinically isolated syndrome. GA mediates its activity by induction of GA-specific T cells that shift the T cell balance from a dominant proinflammatory phenotype (Th1/Th17) to an anti-inflammatory phenotype (Th2/Treg). To characterize the functional pathways by which GA acts on immune cells, the authors conducted gene expression profiling using glatiramoid-stimulated splenocytes. Mice were immunized with GA and harvested splenocytes were reactivated ex vivo with GA or a purported generic GA. Gene expression profiles and functional pathways were evaluated in reactivated splenocytes. Overall, 1,474 genes were significantly upregulated or downregulated by GA. The main functional pathways induced by GA were: increased proliferation and activation of immune cells including T and B lymphocytes, stimulation of antigen presenting cells and differentiation of effector T lymphocytes. T-helper cell differentiation was the most significant canonical pathway associated with gene transcripts altered by GA. These expression patterns were not observed when splenocytes were activated with generic GA. GA-induced functional pathways coincide with known mechanisms of GA activity in MS patients and further support the unique therapeutic effect of this drug.


Low threshold and high speed short cavity distributed feedback hybrid silicon lasers.
In this paper we investigate reducing threshold and improving the efficiency and speed of distributed feedback hybrid silicon lasers. A low threshold current of 8.8 mA was achieved for a 200 μm cavity at 20 °C. A 3 dB bandwidth of 9.5 GHz as well as 12.5 Gb/s direct modulation of DFB laser diode was achieved on the hybrid silicon platform for the first time.


MHC class II compartments: specialized organelles of the endocytic pathway in antigen presenting cells.
Mounting an immune response against foreign, extracellular material requires that this material be internalized by antigen presenting cells, processed to peptide fragments and then displayed on the cell surface for recognition by the T cell receptor on T helper cells. Such peptides, derived from internalized antigens are generally presented to T cells in association with Major Histocompatibility Complex (MHC) class II molecules. Recent work has identified subcompartments of the endosomal/lysosomal system that appear to be important sites for the generation of peptide-MHC class II complexes. These so-called MHC class II compartments receive antigenic fragments from endosomes and lysosomes and load them onto class II molecules. From these compartments, peptide-loaded class II molecules are transported to the plasma membrane, where they can trigger T cells bearing appropriate receptors. This review summarizes recent work characterizing MHC class II compartments as specialized organelles of the endosomal/lysosomal pathway. Interestingly, MHC class II compartments share many features common to organelles present in a wide variety of specialized cells with quite different functions. Modifying the endocytic pathway to serve the needs of specialized cells may be a common mechanism which allows very different cell types to carry out their disparate functions.


Nicotine Content in Swedish-Type Snus Sold in Norway From 2005 to 2020.
Use of snus (moist smokeless tobacco) is widespread in Scandinavia and increasingly popular in the U.S. Snus products vary in terms of product design, portion size, and nicotine content. The aim of this study was to examine variations in the nicotine content in snus sold on the Norwegian market from 2005 to 2020. We calculated the nicotine content in dry snus in milligram per gram (mg/g) and milligram per serving (mg/s), weighted by the products' market share from data on nicotine content, water content, and portion size (both for portion and loose snus) for the ten most sold snus products from each of the three largest manufacturers in 2005, 2010, 2015, and 2020. In all snus products combined, the nicotine content per gram snus (mg/g) increased from 16.3 to 24.1, while nicotine per serving (mg/s) was stable around 13.0. In portion snus, the nicotine content increased for both mg/g and mg/s, most notably from 2005 to 2010. In loose snus, mg/g decreased marginally, while mg/s was stable throughout the period. In a period with increasing snus use, the nicotine content in snus increased per gram snus, but not per serving. The stability in nicotine per serving is likely due to a decreasing market share of loose snus which accounted for 54% of the snus products in 2005 and 5% in 2020, and which traditionally has a high content of nicotine per serving. Use of snus is popular in Scandinavia, most notably in Sweden and Norway, but also increasingly common in Finland, especially among young adults. There are no prior market-based studies of variations in the nicotine content in Swedish snus over time. We found that the average amount of nicotine per gram snus sold on the Norwegian market increased in the period 2005 to 2020, most notably from 2005 to 2010, while the amount of nicotine per serving was stable in the same period, primarily due to a decreasing share of loose snus.


New guidelines for severe community-acquired pneumonia.
We highlight the recent advances in the guidelines for treating patients with severe community-acquired pneumonia (sCAP). sCAP is a significant cause of hospital admissions. We performed an extensive review of the literature, covering studies from the last several years, to summarise the most important points in the diagnosis and treatment of patients hospitalised with sCAP. sCAP is associated with a high clinical burden. Therefore, deep knowledge is necessary for its management. In general, diagnosis, treatment and management are based on many published guidelines. However, the mortality rate is still unacceptably high, indicating the need for clear recommendations in the management of patients with sCAP. The choice of empirical antibiotic therapy for sCAP depends on multiple factors, such as national and local antimicrobial susceptibility data and the characteristics of the patients, including their risk factors for acquiring infections caused by multidrug-resistant pathogens. Currently, there are several published international guidelines. The aim of this review is to explore the areas that require further knowledge and new recommendations for current clinical practice.


