Plurihormonal Pituitary Neuroendocrine Tumours - A Single Centre Experience.
Introduction. Plurihormonal pituitary neuroendocrine tumours (PitNET)/adenomas are pituitary neuroendocrine tumours composed of monomorphous cell populations expressing anterior pituitary transcription factors and/or hormones belonging to more than one cell lineage. Studies dedicated to plurihormonal tumours are rare and quite heterogenous with their results, bearing in mind changes in diagnostic criteria and inconsistent use of antibodies for anterior pituitary transcription factors in the diagnostic immunohistochemical panel. Material and Methods. We retrospectively analysed all patients surgically treated for PitNETs from 2016 to July 2022 in a tertiary healthcare institution. All tumours previously diagnosed PitNETs with the word "plurihormonal" were re-examined and potentially re-classified, according to 2022 WHO classification of endocrine tumours. Results. Among 721 patients surgically treated for PitNET in 5.5 years period, the diagnosis of plurihormonal PitNET was established in 11 tumours (1.3%). All tumours showed diffuse and intensive positivity for anterior pituitary transcription factors PIT1 and SF1. Clinically, all patients presented with acromegaly. Conclusions. Retrospective studies related to newly defined plurihormonal PitNETs with a reassessment of diagnoses are necessary due to their rarity and ambition to investigate their origin and biological behaviour. The fact that the majority of plurihormonal PitNETs are clinically presented with acromegaly and show simultaneous positivity to PIT1 and SF1 transcription factors deserve special attention and need for further research in larger cohorts of these exceptional tumours.


The applicant pool: the genesis of the physician pipeline.
As medical schools across the nation consider the recent call made by the Association of American Medical Colleges to increase numbers of medical school students by 30% by 2015, it is important to explore the characteristics of the applicant pool. Understanding the make-up of the pool of recent applicants to the University of Kentucky College of Medicine can assist us in defining areas where the pool could be expanded in the future. Reviewing data from 2002-2006, we will examine the Kentucky county of origin of our applicants and matriculants. We will describe demographic characteristics of our applicants and matriculants with regard to gender, race and ethnicity, and international backgrounds. We will also look at factors that may discourage or dissuade prospective applicants from seeking admission to medical school including undergraduate grades, denial of the initial application to medical school, and cost considerations.


Duodenogastric reflux after gastric surgery and in gastric ulcer disease: continuous measurement with a sodium ion selective electrode.
Duodenogastric reflux (DGR) was investigated with a sodium ion selective electrode in 10 normal controls, 10 patients with persistent pain after gastric surgery, and five patients with gastric ulcer. During an average study time of two and a half hours, normal controls had reflux for 12% of the study, whereas patients after gastric surgery had reflux for 91% of the study time (p < 0.0002). Patients with a gastric ulcer had reflux on average for 67% of the study (p < 0.001). The patients who had had gastric surgery had several symptoms, but there was no association between the number or nature of symptoms and the severity of DGR as determined by the sodium electrode. Patients with positive bile provocation tests did not show any significant difference in the duration of reflux compared with those with a negative provocation test (79% and 87%). There was also no relation between the results of the provocation test and the number and nature of symptoms. Continuous monitoring of intragastric sodium ions with a selective electrode is a practical means of assessing DGR. Results suggest that symptoms due to DGR may be related to the sensitivity of the gastric lining as well as the amounts of duodenal contents flowing back into the stomach.


Cellular and Molecular Mechanisms of Prion Disease.
Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.


A Literature Review of Painful Hashimoto Thyroiditis: 70 Published Cases in the Past 70 Years.
Painful Hashimoto thyroiditis (pHT) is a rare diagnosis, and optimal treatment remains unclear. To better characterize pHT, PubMed, Embase, Scopus, and Web of Science indexes were searched for case reports or case series reporting pHT, published between 1951 and February 2019. Seventy cases reported in 24 publications were identified. Female predominance (91.4%) and a median age of 39.00 years (interquartile range, 32.50-49.75 years) were observed. Among reported cases, 50.8% had known thyroid disease (including Hashimoto thyroiditis, Graves disease, and seronegative goiters), 83.3% had positive antithyroid peroxidase antibodies, and 71.2% had antithyroglobulin antibodies. Most cases did not have preceding upper respiratory tract symptoms or leukocytosis. Ultrasound features were consistent with Hashimoto thyroiditis. Thyroid function at initial presentation was hypothyroid (35.9%), euthyroid (28.1%), or thyrotoxic (35.9%). Cases evolved into hypothyroidism (55.3%) and euthyroidism (44.7%), whereas none became hyperthyroid after medical treatment. Thyroid size usually decreased after medical treatment. Most cases were empirically treated as subacute thyroiditis with corticosteroids, levothyroxine, or nonsteroidal anti-inflammatory drugs. However, no therapy provided sustained pain resolution. In subgroup analysis, low-dose oral prednisone (<25 mg/d) and intrathyroidal corticosteroid injection showed more favorable outcomes. Total thyroidectomy yielded 100% sustained pain resolution. Diagnosis of pHT is based on clinical evidence of Hashimoto thyroiditis and recurrent thyroid pain after medical treatment. The reference standard of diagnosis is pathology. Total thyroidectomy or intrathyroidal glucocorticoid injection should be considered if low-dose oral prednisone fails to achieve pain control.


Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.
The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer-related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA-binding activity of Runx2 with concomitant reduction in the expression of metastasis-related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA-binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA-binding activity. However, Akt signaling does not appear to interefere with CBFβ-Runx2 interactions. Consequently, expression of multiple metastasis-related genes is decreased and Runx2-mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells.


NMR regulatory analysis: enantiomeric purity determination for (R)-(-)-desoxyephedrine and antipode methamphetamine.
Regulatory enantiomeric purity direct determination for (S)-(+)-methamphetamine, the widely abused DEA schedule II controlled substance, and (R)-(-)-desoxyephedrine, over-the-counter nasal inhaler decongestant were developed using 400 MHz 1H NMR spectroscopy. The efficient enantiomeric differentiation was obtained using a diamagnetic chiral solvating agent to dissimilarly perturb the NMR spectra of the enantiomeric solutes. Nonequivalence behavior was studied in terms of all variables that affect population and intrinsic spectra of the fast diastereomeric solvates. Assignment of enantiomer configuration was based on the relative field position of the resolved enantiomeric signals. Optimization of experimental conditions provided significant resolved enantiomeric signals suitable for quantification. Utilizing the relative intensities of the corresponding enantiomeric signals of the N-CH3 assigned to (S)-(+)-methamphetamine and (R)-(-)-desoxyephedrine, the analysis of synthetic enantiomeric mixtures by the proposed methods demonstrated excellent agreements with the known values of the enantiomers present. The mean +/- SD recovery values for the (R)-(-)-enantiomer was 99.9 +/- 0.4% of added antipode (n = 7). The optically pure enantiomer was used to establish the minimum amount detected by the proposed NMR spectroscopic method.


Respiratory complex I deficiency induces drought tolerance by impacting leaf stomatal and hydraulic conductances.
To investigate the role of plant mitochondria in drought tolerance, the response to water deprivation was compared between Nicotiana sylvestris wild type (WT) plants and the CMSII respiratory complex I mutant, which has low-efficient respiration and photosynthesis, high levels of amino acids and pyridine nucleotides, and increased antioxidant capacity. We show that the delayed decrease in relative water content after water withholding in CMSII, as compared to WT leaves, is due to a lower stomatal conductance. The stomatal index and the abscisic acid (ABA) content were unaffected in well-watered mutant leaves, but the ABA/stomatal conductance relation was altered during drought, indicating that specific factors interact with ABA signalling. Leaf hydraulic conductance was lower in mutant leaves when compared to WT leaves and the role of oxidative aquaporin gating in attaining a maximum stomatal conductance is discussed. In addition, differences in leaf metabolic status between the mutant and the WT might contribute to the low stomatal conductance, as reported for TCA cycle-deficient plants. After withholding watering, TCA cycle derived organic acids declined more in CMSII leaves than in the WT, and ATP content decreased only in the CMSII. Moreover, in contrast to the WT, total free amino acid levels declined whilst soluble protein content increased in CMSII leaves, suggesting an accelerated amino acid remobilisation. We propose that oxidative and metabolic disturbances resulting from remodelled respiration in the absence of Complex I activity could be involved in bringing about the lower stomatal and hydraulic conductances.


A joint model of longitudinal and competing risks survival data with heterogeneous random effects and outlying longitudinal measurements.
This article proposes a joint model for longitudinal measurements and competing risks survival data. The model consists of a linear mixed effects sub-model with t-distributed measurement errors for the longitudinal outcome, a proportional cause-specific hazards frailty sub-model for the survival outcome, and a regression sub-model for the variance-covariance matrix of the multivariate latent random effects based on a modified Cholesky decomposition. A Bayesian MCMC procedure is developed for parameter estimation and inference. Our method is insensitive to outlying longitudinal measurements in the presence of non-ignorable missing data due to dropout. Moreover, by modeling the variance-covariance matrix of the latent random effects, our model provides a useful framework for handling high-dimensional heterogeneous random effects and testing the homogeneous random effects assumption which is otherwise untestable in commonly used joint models. Finally, our model enables analysis of a survival outcome with intermittently measured time-dependent covariates and possibly correlated competing risks and dependent censoring, as well as joint analysis of the longitudinal and survival outcomes. Illustrations are given using a real data set from a lung study and simulation.


Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers.
The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer's disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations - a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid formation of oligomers. The self-assembly process is reversible, so assembled aggregates can dissociate from the membrane surface into the bulk solution to further participate in the aggregation process. Molecular dynamics simulations demonstrate that the transient membrane-Aβ interaction dramatically changes the protein conformation, facilitating the assembly of dimers. The results indicate peptide-membrane interaction is the critical step towards oligomer formation at physiologically low protein concentrations.


