The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus replication and pathogenesis in mice.
After receptor binding and internalization during influenza virus entry, the hemagglutinin (HA) protein is triggered by low pH to undergo irreversible conformational changes that mediate membrane fusion. To investigate how mutations that alter the activation pH of the HA protein influence the fitness of an avian H5N1 influenza virus in a mammalian model, we infected C57BL/6J or DBA/2J mice and compared the replication and virulence of recombinant A/chicken/Vietnam/C58/04 (H5N1) HA-Y231H mutant, wild-type, and HA-H241Q and HA-K582I mutant viruses that have HA activation pH values of 6.3, 5.9, 5.6, and 5.4, respectively. The HA-Y231H mutant virus was highly susceptible to acid inactivation in vitro and was attenuated for growth and virulence in mice, suggesting that an H5N1 HA protein triggered at pH 6.3 is too unstable for the virus to remain fit. Wild-type and HA-H241Q viruses were similar in pathogenicity and grew to similar levels in mice, ducks, and cell cultures derived from both avian and mammalian tissues, suggesting that H5N1 HA proteins triggered at pH values in the range of 5.9 to 5.6 broadly support replication. The HA-K582I mutant virus had greater growth and virulence in DBA/2J mice than the wild type did, although the mutant virus was highly attenuated in ducks. The data suggest that adaptation of avian H5N1 influenza virus for infection in mammals is supported by a decrease in the HA activation pH to 5.4. Identification of the HA activation pH as a host-specific infectivity factor is expected to aid in the surveillance and risk assessment of currently circulating H5N1 influenza viruses.


Hormonal responsiveness to stress is negatively associated with vulnerability to angling capture in fish.
Differences in behavior and physiology amongst individuals often alter relative fitness levels in the environment. However, the ideal behavioral/physiological phenotype in a given environment may be altered by human activity, leading to an evolutionary response in the affected population. One example of this process can be found in fisheries (including recreational freshwater fisheries), where selective capture and harvest of individuals with certain phenotypes can drive evolutionary change. While some life history traits and behavioral tendencies influencing capture likelihood have been studied, the physiological mechanisms driving this vulnerability remain poorly understood. To address this, we assessed how two major physiological characteristics (hormonal responsiveness to stress and metabolic phenotype) and one behavioral characteristic (boldness) impact the likelihood of an individual being captured by anglers. Largemouth bass, Micropterus salmoides, derived from a population artificially selected for differential angling vulnerability were assessed for boldness and for stress responsiveness (as indicated by plasma cortisol levels) following an air-exposure challenge. Largemouth bass were then stocked into a pond where experimental angling trials took place, and a subset of captured and uncaptured fish were afterwards assessed for metabolic phenotype. The results showed that stress responsiveness was the primary driver of angling vulnerability, with individuals that experienced lower rises in cortisol following the air-exposure challenge more likely to be captured. Neither boldness nor metabolic phenotype influenced capture probability. The results from this study indicate that fisheries-induced selective pressure may act on physiology, potentially altering stress responsiveness and its associated behaviors in populations exploited by recreational anglers.


Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats.
The involvement of excitatory amino acid receptors in peripheral nociceptive processing was assessed in two separate experiments. In the first, one knee joint cavity of rats was injected with 0.1 ml of L-glutamate (0.001 mM; 0.1 mM; 1.0 mM), L-aspartate (0.001 mM; 0.1 mM: 1.0 mM), L-arginine (0.1 mM) or different combinations of these amino acids. The animals tested for paw withdrawal latency to radiant heat and withdrawal threshold to von Frey filaments at different time points. Combinations of glutamate/aspartate, aspartate/arginine or glutamate/aspartate/arginine when injected into the joint, in the absence of any other treatment, reduced the paw withdrawal latency and withdrawal threshold immediately after the injection and persisting up to 5 h indicating the development of hyperalgesia and allodynia. Subsequent intra-articular injection of either an NMDA or a non-NMDA glutamate receptor antagonist ((+/-)-2-amino-7-phosphonoheptanoic acid (AP7), 0.2 mM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 0.1 mM) attenuated the thermal hyperalgesia and the mechanical allodynia produced by glutamate/aspartate/arginine. On the other hand, in a second experiment intra-articular injection of AP7, ketamine or CNQX reversed the hyperalgesia and allodynia produced by injection of a mixture of kaolin and carrageenan into the joint. These receptor antagonists, however, did not have an effect on the joint edema. These findings provide evidence for a potential role of peripheral NMDA and non-NMDA receptors in nociceptive transmission.


Generation and characterization of a mutant of influenza A virus selected with the neuraminidase inhibitor BCX-140.
Influenza neuraminidase (NA) plays an important role in viral replication, and characterization of viruses resistant to NA inhibitors will help elucidate the role of active-site residues. This information will assist in designing better inhibitors targeted to essential active-site residues that cannot generate drug-resistant mutations. In the present study we used the benzoic acid-based inhibitor BCX-140 to select and characterize resistant viruses. BCX-140 binds to the NA active site in an orientation that is opposite that of a sialic acid-based compound, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GANA). Thus, the guanidino group of BCX-140 binds to Glu-276, whereas in GANA the guanidino group binds to Glu-119. We passaged influenza A/Singapore/1/57 (H2N2) in Madin-Darby canine kidney cells in the presence of BCX-140, and virus resistant to this inhibitor was selected after six passages. The NA of this mutant was still sensitive to inhibition by BCX-140. However, the mutant virus was resistant to BCX-140 in plaque and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Sequence analysis of hemagglutinin (HA) and NA genes revealed changes in both, although none were in the active site of the NA. Depending on the method of selection of the resistant virus, two types of changes associated with the sialic acid binding site were seen in the HA. One is a change in HA1 of Ala-133 to Thr, a residue close to the binding site, while the other change was Arg-132 of HA1 to Gln, which in HA1 of serotype H3 is a sialic acid contact (Asn-137). Binding studies revealed that both types of resistant viruses had reduced receptor binding affinity compared to that of the wild type. Thus, resistance to BCX-140 was generated by modifying the HA. NA active-site residue 276 may be essential for activity, and thus, it cannot be changed to generate resistance. However, drug-induced changes in the HA can result in a virus that is less dependent on NA activity for growth in cells and, hence, resistant to NA inhibitors.


Biorecognition Layer Based On Biotin-Containing [1]Benzothieno[3,2-b][1]benzothiophene Derivative for Biosensing by Electrolyte-Gated Organic Field-Effect Transistors.
Requirements of speed and simplicity in testing stimulate the development of modern biosensors. Electrolyte-gated organic field-effect transistors (EGOFETs) are a promising platform for ultrasensitive, fast, and reliable detection of biological molecules for low-cost, point-of-care bioelectronic sensing. Biosensitivity of the EGOFET devices can be achieved by modification with receptors of one of the electronic active interfaces of the transistor gate or organic semiconductor surface. Functionalization of the latter gives the advantage in the creation of a planar architecture and compact devices for lab-on-chip design. Herein, we propose a universal, fast, and simple technique based on doctor blading and Langmuir-Schaefer methods for functionalization of the semiconducting surface of C8-BTBT-C8, allowing the fabrication of a large-scale biorecognition layer based on the novel functional derivative of BTBT-containing biotin fragments as a foundation for further biomodification. The fabricated devices are very efficient and operate stably in phosphate-buffered saline solution with high reproducibility of electrical properties in the EGOFET regime. The development of biorecognition properties of the proposed biolayer is based on the streptavidin-biotin interactions between the consecutive layers and can be used for a wide variety of receptors. As a proof-of-concept, we demonstrate the specific response of the BTBT-based biorecognition layer in EGOFETs to influenza A virus (H7N1 strain). The elaborated approach to biorecognition layer formation is appropriate but not limited to aptamer-based receptor molecules and can be further applied for fabricating several biosensors for various analytes on one substrate and paves the way for "electronic tongue" creation.


Platelet aggregation and plasma levels of beta-thromboglobulin in diabetes mellitus.
In view of the tendency toward vascular complications in diabetes mellitus, we studied platelet aggregation and plasma beta-thromboglobulin (beta-TG) levels in 35 healthy controls, 25 non-diabetic patients with ischemic heart disease (IHD) and 85 diabetic patients. Blood platelets from diabetic patients showed no significant hyperaggregation induced by ADP, collagen or epinephrine, as compared with controls and non-diabetic patients with IHD, nor could be demonstrated significant differences in platelet aggregation between diabetics with diabetic microangiopathies and those without diabetic vascular complications. Significantly high levels of plasma beta-TG were observed in diabetics in comparison with those in controls and non-diabetic patients with IHD. Patients with diabetic microangiopathy had more significantly elevated beta-TG levels than diabetics without diabetic microangiopathies. Diabetics without diabetic microangiopathy had similar levels of beta-TG to those of controls and non-diabetic patients with IHD. High levels of plasma beta-TG in diabetics with diabetic microangiopathy seem to indicate a platelet hyperfunction in vivo due to diabetic vascular complications.


[Treatment of nonresectable liver metastases].
A standardized procedure for dealing with nonresectable liver metastases does not currently exist. It is important that an interdisciplinary approach to treatment be taken, in order to look for the optimum solution for each individual patient. High response rates appear to be important, in order to make more patients with nonresectable liver metastases 'resectable' and thus provide a chance of cure. A series of randomized phase II-III trials found a clear increase in response rates and an improvement in the R0 resection rate as a result of more intensive therapy (triple chemotherapy or combination chemotherapy plus cetuximab or bevacizumab). In the NO16966 trial, too, under blinded conditions, more liver metastasis resections were carried out among patients who had received bevacizumab than among patients in the control arm without bevacizumab, although the response rates in the two arms were the same. A gap of 6-8 weeks between the last dose of bevacizumab and surgery is clinically optimal from the point of view of perioperative safety. If neoadjuvant treatment is given, then resection should be carried out as soon as the metastases are resectable. If the patient's response is not adequate, then consideration should be given to an adaptation or change of the treatment regimen. Regular evaluation for secondary resectability is important. Surgically, in addition to 2- or multi-stage surgery, other possible techniques include portal embolization and intraoperative ablation. The goal remains R0 resection. In order to minimize complications, clinicians must select patients carefully, take account of comorbidities, and know the critical resection volume.