Salt reduction in Australia: from advocacy to action.
As part of its endorsement of the World Health Organization's Global Action Plan to prevent non-communicable diseases, the Federal Government of Australia has committed to a 30% reduction in average population salt intake by 2025. Currently, mean daily salt intake levels are 8-9 g, varying by sex, region and population group. A number of salt reduction initiatives have been established over the last decade, but key elements for a co-ordinated population-level strategy are still missing. The objective of this review is to provide a comprehensive overview of existing population-level salt reduction activities in Australia and identify opportunities for further action. A review of the published literature and stakeholder activities was undertaken to identify and document current activities. The activities were then assessed against a pre-defined framework for salt reduction strategies. A range of initiatives were identified from the review. The Australian Division of World Action on Salt and Health (AWASH) was established in 2005 and in 2007 launched its Drop the Salt! Campaign. This united non-governmental organisations (NGOs), health and medical and food industry organisations in a co-ordinated advocacy effort to encourage government to develop a national strategy to reduce salt. Subsequently, in 2010 the Federal Government launched its Food and Health Dialogue (FHD) with a remit to improve the health of the food supply in Australia through voluntary partnerships with food industry, government and non-government public health organisations. The focus of the FHD to date has been on voluntary reformulation of foods, primarily through salt reduction targets. More recently, in December 2014, the government's Health Star Rating system was launched. This front of pack labelling scheme uses stars to highlight the nutritional profile of packaged foods. Both government initiatives have clear targets or criteria for industry to meet, however, both are voluntary and the extent of industry uptake is not yet clear. There is also no parallel public awareness campaign to try and influence consumer behaviour relating to salt and no agreed mechanism for monitoring national changes in salt intake. The Victorian Health Promotion Foundation (VicHealth) has recently instigated a State-level partnership to advance action and will launch its strategy in 2015. In conclusion, salt reduction activities are currently being implemented through a variety of different programs but additional efforts and more robust national monitoring mechanisms are required to ensure that Australia is on track to achieve the proposed 30% reduction in salt intake within the next decade.


Deletion of integron-associated gene cassettes impact on the surface properties of Vibrio rotiferianus DAT722.
The integron is a genetic recombination system that catalyses the acquisition of genes on mobilisable elements called gene cassettes. In Vibrio species, multiple acquired gene cassettes form a cassette array that can comprise 1-3% of the bacterial genome. Since 75% of these gene cassettes contain genes encoding proteins of uncharacterised function, how the integron has driven adaptation and evolution in Vibrio species remains largely unknown. A feature of cassette arrays is the presence of large indels. Using Vibrio rotiferianus DAT722 as a model organism, the aim of this study was to determine how large cassette deletions affect vibrio physiology with a view to improving understanding into how cassette arrays influence bacterial host adaptation and evolution. Biological assays and proteomic techniques were utilised to determine how artificially engineered deletions in the cassette array of V. rotiferianus DAT722 affected cell physiology. Multiple phenotypes were identified including changes to growth and expression of outer membrane porins/proteins and metabolic proteins. Furthermore, the deletions altered cell surface polysaccharide with Proton Nuclear Magnetic Resonance on whole cell polysaccharide identifying changes in the carbohydrate ring proton region indicating that gene cassette products may decorate host cell polysaccharide via the addition or removal of functional groups. From this study, it was concluded that deletion of gene cassettes had a subtle effect on bacterial metabolism but altered host surface polysaccharide. Deletion (and most likely rearrangement and acquisition) of gene cassettes may provide the bacterium with a mechanism to alter its surface properties, thus impacting on phenotypes such as biofilm formation. Biofilm formation was shown to be altered in one of the deletion mutants used in this study. Reworking surface properties may provide an advantage to the bacterium's interactions with organisms such as bacteriophage, protozoan grazers or crustaceans.


Factors Associated with Adherence to Self-Monitoring of Blood Glucose Among Young People with Type 1 Diabetes in China: A Cross-Sectional Study.
Self-monitoring of blood glucose (SMBG) plays a crucial role in the maintenance of glycemic control in young people with type 1 diabetes mellitus (T1DM), but most of them do not perform SMBG as recommended. Few studies comprehensively explored factors that correlate with adherence to SMBG among this population on the basis of a framework. Hence, the aims of this study were to describe adherence to SMBG among young people with T1DM in China and explore its associating factors according to the Self and Family Management (SFM) framework. A cross-sectional study was conducted on young people with T1DM in Hunan Province of China from July to August 2020. Based on the SFM framework, self-reported questionnaires were organized for the collection of data on adherence to SMBG, socio-demographic and clinical factors, resources, health care system, and personal factors. Factors associated with adherence to SMBG were determined through multivariate logistic regression analysis. A total of 165 young people were invited, of which 122 (73.9%) completed the questionnaires. The mean age was 12.41 years (SD = 3.18), and the proportion of young people who adhered to SMBG was 53.3%. Multivariate logistic regression analysis revealed that children aged 8-12 years (OR = 0.188, P = 0.002), from two-parent families (OR = 0.232, P = 0.019), and with better personal factors (eg, with more information of SMBG, OR = 1.072, P = 0.020; lower diabetes-related worry, OR = 0.917, P = 0.031; higher level of pain during SMBG, OR = 1.852, P = 0.001), had better adherence to SMBG. Nearly half of the young people with T1DM were not adherent to SMBG in China. Clinicians need to pay more attention to adolescents from single-parent families with regard to their adherence to SMBG. Providing management strategies of SMBG, including delivering SMBG-related information, decreasing diabetes-related worry, and relieving pain related to SMBG, may improve adherence.