Role of a carboxylesterase in herbicide bioactivation in Arabidopsis thaliana.
Arabidopsis thaliana contains multiple carboxyesterases (AtCXEs) with activities toward xenobiotics, including herbicide esters that are activated to their phytotoxic acids upon hydrolysis. On the basis of their susceptibility to inhibition by organophosphates, these AtCXEs are all serine hydrolases. Using a trifunctional probe bearing a fluorophosphonate together with biotin and rhodamine to facilitate detection and recovery, four dominant serine hydrolases were identified in the proteome of Arabidopsis. Using a combination of protein purification, capture with the trifunctional probe and proteomics, one of these hydrolases, AtCXE12, was shown to be the major carboxyesterase responsible for hydrolyzing the pro-herbicide methyl-2,4-dichlorophenoxyacetate (2,4-D-methyl) to the phytotoxic acid 2,4-dichlorophenoxyacetic acid. Recombinant expression of the other identified hydrolases showed that AtCXE12 was unique in hydrolyzing 2,4-D-methyl. To determine the importance of AtCXE12 in herbicide metabolism and efficacy, the respective tDNA knock-out (atcxe12) plants were characterized and shown to lack expression of AtCXE12 and have greatly reduced levels of 2,4-D-methyl-hydrolyzing activity. Young atcxe12 seedlings were less sensitive than wild type plants to 2,4-D-methyl, confirming a role for the enzyme in herbicide bioactivation in Arabidopsis.


Expression of dual TCR on DO11.10 T cells allows for ovalbumin-induced oral tolerance to prevent T cell-mediated colitis directed against unrelated enteric bacterial antigens.
The triggering Ag for inflammatory bowel disease and animal models of colitis is not known, but may include gut flora. Feeding OVA to DO11.10 mice with OVA-specific transgenic (Tg) TCR generates Ag-specific immunoregulatory CD4(+) T cells (Treg) cells. We examined the ability of oral Ag-induced Treg cells to suppress T cell-mediated colitis in mice. SCID-bg mice given DO11.10 CD4(+)CD45RB(high) T cells developed colitis, and cotransferring DO11.10 CD45RB(low)CD4(+) T cells prevented CD4(+)CD45RB(high) T cell-induced colitis in the absence of OVA. The induction and prevention of disease by DO11.10 CD4(+) T cell subsets were associated with an increase in endogenous TCRalpha chain expression on Tg T cells. Feeding OVA to SCID-bg mice reconstituted with DO11.10 CD4(+)CD45RB(high) attenuated the colitis in association with increased TGF-beta and IL-10 secretion, and decreased proliferative responses to both OVA and cecal bacteria Ag. OVA feeding also attenuated colitis in SCID-bg mice reconstituted with a mix of BALB/c and DO11.10 CD45RB(high) T cells, suggesting that OVA-induced Treg cells suppressed BALB/c effector cells. The expression of endogenous non-Tg TCR allowed for DO11.10-derived T cells to respond to enteric flora Ag. Furthermore, feeding OVA-induced Treg cells prevented colitis by inducing tolerance in both OVA-reactive and non-OVA-reactive T cells and by inducing Ag-nonspecific Treg cells. Such a mechanism might allow for Ag-nonspecific modulation of intestinal inflammation in inflammatory bowel disease.


The unspoken benefit of participation in a clinical trial.
Publicly funded trials do not usually offer financial incentives to volunteers. An intensive level of medical care could act as an additional motivator for participation. Our aim was to establish whether patients may draw any clinical benefit from volunteering in a clinical trial. We analysed the recruitment process of a phase II randomised controlled trial, the Inorganic Nitrate in Angina Study. Two-hundred and thirteen patients with a history of stable angina and who had been under at least annual primary care review were screened for participation by history taking, examination, 12-lead electrocardiography, treadmill test and echocardiography. Thirty-five (16.4%) patients were found to have significant unstable or new clinical pathology, requiring urgent clinical attention. We identified 17 (7.9%) patients with unstable angina. Furthermore, we found new undiagnosed pathologies: amyloidosis in two (0.9%), hypertrophic cardiomyopathy in two (0.9%), left ventricular systolic dysfunction (ejection fraction <45%) in three (1.4%), left ventricular thrombus in one (0.4%), significant valvular disease in five (2.4%) and arrhythmias in six (2.8%). Compared with routine care, patients screened for a clinical trial may come under an increased level of scrutiny that may affect their clinical management. This may act as additional motivator to attract patients to future studies.


Bi-level structured functional analysis for genome-wide association studies.
Genome-wide association studies (GWAS) have led to great successes in identifying genotype-phenotype associations for complex human diseases. In such studies, the high dimensionality of single nucleotide polymorphisms (SNPs) often makes analysis difficult. Functional analysis, which interprets SNPs densely distributed in a chromosomal region as a continuous process rather than discrete observations, has emerged as a promising avenue for overcoming the high dimensionality challenges. However, the majority of the existing functional studies continue to be individual SNP based and are unable to sufficiently account for the intricate underpinning structures of SNP data. SNPs are often found in groups (e.g., genes or pathways) and have a natural group structure. Additionally, these SNP groups can be highly correlated with coordinated biological functions and interact in a network. Motivated by these unique characteristics of SNP data, we develop a novel bi-level structured functional analysis method and investigate disease-associated genetic variants at the SNP level and SNP group level simultaneously. The penalization technique is adopted for bi-level selection and also to accommodate the group-level network structure. Both the estimation and selection consistency properties are rigorously established. The superiority of the proposed method over alternatives is shown through extensive simulation studies. A type 2 diabetes SNP data application yields some biologically intriguing results.


Respiratory failure as a result of drugs, overdoses, and poisonings.
When taking care of critically ill patients, it is paramount to consider all factors that could be contributing to their illness. Even in this brief discussion, it is clear that numerous drugs, procedures, and ingestants are associated with acute respiratory failure from a variety of mechanisms and that a review of all possible drug/poison exposures needs to be done for every patient.


Impact of histologic subtypes and treatment modality among patients with primary central nervous system lymphoma: a SEER database analysis.
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal presentation of lymphoma; however, the data for outcomes of patients with subtypes other than diffuse large B-cell lymphoma (DLBCL) are limited. Therefore, we analyzed overall survival (OS) of adult patients diagnosed with PCNSL by histologic subtype between 1998 and 2014 using the Surveillance, Epidemiology and End Results. A total of 4375 patients were identified. The median age of the patients was 64 years (range: 18-96). DLBCL was the most common histology (N=3,091), followed by follicular lymphoma (FL, N=83), peripheral T-cell lymphoma (PTCL, N=64), marginal zone lymphoma (MZL, N=63), Burkitt lymphoma (BL, N=27), small lymphocytic lymphoma (SLL, N=22), Hodgkin lymphoma (HL, N=13) and others (N=1,012). The 5-year OS rates were 30% in DLBCL, 66% in FL, 33% in PTCL, 79% in MZL, 42% in BL, 38% in SLL and 45% in HL. Radiation alone showed similar OS compared to no treatment in DLBCL, BL and PTCL, while radiation alone was associated with similar OS to chemotherapy or chemo-radiation in FL and MZL. The outcomes of patients with PCNSL are unfavorable; with the exception of FL and MZL which can potentially show prolonged survival with surgical resection or radiation monotherapy.


Identification of 7 000-9 000 Proteins from Cell Lines and Tissues by Single-Shot Microflow LC-MS/MS.
A current trend in proteomics is to acquire data in a "single-shot" by LC-MS/MS because it simplifies workflows and promises better throughput and quantitative accuracy than schemes that involve extensive sample fractionation. However, single-shot approaches can suffer from limited proteome coverage when performed by data dependent acquisition (ssDDA) on nanoflow LC systems. For applications where sample quantities are not scarce, this study shows that high proteome coverage can be obtained using a microflow LC-MS/MS system operating a 1 mm i.d. × 150 mm column, at a flow-rate of 50 μL/min and coupled to an Orbitrap HF-X mass spectrometer. The results demonstrate the identification of ∼9 000 proteins from 50 μg of protein digest from Arabidopsis roots, 7 500 from mouse thymus, and 7 300 from human breast cancer cells in 3 h of analysis time in a single run. The dynamic range of protein quantification measured by the iBAQ approach spanned 5 orders of magnitude and replicate analysis showed that the median coefficient of variation was below 20%. Together, this study shows that ssDDA by μLC-MS/MS is a robust method for comprehensive and large-scale proteome analysis and which may be further extended to more rapid chromatography and data independent acquisition approaches in the future.̀.


Population pharmacokinetic modeling of factor concentrates in hemophilia: an overview and evaluation of best practice.
The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient's individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices of which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. A literature search was performed; publications describing prophylactic population PK models for FVIII and FIX concentrates based on original patient data and constructed using nonlinear mixed-effect modeling were included. The following data were collected: detailed demographics, type of product, assessed and included covariates, laboratory specifications, and validation of models. Included models were scored according to our recommendations for best practice, specifically scoring the quality of data documentation as reported. Respectively, 20 models for FVIII and 7 for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only 4 reported detailed demographics. The wide range of body weights suggested that overweight and obese adults were represented. Twenty-six models reported the assay applied to measure factor levels, whereas only 16 models named reagents used. Eight models were internally validated using a data subset. This overview presents detailed information on clinical and laboratory data used for published population PK models. We provide recommendations on data collection and documentation to increase the reliability of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.


Commercial Multiplex Polymerase Chain Reaction versus Periodic Acid-Schiff Testing for the Diagnosis of Onychomycosis.
Diagnosis of onychomycosis using the periodic acid-Schiff (PAS) test for sensitive identification of hyphae and fungal culture for identification of species has become the mainstay for many clinical practices. With the advent of polymerase chain reaction (PCR) testing, physicians can identify a fungal toenail infection quickly with the added benefit of species identification. We compared PAS testing with multiplex PCR testing from a clinical perspective. A total of 209 patients with clinically diagnosed onychomycosis were recruited. A high-resolution picture was taken of the affected hallux nail, and the nail was graded using the Onychomycosis Severity Index. A proximal sample of the affected toenail and subungual debris were obtained and split into two equal samples. One sample was sent for multiplex PCR testing and the other for PAS testing. The results were analyzed and compared. Six patients were excluded due to insufficient sample size for PCR testing. Of the remaining 203 patients, 109 (53.7%) tested positive with PAS, 77 (37.9%) tested positive with PCR. Forty-one patients tested positive with PAS but negative with PCR, and nine tested positive with PCR but negative with PAS. Physicians should continue the practice of using PAS biopsy staining for confirmation of a fungal toenail infection before using oral antifungal therapy. Because multiplex PCR allows species identification, some physicians may elect to perform both tests.


Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets.
Hematopoietic fate maps in the developing mouse embryo remain imprecise. Definitive, adult-type hematopoiesis first appears in the fetal liver, then progresses to the spleen and bone marrow. Clonogenic common lymphoid progenitors and clonogenic common myeloid progenitors (CMPs) in adult mouse bone marrow that give rise to all lymphoid and myeloid lineages, respectively, have recently been identified. Here it is shown that myelopoiesis in the fetal liver similarly proceeds through a CMP equivalent. Fetal liver CMPs give rise to megakaryocyte-erythrocyte-restricted progenitors (MEPs) and granulocyte-monocyte-restricted progenitors (GMPs) that can also be prospectively isolated by cell surface phenotype. MEPs and GMPs generate mutually exclusive cell types in clonogenic colony assays and in transplantation experiments, suggesting that the lineage restriction observed within each progenitor subset is absolute under normal conditions. Purified progenitor populations were used to analyze expression profiles of various hematopoiesis-related genes. Expression patterns closely matched those of the adult counterpart populations. These results suggest that adult hematopoietic hierarchies are determined early in the development of the definitive immune system and suggest that the molecular mechanisms underlying cell fate decisions within the myeloerythroid lineages are conserved from embryo to adult. (Blood. 2001;98:627-635)


Impact on radiogenic cancer risk of persons exhibiting abnormal sensitivity to ionizing radiation.
Human genotypes are known "that confer both increased susceptibility or resistance to DNA damage and increased cancer risk after exposure to carcinogenic agents, including ionizing radiation" (NAS 1980). The existence of sensitive subgroups at elevated risk, if they are of appreciable size, could have significant impact on the actual distribution of risk. The radiosensitive disorder ataxia-telangiectasia (A-T) serves as a good example: the significant "at risk" group, A-T heterozygotes, is estimated to comprise between 0.5% and 5% of the total population, and has a twofold elevated lifetime risk of fatal neoplasia. Other genetic syndromes that manifest abnormal radiosensitivity are also known, but no estimates are available for the population frequency of all such phenotypes, or for their overall degree of increased risk. As the first part of a program addressing these questions, we have developed a rapid and inexpensive assay for screening members of the general population for abnormal radiosensitivity; such persons would be regarded as at presumptive elevated risk of radiogenic cancer. Our method utilizes lymphoblastoid cell lines and chronic as opposed to acute gamma-ray exposure to amplify the difference between normal and somewhat sensitive strains. A simple "grow-back" assay assesses the survival response. Information on the extent of natural variation in inherited susceptibility to radiogenic cancers could be most useful for radiation protection in the future.


Lecithin: cholesterol acyltransferase in Down's syndrome.
Based on earlier reports indicating that Down's syndrome may represent an atheroma-free human model, two groups of institutionalized subjects were compared with respect to various parameters of their plasma lipid transport system. One group of subjects was comprised of Down's syndrome subjects and the second, a group of mentally retarded individuals. Parameters measured included plasma cholesterol, triglyceride, HDL-cholesterol, apolipoprotein levels (A-I, B, C-III, and E), lecithin:cholesterol acyltransferase (LCAT) activity, body mass and blood pressure. Statistical analyses indicated no significant differences between the two groups except for the lower fractional rate of cholesterol esterification (% cholesterol esterified per hour, p = 0.0049) in the Down's syndrome subjects. Adjustment for the effects of body mass and age revealed no other significant differences between the two groups except for a lower molar rate of esterification (nmol cholesterol esterified X h-1 X ml-1, p less than 0.0063) in the Down's syndrome subjects. Additional differences between the two groups were revealed by partial correlational analyses of LCAT activity with the measured parameters or ratios of these parameters which suggests that the composition and/or metabolism of lipoproteins may differ between these two groups. Whether the lower LCAT activity and the other differences reflected by the correlational analyses contribute to the decreased incidence of atherosclerotic lesions in Down's syndrome remains to be elucidated.


Outcomes of Transcatheter and Surgical Aortic Valve Replacement in Patients on Maintenance Dialysis.
The introduction of transcatheter aortic valve replacement (TAVR) expanded definitive therapy of aortic stenosis to many high-risk patients, but it has not been fully evaluated in the dialysis population. We aimed to evaluate the current trend and in-hospital outcome of surgical aortic valve replacement (SAVR) and TAVR in the dialysis population. Severe aortic stenosis patients on maintenance dialysis who underwent SAVR or TAVR in the Nationwide Inpatient Sample database from January 1, 2005, through December 31, 2014, were included in our comparative analysis. The trends of SAVR and TAVR were assessed. In-hospital mortality, rates of major adverse events, hospital length of stay, cost of care, and intermediate care facility utilization were compared between the 2 groups using both unadjusted and propensity-matched data. Utilization of aortic valve replacement in dialysis patients increased 3-fold; a total of 2531 dialysis patients who underwent either SAVR (n = 2264) or TAVR (n = 267) between 2005 and 2014 were identified. Propensity score matching yielded 197 matched pairs. After matching, a 2-fold increase in in-hospital mortality was found with SAVR compared with TAVR (13.7% vs 6.1%, P = .021). Patients who underwent TAVR had more permanent pacemaker implantation (13.2% vs 5.6%, P = .012) but less blood transfusion (43.7% vs 56.8%, P = .02). Rates of other key morbidities were similar. Hospital length of stay (19 ± 16 vs 11 ± 11 days, P <.001) and non-home discharges (44.7% vs 31.5%, P = .002) were significantly higher with SAVR. Cost of hospitalization was 25% less with TAVR. In patients on maintenance dialysis, TAVR is associated with lower hospital mortality, resource utilization, and cost in comparison with SAVR.


Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model.
Oxidative stress contributes to atherosclerosis, and evidence of enhanced oxidative stress exists in antiphospholipid syndrome (APS). In a non-lupus murine model, we evaluated whether anticardiolipin (aCL) antibodies could affect the oxidant/antioxidant balance as an early biochemical step of APS. Hybridomas producing human and murine aCL and anti-beta(2)-glycoprotein I (abeta2-GPI) monoclonal antibodies were injected into three groups of five female BALB/c severe combined immunodeficiency (SCID) mice. Corresponding hybridomas secreting non-antiphospholipid antibodies of the same isotype were employed as controls. Sera and organs were collected after 30 days. Paraoxonase (PON) activity, peroxynitrite, superoxide, nitric oxide (NO) and nitrotyrosine were measured in plasma. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) was assessed by western blot and immunohistochemistry. PON activity and NO (sum of nitrate and nitrite) levels were reduced in the human aCL IgG group (P<0.002 and P<0.04, respectively), whilst peroxynitrite and superoxide and expression of total antioxidant capacity of plasma were increased (P<0.01). PON and NO were decreased in the murine abeta2-GPI IgG and IgM aCL groups (P<0.03 and P<0.05, respectively). Nitrotyrosine was elevated in the human aCL IgG group (P<0.03). Western blotting showed reduced iNOS expression in the hearts of the IgG aCL group, confirmed by immunostaining. PON inversely correlated with IgG aCL titres (P<0.001), superoxide (P<0.008) and peroxynitrite levels (P<0.0009). Peroxynitrite and total IgG aCL were independent predictors of PON (P<0.0009 and P<0.02, respectively). Superoxide was the only independent predictor of NO (P<0.008) and of nitrotyrosine (P<0.002). aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.


Using a standardized follow-up program to improve coronary heart disease secondary prevention.
To reveal the current status and effectiveness of a standardized follow-up of the secondary prevention of coronary heart disease (CHD) at Peking University First Hospital. The study group comprised 496 patients diagnosed with CHD between January 1, 2007 and December 31, 2009 after a standardized follow-up program began. A group of 300 patients with CHD diagnosed between January 1, 2004 and December 31, 2004 was evaluated as the control group. The study group participants were followed-up every 3 months for 1 year in the outpatient department and were interviewed by telephone between November 2012 and January 2013. Data on the control of risk-factors, medical therapy, and clinical events were collected. At discharge, 75.4% of the study group patients were non-smokers, 51.4% exercised regularly, 42.4% were overweight, 56.7% had blood pressure <140/90 mm Hg (<130/80 in those with diabetes mellitus), 51% had serum low-density-lipoprotein cholesterol <2.60 mmol/L, and 64.2% had fasting plasma glucose <6.11 mmol/L. Antiplatelet medication was used by 99.4% of the study group patients, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers by 64.5%, beta-blockers by 79.1%, and statins by 94.3%. Major adverse cardiac events, the primary clinical outcome, occurred in 22.7% of the study group patients. The proportions of non-smokers (82.2% vs. 73.7%, p=0.014), control of serum lipids (84.4% vs. 45.6%, p<0.001), and use of statins (92.5% vs. 54.3%, p<0.001) at the end of follow-up were significantly greater in the study group than those in the control group. Although some patients with CHD were still not achieving the goals of lifestyle change, control of risk factors, and medication therapy, standardized follow-up helped improve and standardize CHD secondary prevention.


Singleton birth at term: an old alarm or a new debate?
In 2004, Human Reproduction published a debate series focusing on the rising tide of multiple pregnancy associated with IVF. The premise of the primary report in that debate was that by considering IVF outcomes differently-by focusing on healthy singleton birth at term rather than clinical pregnancy, the standard currency at that time-the necessary shift toward reduced numbers of embryos transferred might be accelerated. The choice of end-point in that debate-Birth Emphasizing a Successful Singleton at Term (BESST)-was not an effort to 'dumb down' the complex equation linking risks and benefits. That balance is a dynamic and various mix of issues that clinicians discuss with patients on a daily basis. And BESST was certainly not proposed as a new primary outcome for application to other treatment modalities in reproductive medicine, such as ovulation induction. It was simply a responsible and brave call for change in the accelerating and competitive world of IVF.