Increased Resolution of Structural MRI at 3T Improves Estimation of Regional Cortical Degeneration in Individual Dementia Patients Using Surface Thickness Maps.
Objective measurement of regional cortical atrophy in individual patients would be a highly desirable adjunct for diagnosis of degenerative dementias. We hypothesized that increasing the resolution of magnetic resonance scans would improve the sensitivity of cortical atrophy detection for individual patients. 46 participants including 8 semantic-variant primary progressive aphasia (svPPA), seven posterior cortical atrophy (PCA), and 31 cognitively unimpaired participants underwent clinical assessment and 3.0T brain scans. SvPPA and PCA were chosen because there is overwhelming prior knowledge of the expected atrophy pattern. Two sets of T1-weighted images with 0.8 mm3 (HighRes) and conventional 1.0 mm3 (ConvRes) resolution were acquired. The cortical ribbon was segmented using FreeSurfer software to obtain surface-based thickness maps. Inter-sequence performance was assessed in terms of cortical thickness and sub-cortical volume reproducibility, signal-to-noise and contrast-to-noise ratios. For clinical cases, diagnostic effect size (Cohen's d) and lesion distribution (z-score and t-value maps) were compared between HighRes and ConvRes scans. The HighRes scans produced higher image quality scores at 90 seconds extra scan time. The effect size of cortical thickness differences between patients and cognitively unimpaired participants was 15-20% larger for HighRes scans. HighRes scans showed more robust patterns of atrophy in expected regions in each and every individual patient. HighRes T1-weighted scans showed superior precision for identifying the severity of cortical atrophy in individual patients, offering a proof-of-concept for clinical translation. Studying svPPA and PCA, two syndromes with well-defined focal atrophy patterns, offers a method to clinically validate and contrast automated algorithms.


Ocular Genetics Program: multidisciplinary care of patients with ocular genetic eye disease.
Patients who suffer from ocular genetic diseases have special needs in terms of diagnosis and management of rare entities, low-vision needs, genetic counselling, and psychosocial adjustments that are usually not addressed by an ophthalmologist alone. The Ocular Genetics Program (OGP) at the Hospital for Sick Children, Toronto, was established in 1994 to provide comprehensive, multidisciplinary care of patients with inherited eye disorders. We now assess the benefits of such a program and of integrating research into the care of patients. We report our experience in developing a multidisciplinary ocular genetics program and the results of a pilot patient satisfaction survey that involved 61 patients. The OGP multidisciplinary aspects are described. Of the 61 patients surveyed, 98% stated that they were satisfied with the OGP; 93%-96% of patients were content with "one day of appointments", "understanding of eye problem", and "coordination of ancillary tests such as visual fields test, electrophysiology, and others"; and for 70%-86% of respondents "waiting time to get an appointment", "information received on current research", and "primary health care provider adequately informed" were satisfactory. The OGP is a unique service in Canada, which strives to provide the comprehensive care needed by ocular genetic patients. High patient satisfaction is an indicator of the success of this approach. Long waiting times for appointments and application of laboratory research in clinical care remain challenging.


NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell.
The NHE6 protein is a unique Na(+)/H(+) exchanger isoform believed to localize in mitochondria. It possesses a hydrophilic N-terminal portion that is rich in positively charged residues and many hydrophobic segments. In the present study, signal sequences in the NHE6 molecule were examined for organelle localization and membrane topogenesis. When the full-length protein was expressed in COS7 cells, it localized in the endoplasmic reticulum and on the cell surface. Furthermore, the protein was fully N-glycosylated. When green fluorescent protein was fused after the second (H2) or third (H3) hydrophobic segment, the fusion proteins were targeted to the endoplasmic reticulum (ER) membrane. The localization pattern was the same as that of fusion proteins in which green fluorescent protein was fused after H2 of NHE1. In an in vitro system, H1 behaved as a signal peptide that directs the translocation of the following polypeptide chain and is then processed off. The next hydrophobic segment (H2) halted translocation and eventually became a transmembrane segment. The N-terminal hydrophobic segment (H1) of NHE1 also behaved as a signal peptide. Cell fractionation studies using antibodies against the 15 C-terminal residues indicated that NHE6 protein localized in the microsomal membranes of rat liver cells. All of the NHE6 molecules in liver tissue possess an endoglycosidase H-resistant sugar chain. These findings indicate that NHE6 protein is targeted to the ER membrane via the N-terminal signal peptide and is sorted to organelle membranes derived from the ER membrane.


Hydrophobicity development, alkane oxidation, and crude-oil emulsification in a Rhodococcus species.
The relationship between the phenomena alkane oxidation, extreme hydrophobicity of the cell surface, and crude-oil emulsification in Rhodococcus sp. strain 094 was investigated. Compounds that induce the emulsifying ability simultaneously induced the cytochrome P450-containing alkane oxidizing system and the transition from low to high cell-surface hydrophobicity. Exposed to inducers of crude-oil emulsification, the cells developed a strong hydrophobic character during exponential growth, which was rapidly lost when entering stationary phase. The loss in hydrophobicity coincided in time with the crude-oil emulsification, indicating that the components responsible for the formation of cell-surface hydrophobicity act as excellent emulsion stabilisers only after release from the cells. Rhodococcus sp. strain 094 possessed three distinct levels of cell-surface hydrophobicity. One level of low hydrophobicity was characteristic of cells in late stationary phase and was independent of growth substrate. A second and more hydrophobic level was observed for cells in exponential phase grown on water-soluble substrates, while a third level, characterised by extreme cell hydrophobicity, was observed for cells in exponential phase cultivated on hydrophobic substrates such as hexadecane. The production of the oil-emulsifying agents seems to require external sources of nitrogen and phosphate.


Psychotherapy for Borderline Personality Disorder: Progress and Remaining Challenges.
The main purpose of this review was to critically evaluate the literature on psychotherapies for borderline personality disorder (BPD) published over the past 5 years to identify the progress with remaining challenges and to determine priority areas for future research. A systematic review of the literature over the last 5 years was undertaken. The review yielded 184 relevant abstracts, and after applying inclusion criteria, 16 articles were fully reviewed based on the articles' implications for future research and/or clinical practice. Our review indicated that patients with various severities benefited from psychotherapy; more intensive therapies were not significantly superior to less intensive therapies; enhancing emotion regulation processes and fostering more coherent self-identity were important mechanisms of change; therapies had been extended to patients with BPD and posttraumatic stress disorder; and more research was needed to be directed at functional outcomes.


Clinical outcomes of asymptomatic low-grade esophagitis: results from a multicenter Chinese cohort.
Asymptomatic low-grade (Los Angeles Classification Grades A and B) esophagitis is common in clinical practice with unclear clinical outcomes. This study aimed to explore the clinical outcomes of asymptomatic low-grade esophagitis. This was a multicenter cohort study conducted by three academic hospitals in China. Asymptomatic low-grade esophagitis patients between January 2015 and December 2019 were included. Mucosal healing condition 1 year after initial diagnosis, symptom outcomes, and proton-pump inhibitor (PPI) use within 1 year after initial diagnosis were studied and compared. A total of 248 asymptomatic low-grade esophagitis patients were included. Esophagitis disappeared in 76.2% of patients 1 year after initial diagnosis. In terms of symptom outcomes, 89.9% of patients did not present gastroesophageal reflux disease (GERD) symptoms within 1 year after initial diagnosis. No significant difference was found in the proportion of patients who presented GERD symptoms and in the proportion of patients with persistent esophagitis between the PPI group and the non-PPI group (all P > 0.05). Patients with initial Grade B esophagitis were more likely to present follow-up GERD symptoms (16.0% vs 7.5%, P = 0.041) and had more severe follow-up esophagitis than those with Grade A (P < 0.001). Patients with follow-up GERD symptoms were more likely to have persistent esophagitis than those without. This study demonstrated that asymptomatic low-grade esophagitis had relatively benign clinical outcomes. Patients with initial Grade B esophagitis and patients with follow-up GERD symptoms were more likely to be those who are in genuine need of further follow-up and treatments.


Bim is a direct target of a neuronal E2F-dependent apoptotic pathway.
The inappropriate expression/activation of cell-cycle-related molecules is associated with neuron death in many experimental paradigms and human neuropathologic conditions. However, the means whereby this links to the core apoptotic machinery in neurons have been unclear. Here, we show that the pro-apoptotic Bcl-2 homology 3 domain-only molecule Bcl-2 interacting mediator of cell death (Bim) is a target of a cell-cycle-related apoptotic pathway in neuronal cells. Induction of Bim in NGF-deprived cells requires expression and activity of cyclin-dependent kinase 4 (cdk4) and consequent de-repression of E2 promoter binding factor (E2F)-regulated genes including members of the myb transcription factor family. The Bim promoter contains two myb binding sites, mutation of which abolishes induction of a Bim promoter-driven reporter by NGF deprivation or E2F-dependent gene de-repression. NGF deprivation significantly increases endogenous levels of C-myb and its occupancy of the endogenous Bim promoter. These findings support a model in which apoptotic stimuli lead to cdk4 activation, consequent de-repression of E2F-regulated mybs, and induction of pro-apoptotic Bim.