Ethnic variation in allele distribution of the androgen receptor (AR) (CAG)n repeat.
The androgen receptor (AR) is important in reproductive organ development, as well as tissue homeostasis of the pancreas, liver, and skeletal muscle in adulthood. The trinucleotide (CAG)(n) repeat polymorphism in exon 1 of the AR gene is thought to regulate AR activity, with longer alleles conferring reduced receptor activity. Therefore, the evaluation of the allelic distribution of the AR (CAG)(n) repeat in various ethnic groups is crucial in understanding the interindividual variability in AR activity. We evaluated ethnic variation of this AR polymorphism by genotyping individuals from the multiethnic Hyperglycemia and Adverse Pregnancy Outcome study cohort. We genotyped 4421 Caucasian mothers and 3365 offspring of European ancestry; 1494 Thai mothers and 1742 offspring; 1119 Afro-Caribbean mothers and 1142 offspring; and 780 Hispanic mothers and 770 offspring of Mexican ancestry from Bellflower, California. The distributions of (CAG)(n) alleles among all 4 ethnic groups are significantly different (P < .0001). Pairwise tests confirmed significant differences between each pair of ethnicities tested (P < 10(-28)). The relative AR (CAG)(n) repeat length in the different groups was as follows: Afro-Caribbean (shortest repeat lengths and greatest predicted AR activity) < Caucasian < Hispanic < Thai (longest repeat length and lowest predicted AR activity). Significant interethnic differences in the allele frequencies of the AR exon 1 (CAG)(n) polymorphism exist. Our results suggest that there may be potential ethnic differences in androgenic pathway activity and androgen sensitivity.


Leveraging transcript quantification for fast computation of alternative splicing profiles.
Alternative splicing plays an essential role in many cellular processes and bears major relevance in the understanding of multiple diseases, including cancer. High-throughput RNA sequencing allows genome-wide analyses of splicing across multiple conditions. However, the increasing number of available data sets represents a major challenge in terms of computation time and storage requirements. We describe SUPPA, a computational tool to calculate relative inclusion values of alternative splicing events, exploiting fast transcript quantification. SUPPA accuracy is comparable and sometimes superior to standard methods using simulated as well as real RNA-sequencing data compared with experimentally validated events. We assess the variability in terms of the choice of annotation and provide evidence that using complete transcripts rather than more transcripts per gene provides better estimates. Moreover, SUPPA coupled with de novo transcript reconstruction methods does not achieve accuracies as high as using quantification of known transcripts, but remains comparable to existing methods. Finally, we show that SUPPA is more than 1000 times faster than standard methods. Coupled with fast transcript quantification, SUPPA provides inclusion values at a much higher speed than existing methods without compromising accuracy, thereby facilitating the systematic splicing analysis of large data sets with limited computational resources. The software is implemented in Python 2.7 and is available under the MIT license at https://bitbucket.org/regulatorygenomicsupf/suppa.


A case of bacteremia by Neisseria gonorrhoeae coincident with massive hemorrhage of esophageal varices.
A 42-yr-old man with hepatitis B virus associated liver cirrhosis was admitted to the emergency room because of multiple seizures, a history of chills and myalgia over the previous 2 weeks, and 3 days of melena. He was febrile with a temperature of 38.0°C. There were no symptoms and signs related to the genitourinary system, skin, or joints. Three sets of blood cultures were obtained and oxidase-positive, gram-negative diplococci were detected after 25.9-26.9 hr of incubation in all aerobic vials. The organism was positive for catalase and oxidase, and was identified as Neisseria gonorrhoeae, using a Vitek Neisseria-Haemophilus Identification card (bioMérieux Vitek, Inc., USA). Further, 16S rRNA sequencing of this isolate revealed a 99.9% homology with the published sequence of N. gonorrhoeae strain NCTC 83785 (GenBank Accession No. NR_026079.1). Acute bleeding by variceal rupture seems to be a likely route of introduction of N. gonorrhoeae from the mucosa into the blood. To the best of our knowledge, this is the first case of gonococcal bacteremia in Korea.


Dynamics in hybrid complex systems of switches and oscillators.
While considerable progress has been made in the analysis of large systems containing a single type of coupled dynamical component (e.g., coupled oscillators or coupled switches), systems containing diverse components (e.g., both oscillators and switches) have received much less attention. We analyze large, hybrid systems of interconnected Kuramoto oscillators and Hopfield switches with positive feedback. In this system, oscillator synchronization promotes switches to turn on. In turn, when switches turn on, they enhance the synchrony of the oscillators to which they are coupled. Depending on the choice of parameters, we find theoretically coexisting stable solutions with either (i) incoherent oscillators and all switches permanently off, (ii) synchronized oscillators and all switches permanently on, or (iii) synchronized oscillators and switches that periodically alternate between the on and off states. Numerical experiments confirm these predictions. We discuss how transitions between these steady state solutions can be onset deterministically through dynamic bifurcations or spontaneously due to finite-size fluctuations.