Is a smartphone application as accurate as a traditional goniometer for assessing finger joint angles in Dupuytren's disease?
Smartphone applications are available using the smartphone accelerometer to measure angles. This study compared finger joint angle measurements using a traditional goniometer (TG) versus a smartphone application (SPA) in a group of patients with Dupuytren's disease, to determine if they were equally accurate. This was a clinical measurement case series. A group of patients with Dupuytren's disease were invited to participate. The Apple iPhone 7 "Measure" application was used. Participants were asked to place their hand as flat as possible on the table in a clinic room. Each joint of the ring and little fingers was measured using the TG and the SPA. Power calculation by paired t-test determined a sample size of 25. 28 hands were measured. The Pearson correlation coefficients for the various finger joints were: metacarpophalangeal joint (MCPJ), 0.989; proximal interphalangeal joint (PIPJ), 0.997; and distal interphalangeal joint (DIPJ), 0.977. The root mean square errors (RMSE) for the various joints were: MCPJ, 3.190; PIPJ, 2.019; and DIPJ, 1.897. Bland-Altman analysis showed the two methods to be in agreement. The SPA was consistent, reliable and in agreement with a TG for assessing ring and little finger joint angles. The SPA could be used by healthcare professionals instead of a TG.


Burden of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Asthmatic Children.
Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are the leading causes of acute respiratory illness in children. Clinical burden of each infection on the respiratory distress in asthmatic patients remains unclear. The purpose of the study was to clarify the effect of these infections on the severity of asthmatic children in the seasonal outbreaks. A total of 1,217 pediatric inpatients with hMPV (n = 114) or RSV (n = 1,103) infection in Yamaguchi prefecture, Japan, between 2011 and 2014 were enrolled. Bronchial asthma was defined as having more than 3 episodes of wheezing illness over 1 year of age. Infection was determined by the positive antigen test for each virus in the nasal specimens. The number of patients peaked at age 12-15 months in hMPV infection and at age 0-3 months in RSV infection. The proportion of hypoxic patients (40-50%) did not differ at any age between hMPV-infected and RSV-infected children. In the analysis of date from > 1 year old patients with hypoxia, hMPV-infection group was older (P = 0.036), and more frequently had history of asthma (P = 0.015) or abnormal chest roentgenogram (P < 0.001) than RSV-infection group. Multivariate analysis indicated that the hypoxia-associated factors were history of asthma in both hMPV (odds ratio [OR]: 15.8; P < 0.001) and RSV infections (OR, 2.2; P = 0.005), higher body temperature in hMPV infection (OR, 2.2; P = 0.009), and younger age in RSV infection (OR, 1.4; P = 0.004). Outbreaks of hMPV, rather than, RSV infection may have a greater impact on the development of hypoxic respiratory illness in asthmatic children.


All-trans-retinoic acid inhibits the growth of human rhabdomyosarcoma cell lines.
We have been evaluating the role of all-trans-retinoic acid (RA) in the differentiation and growth of human rhabdomyosarcoma (RMS) cell lines. Treatment of both embryonal (RD) and alveolar (RH30) human RMS cell lines with all-trans-RA resulted in a dose-dependent inhibition of cell growth with a maximal inhibition of 92 and 66%, respectively, at 5 x 10(-6) M. When 13-cis-RA was used under identical experimental conditions, maximal growth inhibition was 41 and 37%, respectively. This stereo-specific growth inhibition was not associated with morphological or biochemical evidence of myogenic differentiation. Furthermore, all-trans-RA demonstrated no evidence of competition with binding of insulin-like growth factor II (IGF-II), an autocrine growth factor in RMS, to its membrane receptor as evaluated by an [125I]IGF-I-receptor-binding assay. Attempts to rescue all-trans-RA growth-inhibited RMS cells with exogenous IGF-II resulted in no increase in growth compared to cells treated with all-trans-RA alone. We conclude that RA inhibits the growth of human RMS cell lines in a dose-dependent, stereo-specific manner, is not associated with differentiation, and does not appear to be directly related to IGF-II.


Single-shot phase imaging with a coded aperture.
We present a method of quantitatively acquiring a large complex field, containing not only amplitude information but also phase information, based on single-shot phase imaging with a coded aperture (SPICA). In SPICA, the propagating field from an object illuminated by partially coherent visible light is sieved by a coded mask, and the sieved field propagates to an image sensor, where it is captured. The sieved field is recovered from the single captured intensity image via a phase retrieval algorithm with an amplitude support constraint using the mask pattern, and then the object's complex field is reconstructed from the recovered sieved field by an algorithm employing a sparsity constraint based on compressive sensing. The system model and the theoretical bounds of SPICA are derived. We also verified the concept with numerical demonstrations.


Cognitive-Behavioral and Psychodynamic Therapy in Adolescents with Social Anxiety Disorder: A Multicenter Randomized Controlled Trial.
Although social anxiety disorder (SAD) has an early onset and is frequently found in adolescence, evidence for psychotherapeutic treatments of SAD in adolescents is rather scarce. Within the Social Phobia Psychotherapy Research Network (SOPHO-NET), we examined the efficacy of cognitive-behavioral (CBT) and psychodynamic therapy (PDT) compared to a waiting list (WL) in these patients. In a multicenter randomized controlled superiority trial, 107 patients, aged 14-20 years, were randomized to CBT (n = 34), PDT (n = 34), or WL (n = 39). Assessments were made at baseline, at the end of treatment, and 6 and 12 months after termination. The Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA) applied by raters masked to the treatment condition was used as the primary outcome. As secondary outcomes, rates of response and remission and the Social Phobia Anxiety Inventory (SPAI) were used. Both treatments were superior to WL in the LSAS-CA (CBT: p = 0.0112, d = 0.61, 95% CI 0.14-1.08; PDT: p = 0.0261, d = 0.53, 95% CI 0.06-1.00). At the end of treatment, response rates were 66, 54, and 20% for CBT, PDT, and WL. The corresponding remission rates were 47, 34, and 6%, respectively. CBT and PDT were significantly superior to WL regarding remission (CBT: p = 0.0009, h = 1.0; PDT: p = 0.0135, h = 0.74), response (CBT: p = 0.0004, h = 0.97; PDT: p = 0.0056, h = 0.72), and the SPAI (CBT: p = 0.0021, d = 0.75, 95% CI 0.27-1.22; PDT: p = 0.0060, d = 0.66, 95% CI 0.19-1.13). Treatment effects were stable at 6- and 12-month follow-ups. These results are comparable to the large SOPHO-NET trial in adults (n = 495). Early treatments for social anxiety are needed in order to prevent chronic manifestation of SAD.


Integral equation theory for two-dimensional polymer melts.
The polymer reference interaction site model theory is investigated for two-dimensional polymer melts composed of freely-jointed hard disk chains and tangent-disk rods. Exact results for the intramolecular pair correlation functions are input into the theory, and predictions of the theory for the intermolecular pair correlation functions are tested via comparison with simulation. The theory is not as accurate for this system as it is for three-dimensional polymer melts, and the quantitative predictions are not good except at the highest area fractions. Possible reasons for the deficiency in the theory are discussed.


Evidence for a post-Columbian introduction of human T-cell lymphotropic virus [type I] [corrected] in Latin America.
To investigate the origin and dissemination of human T-cell lymphotropic virus type I in Latin America, we performed phylogenetic analysis on the LTR and env sequences of 13 HTLV-I isolates from Peruvians of four different ethnic groups: blacks and some mulattos of African origin; Quechuas of Inca origin; Nikkei of Japanese descendance; and Mestizos, a mixed population of white and Indian origin. All Peruvian samples could be situated within the cosmopolitan subtype HTLV-Ia, yet one sample showed an indeterminate Western blot pattern, lacking reactivity towards the HTLV-I type specific MTA1 peptide. Within the LTR, we could confirm the previously reported subdivision into four subgroups--one big transcontinental clade A, a Japanese clade B, a West African/Caribbean clade C and a North African clade D--and we identified a new separate subgroup E of black Peruvian strains. The clustering of the Peruvian samples seemed to depend on the ethnic origin of the host. The largest heterogeneity was observed in the black Peruvian samples. The mitochondrial DNA type of one of these black Peruvian strains of subgroup E was identical to that of West African source populations of the slave trade. Both findings support the idea of multiple post-Columbian introductions of African HTLV-Ia strains into the black Latin American population. Additionally, a tight cluster of Nikkei and Japanese samples implied a separate and rather recent transmission of a Japanese lineage of HTLV-I into Peru. A well-supported cluster of Latin American strains (including Peruvian Quechuas and Colombian Amerindians) could be situated within the transcontinental group. Molecular clock analysis of the Latin American and Japanese clade resulted in an equal evolutionary rate for those strains. Along with the anthropologically documented peopling of the Americas, the analysis was more in favour of a recent (400 to 100 years ago) introduction of HTLV-Ia into the American continent rather than a Palaeolithic introduction.


Albuminuria is evident in the early stages of diabetes onset: results from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).
Albuminuria is a common complication of diabetes and a leading cause of end-stage renal disease. We determined the prevalence of and factors associated with albuminuria in an Australian population and examined the association of albuminuria with glucose tolerance. The Australian Diabetes, Obesity, and Lifestyle Study included 11,247 adults aged 25 years and older from 42 randomly selected areas of Australia. Microalbuminuria is defined as an albumin-creatinine ratio of 22 to 220 mg/g (2.5 to 25 mg/mmol) in men and 31 to 220 mg/g (3.5 to 25 mg/mmol) in women, and macroalbuminuria is defined as an albumin-creatinine ratio of 220 mg/g or greater (> or =25.0 mg/mmol). Overall, 25.3% of patients with diabetes mellitus (known [KDM] and newly diagnosed [NDM], type 1 and type 2) had evidence of albuminuria (21.0%, microalbuminuria; 4.3%, macroalbuminuria). Prevalence increased with increasing glycemia (normal glucose tolerance [NGT], 5.1%; impaired fasting glucose [IFG], 9.3%; impaired glucose tolerance, 11.0%; NDM, 17.8%; and KDM, 32.6% [type 2 only]). Patients with diabetes (KDM and NDM) and IFG had an increased risk for albuminuria compared with those with NGT independent of age, sex, and other known risk factors for albuminuria. Logistic regression modeling identified age, duration of diabetes, systolic blood pressure, current smoking, body mass index, and glycated hemoglobin level as independent risk factors for albuminuria. This Australian population-based study shows that albuminuria is common among patients with established diabetes, is present before the onset of diabetes, and becomes more prevalent with worsening glucose tolerance.