[Fold formations in the proximal ureter].
Over a period of thirteen years in 28 children (age 4 weeks to 11 years) mucosal membranes of the proximal ureter were diagnosed by intravenous urography. In 61% of all cases the anomalies were demonstrated within the first year of life. Predominantly boys were affected (75%). Most of the associated anomalies (n = 15) were related to the urogenital system (n = 7). The membranes were bilateral in 12 cases and either separate (n = 15) or multiple (n = 25), resulting in a cork-screw-like structure. Minor signs of obstruction of the corresponding renal pelvis were found in 45%, independent of the number of membranes. Urinary tract infection (UTI) occurred in half of all cases. Kidney length was not reduced in any child. The mean serum creatinin (SCR) level was 0.6 +/- 0.4 mg/dl. Surgical correction was never performed. The clinical follow-up investigation (n = 14) after a mean period of 5.1 (1-14) years revealed recurrent UTI in only 2 patients. The mean SCR level remained normal (0.5 +/- 0.3 mg/dl). The tendency of involution of the membranes, supposed by the clinically benign course, is demonstrated to serve as an example. Although a predisposing effect to UTI cannot be excluded, ureteral membranes must be regarded as harmless and transitory anomalies of the growing ureter in childhood which do not require urologic intervention.


Achieving independent control of core diameter and carbon shell thickness in Pd-C core-shell nanoparticles by gas phase synthesis.
Pd-C core-shell nanoparticles with independently controllable core size and shell thickness are grown by gas phase synthesis. First, the core size is selected by electrical mobility values of charged particles, and second, the shell thickness is controlled by the concentration of carbon precursor gas. The carbon shell grows by adsorption of carbon precursor gas molecules on the surface of nanoparticles, followed by sintering. The presence of a carbon shell on Pd nanoparticles is potentially important in hydrogen-related applications operating at high temperatures or in catalytic reactions in acidic/aqueous environments.


Household environmental factors and children's respiratory health: comparison of two cross-sectional studies over 25 years in Wuhan, China.
Over the recent decades, residential lifestyle and household environment have changed substantially with rapid development of industrialization and urbanization in China. Whether the prevalence of respiratory diseases changed is still lack of evidence. The objective of this study is to assess potential changes in children's respiratory disease prevalence and associated household environmental factors in Wuhan over a 25-year time interval. Two cross-sectional studies in the Period 1 (1993 to 1996) and Period 2 (2017 to 2018) were compared in this research. Elementary school children in period 1 (N=2,517) and in period 2 (N=3,152) were recruited in Wuhan, China. The respiratory health condition, home environmental factors, and family socioeconomic status of each subject were acquired through questionnaire survey using the same protocols in both periods. We used the Chi-square test to analyze the difference of household environmental factors (focused on three indoor air quality determinants) and children's respiratory health condition between two periods. Logistic regression models were used to assess the impacts of household environmental determinants on children's respiratory diseases and symptoms between the two studies, by adjusting a set of covariates. The three indoor air quality determinants have reduced substantially in prevalence from period 1 to period 2: environment tobacco smoke (ETS) from 86.6% to 45.9%, household coal use from 47.6% to 4.9%, and kitchen smoke from 58.9% to 7.3%. The prevalence of certain respiratory symptoms in children significantly decreased, such as cough with colds (51.1% to 41.6%) and phlegm with colds (22.3% to 17.7%). The prevalence of asthma was 2.5% and 2.4% and that of bronchitis was 27.1% and 29.8% in both periods. Coal use was a risk factor for asthma in period 1 (OR =2.34, 95% CI: 1.30-4.23), while it was not significantly associated with prevalence of asthma in period 2 (OR =0.60, 95% CI: 0.08-4.51). Household indoor air quality determinants and respiratory health condition of children in Wuhan has been improved over the last 25 years. At present, kitchen smoke is an important factor affecting the prevalence of wheeze whatever child has a cold or not and reducing exposure to ETS could be beneficial to protect children to be less likely to develop bronchitis.


Tat-CIAPIN1 Prevents Pancreatic β-Cell Death in hIAPP-Induced RINm5F Cells and T2DM Animal Model.
It is well known that the cytokine-induced apoptosis inhibitor 1 (CIAPIN1) protein plays an important role in biological progresses as an anti-apoptotic protein. Human islet amyloid peptide (hIAPP), known as amylin, is caused to pancreatic β-cell death in type 2 diabetes mellitus (T2DM). However, the function of CIAPIN1 protein on T2DM is not yet well studied. Therefore, we investigated the effects of CIAPIN1 protein on a hIAPP-induced RINm5F cell and T2DM animal model induced by a high-fat diet (HFD) and streptozotocin (STZ). The Tat-CIAPIN1 protein reduced the activation of mitogen-activated protein kinase (MAPK) and regulated the apoptosis-related protein expression levels including COX-2, iNOS, Bcl-2, Bax, and Caspase-3 in hIAPP-induced RINm5F cells. In a T2DM mice model, the Tat-CIAPIN1 protein ameliorated the pathological changes of pancreatic β-cells and reduced the fasting blood glucose, body weight and hemoglobin Alc (HbAlc) levels. In conclusion, the Tat-CIAPIN1 protein showed protective effects against T2DM by protection of β-cells via inhibition of hIAPP toxicity and by regulation of a MAPK signal pathway, suggesting CIAPIN1 protein can be a therapeutic protein drug candidate by beneficial regulation of T2DM.


Something to smile about: the interrelationship between attractiveness and emotional expression.
Previous studies have suggested a link between the processing of the emotional expression of a face and how attractive it appears. In two experiments we investigated the interrelationship between attractiveness and happiness. In Experiment 1 we presented morphed faces varying in attractiveness and happiness and asked participants to choose the more attractive of two simultaneously presented faces. In the second experiment we used the same stimuli as in Experiment 1 and asked participants to choose the happier face. The results of Experiment 1 revealed that the evaluation of attractiveness is strongly influenced by the intensity of a smile expressed on a face: A happy facial expression could even compensate for relative unattractiveness. Conversely, the findings of Experiment 2 showed that facial attractiveness also influences the evaluation of happiness: It was easier to choose the happier of two faces if the happier face was also more attractive. We discuss the interrelationship of happiness and attractiveness with regard to evolutionary relevance of positive affective status and rewarding effects.


Comparative effectiveness of exercise training program in patients with heart failure: protocol for a systematic review of randomised controlled trials and network meta-analysis.
Heart failure (HF) is an end-stage of numerous heart diseases including hypertension, coronary heart disease and arrhythmia, in which the heart is unable to perform its circulatory function with sufficient efficiency due to structural or functional dysfunction (systolic or diastolic alterations). Strategies such as exercise rehabilitation may improve cardiac function, exercise capacity and health-related quality of life and reduce anxiety and depression in patients with HF. However, the relative effectiveness as well as the hierarchy of exercise interventions have not been well established, although various exercise options are available. Therefore, this protocol proposes to conduct a network meta-analysis (NMA) aiming to compare the effectiveness of different types of exercise training in patients with HF. PubMed, Embase and the Cochrane Library will be searched from inception to March 2021 for relevant randomised controlled trials. Other resources, such as Google Scholar and Clinical Trials.gov will also be considered. Studies assessing exercise rehabilitation in patients with HF will be selected. Two independent reviewers will identify eligible trials. The PEDro risk of bias assessment tool will be used to assess the quality of the included studies. Bayesian NMA will be used when possible to determine the comparative effectiveness of the different exercise interventions. The mean ranks and surface will estimate the ranking probabilities for the optimal intervention of various treatments under the cumulative ranking curve. Subgroup, sensitivity and meta-regression will be conducted to explain the included studies' heterogeneity if possible. We will also use the Grading of Recommendations, Assessment, Development, and Evaluation system to assess the strength of evidence. This systematic review and NMA will synthesise evidence on the effectiveness of the different exercises in patients with HF. The results will be submitted to a peer-reviewed journal. No ethical approval will be required because the data used for the review will be exclusively extracted from published studies. CRD42020165870.


Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS.
The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.


Regulation of protein synthesis in rabbit reticulocyte lysates: purification and characterization of heme-reversible translational inhibitor.
To define the mechanism of regulation of the protein kinase that is activated in heme deficiency and that inhibits initiation of protein synthesis, we have isolated and purified the heme-reversible form of the protein kinase from rabbit reticulocytes. The inhibitory activity is found in a single band after polyacrylamide gel electrophoresis under nondenaturing conditions. It migrates as a 95,000-dalton polypeptide in 15% sodium dodecyl sulfate/polyacrylamide gels. This purified inhibitor becomes self-phosphorylated in the presence of ATP; the phosphorylated protein and the inhibitory activity copurify. The inhibitor produces characteristic biphasic kinetics of inhibition in reticulocyte lysates and phosphorylates the 38,000-dalton subunit of eukaryotic initiation factor 2 (eIF-2); the inhibition is reversed by added eIF-2. In contrast to the heme-irreversible inhibitor, this heme-reversible inhibitor is no longer inhibitory after incubation with 20 micron hemin. Incubation with hemin also inhibits self-phosphorylation. Preincubation of the heme-reversible inhibitor in the presence of ATP potentiates the inhibition of protein synthesis in the subsequent incubation, as does treatment with N-ethylmaleimide. Phosphorylation of the heme-reversible inhibitor and inhibition of protein synthesis in the lysate due to phosphorylation of eIF-2 appear to be related. These findings suggest that hemin acts directly on the heme-reversible inhibitor.


H pylori infection among 1000 southern Iranian dyspeptic patients.
To describe the frequency of H pylori infection among 1000 southern Iranian dyspeptic patients. A prospective study was performed in a referral hospital in south of Iran from 1999 to 2005. One thousand dyspeptic patients (518 males, mean +/- SD age of 49.12 +/- 12.82 years) consecutively underwent upper gastrointestinal endoscopy. Multiple gastric antral biopsy samples were taken from all patients for rapid urease test and histopathologic examination (96.9% satisfactory samples). Patients were considered H pylori-infected if one or both tests were positive. Six hundred and seventy-one patients (67.1%, 95% confidence interval [CI]: 64.2%-70.0%) were H pylori-infected. H pylori positivity was significantly more frequent in patients with peptic ulcer disease (PUD) than in those with non-ulcer dyspepsia (P < 0.001). Male-to-female ratio for duodenal and gastric ulcers was 2.7:1 and 1.5:1, respectively. Moreover, the duodenal-to-gastric ulcer ratio was 1.95:1. The frequency of H pylori infection among those with endoscopic diagnosis of gastritis, duodenal ulcer, gastric ulcer, and normal mucosa was 70.1% (398/568), 86.2% (150/174), 71.9% (64/89), and 33.5% (54/161), respectively. H pylori infection, male sex, and older age were independently associated with PUD in multivariate analysis. H pylori positivity was associated with chronic gastritis, and chronic active gastritis with odds ratios of 34.21 (95% CI: 12.19%-96.03%) and 81.21 (95% CI: 28.85%-228.55%), respectively. H pylori and PUD are highly frequent in dyspeptic patients from south of Iran. H pylori is a cardinal risk factor for chronic active or inactive gastritis.