Time-dependency, predictors and clinical impact of infarct transmurality assessed by magnetic resonance imaging in patients with ST-elevation myocardial infarction reperfused by primary coronary percutaneous intervention.
Previous studies analyzing the relation between time-to-reperfusion, infarct size, microvascular obstruction (MO) and infarct transmurality in patients with ST-elevation myocardial infarction (STEMI) reperfused by primary percutaneous coronary intervention (PCI) reported inconsistent results. Furthermore, it remains unclear, if transmural infarction is associated with adverse clinical outcome. The present study included STEMI patients reperfused by primary PCI (n = 322) within 720 min after symptom-onset undergoing contrast-enhanced magnetic resonance imaging (CMR) at a median of 3 days after the index event [interquartile range (IQR) 2-4]. Patients were subcategorized into tertiles according to time-to-reperfusion. Infarct size and MO were assessed approximately 15 min after gadolinium-injection. Infarct transmurality was assessed by a score with late-enhancement grading as <25, 25-50, 51-75 and >75% transmurality analyzing all 17 left ventricular segments. Clinical follow-up was performed after 20 months (IQR 13;29). The primary endpoint was defined as a composite of death and congestive heart failure. The median time-to-reperfusion was 230 min (IQR 153;390). Infarct size and MO did not increase significantly with longer time-to-reperfusion (p = 0.16 and p = 0.44, respectively). In contrast to infarct size and MO, the infarct transmurality score progressed significantly with increasing ischemic time (p < 0.001). In multivariable logistic regression analysis, time-to-reperfusion was identified as an independent predictor for transmural infarction (p = 0.03). However, transmural infarction was not predictive of the primary composite clinical endpoint (p = 0.22). In conclusion, in STEMI patients reperfused by primary PCI, time-to-reperfusion was an independent predictor for transmural infarction but not for infarct size and MO. However, transmural infarction was not predictive of death and congestive heart failure.


Holistic Characterization of a Salmonella Typhimurium Infection Model Using Integrated Molecular Imaging.
A more complete and holistic view on host-microbe interactions is needed to understand the physiological and cellular barriers that affect the efficacy of drug treatments and allow the discovery and development of new therapeutics. Here, we developed a multimodal imaging approach combining histopathology with mass spectrometry imaging (MSI) and same section imaging mass cytometry (IMC) to study the effects of Salmonella Typhimurium infection in the liver of a mouse model using the S. Typhimurium strains SL3261 and SL1344. This approach enables correlation of tissue morphology and specific cell phenotypes with molecular images of tissue metabolism. IMC revealed a marked increase in immune cell markers and localization in immune aggregates in infected tissues. A correlative computational method (network analysis) was deployed to find metabolic features associated with infection and revealed metabolic clusters of acetyl carnitines, as well as phosphatidylcholine and phosphatidylethanolamine plasmalogen species, which could be associated with pro-inflammatory immune cell types. By developing an IMC marker for the detection of Salmonella LPS, we were further able to identify and characterize those cell types which contained S. Typhimurium.


Phase shifting two coupled circadian pacemakers: implications for jet lag.
Flights across time zones produce an abrupt displacement of the environmental time cues (zeitgebers), and the endogenous circadian timing system resynchronizes only gradually to the new schedule. A coupled two-oscillator model can simulate the human circadian system in temporal isolation and in artificial zeitgeber cycles. The model is here shown to explain the major features of resynchronization of circadian rhythms after time zone shifts, i.e., the rate of adjustment depends on the rhythm being measured, the number of time zones crossed, the flight direction (eastward or westward), and the strength of the zeitgebers in the new time zone. Investigations of the contribution of different model parameters to system performances suggest that intersubject differences in pacemaker periods may be a major factor in the observed variability in the effects of time zone shifts on circadian rhythms. With individualized period estimate the models can simulate case studies in which four subjects recorded their sleep-wake and core body temperature rhythms throughout simple and complex patterns of transmeridian flights.


Density-Gradient Centrifugation: Non-Ideal Sedimentation and the Interaction of Major and Minor Components.
A small amount of southern bean mosaic virus was contained in a narrow zone after density-gradient centrifugation, but in a much wider zone after centrifugation with a large amount of a second virus. Zone-spreading of a major component by non-ideal sedimentation in density-gradient centrifugation can cause zone spreading of a minor component that the major component overlaps.


Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial.
The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion. ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2-5 × 106 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1-2·5 × 108 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT02435849. Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8-23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 [95% CI 8·9-17·6] for the PedsQL total score and 16·8 [9·4-24·3] for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale. These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit-risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. Novartis.


No generally increased risk of cancer after total hip arthroplasty performed due to osteoarthritis.
Previous studies on the risk of cancer after total hip arthroplasty (THA) contradict each other, and many are hampered by small cohort sizes, residual confounding, short observation times or a mix of indications underlying the THA procedure. We evaluated the risk of cancer after total hip arthroplasty due to osteoarthritis in a nationwide cohort by comparing cancer incidences in individuals exposed to total hip arthroplasty due to osteoarthritis and in unexposed, sex-, age- and residence matched individuals. To address some previous studies' shortcomings, information on comorbidity and socioeconomic background were obtained and adjusted for. We included 126,276 patients exposed to a cemented THA between 1992 and 2012, and 555,757 unexposed individuals. Follow-up started on the day of surgery for exposed individuals and respective date for matched, unexposed individuals, and ended on the day of death, emigration, censuring or December 31st, 2012, whichever came first. The Swedish Hip Arthroplasty Registry (SHAR), the Swedish Cancer Registry, the Swedish National Patient Registry and Statistics Sweden were accessed to obtain information on procedural details of the THA, cancer diagnoses, comorbidities, and socioeconomic background. The primary outcome measure was the occurrence of any cancer after the index date. Exposed individuals had a slightly lower adjusted risk of developing any cancer than unexposed individuals (hazard ratio [HR] 0.97; CI 0.95-0.99). The only cancer with a statistically significant risk increase in exposed individuals was skin melanoma (HR 1.15; CI 1.05-1.24). We attained similar risk estimates in analyses stratified by sex, in individuals with minimum 5 years of follow-up, in an analysis including individuals with a history of previous cancer, and in patients with cementless THA. In this study on a large and well-defined population with long follow-up, we found no increased overall risk of cancer after THA. These reassuring findings could be included in the guidelines on preoperative information given to THA patients.