Outcomes of activity-based assessment (BIA) compared with standard assessment in occupational therapy.
This study was aimed at investigating the outcomes of an activity-based assessment (BIA) compared with standard assessment (SA) for evaluating clients undergoing psychiatric occupational therapy. Patients admitted to a psychiatric occupational therapy unit were randomized into the BIA or the SA assessment. The outcome indicators were (a) clients' satisfaction with the occupational therapy during the assessment period, (b) clients' awareness of capacities and occupational problems, (c) satisfaction with the assessment among the referring physicians, and (d) outcomes of the intervention following the assessment, in terms of changes in occupational performance and satisfaction. The groups did not differ in awareness of occupational problems, but the BIA group was more satisfied than the SA group with the support of their contact person and with the group leader during the period of assessment. Furthermore, physicians receiving feedback on patients in the BIA group were more satisfied than those receiving feedback on patients in the SA group. However, the groups did not differ concerning change during the treatment period in occupational performance or satisfaction. Thus, there was no difference between the assessment methods regarding the outcomes of the treatment following assessment. Minor advantages from the patients' perspective were found, in terms of better satisfaction in the BIA group, and from the referring physicians' perspective the BIA clearly seemed more satisfying than the SA. Thus, the findings showed that the BIA possessed better qualities than the SA regarding the indicators pertaining to satisfaction, but not concerning awareness of capacities and problems or the outcome of the subsequent treatment.


Speech intelligibility, loneliness, and sense of coherence among deaf and hard-of-hearing children in individual inclusion and group inclusion.
This study examined the sense of coherence and loneliness of 19 children aged 12-14 years with severe to profound hearing loss. These feelings and their interrelations with speech intelligibility (SI) were examined in 2 settings: in special classes within regular schools (group inclusion) or individuals integrated into regular classes (individual inclusion). Two self-report measures (Loneliness Questionnaire and Sense of Coherence Scale) and one SI measure were utilized. Results indicated no significant differences between sense of coherence and loneliness scores of children in the 2 settings. Children in group inclusion received a significantly lower average SI score than did children who were in individual inclusion. Examination of the relations between SI and loneliness and coherence in each educational setting revealed no significant relations among these measures for the children in the group inclusion, whereas significant correlations did emerge for the children who were in individual inclusion. The study emphasized the importance of good SI not only for basic communication but also as a factor that affects the child's social and emotional feelings. In selecting a school setting, it is important to look beyond academic factors and not to ignore the significant effect of SI on the child's well being in school.


Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor.
A major unanswered question concerning "pain" circuitry is the extent to which different populations of primary afferent nociceptor engage the same or different ascending pathways. In the present study, we followed the transneuronal transport of a genetically expressed lectin tracer, wheat germ agglutinin, in Na(V)1.8-expressing nociceptors of the nonpeptide class. We found that interneurons of lamina II are at the origin of the major ascending circuits targeted by the nonpeptide nociceptors. These interneurons contact lamina V projection neurons, which in turn predominantly target fourth-order neurons in the amygdala, hypothalamus, bed nucleus of the stria terminalis, and to a remarkable extent, the globus pallidus. These circuits differ greatly from the lamina I-based projection that is targeted by the peptide class of nociceptors. Our results indicate that parallel, perhaps independent pain pathways arise from different nociceptor classes and that motor as well as limbic targets predominate in the circuits that originate from the nonpeptide population.


Targeting the PI3K Pathway in Head and Neck Squamous Cell Carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosal epithelia in the head and neck region. The most common risk factors are tobacco use, alcohol consumption, and HPV infection, particularly in the oropharynx. The HPV-positive HNSCC is biologically and clinically distinct from the HPV-negative HNSCC; however, deregulations within the phosphatidylinositol 3-kinase (PI3K) pathway are frequent in both HPV-positive and HPV-negative HNSCC as it is the most frequently altered oncogenic pathway with a gain-of-function in HNSCC. This article reviews the basic biology and clinical data from the trials involving anticancer agents targeting the PI3K pathway in HNSCC. It also discusses the difficulties of translating the preclinical data to tangible clinical efficacy of these agents in patients with HNSCC even when there is significant preclinical data suggesting the PI3K pathway is a promising therapeutic target in HNSCC. We conclude that additional studies to determine appropriate patient selection for the activation of PI3K pathway and to develop targeted agents either as a monotherapy or combination therapy with favorable toxicity profiles are required before a broader clinical application.


[Use of the Triangle of Care Card and its influence on the cooperation with caregivers and clients].
Although there is consensus on the importance of involving informal caregivers of people with severe mental illness, interventions are needed to support this. To explore whether the use of the 'Triangle of Care Card', an instrument developed to help strengthen the role of care-givers in their contact with workers, increases quality of cooperation and care. Three outpatient mental health teams and twelve teams for supported housing started working with the card. Information from files and questionnaires were used to monitor change and compare this with the changes during the same year in ten other teams. Use of the Triangle of Care Card was sparse. When it was used, a broader range of subjects were discussed, including the needs of caregivers. Also, clients were more involved. In teams where the card was introduced, the clients' networks became more apparent and there was an increase in face-to-face meetings with members of this network. Introduction of the Triangle of Care Card leads to change in the involvement of caregivers. However, implementation is problematic and therefore the increase in quality of the cooperation with caregivers and quality of care is yet small.


What constitutes vulnerable self-esteem? Comparing the prospective effects of low, unstable, and contingent self-esteem on depressive symptoms.
A growing body of longitudinal studies suggests that low self-esteem is a risk factor for depression. However, it is unclear whether other characteristics of self-esteem, besides its level, explain incremental or even greater variance in subsequent depression. We examined the prospective effects of self-esteem level, instability (i.e., the degree of variability in self-esteem across short periods), and contingency (i.e., the degree to which self-esteem fluctuates in response to self-relevant events) on depressive symptoms in 1 overarching model, using data from 2 longitudinal studies. In Study 1, 372 adults were assessed at 2 waves over 6 months, including 40 daily diary assessments at Wave 1. In Study 2, 235 young adults were assessed at 2 waves over 6 weeks, including about 6 daily diary assessments at each wave. Self-esteem contingency was measured by self-report and by a statistical index based on the diary data (capturing event-related fluctuations in self-esteem). In both studies self-esteem level, but not self-esteem contingency, predicted subsequent depressive symptoms. Self-esteem instability predicted subsequent depressive symptoms in Study 2 only, with a smaller effect size than self-esteem level. Also, level, instability, and contingency of self-esteem did not interact in the prediction of depressive symptoms. Moreover, the effect of self-esteem level held when controlling for neuroticism and for all other Big Five personality traits. Thus, the findings provide converging evidence for a vulnerability effect of self-esteem level, tentative evidence for a smaller vulnerability effect of self-esteem instability, and no evidence for a vulnerability effect of self-esteem contingency.


Improvement of Corneal Nerve Regeneration in Diabetic Rats Using Wharton's Jelly-Derived Mesenchymal Stem Cells and their Conditioned Medium.
To investigate the efficacy of Wharton's jelly mesenchymal stem cells (WJSCs) and their conditioned medium (CM) for corneal nerve regeneration in rats with diabetic keratopathy. Streptozotocin (STZ)-induced male diabetic (DM) rats (250-300 g) were divided into four groups (n=7/group): Control, DM, DM with WJSCs (DM+WJ), and DM with CM treatment (DM+CM). DM+WJ and DM+CM group received WJSCs or CM, respectively, topically with eye drops. Corneal sensibility, corneal epithelial layer integrity, histology, expression of GAP-43 and TUBB3 on mRNA level and their immunohistochemical expression were examined after two weeks of treatment. There were changes in corneal sensibility and corneal integrity between normal control and diabetic groups with/without WJSC or CM injection. Total central corneal thickness was significantly higher in DM+CM (249.81 ± 43.85 μm) than in control (174.72 ± 44.12 μm, P=0.004) and DM groups (190.15 ± 9.63 μm, P=0.03). GAP-43 mRNA expression levels of DM+WJ and DM+CM groups were higher compared with DM and control groups. TUBB3 mRNA level was increased after CM (P=0.047), but not after WJSCs treatment (P=1.00). GAP-43 and TUBB3 immunohistochemical expression of nerve fibers along the epithelial layer significantly increased in DM+WJ and DM+CM compared with DM group. Our findings showed that WJSCs and their CM improved corneal nerve regeneration in rats with diabetic keratopathy.


Interference control of nonlinear excitation in a multi-atom cavity quantum electrodynamics system.
We show that by manipulating quantum interference in a multi-atom cavity quantum electrodynamics (CQED) system, the nonlinear excitation of the cavity-atom polariton can be resonantly enhanced while the linear excitation is suppressed. Under the appropriate conditions, it is possible to selectively enhance or suppress the polariton excitation with two free-pace laser fields. We report on an experiment with cold Rb atoms in an optical cavity and present experimental results that demonstrate such interference control of the CQED excitation and its direct application to studies of all-optical switching and cross-phase modulation of the cavity-transmitted light.