Do elective surgical and medical admissions impact emergency department length of stay measurements?
Emergency department access block is a growing problem in emergency departments across Canada. Access block is defined as hospital occupancy >85% causing emergency department overcrowding. Hospital overcrowding leads to prolonged emergency department wait times, and delays in the transfer of admitted patients from the emergency department to inpatient beds. The relationship between elective admissions to hospital and emergency department wait times has not been adequately assessed. We undertook a simple linear regression analysis of the impact of elective admissions to hospital on emergency department length of stay. Linear regression analysis of the number of daily elective admissions to adult acute care beds in the Calgary Health Region in the year 2004 and the daily median emergency department length of stay was done to establish the relationship between elective admissions and Emergency Department length of stay. 37,007 patients were admitted to adult acute care beds via the emergency department and 46,020 patients were admitted to adult acute care beds by all other routes. Regression analysis determined that there was no relationship between daily emergency department length of stay and the number of elective admissions per day. For the year 2004, in the Calgary Health Region, elective acute care admissions to hospital had no relationship to emergency department length of stay for patients admitted via the emergency department. Further study is required to determine causative factors that prolong Emergency Department length of stay. Emergency departments across Canada continue to struggle with the demands of providing high quality care with diminishing resources.


Immunocytochemical analysis of the cellular infiltrate in brain lesions in subacute sclerosing panencephalitis.
We studied lymphocyte subsets and major histocompatibility complex (MHC) class II antigens in frozen brain tissues from three patients with subacute sclerosing panencephalitis (SSPE) using immunocytochemical techniques. Perivascular cuffs consisted predominantly of T cells and MHC class II-positive cells. In the parenchymal lesions, there were frequent B and CD4+ cells. MHC class II-positive cells were also diffusely distributed throughout the parenchyma. There were more CD4+ than CD8+ cells both in the parenchyma and in the perivascular cuffs. These findings suggest an overrepresentation of CD4+ cells in SSPE lesions and that CD4+ cells may be involved in the pathogenesis of SSPE.


Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations.
Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2, EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson's disease (PD) or parkinsonism. Changes in a long list of additional genes have been suggested as causes for parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1), frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11, UCHL1). This review summarizes the clinical features of diseases caused by mutations in these genes, and their frequencies. Point mutations and multiplications in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early-onset parkinsonism with a low risk for cognitive decline and a pathological process usually restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity of several mutations remains unconfirmed. Although some mutations occur with high frequency in specific populations, worldwide all are very rare. The genetic cause of the majority of patients with sporadic or hereditary PD remains unknown in most populations. Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted individually based on clinical phenotype and estimated frequency of the mutation in the patient's population.


Parameters of passive fit using a new technique to mill implant-supported superstructures: an in vitro study of a novel three-dimensional force measurement-misfit method.
The objectives of this study are to describe, in vitro, a novel technique to measure the misfit of digitally designed and manufactured implant-supported frameworks according to a new concept based on computer-guided surgery in combination with previously placed mini-implants. Also, the digitally created framework and an impression-based milled structure were compared using strain gauge measurements. Acrylic resin and plaster models were prepared to represent the edentulous mandible. After insertion of three mini-implants in the acrylic resin model, a cone-beam computed tomographic scan was performed. The data were imported to planning software, where six implants were virtually inserted. A drill guide and titanium framework were designed and milled using a fully digital computer-aided design/computer-assisted machining protocol. Six implants were inserted using the drill guide attached to the mini-implants. After an impression was made of the acrylic resin model with six implants, the second model (plaster model) was prepared. A second milled titanium structure was fabricated following optical scanning of the acrylic resin model. Strain gauge measurements were done on both structures attached to both models. To validate the results, a high-accuracy industrial optical scanning system was used to capture all connection geometry and the measurements were compared. The accuracy of the digital superstructures was 19, 22, and 10 Microm with standard deviations (SD) of 19.2 (17.9), 21.5 (28.3), and 10.3 (10.1) Microm for the x-, y-, and z-axes, respectively. For the impression-based superstructure the measured misfit was 11, 20, and 17 Microm, with SD 11.8 (10.5), 19.7 (11.7), and 16.7 (8.2) Microm for the x-, y-, and z-axes, respectively. The misfit of the digitally designed and produced superstructure on the digitally planned and inserted implants was clinically insignificant.


Structures and electron affinities of triatomic molecules consisting of Al, P and X (X = B, Al, Ga; C, Si, Ge; N, P, As; O, S and Se).
The structures and electronic properties of the triatomic molecules containing Al, P, X atoms (X = B, Al, Ga; C, Si, Ge; N, P, As; O, S and Se) and their anions are investigated at the B3LYP/cc-PVTZ and the B3LYP/aug-cc-PVTZ levels. The results show that the most stable structures of the anions are AlXP(-) (X = B, C, N) and PAlX(-) (X = S, Se), while for the neutral molecules, the most stable structures are PXAl (X = C, N and O). The order of the VDEs of the anions molecules and the AEAs of the neutral species are C < N < O < Si approximately Ge < P approximately As < Al = Ga < B < S approximately Se and C < O < N < Si approximately Ge < P approximately As < B < Al approximately Ga < S approximately Se, respectively.


MToS: A Tree of Shapes for Multivariate Images.
The topographic map of a gray-level image, also called tree of shapes, provides a high-level hierarchical representation of the image contents. This representation, invariant to contrast changes and to contrast inversion, has been proved very useful to achieve many image processing and pattern recognition tasks. Its definition relies on the total ordering of pixel values, so this representation does not exist for color images, or more generally, multivariate images. Common workarounds, such as marginal processing, or imposing a total order on data, are not satisfactory and yield many problems. This paper presents a method to build a tree-based representation of multivariate images, which features marginally the same properties of the gray-level tree of shapes. Briefly put, we do not impose an arbitrary ordering on values, but we only rely on the inclusion relationship between shapes in the image definition domain. The interest of having a contrast invariant and self-dual representation of multivariate image is illustrated through several applications (filtering, segmentation, and object recognition) on different types of data: color natural images, document images, satellite hyperspectral imaging, multimodal medical imaging, and videos.


Biomechanical analysis of an ovine rotator cuff repair via porous patch augmentation in a chronic rupture model.
Rotator cuff repair is a commonly performed procedure, but many of these repairs fail in the postoperative term. Despite advances in surgical methods to optimize the repair, failure rates still persist clinically, thereby suggesting the need for novel mechanical or biological augmentation strategies. Nonresorbable implants provide an appealing approach because patch materials may confer acute mechanical stability and act as a conductive scaffold for tissue ingrowth at the site of the tendon insertion. The polyurethane scaffold mesh will confer greater biomechanical function relative to a nonaugmented repair after 12 weeks in vivo using a chronic ovine model of rotator cuff repair. Controlled laboratory study. After development of the chronic rupture model, the tensile failure properties of the nonresorbable mesh-augmented repair (n, 9) were compared with those of a surgical control in an ovine model (n, 8). Rotator cuff repair with the scaffold mesh in the chronic model resulted in a significant 74.2% increase in force at failure relative to the nonaugmented surgical control (P = .021). Apparent increases in stiffness (55.4%) and global displacement at failure (21.4%) in the mesh-augmented group relative to nonaugmented controls were not significant (P = .126 and P = .123, respectively). At the study endpoint, the augmented shoulders recovered 37.8% and 40.7% of the force at failure and stiffness, respectively, of intact, nonoperated controls. Using the previously described chronic rupture model, this study demonstrated that repair of a chronic tendon tear with the polyurethane scaffold mesh provides greater mechanical strength in the critical healing period than that of traditional suture anchor repair. This device could be used to enhance the surgical repair of the rotator cuff and consequently improve long-term clinical outcome.


The end of the secular trend in Norway: spatial trends in body height of Norwegian conscripts in the 19th, 20th and 21st century.
Aim: We aimed to examine the distribution and secular changes of conscript body height in the geographic network of Norway since 1878 and to study its association with the degree of urbanization, and population density. Material and methods: Data on body height of Norwegian military conscripts were provided by the Statistics Norway Department (SSB). The sample comprised eight cohorts with the following measurement years: 1st 1877, 1878 and 1880, 2nd 1895-1897, 3rd 1915-1917, 4th 1935-1937, 5th 1955-1957, 6th 1975-1977, 7th 1995-1997, and 8th 2009-2011. For determining neighborhood correlations, a network was created consisting of neighboring counties, sharing a common border. Results: Average body height of Norwegian men increased by 10.9 cm between 1878 and 2010, but this trend was heterogeneous. Some counties increased by more than 1 cm per decade (Finmark) others by only 7 mm per decade (Sor-Trondelag). Urban counties and counties with higher population density showed stronger height trends than rural counties. The largest spread in body height between the various counties was observed in 1936 when for the first time people living in the more urban counties got taller than rural people. The height advantage of urban counties however, disappeared after 1996. At this time, also the secular trend in height had come to a halt. The secular trend in height had become obvious after the dissolution of the union between Norway and Sweden in 1905 and World War I, and was strongest between 1936 and 1956. During this period maximum between-county heterogeneity in height existed with body height differences of more than 6 cm between the tallest and the shortest county. The end of this period was characterized by social democratic reforms that flattened the income distribution, eliminated poverty, and ensured social services after World War II. Conclusion: The temporal coincidence between the trends in height, the degree of urbanization and the onset of the political transition of Norway from a Swedish province into an independent democratic wealthy modern European state after World War I and particularly after World War II, and the abatement of this trend after this period of transition had stabilized, suggest social and political components interfering with the regulation of physical growth in humans.