Are there characteristics of infectious diseases that raise special ethical issues?
This paper examines the characteristics of infectious diseases that raise special medical and social ethical issues, and explores ways of integrating both current bioethical and classical public health ethics concerns. Many of the ethical issues raised by infectious diseases are related to these diseases' powerful ability to engender fear in individuals and panic in populations. We address the association of some infectious diseases with high morbidity and mortality rates, the sense that infectious diseases are caused by invasion or attack on humans by foreign micro-organisms, the acute onset and rapid course of many infectious diseases, and, in particular, the communicability of infectious diseases. The individual fear and community panic associated with infectious diseases often leads to rapid, emotionally driven decision making about public health policies needed to protect the community that may be in conflict with current bioethical principles regarding the care of individual patients. The discussion includes recent examples where dialogue between public health practitioners and medical-ethicists has helped resolve ethical issues that require us to consider the infected patient as both a victim with individual needs and rights and as a potential vector of disease that is of concern to the community.


Abomasal cannulation in the milk-fed calf using a 7 mm polyurethane tube.
The main objective of this study was to develop a simple and effective surgical technique for abomasal cannulation in neonatal calves. General anaesthesia was induced in 12, 3-day-old male dairy calves and a polyurethane cannula surgically implanted in the abomasal body (n = 12) and pyloric antrum (n = 6) through a right paracostal incision. Fifteen cannulae remained in situ from day 3 to 34 of life (mean: 29 days), and three cannulae were extruded 13-14 days after placement. Calves were clinically healthy and gained weight during the study. Cannulae were well tolerated by the calves and abomasal contents did not leak from the cannula sites. Necropsy examination revealed firm adhesions between the abomasum and parietal peritoneum at the cannula sites with no evidence of leakage or peritonitis. We conclude that surgical placement of polyurethane tubes designed for percutaneous endoscopic gastrostomy provided a useful method for cannulation of the abomasum of neonatal calves. The cannulation technique can be used for experimental studies, as well as for nutritional and fluid support of sick calves that cannot be managed by oral treatment.


Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus.
A 64-year-old woman presented with bullous and ulcerating lichen sclerosus et atrophicus (LSA) on the neck, trunk, genital and perigenital area and the extremities. Histology of lesional skin showed the typical manifestations of LSA; in one of the biopsies spirochaetes were detected by silver staining. Despite treatment with four courses of ceftriaxone with or without methylprednisone for up to 20 days, progression of LSA was only stopped for a maximum of 1 year. Spirochaetes were isolated from skin cultures obtained from enlarging LSA lesions. These spirochaetes were identified as Borrelia afzelii by sodium dodecyl sulphate--polyacrylamide gel electrophoresis and polymerase chain reaction (PCR) analyses. However, serology for B. burgdorferi sensu lato was repeatedly negative. After one further 28-day course of ceftriaxone the lesions stopped expanding and sclerosis of the skin was diminished. At this time cultures for spirochaetes and PCR of lesional skin for B. afzelii DNA remained negative. These findings suggest a pathogenetic role for B. afzelii in the development of LSA and a beneficial effect of appropriate antibiotic treatment.


Improving enteral nutrition tolerance and protein intake maybe beneficial to intensive care unit patients.
Enteral nutrition (EN) is important for critically ill patients. This study investigated the current situation of EN treatment in SHANGHAI intensive care units (ICUs). We hypothesized that improving EN practice in SHANGHAI may benefit the prognosis of ICU patients. Clinical information on EN use was collected using clinic information forms in 2019. The collected data included the patient's general clinical information, EN prescription status, EN tolerance status, and clinical outcomes. The observation time points were days 1, 3, and 7 after starting EN. A total of 491 patients were included. The proportion of EN intolerance (defined as < 20 kcal/kg/day) decreased, with rates of intolerance of 100%, 82.07%, 70.61%, and 52.23% at 1, 3, 7, and 14 days, respectively. Age, mNutric score, and protein intake < 0.5 g/kg/day on day 7 were risk factors for 28-day mortality.The EN tolerance on day 7 and protein intake > 0.5 g/kg/day on day 3 or day 7 might affect the 28-day mortality. Risk factors with EN tolerance on day 7 by logistic regression showed that the AGI grade on day 1 was a major factor against EN tolerance. The proportion of EN tolerance in SHANGHAI ICU patients was low. Achieving tolerance on day 7 after the start of EN is a protective factor for 28-day survival. Improving EN tolerance and protein intake maybe beneficial for ICU patients.


Optical cellular logic image processor: implementation and programming of a single channel digital optical circuit.
A diode-laser driven all-optical iterative processor has been constructed and tested. Results are presented showing operation equivalent to a single channel of the cellular logic image processor architecture. Functional features of the circuit include optically programmable logic, thresholding, and data synchronization. Essential elements such as cascadability, logic-level restoration, and data feedback have been demonstrated with the optical processor controlled by a conventional electronic computer. Serial processing algorithms for word recognition, comparison, full addition, and subtraction have been implemented. Comments on the reliability of operation and future plans for expansion are made.


Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology.
A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.