Upper airway and tracheostomy management in patients with COVID-19: A long-term acute care hospital (LTACH).
Describe the tracheostomy and ventilation management of patients admitted due to COVID-19 as facilitated by speech language pathologists (SLPs) and otolaryngologists within the long-term acute care hospital (LTACH) setting. Retrospective cohort study. Long-term acute care hospital. A retrospective chart review was conducted on all patients admitted to RML Specialty Hospital for respiratory failure secondary to COVID-19 from April 1, 2020 to November 30, 2021. Demographic information, laryngeal findings, and tracheostomy management was reviewed. Descriptive statistics and chi-square analysis were performed. Amongst the 213 subjects, 80.0 % arrived on mechanical ventilation. 23.0 % required otolaryngology consultation during LTACH stay due to poor Passy Muir Valve (PMV) or tracheostomy capping tolerance. 35 (71.4 %) of those consulted had abnormal laryngeal findings on exam with subglottic/tracheal stenosis and laryngeal edema being most common at 38.8 % and 20.4 %, respectively. 28.6 % of those with laryngeal findings were decannulated by discharge. Mechanical ventilator weaning and decannulation success were 86.6 % and 62.5 %, respectively. No association (p > 0.05) between number of intubations and abnormal laryngeal findings were found. No association (p > 0.05) between number of intubations or prone-positioning and decannulation success at discharge were found. LTACHs can serve a specific role in upper airway rehabilitation and tracheostomy care in the post COVID-19 period. SLPs and otolaryngologists should be involved in the care of these patients to help facilitate decannulation and return to normal laryngeal function.


[Analysis of Regularity of Acupoint Selection in Acupuncture Treatment of Urticaria Based on Data Mining Technology].
To analyze the regularity of acupoint selection, main acupoints and theoretical basis in acupuncture treatment of urticaria. Papers collected from the time of establishment of each database to September of 2017 were retrieved from databases CNKI, CBM, VIP and WF by using keywords of "acupuncture" "moxibustion" "blood-letting therapy" "autohemotherapy" "cupping" "acupoint catgut embedding" "auricular points" "acupoint injection" "fire-needle" (or red-hot needle), "dermal needle" "needle-embedding" "urticaria" in both Chinese and English. The collected papers were brought into analysis according to the inclusion and exclusion criteria, from which the prescriptions for acupuncture treatment of urticaria were subjected into descriptive statistical analysis, association rule analysis, and cluster analysis by using Access 2010, Clementine 18.0 and Stata software. Outcomes of analysis indicated that the treatment methods of urticaria with acupuncture and moxibustion, with different emphases, may be classified into eight categories. For treating the exterior syndrome of urticaria, acupoints of the Bladder Meridian, Governor Vessel and Conception Vessel were often employed to harmonize Ying and Wei and to dispel the pathogenic wind, while for treating the interior syndrome, acupoints of the Large Intestine Meridian, Spleen Meridian, and Stomach Meridian were usually used to invigorate the spleen to dispel dampness and to regulate blood circulation. The top five frequently used acupoints were Quchi (LI 11), Xuehai (SP 10), Zusanli (ST 36), Sanyinjiao (SP 6) and Geshu (BL 17). It was crucial to make use of the specific acupoints with adequate meridian-qi, such as He-Sea points, Back-Shu points, and Yuan-Primary points. There were some fixed forms in the combination of acupoints, including LI 11, SP 10, Dazhui (GV 14) and auricular Lung, Shenmen, Fengxi, Adrenal gland, which had the highest confidence coefficient for the meridian points and ear acu-points, respectively. The outcomes of cluster analysis about the acupoint prescriptions showed that 12 acupoint groups as the SP 6-Hegu (LI 4)-LI 11-SP 10-ST 36, etc. were frequently used. The regularity of acupuncture treatment of urticaria can be discovered using data mining technology, resulting in an in-depth understanding and having a solid theoretical basis.


Salivary metabolite signatures of oral cancer and leukoplakia through gas chromatography-mass spectrometry.
Saliva contains a large array of metabolites, many of which can be informative for the detection of diseases. Gas chromatography-mass spectrometry (GC-MS) is a system that has long been used for metabolite profiling owing to its sensitivity, specificity, reproducibility and synchronized analysis; it has relatively broad coverage of compound classes including sugars, sugar alcohols, glycosides and lipophilic compounds. The present study was conducted to explore the use of GC-MS in assessing variation in salivary metabolites and to recognize the metabolites which can be used as disease diagnostic tools and metabolite markers for detection of oral squamous cell carcinoma. The present study included clinically and histopathologically confirmed oral squamous cell carcinoma (OSCC) and oral leukoplakia patients (OLK) and the control group. Patients were divided into three groups: OSCC (n = 30), OLK (n = 30) and healthy individuals as controls (n = 30). Patients were refrained from eating, drinking, smoking or oral hygiene procedures for at least 1.5 h before the collection. Saliva was collected between 9.00 and 10.00 am. Samples were stored at -80°C. Filtered samples were used for GC-MS. Fifteen compounds differed significantly between control, OLK and OSCC. These metabolites were decanedioic acid, 2-methyloctacosane, eicosane, octane, 3,5-dimethyl, pentadecane, hentriacontane, 5, 5-diethylpentadecane, nonadecane, oxalic acid, 6-phenylundecanea, l-proline, 2-furancarboxamide, 2-isopropyl-5-methyl-1-heptanol, pentanoic acid, Docosane. The findings of the study suggest the application of salivary metabolomics as a promising tool in the identification of tumor-specific biomarkers in early diagnosis and prediction of OSCC and oral leukoplakia. In future, standardizing the protocol for salivary analysis and overcoming some of the limitations will be helpful to establish salivary metabolomics as a reliable, the highly sensitive and specific method for clinical use as an independent diagnostic aid.


Risk patterns and correlated brain activities. Multidimensional statistical analysis of FMRI data in economic decision making study.
Decision making usually involves uncertainty and risk. Understanding which parts of the human brain are activated during decisions under risk and which neural processes underly (risky) investment decisions are important goals in neuroeconomics. Here, we analyze functional magnetic resonance imaging (fMRI) data on 17 subjects who were exposed to an investment decision task from Mohr, Biele, Krugel, Li, and Heekeren (in NeuroImage 49, 2556-2563, 2010b). We obtain a time series of three-dimensional images of the blood-oxygen-level dependent (BOLD) fMRI signals. We apply a panel version of the dynamic semiparametric factor model (DSFM) presented in Park, Mammen, Wolfgang, and Borak (in Journal of the American Statistical Association 104(485), 284-298, 2009) and identify task-related activations in space and dynamics in time. With the panel DSFM (PDSFM) we can capture the dynamic behavior of the specific brain regions common for all subjects and represent the high-dimensional time-series data in easily interpretable low-dimensional dynamic factors without large loss of variability. Further, we classify the risk attitudes of all subjects based on the estimated low-dimensional time series. Our classification analysis successfully confirms the estimated risk attitudes derived directly from subjects' decision behavior.


Hydroxyproline heterooligosaccharides in Chlamydomonas.
Most of the hydroxyproline in Chlamydomonas reinhardtii is glycosidically linked to oligosaccharides and a monosaccharide that are different from the arabinosides found in hydroxyproline-containing plant cell walls previously examined. Of particular interest is the presence of hydroxyproline-O-galactose. These differences may be common to the volvocalean green algae and may be related to lower tensile strength of the cell walls of this group of plants.


Muscle Atrophy at Presentation of Cubital Tunnel Syndrome: Demographics and Duration of Symptoms.
Background: The purpose of this study is to describe the demographics and duration of symptoms of patients with cubital tunnel syndrome who present with muscle atrophy. Methods: We identified 146 patients who presented to the hand surgery clinic at a single institution over a 5-year period with an initial diagnosis of cubital tunnel syndrome based on history and physical examination. Medical records were retrospectively reviewed to determine if there was a difference in demographic data, physical examination findings, and duration of symptoms in patients who presented with muscle atrophy from those with sensory complaints alone. Results: A total of 17/146 (11.6%) of patients presented with muscle atrophy, all of which were men. In all, 17.2% of men presented with atrophy. Age by itself was not a predictor of presentation with atrophy; however, younger patients with atrophy presented with significantly shorter duration of symptoms. Patients under the age of 29 years presenting with muscle atrophy on average had symptoms for 2.4 months compared with 16.2 months of symptoms for those over 55 years of age. Conclusions: Men with cubital tunnel syndrome are more likely to present with muscle atrophy than women. Age is not necessarily a predictor of presentation with atrophy. There is a subset population of younger patients who presents with extremely short duration of symptoms that rapidly develops muscle atrophy.


Patient participation in general practice: who participates?
A postal survey of 4066 men and women aged between 16 and 64 years was carried out in a general practice in Oxfordshire which had a patient participation group, established in 1972. The aim of the survey was to ascertain the knowledge and use of the group among adults aged 16-64 years. The adjusted response rate was 73%. Despite the length of the group's existence only 45% of these patients were aware of it and only 7% had ever attended a meeting. Awareness of the group and sometime attendance were significantly less in men, patients aged between 16 and 29 years, those in social classes 4 and 5, single people and those who smoked. Patients who consulted more than four times per year were more likely to be aware of the group than less frequent consulters. The possible reasons for the unrepresentative nature of the patients attending the group are discussed, together with implications for practice policies and development. Various strategies for making the group more representative are proposed, including advertising within the practice and elsewhere, and the formation of special interest groups for patients with defined medical and social needs, in the hope that this will make the concept of patient participation more relevant.


An overview of the outreach of the 2019-2021 Endo-ERN knowledge generation webinars.
The current study aims to assess the development of the knowledge generation program of the European Reference Network on Rare Endocrine Conditions (Endo-ERN) from its start in 2019 until December 2021, with special reference to webinars. We analyzed the number of webinars and live/postevent participants and whether participation and engagement of the attendees changed over time. A total of 30 (86%) self-prepared webinars comprising 300 h of knowledge and competence sharing were broadcasted (2019 - 3; 2020 - 13; 2021 - 14). A total of six webinars were broadcasted live prior to the coronavirus disease 2019 pandemic (https://endo-ern.eu/events/webinars/). The most active main thematic group (MTG) was MTG3 Genetic Disorders of Glucose and Insulin Homeostasis with eight (27%) webinars. Two (25%) MTGs fulfilled the goal to prepare at least two to three webinars per year. Patients were actively involved in 20% of the accounted webinars as both creators and presenters. The total number of live and postevent participants was 3023. The availability of the webinars after the live broadcast increased their outreach with a larger number of postevent viewers (n = 1629, 54%). Within the formal structured evaluation of the webinars, 40-85% of the participants replied on separate occasions and helped improve content. The free webinar access is among the perceived reasons for the rapidly increasing number of total hits to the Endo-ERN website. In conclusion, for its short existence, the Endo-ERN rapidly developed educational outreach, and further efforts to attract creators and learners are warranted.