Effect of ascorbic acid on the human electroencephalogram.
Controversy exists over whether ascorbic acid (vitamin C) in doses in excess of known physiological requirements has demonstrable biological effects. The present study reports that such megadoses of vitamin C do significantly effect an objective electrophysiological measure, i.e., electroencephalogram (EEG) driving responses to photic stimulation. Four thousand milligrams of vitamin C administered 27 and 3 hours prior to assessment produced an effect on the EEGs of 18 healthy adolescent human males that was significantly different from a placebo. Fifty milligrams of ascorbic acid administered in this manner did not produce an effect on the EEG significantly different from placebo administration.


The Influence of Socioeconomic Characteristics on Anthropometry, Nutrition Knowledge, and Attitude of People Living With HIV/AIDS Attending Special Treatment Center (STC) National Hospital Abuja, Nigeria.
The work is on the influence of socioeconomic status of people living with HIV/AIDS (PLWHA) on their anthropometry, nutrition knowledge, and attitude, attending special treatment center (STC) in National Hospital Abuja, Nigeria. A cross-sectional study design was carried out in the STC and a total of two hundred and seventy [270 (150 men and 120 women)] PLWHA were used for the study. The PLWHA attend STC once in 2 months and subjects were grouped into 16 giving 4 groups per week since the center runs Monday through Thursday weekly and by 2 months, there were altogether 32 groups. Socioeconomic characteristics, nutrition knowledge and attitude, and anthropometric data were collected. Data were analyzed using descriptive statistics, chi-square, and regression analysis. The study revealed that 41.1% of PLWHA had poor knowledge of nutrition, 29.1% had both fair and good knowledge while 0.7% had excellent knowledge. A total of 52.8% had a positive attitude toward nutrition. The skinfold status of the respondents showed that 56.0% were malnourished, while their body mass index (BMI) revealed that 49.3% were normal. Gender (being female) and age (being young) had a significant (P < 0.01) influence on the BMI of PLWHA, while being female significantly influenced their skinfold status. Self-employed and being female were strongest (P < 0.01) positive predictors of nutrition knowledge, while low education had a negative influence on their attitude toward nutrition. Good nutrition knowledge, attitude, and improved socioeconomic characteristics are important tools in the care process of PLWHA, for sustainable healthy PLWHA, leading to a healthy society at large.


Implants designed for finger joints. A roentgenorgraphic study and a study of implant wear and tear.
Two types of flexible finger implants (one intramedullary movable, the Silastic Finger Joint Implant, Swanson design, and the other presumable intramedullary fixed, the Niebauer T-M Cutter Metacarpophalangeal Joint Prosthesis) were subjected to animal trials. Forty-four Swanson implants and 33 Niebauer implants were implanted in the knee joint of rabbits. Roentgenographic examinations were carried out immediately after surgery and then at monthly intervals. The joint was examined in the lateral projection in a flexed and in an extended position to obtain better information about the behaviour of the implant. The Swanson implant was assessed as being intramedullary movable. The Niebauer implant was found to bend within other parts than just the thin central part of the midsection as it is supposed to do. Intramedullary bone formation was seen along the distal stem of the Swanson implant. It developed in a very typical manner considered to be related to the motion of the stem. A similar phenomenon was seen along the distal stem of some of the Niebauer implants and was considered a sign of insufficient fixation of the stem. Cortical erosion and periosteal callus formation were found in the femur at the site at which the proximal stem of the Swanson implant was in direct contact with the bone. The implants were examined at autopsy both in situ and after removal. The Swanson implants showed consistently a wearing of the surface and a permanent deformation. Isolated cracks were seen in 8/44 implants, while fractures, either isolated or in combination with cracks and/or fragmentation, were seen in 22/44 implants. It was not possible to evaluate deformation of the Niebauer implants. Slight wearing was seen in 4/32 implants. Cracks, fragmentations and fractures were seen either isolated (except for the fragmentations) or in different combinations with no specific pattern in 25/32 implants. The combination of inelastic dacron fibres and elastic silicone rubber in one functional unit as in the Niebauer implant was considered the main cause of the damage.


Enhanced isochoric heating from fast electrons produced by high-contrast, relativistic-intensity laser pulses.
Thin, mass-limited targets composed of V/Cu/Al layers with diameters ranging from 50 to 300 microm have been isochorically heated by a 300 fs laser pulse delivering up to 10 J at 2x10{19} W/cm{2} irradiance. Detailed spectral analysis of the Cu x-ray emission indicates that the highest temperatures, of the order of 100 eV, have been reached when irradiating the smallest targets with a high-contrast, frequency-doubled pulse despite a reduced laser energy. Collisional particle-in-cell simulations confirm the detrimental influence of the preformed plasma on the bulk target heating.


Direct determination of metformin in urine by adsorptive catalytic square-wave voltammetry.
A new adsorptive catalytic voltammetric method for voltammetric determination of metformin based on the catalytic hydrogen evolution reaction at a hanging mercury drop electrode was developed. The electrode reaction was analyzed under conditions of linear sweep voltammetry (LSV), differential pulse voltammetry (DPV) and Osteryoung-type square-wave voltammetry (SWV). The peak current depends on pH of the medium, concentration and chemical composition of the buffer solution, and instrumental parameters. The optimal conditions for quantitative determination were obtained in an acetate buffer at pH 4.7. The voltammetric procedure was characterized with respect to the repeatability, precision and the recovery. The detection and quantification limits were found to be 1.8 x 10(-8) and 5.9 x 10(-8) mol l(-1) for SWV, 3.2 x 10(-8) and 1.0 x 10(-7) mol l(-1) for DPV, and 7.7 x 10(-8) and 2.5 x 10(-7) mol l(-1) for LSV, respectively. The SW voltammetric method, as the most sensitive one, was applied for determination of metformin in human urine. The voltammetric method has been validated by using HPLC with UV detection.


The time of onset and duration of 5-methoxypsoralen photochemoprotection from UVR-induced DNA damage in human skin.
Sites of previously unexposed buttock skin of eight human volunteers (skin type II) were treated daily for 3, 5, 8, or 10 days with suberythemogenic doses of solar-simulated radiation (SSR) in the presence of a UVB sunscreen containing 5-methoxypsoralen (5-MOP) at 30 p.p.m., or daily for 10 days with SSR+the same sunscreen without 5-MOP. One week after cessation of treatment, these sites, together with a control unexposed site, were challenged with 2 minimal erythema doses (2 MED) of SSR. Biopsy samples were taken within 15 min of the challenge dose, and were incubated for 1 h in tritiated thymidine. UV-induced DNA damage was measured indirectly by unscheduled DNA synthesis (UDS), and directly using a monoclonal antibody to thymine dimers, and automated image analysis. The level of pigmentation was assessed in sections in a semiquantiative fashion with Masson-Fontana staining, and the number of layers in the stratum corneum was used to assess changes in epidermal thickness. Using the UDS and dimer measurements, the level of photochemoprotection afforded by 5-MOP was determined from the reduction in the level of DNA damage observed. The photochemoprotection was expressed as a ratio of the 5-MOP-treated sites compared with the sites that did not receive 5-MOP treatment. The onset of 5-MOP photochemoprotection was shown to occur after three to five daily exposures, and became maximal after eight daily exposures. The onset of this protection coincided with increases in melanin and in stratum corneum thickness. In an extension of this study, it was found that following 10 daily exposures, 5-MOP photochemoprotection declined at a rate of about 5% per week, and in spite of several cycles of epidermal cell replacement, some protection still persisted up to 14 weeks after the end of the tanning protocol. The sites treated with sunscreen without 5-MOP was good correlation between the photochemoprotection endpoints of UDS and thymine dimer levels. The importance of 5-MOP photochemoprotection in the risk-benefit assessment of sunscreens used in suntanning is discussed.


Participants' understanding of the process of psychological research: informed consent.
Sixty-five undergraduates participating in a wide range of psychological research experiments were interviewed in depth about their research experiences and their views on the process of informed consent. Overall, 32% of research experiences were characterized positively and 41% were characterized negatively. One major theme of the negative experiences was that experiments were perceived as too invasive, suggesting incomplete explication of negative aspects of research during the informed consent process. Informed consent experiences were viewed positively 80% of the time. However, most of the participants had a limited view of the purpose of informed consent: less than 20% viewed the process as a decision point. Results suggest a number of common pitfalls to standard informed consent practices that have not generally been recognized. Results are discussed in terms of both ethical and methodological implications. Suggestions for improving the informed consent process are also provided.


The effect of quercetin on bone healing in an experimental rat model.
This study aims to evaluate the effect of quercetin on fracture healing in an open fracture model in rats. A total of 80 Wistar-Albino male rats were used in this study. The rats were divided into 10 groups. Daily oral treatment of 100 mg/kg of quercetin dissolved in corn oil were given to four groups, whereas the other four group of control rats were treated with corn oil only. Histopathological and radiological examinations of fracture healing were performed at the end of Weeks 2 and 4 in these rats, while biomechanical and biochemical examinations were performed at the end of Weeks 4 and 6, since harder callus was required. Among the rats in the last two group that were not subjected to the open fracture model, one group was given only quercetin for three weeks and the other for six weeks, and the biochemical markers in the blood were compared between these two groups. Computed tomography images were taken for radiological evaluation. The modified Lane and Sandhu scoring system was used for histological evaluation. The 3-point bending test was performed for biomechanical evaluation. For biochemical evaluation, plasma alkaline phosphatase (ALP), acid phosphatase (AP), total antioxidant status (TAS) and total oxidant status (TOS) levels were measured. Radiologically, there was no significant difference between the early-stage results of quercetin and control groups (p=0.247), while quercetin caused a significant increase in callus tissue in terms of latestage results (p=0.012). Histopathologically, there was no significant difference in the early stage (p=0.584); however, in the late stage, a borderline significant increase was observed in the quercetin group compared to the control group (p=0.091). Biomechanical analysis showed that quercetin significantly increased the fracture strength in the healing bone both in the early period (p=0.036) and in the late period (p=0.027). Among biochemical markers, TOS and AP were found to be significantly decreased in the quercetin group. In the non-operated and quercetin given groups, TAS levels was significantly higher (p=0.001) and AP levels were borderline significantly lower at the end of Week 6 (p=0.063). Quercetin did not have a significant effect on bone healing in the early period, but significantly promoted bone healing in the late period in rats. We recommend the use of quercetin, a strong antioxidant, in cases with high oxidative stress and conditions such as diabetes, smoking, and malnutrition which may inhibit fracture union, although further clinical studies are needed to confirm these findings.