Prospective Study of Dietary Phytoestrogen Intake and the Risk of Colorectal Cancer.
Dietary phytoestrogen intake has been inversely associated with the risk of prostate and breast cancer and might also affect the risk of colorectal cancer. We evaluated the associations between dietary lignan intake, dietary isoflavonoid intake, dietary coumestrol intake, and dietary enterolignans and equol intake, and risk of colorectal cancer. Data from the Women's Lifestyle and Health (WLH) Cohort study was used. The WLH study is a prospective population-based cohort study including 48,268 Swedish women aged 30-49 years at the time of enrolment in 1991-92. Follow-up for colorectal cancer incidence, death, and emigration until the end of 2010 was performed through record linkage to the Swedish Cancer Registry and Total Population Register. During follow-up 206 incident colorectal cancer cases were identified. Cox proportional hazards models were fitted to estimate adjusted risk ratios with 95% confidence intervals. We found no statistically significant association between the intake of dietary lignans, dietary isoflavonoids, coumestrol, or enterolignans and equol, and risk of colorectal cancer. We found no association between dietary phytoestrogen intake and the risk of colorectal cancer. However, since the number of cancer cases was small, our results need to be confirmed. Future studies should investigate colon and rectal cancer separately.


[Therapy of hemophilic hemarthrosis].
Haemarthroses in haemophiliacs can usually be limited by substituting the missing coagulation factor and are spontaneously reabsorbed within a few days. In rare cases, however, the blood remains inside the joint, leading to increasing destruction of the latter. This pathological development can be prevented right at the commencement phase by removing the effusion, which is generally in liquid form, by puncture, and the intraarticular clot by arthrotomy in good time. Experiences with this therapeutic concept, which can be described as "orthopedic early treatment of haemophilic haemarthrosis", are presented and discussed.


Awareness of hormesis will enhance future research in basic and applied neuroscience.
Hormesis is defined operationally as responses of cells or organisms to an exogenous or intrinsic factor (chemical, temperature, psychological challenge, etc.) in which the factor induces stimulatory or beneficial effects at low doses and inhibitory or adverse effects at high doses. The compendium of articles by Calabrese entitled "Neuroscience and Hormesis" provides a broad range of examples of neurobiological processes and responses to environmental factors that exhibit biphasic dose responses, the signature of hormesis. Nerve cell networks are the "first responders" to environmental challenges--they perceive the challenge and orchestrate coordinated adaptive responses that typically involve autonomic, neuroendocrine, and behavioral changes. In addition to direct adaptive responses of neurons to environmental stressors, cells subjected to a stressor produce and release molecules such as growth factors, cytokines, and hormones that alert adjacent and even distant cells to impending danger. The discoveries that some molecules (e.g., carbon monoxide and nitric oxide) and elements (e.g., selenium and iron) that are toxic at high doses play fundamental roles in cellular signaling or metabolism suggest that during evolution, organisms (and their nervous systems) co-opted environmental toxins and used them to their advantage. Neurons also respond adaptively to everyday stressors, including physical exercise, cognitive challenges, and dietary energy restriction, each of which activates pathways linked to the production of neurotrophic factors and cellular stress resistance proteins. The development of interventions that activate hormetic signaling pathways in neurons is a promising new approach for the preventation and treatment of a range of neurological disorders.


Early Protein Intake Is Associated with Body Composition and Resting Energy Expenditure in Young Adults Born with Very Low Birth Weight.
Suboptimal nutrition during fetal life and early childhood may be important in early programming of health and disease. Preterm infants born with very low birth weight (VLBW; <1500 g) frequently receive inadequate neonatal nutrition; the long-term consequences are poorly known. We evaluated the association between early macronutrient intake and body composition in young adults born with VLBW. We collected comprehensive information on daily nutritional intake during the initial hospital stay for 127 participants of the Helsinki Study of Very Low Birth Weight Adults. We calculated mean daily intakes of energy, protein, fat, and carbohydrate during the first 9 wk of life. At the mean age of 22.5 y, the subjects underwent measurements of weight, height, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure. The associations were examined by linear regression. We found that energy, protein, and fat intakes during the first 3 wk of life, all below current recommendations, predicted adult body composition. When adjusted for sex, age, birth weight SD score, and gestational age, a 1 g · kg(-1) · d(-1) higher protein intake predicted 11.1% higher lean body mass (LBM) (95% CI: 3.7%, 18.9%) and 8.5% higher resting energy expenditure (REE) (95% CI: 0.2%, 17.0%). Among those born before 28 wk of gestation, the numbers were 22.5% (95% CI: 1.9%, 47.4%) for LBM and 22.1% (95% CI: 3.6%, 44.0%) for REE. Similar associations were seen with energy (P = 0.01, P = 0.05) and fat (P < 0.01, P = 0.03) but not with carbohydrate. Energy intake was also associated with BMI (P = 0.01) and fat intake with BMI (P < 0.01) and percentage body fat (P = 0.05). The results were little changed when adjusted for prenatal and postnatal characteristics. At relatively low neonatal protein intake levels, additional protein intake is reflected in a healthier body composition, accompanied by a higher metabolic rate, in young adults born with VLBW 20 y earlier.