Diverse circular ssDNA viruses discovered in dragonflies (Odonata: Epiprocta).
Viruses with circular ssDNA genomes that encode a replication initiator protein (Rep) are among the smallest viruses known to infect both eukaryotic and prokaryotic organisms. In the past few years an overwhelming diversity of novel circular Rep-encoding ssDNA (CRESS-DNA) viruses has been unearthed from various hosts and environmental sources. Since there is limited information regarding CRESS-DNA viruses in invertebrates, this study explored the diversity of CRESS-DNA viruses circulating among insect populations by targeting dragonflies (Epiprocta), top insect predators that accumulate viruses from their insect prey over space and time. Using degenerate PCR and rolling circle amplification coupled with restriction digestion, 17 CRESS-DNA viral genomes were recovered from eight different dragonfly species collected in tropical and temperate regions. Nine of the genomes are similar to cycloviruses and represent five species within this genus, suggesting that cycloviruses are commonly associated with insects. Three of the CRESS-DNA viruses share conserved genomic features with recently described viruses similar to the mycovirus Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1, leading to the proposal of the genus Gemycircularvirus. The remaining viruses are divergent species representing four novel CRESS-DNA viral genera, including a gokushovirus-like prokaryotic virus (microphage) and three eukaryotic viruses with Reps similar to circoviruses. The novelty of CRESS-DNA viruses identified in dragonflies using simple molecular techniques indicates that there is an unprecedented diversity of ssDNA viruses among insect populations.


Degradation of chlorophenoxyacetic acids by the lignin-degrading fungus Dichomitus squalens.
We have examined the degradation of 14C ring- and side-chain-labelled 2,4,5-trichlorophenoxyacetic acid by Dichomitus squalens and Phanerochaete chrysosporium. The effects of Mn2+ on the degradation of these radiolabeled substrates by D. squalens and the effect of nitrogen limitation on their degradation by D. chrysosporium suggested that in both fungi, side-chain cleavage was catalysed by a mechanism independent of the lignin degradation system, whereas the degradation of the aromatic ring was dependent on the lignin degradative system. Using unlabelled substrates, a pathway for the degradation of chlorophenoxyacetic acids was elucidated in D. squalens. Time courses for the degradation of unlabelled chlorophenoxyacetic acids by D. squalens demonstrated that the corresponding chlorophenol was the initial product formed. The chlorophenol intermediate was xylosylated to form the chlorophenolxyloside. In turn, the chlorophenolxyloside could be hydrolysed by an intracellular -xylosidase to regenerate the chlorophenol. The chlorophenol product of the xylosidase reaction was oxidatively dechlorinated to form 2-chloro-p-benzoquinone which could undergo subsequent further dechlorination and ring-opening reactions, as has been reported previously for P. chrysosporium.


Streptococcus mutans Displays Altered Stress Responses While Enhancing Biofilm Formation by Lactobacillus casei in Mixed-Species Consortium.
Like Streptococcus mutans, lactobacilli are commonly isolated from carious sites, although their exact role in caries development remains unclear. This study used mixed-species models to analyze biofilm formation by major groups of oral lactobacilli, including L. casei, L. fermentum, L. rhamnosus, L. salivarius ssp. salivarius, and L. gasseri. The results showed that lactobacilli did not form good biofilms when grown alone, although differences existed between different species. When grown together with S. mutans, biofilm formation by L. gasseri and L. rhamnosus was increased by 2-log (P < 0.001), while biofilms by L. fermentum reduced by >1-log (P < 0.001). L. casei enhanced biofilm formation by ~2-log when grown with S. mutans wild-type, but no such effects were observed with S. mutans deficient of glucosyltransferase GtfB and adhesin P1. Both S. mutans and L. casei in dual-species enhanced resistance to acid killing with increases of survival rate by >1-log (P < 0.001), but drastically reduced the survival rates following exposure to hydrogen peroxide (P < 0.001), as compared to the respective mono-species cultures. When analyzed by RNA-seq, more than 134 genes were identified in S. mutans in dual-species with L. casei as either up- or down-regulated when compared to those grown alone. The up-regulated genes include those for superoxide dismutase, NADH oxidase, and members of the mutanobactin biosynthesis cluster. Among the down-regulated genes were those for GtfB and alternative sigma factor SigX. These results further suggest that interactions between S. mutans and oral lactobacilli are species-specific and may have significant impact on cariogenic potential of the community.


An open-Label, 2 × 2 factorial, randomized controlled trial to evaluate the safety of apixaban vs. vitamin K antagonist and aspirin vs. placebo in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention: Rationale and design of the AUGUSTUS trial.
The optimal antithrombotic strategy for patients with atrial fibrillation (AF) who develop acute coronary syndrome (ACS) and/or the need for percutaneous coronary intervention (PCI) is uncertain. The risk of bleeding is a major concern when oral anticoagulation is required to prevent stroke, and concomitant therapy with antiplatelet agents is required to minimize recurrent ischemic events. AUGUSTUS is an international, multicenter randomized trial with a 2 × 2 factorial design to compare apixaban with vitamin K antagonists and aspirin with placebo in patients with AF who develop ACS and/or undergo PCI and are receiving a P2Y12 inhibitor. Patients will be evaluated for eligibility during their ACS and/or PCI hospitalization. The primary outcome is the composite of major and clinically relevant nonmajor bleeding defined by the International Society on Thrombosis and Haemostasis. A key secondary outcome is the composite of all-cause death and all-cause hospitalization. Other secondary objectives are to evaluate ischemic outcomes including the composite of death, myocardial infarction, stroke, stent thrombosis, urgent revascularization, and all-cause hospitalization and each individual component. The aim is to enroll approximately 4,600 patients from around 500 sites in 33 countries. AUGUSTUS will provide insight into the optimal oral antithrombotic therapy strategy for patients with AF and concomitant coronary artery disease. The unique 2 × 2 factorial design will delineate the bleeding effects of various anticoagulant and antiplatelet therapies and generate evidence to guide the selection of the optimal antithrombotic regimen for this challenging group of patients. It is the largest and only prospective randomized trial to investigate in a blinded fashion the risk and benefits of aspirin on top of a non-vitamin K antagonist oral anticoagulant and P2Y12 receptor inhibition.


Action of peptidase inhibitors on methionine5-enkephalin-arginine6-phenylalanine7 (YGGFMRF) and methionine5-enkephalin (YGGFM) metabolism and on electroacupuncture antinociception.
In the spinal cord Met5-enkephalin-Arg6-Phe7 (YGGFMRF) is located in small interneurons of the dorsal and ventral horns. From these storage sites, YGGFMRF can be released by perfusing the subarachnoidal spaces of the spinal cord with artificial spinal fluid containing substance P. In vitro YGGFMRF can be hydrolyzed readily by a dipeptidyl carboxypeptidase. In order to ascertain whether this reaction is physiologically relevant, we measured the content of YGGFMRF and Met5-enkephalin (YGGFM) in subarachnoidal space perfusate in presence and in absence of captopril, bestatin and thiorphan using substance P to activate the release of opioid peptides. Without peptidase inhibitors, the efflux of YGGFMRF and YGGFM was hardly detectable. The addition of captopril to the perfusion medium increased the substance P (10(-7) M)-induced release of YGGFMRF markedly but it increased the efflux of YGGFM to a much smaller extent. When captopril and bestatin were added together the amount of YGGFMRF present in the perfusate was further increased slightly. In contrast, the YGGFM content in the same perfusate was increased greatly by bestatin and only slightly by thiorphan. To characterize the pharmacological profile of these peptidase inhibitors, we compared electroacupuncture antinociception with and without intrathecal injections of captopril and bestatin. This antinociception, as measured by tail-flick latency, was potentiated by the intrathecal injection of captopril and bestatin. These results taken together suggest that YGGFMRF released in the perfusate of the arachnoidal space by substance P is metabolized by both dipeptidyl carboxypeptidase and aminopeptidase.


Hydrogenation of diamond nanowire surfaces for effective electrostatic charge storage.
We report a novel versatile method for writing charged areas on diamond nanowire (DNW) surfaces using an atomic force microscopy (AFM) tip. Transmission electron microscopy (TEM) investigations revealed the existence of abundant plate-like diamond aggregates, which were encased in layers of graphite, forming nano-sized diamond-graphite composites (DGCs) on DNW surfaces. These DGCs are the main feature, acting as charge-trapping centers and storing electrostatic charge. A hydrogenation process has been observed effectively enhancing the charge-trapping properties of these DNW materials. The effective charge trapping properties with hydrogenation are ascribed to the disintegration of the DGCs into smaller pieces, with an overall increase in the metallic nanographitic phase fractions in a dielectric diamond matrix. Moreover, the written charge on the surface can be easily modified, re-written, or completely erased, enabling application in diamond-based re-writable electronic devices. However, excessive hydrogenation degrades the charge-trapping properties, which is attributed to the etching of the DGCs from the surface. This study demonstrates the potential importance of a simple hydrogenation process in effective electrostatic charge trapping and storage for diamond related nanocarbon materials and the role of DGCs to further enhance it.