[Clinical study on ginkgolide nebulised inhalation in treating bronchial asthma].
To observe the effect of ginkgolide nebulised inhalation in treating bronchial asthma. Asthma patients of mild to moderate degree were randomly divided into three groups: the treated group treated by ginkgolide nebulised inhalation 10 mg/ml, twice daily, for 6 weeks in total, the positive control group, treated by cromlyn sodium nebulised inhalation 20 mg/10 ml, twice daily, for 6 weeks in total and the negative control group treated by normal saline 10 ml, twice daily, for 4 weeks in total. The changes on symptomatic scoring (Chetta' s method), pulmonary function (FEV1, PEF), serum eosinophil count, eosinophil cationic protein (ECP, determined by RIA), as well as airway response to ultrasonically nebulised distilled water (UNDW), and adverse reaction occurred in patients were observed. Results The symptomatic scorings in the treated and the positive control group were reduced from 5.1+/-2.3 and 6.0+/-2.6 to 1.6+/-1.7 and 1.6+/-1.7, respectively (both P<0.01) after 6 weeks of treatment. In the treated group, ECP was reduced from 6.7 microg/L to 4.3 microg/L (P<0.05), FEV1 and PEF were improved (P<0.05, P<0.01), while in positive control group, only improvement of FEV1 was found (P < 0.05). UNDW in the above two groups were reduced (P<0.01). Although decrease of symptomatic scoring was found in the negative control group, yet ECP, pulmonary function and airway response showed no improvement (P >0.05). Adverse reactions revealed were mainly chest stuffiness, stimulating cough, especially in the treated group, but were tolerable to most patients. Conclusion Ginkgolide has the action of fighting against asthmatic airway inflammation, which provides new means for treating bronchial asthma.


Prognostic Assessment and Risk Stratification in Patients With Postoperative Major Salivary Acinar Cell Carcinoma.
To investigate the clinicopathological features and prognosis of postoperative major salivary acinar cell carcinoma (MSACC) and develop a prognostic model. Retrospective cohort analysis of a public database. Patients with MSACC were identified from the Surveillance, Epidemiology, and End Results database (1975-2019). Overall survival (OS) was evaluated using Kaplan-Meier curves and a log-rank test. Univariate and multivariate Cox analyses were performed to explore independent prognostic factors. The prognostic model was constructed using screened variables and further visualized with a nomogram and web calculator, and assessed by concordance index, the area under the curve, calibration curve, and decision-making curve analysis. An upward trend in the incidence of MSACC was observed throughout the study period. A total of 1398 patients were enrolled (training cohort: 978; validation cohort: 420), and the 5- and 10-year OS rates were 97.7% and 81.6%, respectively. Age, marital status, sex, histological grade, T stage, and lymph node status were identified as prognostic factors for OS. A novel nomogram was developed and showed excellent discrimination and clinical applicability. Additionally, a web calculator was designed to dynamically predict patient survival. Based on the nomogram-based score, a risk stratification system was constructed to distinguish patients with different risks. The OS of high-risk patients was significantly lower than that of the low-risk subgroup. Long-term survival in postoperative MSACC was influenced by 6 prognostic factors. The proposed model enables individualized survival prediction and risk stratification, prompting us to be vigilant in high-risk subgroups and consider timely adjustment of subsequent treatment.


Lack of evidence for selection favouring MHC haplotypes that combine high functional diversity.
High rates of gene duplication and the highest levels of functional allelic diversity in vertebrate genomes are the main hallmarks of the major histocompatibility complex (MHC), a multigene family with a primordial role in pathogen recognition. The usual tight linkage among MHC gene duplicates may provide an opportunity for the evolution of haplotypes that associate functionally divergent alleles and thus grant the transmission of optimal levels of diversity to coming generations. Even though such associations may be a crucial component of disease resistance, this hypothesis has been given little attention in wild populations. Here, we leveraged pedigree data from a barn owl (Tyto alba) population to characterize MHC haplotype structure across two MHC class I (MHC-I) and two MHC class IIB (MHC-IIB) duplicates, in order to test the hypothesis that haplotypes' genetic diversity is higher than expected from randomly associated alleles. After showing that MHC loci are tightly linked within classes, we found limited evidence for shifts towards MHC haplotypes combining high diversity. Neither amino acid nor functional within-haplotype diversity were significantly higher than in random sets of haplotypes, regardless of MHC class. Our results therefore provide no evidence for selection towards high-diversity MHC haplotypes in barn owls. Rather, high rates of concerted evolution may constrain the evolution of high-diversity haplotypes at MHC-I, while, in contrast, for MHC-IIB, fixed differences among loci may provide barn owls with already optimized functional diversity. This suggests that at the MHC-I and MHC-IIB respectively, different evolutionary dynamics may govern the evolution of within-haplotype diversity.


The Thermoplasma acidophilum Lon protease has a Ser-Lys dyad active site.
A gene with significant similarity to bacterial Lon proteases was identified during the sequencing of the genome of the thermoacidophilic archaeon Thermoplasma acidophilum. Protein sequence comparison revealed that Thermoplasma Lon protease (TaLon) is more similar to the LonB proteases restricted to Gram-positive bacteria than to the widely distributed bacterial LonA. However, the active site residues of the protease and ATPase domain are highly conserved in all Lon proteases. Using site-directed mutagenesis we show here that TaLon and EcLon, and probably all other Lon proteases, contain a Ser-Lys dyad active site. The TaLon active site mutants were fully assembled and, similar to TaLon wild-type, displayed an apparent molar mass of 430 kDa upon gelfiltration. This would be consistent with a hexameric complex and indeed electron micrographs of TaLon revealed ring-shaped particles, although of unknown symmetry. Comparison of the ATPase activity of Lon wild-type from Thermoplasma or Escherichia coli with respective protease active site mutants revealed differences in Km and V values. This suggests that in the course of protein degradation by wild-type Lon the protease domain might influence the activity of the ATPase domain.


Phase space volume scaling of generalized entropies and anomalous diffusion scaling governed by corresponding non-linear Fokker-Planck equations.
Many physical, biological or social systems are governed by history-dependent dynamics or are composed of strongly interacting units, showing an extreme diversity of microscopic behaviour. Macroscopically, however, they can be efficiently modeled by generalizing concepts of the theory of Markovian, ergodic and weakly interacting stochastic processes. In this paper, we model stochastic processes by a family of generalized Fokker-Planck equations whose stationary solutions are equivalent to the maximum entropy distributions according to generalized entropies. We show that at asymptotically large times and volumes, the scaling exponent of the anomalous diffusion process described by the generalized Fokker-Planck equation and the phase space volume scaling exponent of the generalized entropy bijectively determine each other via a simple algebraic relation. This implies that these basic measures characterizing the transient and the stationary behaviour of the processes provide the same information regarding the asymptotic regime, and consequently, the classification of the processes given by these two exponents coincide.


Comparison of vascular function and structure of iliac artery in spontaneously hypertensive and hereditary hypertriglyceridemic rats.
The aim of this study was to compare the vascular reactivity and morphology of iliac artery (IA) in adult spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic (hHTG) rats. The isolated rings of iliac artery (IA) from Wistar rats (controls), SHR and hHTG rats were used for measurement of relaxant responses to acetylcholine (ACh) and contractile responses to noradrenaline (NA). Morphological changes of IA were measured using light microscopy. Systolic blood pressure (BP) measured by plethysmographic method was increased in SHR approximately by 88 % and in hHTG rats by 44 % compared to controls. BP increase was accompanied by cardiac hypertrophy. In both SHR and hHTG groups (experimental groups) reduced relaxation to ACh and enhanced maximal contraction and sensitivity to adrenergic stimuli were observed. The sensitivity to NA in SHR was higher also in comparison with hHTG. Geometry of IA in both experimental groups revealed increased wall thickness and wall cross-sectional area, in SHR even in comparison with hHTG. Inner diameter was decreased in both experimental groups. Thus, independently of etiology, hypertension in both models was connected with impaired endothelial function accompanied by structural alterations of IA. A degree of BP elevation was associated with arterial wall hypertrophy and increased contractile sensitivity.


Improved survival after resuscitation with norepinephrine in a murine model of uncontrolled hemorrhagic shock.
Recent studies have challenged current guidelines on fluid resuscitation. However, studies on resuscitation using norepinephrine in uncontrolled hemorrhagic shock are lacking. The authors examined the effects of norepinephrine in combination with saline infusion in uncontrolled hemorrhage in rats. Rats subjected to a 15-min controlled hemorrhage (withdrawal of 3 ml blood/100 g body mass) followed by a 60-min uncontrolled hemorrhage (75% tail amputation) were randomly assigned to one of several treatment groups (10 rats/group) receiving different doses of norepinephrine (0 [NE0], 5 [NE5], 50 [NE50], or 500 [NE500] microg.100 g(-1).h(-1)). In the four hypotensive resuscitation groups (n = 40), mean arterial pressure was not allowed to fall below 40 mmHg by titrated infusion of normal saline. In the four normotensive resuscitation groups (n = 40), it was not allowed to fall below 80 mmHg. The endpoint was survival at 210 min. There was a significant difference (P < 0.05) in survival rate among groups. Among the hypotensive rats, 6 (60%) survived in the NE0 and NE5 dose groups, 9 (90%) survived in the NE50 dose group, and none survived in the NE500 dose group. Among the normotensive rats, none survived in the NE0 group, 4 (40%) survived in the NE5 dose group, all 10 (100%) survived in the NE50 group, and none survived in the NE500 group. The early use of norepinephrine in uncontrolled hemorrhagic shock in rats significantly improved survival when infused at a rate of 50 microg.100 g(-1).h(-1) in normotensive and hypotensive resuscitation strategies.