Diverse CD8+ T-cell responses to renal cell carcinoma antigens in patients treated with an autologous granulocyte-macrophage colony-stimulating factor gene-transduced renal tumor cell vaccine.
A phase I clinical trial with granulocyte-macrophage colony-stimulating factor tumor cell vaccines in patients with metastatic renal cell carcinoma (RCC) showed immune cell infiltration at vaccine sites and delayed-type hypersensitivity (DTH) responses to autologous tumor cells indicative of T-cell immunity. To further characterize RCC T-cell responses and identify relevant RCC-associated antigens, we did a detailed analysis of CD8+ T-cell responses in two vaccinated RCC patients who generated the greatest magnitude of DTH response and also displayed a strong clinical response to vaccination (>90% reduction in metastatic tumor volume). Three separate CD8+ T-cell lines (and subsequent derived clones) derived from patient 24 recognized distinct RCC-associated antigens. One recognized a shared HLA-A*0201-restricted antigen expressed by both renal cancer cells and normal kidney cells. This recognition pattern correlated with a positive DTH test to normal kidney cells despite no evidence of impairment of renal function by the patient's remaining kidney after vaccination. A second line recognized a shared HLA-C7-restricted antigen that was IFN-gamma inducible. A third line recognized a unique HLA-A*0101-restricted RCC antigen derived from a mutated KIAA1440 gene specific to the tumor. In addition, two independent CTL lines and three clones were also generated from patient 26 and they recognized autologous tumor cells restricted through HLA-A*0205, HLA-A/B/C, and HLA-B/C. These results show that paracrine granulocyte-macrophage colony-stimulating factor tumor vaccines may generate a diverse repertoire of tumor-reactive CD8+ T-cell responses and emphasize the importance of polyvalency in the design of cancer immunotherapies.


The three-dimensional organization of ribosomal genes and the architecture of the nucleoli vary with G1, S and G2 phases.
The three-dimensional (3-D) organization of the nucleolus, a defined nuclear territory containing tandem repeats of the ribosomal genes (rDNA), was investigated in PtK1 cells. Identification of the interphase stages was performed in single cells using DNA quantification by cytometry for the G1 and G2 phases while the S phase was identified by immunolabelling of the proliferating cell nuclear antigen (PCNA). The 3-D organization of the rDNA in the nucleolus was analyzed by fluorescence in situ hybridization using confocal microscopy. All the rDNA was located inside the nucleolar structures during all stages and the two rDNA loci were orthogonal. The rDNA was heterogeneously distributed in each nucleolus during G1, S and G2, with alternate sites of clustered genes (spots) and of genes in more extended configurations. The number of spots (4 to 6 in G1) increased during S phase (7 to 12) and their 3-D organization was progressively relaxed from G1 to G2. Double spots in G2 could reflect a similar gene organization of two chromatids. During mid-S phase, PCNA co-localized with some clustered genes (spots), indicating that rDNA replication occurs inside nucleoli and at different sites of the same locus simultaneously. The evaluation of the rDNA transcription units in 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB)-treated cells indicated a mean of 16 units per G1 nucleus and 25 units per G2 nucleus. For G1 and G2, the fine 3-D structure of nucleoli was reconstructed using ultrathin serial sections after specific contrast of DNA and RNA, digitization of the serial section images and computer-assisted 3-D architecture. Fibrillar centers (FCs) formed discrete structures (about 10 in G1 and 20 in G2) connected by a network of the dense fibrillar component. The 3-D arrangement of the FCs in G1 and G2 are similar to the rDNA spots. In conclusion, the architecture of the nucleoli during interphase reflects the distribution of the rDNA that is characterized by alternation of clustered and extended genes.


Do Viruses From Managed Honey Bees (Hymenoptera: Apidae) Endanger Wild Bees in Native Prairies?
Populations of wild and managed pollinators are declining in North America, and causes include increases in disease pressure and decreases in flowering resources. Tallgrass prairies can provide floral resources for managed honey bees (Hymenoptera: Apidae, Apis mellifera Linnaeus) and wild bees. Honey bees kept near prairies may compete with wild bees for floral resources, and potentially transfer viral pathogens to wild bees. Measurements of these potential interactions are lacking, especially in the context of native habitat conservation. To address this, we assessed abundance and richness of wild bees in prairies with and without honey bee hives present, and the potential spillover of several honey bee viruses to bumble bees (Hymenoptera: Apidae, Bombus Latrielle). We found no indication that the presence of honey bee hives over 2 yr had a negative effect on population size of wild bee taxa, though a potential longer-term effect remains unknown. All levels of viruses quantified in bumble bees were lower than those observed in honey bees. Higher levels of deformed wing virus and Israeli acute paralysis virus were found in Bombus griseocollis DeGeer (Hymenoptera: Apidae) collected at sites with hives than those without hives. These data suggest that the presence of honey bees in tallgrass prairie could increase wild bee exposure to viruses. Additional studies on cross-species transmission of viruses are needed to inform decisions regarding the cohabitation of managed bees within habitat utilized by wild bees.


In safe hands: child health data storage, linkage and consent for use.
While there is potential for societal benefit from linkage and integration of large datasets, there are gaps in our understanding of the implications for children and young people, and limited inclusion of their views within this discourse. We aimed to understand the views and expectations of children, young people and their parents/caregivers in Aotearoa New Zealand regarding child health data storage, linkage and consent for use. This qualitative study included 24 Māori and non-Māori children, young people and their families across five focus groups, recruited from a community-based health service. A mixed Māori and non-Māori research team facilitated participant recruitment and data collection. Child, adolescent and parent/caregiver groups were held separately. Sessions were audio-recorded and the verbatim transcripts were analysed thematically. We identified three themes: (i) I am more than a number: seeing patients as people; (ii) In safe hands: data as power; and (iii) What are your intentions with my data? Consent as an active relationship. A key challenge was the reductive and stigmatizing potential of data integration for minoritised groups. Hypothetical discussions of data sharing and linkage were contingent on trust between the participant and the health professional, with negotiated data ownership. Consent was conceived as an active relationship needing renewal and renegotiation as children reached adulthood. Current consent processes for ongoing use of child data require further deliberation. Without a strong ethical and child rights-based approach to issues of child health data management, consent and linkage, we risk exacerbating health inequities and experiences of breach of trust.