Anticancer agents for treatment of tumors in the central nervous system by correspondent substituent substitution and elucidation by pattern recognition methods.
Within the United States, primary brain tumors account for 20 to 25 percent of all pediatric cancers. Chemotherapy utilizing a nitrosourea, notably semustine (MeCCNU) and carmustine (BCNU), has shown significant success in the treatment of tumors found in the central nervous system. In silico optimization of molecular properties by substituent substitution that is followed by pattern recognition analysis is utilized in this study to develop 14 novel anti-cancer drugs for the treatment of malignant cancers of the central nervous system. These 14 agents exhibit molecular properties that are suitable for penetration through the blood-brain barrier (BBB). All 14 agents are nitrosoureas having values of Log P ranging from 2.188 to 2.942, and having a constant total of 5 oxygens and nitrogens with zero violations of the Rule of 5 which indicates favorable bioavailability. Value of Log BB (Log [Cbrain/Cblood]) for these agents does not vary from - 0.441 (BB value of 0.362). The formula weight of the agents is highly correlated to molecular volume (r= 0.9848) and total number of atoms (r= 0.9948), but not correlated to number of rotatable bonds (r= 0.1814). Analysis of similarity (ANOSIM) indicated that all 14 new constructs are similar to the parent compound semustine. The Log P value for all 14 agents predicts favorable attributes for penetrating the BBB. Multiple regression analysis established that number of atoms, number of rotatable bonds, and molecular volume are strong prognosticators for molecular weight of this assemblage of pharmaceuticals. This study attests to the efficacy of in silico optimization of molecular substituents followed by pattern recognition analysis to develop new drug designs based on a successful nitrosourea framework for the treatment of malignant tumors of the brain.


Evolution in group-structured populations can resolve the tragedy of the commons.
Public goods are the key features of all human societies and are also important in many animal societies. Collaborative hunting and collective defence are but two examples of public goods that have played a crucial role in the development of human societies and still play an important role in many animal societies. Public goods allow societies composed largely of cooperators to outperform societies composed mainly of non-cooperators. However, public goods also provide an incentive for individuals to be selfish by benefiting from the public good without contributing to it. This is the essential paradox of cooperation-known variously as the Tragedy of the Commons, Multi-person Prisoner's Dilemma or Social Dilemma. Here, we show that a new model for evolution in group-structured populations provides a simple and effective mechanism for the emergence and maintenance of cooperation in such a social dilemma. This model does not depend on kin selection, direct or indirect reciprocity, punishment, optional participation or trait-group selection. Since this mechanism depends only on population dynamics and requires no cognitive abilities on the part of the agents concerned, it potentially applies to organisms at all levels of complexity.


School air quality related to dry cough, rhinitis and nasal patency in children.
Controls for indoor air quality (IAQ) in schools are not usually performed throughout Europe. The aim of this study was to assess the effects of IAQ on respiratory health of schoolchildren living in Norway, Sweden, Denmark, France and Italy. In the cross-sectional European Union-funded HESE (Health Effects of School Environment) Study, particulate matter with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)) and CO(2) levels in a day of normal activity (full classroom) were related to wheezing, dry cough at night and rhinitis in 654 children (10 yrs) and to acoustic rhinometry in 193 children. Schoolchildren exposed to PM(10) >50 microg x m( -3) and CO(2) >1,000 ppm (standards for good IAQ) were 78% and 66%, respectively. All disorders were more prevalent in children from poorly ventilated classrooms. Schoolchildren exposed to CO(2) levels >1,000 ppm showed a significantly higher risk for dry cough (OR 2.99, 95% CI 1.65-5.44) and rhinitis (OR 2.07, 95% CI 1.14-3.73). By two-level (child, classroom) hierarchical analyses, CO(2) was significantly associated with dry cough (OR 1.06, 95% CI 1.00-1.13 per 100 ppm increment) and rhinitis (OR 1.06, 95% CI 1.00-1.11). Nasal patency was significantly lower in schoolchildren exposed to PM( 10) >50 microg x m(-3) than in those exposed to lower levels. A poor IAQ is frequent in European classrooms; it is related to respiratory disturbances and affects nasal patency.


The adverse effect of gentamicin on cell metabolism in three cultured mammary cell lines: "Are cell culture data skewed?"
Many cells are cultured in media that contains an antibiotic to prevent bacterial contamination. Mycoplasma and other bacterial contamination is a serious problem for those involved in cell culture. Antibiotics in the media helps prevent this contamination and make life easier for the investigators; as performing cell culture experiments in antibiotic free media is difficult and requires vigorous sterile technique. There are many reports of antibiotics causing mitochondrial damage. In this study, we tested the effect of gentamicin in culture media on human mammary epithelial MCF-12A and breast cancer MCF-7 and MDA-MB-231 cell lines by real time PCR, immunofluorescent microscopy, lactate assay, DNA damage assay. We found that the addition of gentamicin in media upregulated the gene expression of hypoxia inducer factor 1 alpha (HIF1a), glycolytic enzymes and glucose transporters, compared to the cells cultured in gentamicin free media. Gentamicin also increased the lactate production and inhibited mitochondrial membrane potential of the cell lines. Furthermore, the antibiotics in media induced mitochondrial reactive oxygen species causing DNA damage. We found an increase of 8-hydroxy-2'-deoxyguanosine a product of DNA oxidative damage in the media of MCF-12A, MCF-7 and MDA-MB-231 cell lines. These results showed that normal epithelial and breast cancer cells cultured in the media with gentamicin had increased HIF1a, aerobic glycolysis and DNA oxidative damage. If we use these unhealthy cells in the experiment, all data will be different, compared to cells grown in gentamicin free media. We have studied the detrimental effects of three antibiotics on mitochondrial function in the untransformed MCF-12A human mammary cell line and two human mammary cancer cell lines, MCF-7 and MB-MDA-231. The metabolic changes in all cell lines were dramatically different between those in antibiotic free media versus antibiotic containing media. There was a marked difference in gene expression of glycolytic enzymes, reactive oxygen species production and effects on membrane potential. Ironically, our first studies were done in media containing gentamicin, and repeated studies were done in gentamicin free media. The results were very different. The purpose of this report is to emphasize that metabolic cell culture data may be inaccurate because experiments were performed in cell culture media containing antibiotics. We will present evidence to support this theory.


Stereotactic body radiotherapy for head and neck cancer: an addition to the armamentarium against head and neck cancer.
In the recent years, stereotactic body radiation therapy (SBRT) has emerged as a potential therapy for head and neck malignancies. Although early results appear to be promising, serious acute and late effects have been observed, mainly in patients who have had prior external beam radiotherapy. This review will discuss the radiobiology of SBRT, clinical rationale and outcomes for SBRT in head and neck cancers and focus on the benefits and potential limitations in both de novo and re-irradiation settings.


Intrauterine exposure to perfluorinated compounds and overweight at age 4: A case-control study.
The aims were to investigate the association between maternal serum levels of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorononanoic acid (PFNA) in early pregnancy and overweight in the child at 4 years and to assess potential heterogeneity in exposure effect between strata with different levels of other risk factors for overweight. We used a case-control design and included 354 cases (ISO-BMI ≥ 18 kg/m2) and 2 controls per case (ISO-BMI ≤17 kg/m2) from child health care centers in Malmö, Sweden. Controls were selected stratified on risk scores for overweight in a propensity score framework. Maternal serum levels were analyzed in biobanked samples collected by routine around gestational week 14. Logistic regression was used to estimate odds ratios between quartiles of maternal serum levels and child overweight at age 4. There were no consistent monotonic exposure-response relationships. We found some significant odds ratios in specific quartiles but these were regarded as spurious findings. The absence of an effect was consistent over risk strata. We did not find evidence of an association between maternal serum levels of PFOS, PFOA, PFHxS and PFNA in early pregnancy and child overweight at age 4. The level of other risk factors for overweight did not affect children's susceptibility to prenatal PFAS exposure.


Referral facility CT perfusion prior to inter-facility transfer in patients undergoing mechanical thrombectomy.
The use of CT perfusion (CTP) imaging at a referring hospital is feasible and may shorten the door to puncture time for patients with acute ischemic stroke. We conducted a single center retrospective review of a prospectively maintained database of consecutive ischemic stroke patients transferred to our center for consideration of endovascular therapy. Patients were divided into two groups. Group 1 consisted of patients transferred from facilities where CTP (using automated RAPID software) was routinely performed and group 2 consisted of patients transferred from facilities that did not perform perfusion imaging. We identified a total of 132 patients, all of whom were transferred to our center, from April 2014 to April 2017. There were no differences in baseline characteristics between the two groups. A total of 34 patients were transferred from a facility after CTP (group 1) and 98 were transferred from a facility with no CTP (group 2). Door to puncture time was significantly shorter for patients in group 1 compared with those in group 2 (median 12 (IQR 8-16) min and 48.5 (32.8-71.8) min, respectively; P<0.001). Despite obtaining additional pre-transfer imaging in group 1, there was no difference in door in and door out times at the referring facilities compared with group 2. We found that triaging from a primary stroke center after CTP RAPID was feasible and significantly reduced the door to puncture time without any significant delay in the transfer process.


A standard curve based method for relative real time PCR data processing.
Currently real time PCR is the most precise method by which to measure gene expression. The method generates a large amount of raw numerical data and processing may notably influence final results. The data processing is based either on standard curves or on PCR efficiency assessment. At the moment, the PCR efficiency approach is preferred in relative PCR whilst the standard curve is often used for absolute PCR. However, there are no barriers to employ standard curves for relative PCR. This article provides an implementation of the standard curve method and discusses its advantages and limitations in relative real time PCR. We designed a procedure for data processing in relative real time PCR. The procedure completely avoids PCR efficiency assessment, minimizes operator involvement and provides a statistical assessment of intra-assay variation. The procedure includes the following steps. (I) Noise is filtered from raw fluorescence readings by smoothing, baseline subtraction and amplitude normalization. (II) The optimal threshold is selected automatically from regression parameters of the standard curve. (III) Crossing points (CPs) are derived directly from coordinates of points where the threshold line crosses fluorescence plots obtained after the noise filtering. (IV) The means and their variances are calculated for CPs in PCR replicas. (V) The final results are derived from the CPs' means. The CPs' variances are traced to results by the law of error propagation. A detailed description and analysis of this data processing is provided. The limitations associated with the use of parametric statistical methods and amplitude normalization are specifically analyzed and found fit to the routine laboratory practice. Different options are discussed for aggregation of data obtained from multiple reference genes. A standard curve based procedure for PCR data processing has been compiled and validated. It illustrates that standard curve design remains a reliable and simple alternative to the PCR-efficiency based calculations in relative real time PCR.