Leptospiral infection in school-children from Trinidad and Barbados.
A serological survey for leptospiral agglutinins was undertaken between 1980 and 1983 in over 500 Barbadian and 500 Trinidadian school-children aged 7-14 years. The children were selected randomly from urban and rural schools, and examined three times at approximately annual intervals. A total of 12.5% of the Barbadian children and 9.5% of the Trinidadian children were seropositive at a titre of 50 using the microscopic agglutination test. On both islands, seroprevalence was higher in males than females, the difference being significant in rural schools. There was no evidence of a difference in prevalence between urban and rural schools, or between junior and secondary age-ranges. Analysis of the association of serology with socio-economic and behavioural factors showed a significant association in Trinidad with father's occupation, but most other variables on both islands showed only weak non-significant associations. Fourteen children in Trinidad and three in Barbados seroconverted. Seroconversion in Trinidad occurred at a rate of 1.6% per annum and was significantly associated with livestock contact and with absence of a tapped water supply. In Trinidad, Autumnalis was the most commonly recorded serogroup, but this accounted for less than a quarter of seropositives. In Barbados, Panama accounted for over half the seropositives and was about four times more common than the next most common serogroup, Autumnalis. In Barbados, 39 persons aged 19 or less were hospitalized with leptospirosis between November 1979 and December 1986. Average annual incidence rates were 2.2, 4.9 and 13.3 per 100,000 in the 5-9, 10-14 and 15-19 age-groups, respectively.


Auditory responses in the cochlear nucleus of awake mustached bats: precursors to spectral integration in the auditory midbrain.
In the cochlear nucleus (CN) of awake mustached bats, single- and two-tone stimuli were used to examine how responses in major CN subdivisions contribute to spectrotemporal integrative features in the inferior colliculus (IC). Across CN subdivisions, the proportional representation of frequencies differed. A striking result was the substantial number of units tuned to frequencies <23 kHz. Across frequency bands, temporal response patterns, latency, and spontaneous discharge differed. For example, the 23- to 30-kHz representation, which comprises the fundamental of the sonar call, had an unusually high proportion of units with onset responses (39%) and low spontaneous rates (53%). Units tuned to 58-59 kHz, corresponding to the sharply tuned cochlear resonance, had slightly but significantly longer latencies than other bands. In units tuned to frequencies >30 kHz, 31% displayed a secondary excitatory peak, usually between 10 and 22 kHz. The secondary peak may originate in cochlear mechanisms for some units, but in others it may result from convergent input onto CN neurons. In 20% of units tested with two-tone stimuli, suppression of best frequency (BF) responses was tuned at least an octave below BF. These properties may underlie similar IC responses. However, other forms of spectral interaction present in IC were absent in CN: we found no facilitatory combination-sensitive interactions and very few combination-sensitive inhibitory interactions of the dominant IC type in which inhibition was tuned to 23-30 kHz. Such interactions arise above CN. Distinct forms of spectral integration thus originate at different levels of the ascending auditory pathway.


Haemodynamic effects of sustained treatment with prazosin and metoprolol, alone and in combination, in borderline hypertensive heart failure.
The sustained haemodynamic effects of prazosin (20-30 mg) and metoprolol (400-800 mg) alone and combined (half-dose) were evaluated in five patients with hypertension, left ventricular hypertrophy, and radiological cardiac enlargement. Measurements were made at rest and during isometric handgrip exercise. Blood pressure at rest was equally well controlled on each regimen. The heart rate and cardiac output (thermodilution) were reduced by metoprolol, even when combined with prazosin. Systolic ejection time was prolonged by metoprolol, but there were no changes in left ventricular dimensions at rest. During isometric handgrip the pressure increments were similar on each of the three regimens, although absolute diastolic pressure was lower on combined therapy. The arterial pressure increment on prazosin therapy was predominantly due to a rapid rise in heart rate and cardiac output, whereas with metoprolol and combined therapy the major contribution to the response was by peripheral vasoconstriction. Moreover, with the latter regimens there was a rapid rise in pulmonary artery occluded pressure, which did not occur with prazosin therapy. In conclusion, metoprolol alone, or combined with prazosin, caused significant depression of cardiac function, which was apparent only when the patients were subjected to the haemodynamic stress of isometric exercise.


A long-term follow-up study of a cohort of referrals to an adult mental health clinical psychology department.
The study, using the SCL-90-R, investigated the long-term outcome of clinical psychology interventions with adults by contacting 95 clients between five and eight years after initial contact. Post-treatment improvements in global psychological well-being were generally maintained at long-term follow-up. About a quarter of clients, however, did not report any improvement in the initial problem and about a half had received help from other services since ending contact with the department. The study provides encouraging evidence of long-term benefits for many clients, but we suggest a reconsideration of the optimal provision of psychological help for people whose problems may be enduring and/or recurrent.


Basal cell carcinoma with sebaceous differentiation.
Some authors have used sebaceous epithelioma as a synonym for basal cell carcinoma (BCC) with sebaceous differentiation. However, our review of the literature revealed that definite cases of BCC with sebaceous differentiation that provide adequate clinical and histopathologic information are scarce. We present the case of a 72-year-old woman with a pigmented nodular lesion on her right ala nasi region, clinically diagnosed as pigmented BCC. Histopathologically, this nodular lesion, which was completely excised, showed typical features of BCC. It was noteworthy that within one aggregation of the presented BCC, tiny and small duct-like structures lined by cornified layers with a crenulated inner surface were seen. Vacuolated cells were scattered within a few aggregations, and they had foamy, bubbly cytoplasm and starry nuclei. The vacuolated cells were immunohistochemically positive for epithelial membrane antigen (EMA). These histopathologic findings demonstrated unquestionable sebaceous differentiation in this BCC, namely BCC with sebaceous differentiation, which should be distinguishable from both sebaceoma and sebaceous carcinoma. The small duct-like structures lined by eosinophilic cuticle, indicating apocrine differentiation, were also observed in this BCC.


Demonstration of the low affinity alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-R alpha) on human trophoblast and uterine cells.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a classical haematopoietic cytokine which has also been implicated in placental growth and development. In this study we have performed a detailed immunohistological localization of the low affinity GM-CSF receptor (GM-CSF-R alpha) in human first trimester implantation site and non-pregnant endometrium. We have also investigated receptor expression and GM-CSF binding in vitro by normal first trimester trophoblast using flow cytometric analysis and compared this with JEG-3 and JAR choriocarcinoma cells. In the first trimester, the GM-CSF-R was found to be present on villous cytotrophoblast and all populations of extravillous trophoblast. Expression by villous syncytiotrophoblast was weak or absent, but this increased markedly by term. GM-CSF-R were also expressed by fetal Hofbauer cells within the mesenchyme of the chorionic villi and by uterine glandular epithelium and decidual macrophages within maternal decidua. GM-CSF-R was not expressed by glands in proliferative phase endometrium but began to appear during the secretory phase, suggesting hormonal regulation of the receptor on uterine glandular epithelium. Flow cytometric comparison of normal isolated first trimester trophoblast and JEG-3 and JAR choriocarcinoma cells revealed two- to threefold higher surface expression of GM-CSF-R by choriocarcinoma cells and higher binding capacity for rhGM-CSF than normal trophoblast. These results suggest that GM-CSF may regulate growth and development of human trophoblast. GM-CSF may also influence placental development and function by acting via decidual and fetal macrophages, and uterine glandular epithelium, which are the other cell populations to express the receptor.


Advances in nanoparticle-based mRNA delivery for liver cancer and liver-associated infectious diseases.
The liver is a vital organ that functions to detoxify the body. Liver cancer and infectious diseases such as influenza and malaria can fatally compromise liver function. mRNA delivery is a relatively new means of therapeutic treatment which enables expression of tumor or pathogenic antigens, and elicits immune responses for therapeutic or prophylactic effect. Novel nanoparticles with unique biological properties serving as mRNA carriers have allowed mRNA-based therapeutics to become more clinically viable and relevant. In this review, we highlight recent progress in development of nanoparticle-based mRNA delivery systems for treatment of various liver diseases. First, we present developments in nanoparticle systems used to deliver mRNAs, with specific focus on enhanced cellular uptake and endosomal escape achieved through the use of these nanoparticles. To provide context for diseases that target the liver, we provide an overview of the function and structure of the liver, as well as the role of the immune system in the liver. Then, mRNA-based therapeutic approaches for addressing HCC are highlighted. We also discuss nanoparticle-based mRNA vaccines for treating hepatotropic infectious diseases. Finally, we present current challenges in the clinical translation of nanoparticle-based mRNA delivery systems and provide outlooks for their utilization in treating liver-related diseases.