The role of actin in the apoptotic cell death of P19 embryonal carcinoma cells.
The P19 mouse embryonal carcinoma cell line was used as a model for a study of apoptosis accompanying differentiation induced by all-trans retinoic acid (ATRA). Apoptosis was detected both on the basis of morphological features (nuclear fragmentation, blebbing of plasma membrane, and formation of apoptotic bodies), and by using DNA electrophoresis and flow-cytometric measurement of DNA content. Actin cytoskeleton was studied both on morphological and submicroscopic levels. ATRA-treated cells manifested apoptosis-specific changes in the distribution of actin foremost in association with their entry into executive phase of apoptosis, when F-actin cables participated in cell disintegration into apoptotic bodies. Using immunogold labeling, actin was also identified in centers of fragmenting apoptotic nuclei, in the disintegration of which it is likely involved as well. At the same time, a cleavage of actin by active caspase-3 was proved, resulting in the emergence of 32 kDa fragment, termed fractin. Measurement of F-actin and fractin content using flow cytometry showed an unequivocal decrease of F-actin and synchronous increase of fractin in the apoptotic population as compared to non-treated cells. Therefore, our results proved both actin proteolysis and active involvement of specific actin structures in the final cell disintegration during apoptosis in the P19 cells.


The effect of CXCL12 processing on CD34+ cell migration in myeloproliferative neoplasms.
Primary myelofibrosis (PMF) and polycythemia vera (PV) are chronic myeloproliferative neoplasms. PMF and, to a lesser degree, PV are characterized by constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interaction between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal role in determining the trafficking of CD34(+) cells between the bone marrow (BM) and the PB. PMF, but not PV, is associated with downregulation of CXCR4 by CD34(+) cells due to epigenetic events. Both PV and PMF patients have elevated levels of immunoreactive forms of CXCL12 in the BM and PB. Using electrospray mass spectrometry, the PB and BM plasma of PV and PMF patients was shown to contain reduced amounts of intact CXCL12 but significant amounts of several truncated forms of CXCL12, which are lacking in normal PB and BM plasma. These truncated forms of CXCL12 are the product of the action of several serine proteases, including dipeptidyl peptidase-IV, neutrophil elastase, matrix metalloproteinase-2 (MMP-2), MMP-9, and cathepsin G. Unlike CXCL12, these truncates either lack the ability to act as a chemoattractant for CD34(+) cells and/or act as an antagonist to the action of CXCL12. These data suggest that proteolytic degradation of CXCL12 is characteristic of both PV and PMF and that the resulting truncated forms of CXCL12, in addition to the reduced expression of CXCR4 by CD34(+) cells, lead to a profound mobilization of HSC/HPC in PMF.


Charge-Transfer Effect and Enhanced Photoresponsivity of WS2- and MoSe2-Based Field Effect Transistors with π-Conjugated Polyelectrolyte.
The characteristics of field effect transistors (FETs) fabricated using two-dimensional (2D) transition-metal dichalcogenides (TMDCs) can be modulated by surface treatment of the active layers. In this study, an ionic π-conjugated polyelectrolyte, poly(9,9-bis(4'-sulfonatobutyl)fluorene-alt-1,4-phenylene) potassium (FPS-K), was used for the surface treatment of MoSe2 and WS2 FETs. The photoluminescence (PL) intensities of monolayer (1L)-MoSe2 and 1L-WS2 clearly decreased, and the PL peaks were red-shifted after FPS-K treatment, suggesting a charge-transfer effect. In addition, the n-channel current of both the MoSe2 and WS2 FETs increased and the threshold voltage (Vth) shifted negatively after FPS-K treatment owing to the charge-transfer effect. The photoresponsivity of the MoSe2 FET under light irradiation (λex = 455 nm) increased considerably, from 5300 A W-1 to approximately 10 000 A W-1, after FPS-K treatment, and similar behavior was observed in the WS2 FET. The results can be explained in terms of the increase in electron concentration due to photogating. The external quantum efficiency and photodetectivity of both FETs were also enhanced by the charge-transfer effect resulting from surface treatment with FPS-K containing mobile cations (K+) and fixed anions (SO3-), as well as by the photogating effect. The variation in charge-carrier density due to the photogating and charge-transfer effects is estimated to be approximately 2 × 1012 cm-2. The results suggest that π-conjugated polyelectrolytes such as FPS-K can be a promising candidate for the passivation of TMDC-based FETs and obtaining enhanced photoresponsivity.


Storage artifact increases helper T lymphocytes and helper-to-suppressor T lymphocyte ratio to normal levels in a patient with acquired immune deficiency related complex.
An increase in both the helper/suppressor T lymphocyte ratio and the absolute number of helper T lymphocytes from subnormal to normal values was observed on overnight storage of a lymphocyte preparation from a patient with acquired immune deficiency related complex. Storage of lymphocyte preparations did not significantly alter the helper/suppressor ratio for four additional patients with acquired immune deficiency related complex but produced increases for one patient with Crohn's disease and two patients with sickle cell disease. Overnight storage of heparinized blood at room temperature did not alter the helper/suppressor ratio for one healthy volunteer and one patient with acquired immune deficiency related complex but produced increases for one patient with Crohn's disease and one patient with acute infectious mononucleosis, resulting in a change from a subnormal to a normal value in the latter patient. We suggest that physicians and laboratory directors consider storage artifacts when evaluating results of tests for absolute numbers of helper T lymphocytes or helper/suppressor T lymphocyte ratios performed on patients.