Associations between antipsychotics and risk of violent crimes and suicidal behaviour in personality disorder.
Despite uncertain benefits, people with personality disorder are commonly treated with antipsychotic medication. To investigate the association between antipsychotics and violent crimes and suicidal behaviour in individuals with personality disorder. We used nationwide Danish registries to identify all individuals with diagnosed personality disorder aged 18-64 years during 2007 to 2016. Antipsychotics were recorded in dispensed prescriptions, and individuals were followed up for police-recorded suspicions for violent crimes and healthcare presentations of suicidal behaviour. We applied a within-individual design where outcome rates for individuals with personality disorder during medicated periods were compared with rates during non-medicated periods. The cohort included 166 328 people with diagnosed personality disorder, of whom 79 253 were prescribed antipsychotics, presented at least one outcome and were thus included in the within-individual analyses. Compared with periods when individuals were not on antipsychotic medication, violent crime suspicions were 40% lower (incident rate ratio (IRR) 0.60, 95% CI 0.55 to 0.63) in men and 10% lower (IRR 0.90, 95% CI 0.79 to 1.01) in women, while rates of suicidal behaviour were 32% lower both in men (IRR 0.68, 95% CI 0.66 to 0.71) and in women (IRR 0.68, 95% CI 0.65 to 0.70). In subgroup analyses, the magnitude of the association varied across specific personality disorders for criminal outcomes but less for suicidal behaviour, with largest association in dissocial personality disorder for violent criminality (IRR 0.53, 95% CI 0.47 to 0.59). Treatment with antipsychotics was associated with reduced risks for violent crime suspicions and suicidal behaviour among individuals with personality disorder. Potential effects of antipsychotics on suicidal behaviour and violence should be taken into account when considering treatment options for people with personality disorders.


Telomere status in chronic lymphocytic leukemia with TP53 disruption.
In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.


Needle phobia and stress-reducing medical devices in pediatric and adult chemotherapy patients.
Needle phobia--fear of medical devices--is a significant problem in pediatric and adult chemotherapy patients. Stress-reducing medical devices is a new, effective cognitive therapy for needle phobia. Twenty-five pediatric and 25 adult chemotherapy patients were randomly exposed to conventional or stress-reducing decorated butterfly needles and syringes. Emotional stress responses were determined with the Visual Aversion Scale, Visual Analogue Fear Scale, Visual Analogue Anxiety Scale, and Visual Overall Stress Score for each needle and syringe design. Sixty-eight percent of the pediatric and 52% of the adult patients were overtly needle phobic, but children demonstrated significantly more aversion and stress (P < .001). Stress-reducing medical devices effectively and significantly reduced aversion, anxiety, fear, and overall stress, and were 76% effective in preventing overt needle phobia in children and 92% effective in adults (P < .001). One hundred percent of children and adults felt that stress-reducing medical devices should be available in chemotherapy clinics. Needle phobia and stress in pediatric and adult chemotherapy patients are significantly reduced by the use of stress-reducing medical devices.


Evolution of diel activity patterns in skinks (Squamata: Scincidae), the world's second-largest family of terrestrial vertebrates.
Many animals have strict diel activity patterns, with unique adaptations for either diurnal or nocturnal activity. Diel activity is phylogenetically conserved, yet evolutionary shifts in diel activity occur and lead to important changes in an organism's morphology, physiology, and behavior. We use phylogenetic comparative methods to examine the evolutionary history of diel activity in skinks, one of the largest families of terrestrial vertebrates. We examine how diel patterns are associated with microhabitat, ambient temperatures, and morphology. We found support for a nondiurnal ancestral skink. Strict diurnality in crown group skinks only evolved during the Paleogene. Nocturnal habits are associated with fossorial activity, limb reduction and loss, and warm temperatures. Our results shed light on the evolution of diel activity patterns in a large radiation of terrestrial ectotherms and reveal how both intrinsic biotic and extrinsic abiotic factors can shape the evolution of animal activity patterns.


Bipotential roles of ceramide in the growth of hippocampal neurons: promotion of cell survival and dendritic outgrowth in dose- and developmental stage-dependent manners.
Ceramide is now regarded as a lipid messenger molecule involved in a variety of cellular processes, including growth, differentiation, and cell death. Previously, we demonstrated that ceramide is required for cell survival and dendritic growth of cerebellar Purkinje neurons (Furuya et al.: J Neurochem 65: 1551-1561, 1995). Here, we show that ceramide plays growth-supportive roles in hippocampal neurons at immature stages of development. Application of cell-permeable N-hexanoyl-D-erythro-sphingosine (C6-ceramide) at a concentration of 3 microM promoted cell survival and dendritic outgrowth of the immature neurons. A structurally related compound, N-hexanoyl-D-erythro-dihydrosphingosine (C6-dihydroceramide), was ineffective, showing a requirement of 4-5 double bonds in the sphingosine moiety for activity. Incorporation of 5-bromo-2'-deoxyuridine into neurons was not altered by the treatment with C6-ceramide, indicating that C6-ceramide did not facilitate neuronal proliferation but protected hippocampal neurons against basal cell death. The survival-promoting activity of C6-ceramide, however, appeared to be biphasic; C6-ceramide at a concentration of 10 microM caused retraction of the dendrites and detachment of the neurons from the culture plate followed by cell death. In contrast to the immature neurons, the treatment of mature hippocampal neurons with C6-ceramide did not support cell survival but caused nonnecrotic cell death, even at a concentration of 3 microM. These results suggest strongly that ceramide regulates the fate of hippocampal neurons, depending on its concentration and on the developmental stage.


Association of host tropism of Middle East syndrome coronavirus with the amino acid structure of host cell receptor dipeptidyl peptidase 4.
The Middle East syndrome coronavirus (MERS-CoV) is a recently emerging betacoronavirus with high fatality. Recently, dipeptidyle peptidase (CD26, DPP4) was identified as the host cell receptor for MERS-CoV. Interestingly, despite of common presence of DPP4 receptors the binding and infection of various cells shows imminent variability. In this report, we provide a tool for prediction of the host tropism of the virus based on the host receptor binding interface. We found out that, in the binding of MERS-CoV to cells the amino acid residues in lancets 4 and 5 of DPP4 receptor, namely K267, Q286, T288, R317, R336, Q344 A291, L294, and I295 are involved. Changes in these residues correspond to profound decrease in virus binding to cells. The nine residues at the interface between the virus spikes and the lancets 4 and 5 of host DPP4 can be used as a predictive tool for the host tropism and virus affinity to host cell receptors.


Skin electroporation of a plasmid encoding hCAP-18/LL-37 host defense peptide promotes wound healing.
Host defense peptides, in particular LL-37, are emerging as potential therapeutics for promoting wound healing and inhibiting bacterial growth. However, effective delivery of the LL-37 peptide remains limiting. We hypothesized that skin-targeted electroporation of a plasmid encoding hCAP-18/LL-37 would promote the healing of wounds. The plasmid was efficiently delivered to full-thickness skin wounds by electroporation and it induced expression of LL-37 in the epithelium. It significantly accelerated reepithelialization of nondiabetic and diabetic wounds and caused a significant VEGFa and interleukin (IL)-6 induction. IL-6 was involved in LL-37-mediated keratinocyte migration in vitro and IL-6 neutralizing antibodies delivered to mice were able to suppress the wound healing activity of the hCAP-18/LL-37 plasmid. In a hindlimb ischemia model, electroporation of the hCAP-18/LL-37 plasmid increased blood perfusion, reduced muscular atrophy, and upregulated the angiogenic chemokines VEGFa and SDF-1a, and their receptors VEGF-R and CXCR-4. These findings demonstrate that a localized gene therapy with LL-37 is a promising approach for the treatment of wounds.


A dedicated tracheobronchial stent.
A dedicated tracheobronchial stent to be used in the treatment of external compression of the main airway is described. This stent is made of molded silicone. Its outside surface bears regularly placed studs to prevent displacement. First results are encouraging. So far, 118 prostheses have been placed in 66 patients. Tolerance was excellent and complications were rare. Migration occurred 12 times: in seven cases an early prototype that was poorly designed had been used. Obstruction was noted in two cases without major problems. Mean follow-up at the time of this writing is three months, with the longest follow-up 19 months.


Correlation of forkhead box transcription factor O1 and myosin heavy chain isoforms in porcine skeletal muscle.
We examined the expression of myosin heavy chain (MyHC) isoforms and forkhead box transcription factor O1 (FoxO1) in porcine soleus and extensor digitorum longus (EDL) muscles to clarify the correlation of FoxO1 and the relative abundance of transcripts of MyHC isoforms. Soleus muscle was found to be redder than EDL muscles in pigs, and immunohistochemical fast MyHC staining showed more oxidative type I fibers compared to EDL. qRT-PCR quantification of MyHC isoforms I, IIa, IIx, and IIb showed that expression of MyHC I and MyHC IIa mRNAs was much higher, whereas expression of MyHC IIx and MyHC IIb mRNAs was much lower in porcine soleus muscle compared to EDL muscle. Expression of FoxO1 mRNA and p-FoxO1 protein was significantly more abundant in porcine soleus muscle compared to EDL muscle. The expression of phosphorylated FoxO1 (p-FoxO1) was positively correlated with the expression of MyHC I (R = 0.9747, P < 0.01) and negatively correlated with the expression of MyHC IIx (R = -0.9963, P < 0.01) and MyHC IIb (R = -0.9834, P < 0.01). Taken together, these results suggested that FoxO1 may play a pivotal role in the determination of muscle fiber type.


Neuropsychological impairment and return to work following severe closed head injury: implications for clinical management.
To study the rate and timing of return to work following severe closed head injury, and to compare the neuropsychological functioning of patients who successfully return to work with that of patients who fail to return to work. The vocational status, level of cognitive functioning and personality functioning of a consecutive series of 66 patients who survived severe closed head injury was assessed between six months and three years postinjury. The level of cognitive and personality functioning of patients who returned to work were compared with that of patients who failed to return to work. Twenty five percent of patients failed to return to work, and a further 17% returned to work under special conditions of employment. Failure to return to work was related to the degree of neuropsychological impairment (cognitive deficit and adverse personality change), injury severity (duration of posttraumatic amnesia), and age. Multiple regression analysis found the total number of neuropsychological symptoms to be the strongest predictor of the patients' return to work. These findings suggest that neuropsychological symptoms are the main mechanism through which severe brain injury affects the ability to return to work. It is recommended that vocational rehabilitation of severe closed head injury patients be based on a comprehensive neuropsychological assessment.