A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: evidence for differential regulation of transcription by pulse frequency in vivo.
Previous results have shown that the pattern of GnRH pulses (amplitude and frequency) can differentially regulate expression of gonadotropin subunit cytoplasmic messenger RNA (mRNA) concentrations. The present study examined the effect of GnRH pulses on alpha, LH-beta and FSH-beta transcription rates as determined by nuclear runoff transcription assay. GnRH pulses (saline to controls) were given to castrate, testosterone-replaced male rats, and the rate of subunit gene transcription was measured in isolated pituitary nuclei. The effect of GnRH treatment duration was examined by giving GnRH pulses (25 ng/pulse at 30-min intervals) for 1, 4, or 24 h. The basal transcription rates [expressed as parts per million (ppm)] were 82 +/- 25 for alpha; 39 +/- 19 for LH-beta and 27 +/- 6 ppm for FSH-beta, and transcription rates of all 3 subunits were elevated at 1 h (3-5-fold vs. saline controls). After 4 h of GnRH pulses, alpha and FSH-beta transcription rates were reduced vs. 1 h, but LH-beta mRNA synthesis rate was maintained. At 24 h, the alpha transcription rate was still increased (66%), but LH-beta and FSH-beta transcription rates had fallen to basal levels despite the continuing pulsatile GnRH stimulus. The second experiment investigated the effect of the duration of GnRH pulses (25 ng/pulse, every 30 min for 4 h or 24 h), on cytoplasmic subunit mRNA concentrations to assess if the initial 4-h increase in transcription rate would induce a rise in cytoplasmic mRNAs. After 4 h of GnRH pulses, alpha and LH-beta mRNAs were unchanged, but FSH-beta mRNA had increased by 36% (P less than 0.05) compared to controls. All 3 subunit mRNAs were increased (approximately 2-fold) by 24 h of GnRH pulses. Administering GnRH pulses for 4 h followed by 20 h of saline pulses did not increase alpha mRNA; LH-beta was slightly increased (P less than 0.05), but FSH-beta mRNA concentrations were similar to levels seen after 24 h of continued GnRH pulses. The third experiment examined the effects of a continuous GnRH infusion and different GnRH pulse frequencies on gonadotropin subunit transcription rates. GnRH (25 ng/pulse) was given at intervals of 8, 30, or 120 min for 4 h (saline to controls). The continuous GnRH infusion (200 ng/h) did not increase the transcription rate of any of the three subunit mRNAs. alpha-subunit transcription rate was increased 2.7- or 4-fold by GnRH pulses given every 8 or 30 min, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)


The effect of transferring pronuclear embryos on pregnancy outcome after in vitro fertilization.
In a prospective clinical trial the pregnancy rate in patients matched for infertility status, degree of hyperstimulation, and number of oocytes recovered was unaffected by whether embryos were transferred while still pronuclear (day 1) or after they had undergone cleavage (day 2). The pregnancy rates per transfer were 27% and 22%, respectively, for the two transfer times. Unlike results of a previous study, no difference was detected in the outcome of pregnancies from the two groups.


Predictors of Implicit and Explicit Internalized Stigma in a Sample With Different Mental Illness Diagnoses.
This research aimed to study implicit and explicit internalized stigma and its relationship with other variables in a sample of people with distinct mental illness diagnoses ( N = 160). Descriptive analysis, mean differences, correlations, and stepwise regression models were conducted. Implicit and explicit internalized stigma was found throughout the sample with differences depending on certain sociodemographic variables. Regression models revealed symptomatology, physical environment, personality traits, references to mental illness, and the time taken to seek professional help as predictors of explicit internalized stigma. At the implicit level, only self-esteem was found as a predictor explaining a low percentage of the variance. The results obtained underline the differences between implicit and explicit stigma, suggesting different relevant variables for interventions focused on prevention and internalized stigma reduction.


[Transurethral resection in the treatment of benign prostatic hypertrophy: analysis of its results].
To analyze the results achieved with transurethral resection in the treatment of benign prostatic hyperplasia. We analyzed the results achieved with transurethral resection in 400 patients with benign prostatic hyperplasia who had been treated at the Joaquín Albarrán teaching hospital. The procedure was utilized for prostates weighing up to 50 gm and middle lobe involvement independent of its size. Sterile water was used as irrigant since it permits excellent vision, it is low-cost and carries a low risk of complications associated with intraoperative osmotic diuresis. 4.75% of the cases required blood transfusion (not more than two units). The intraoperative complication rate was 2.75%; hemorrhage (2%), capsular perforation (0.5%), and one death from myocardial infarction (0.25%). Hematuria resolved within 48 h postoperatively in 83.75% and the urethral catheter was removed in 82.75% within the first 72 h. Urinary tract infection was the most common postoperative complication; 8.5% were acute and 3.25% presented late. Urethral stenosis was observed in 2.25% and sclerosis of the neck was observed in 1.75%. Good results were achieved in 360 patients (90%). The mean length of hospital stay was 3.8 days. There were two deaths (0.5%); both were due to myocardial infarction. Transurethral resection in the treatment of benign prostatic hyperplasia achieved good results in 90% of our patients. The length of hospital stay was short and the mortality rate was low.


In vivo predictive release methods for medicated chewing gums.
Understanding the performance of a drug product in vivo plays a key role in the development of meaningful in vitro drug release methodology. In case of functional chewing gums, the mode and the mechanism of release and the site of application differ significantly from other conventional solid oral dosage forms and require a special consideration to extract meaningful information from clinical studies. In the current study, suitable drug release methodology was developed to predict the in vivo performance of an investigated chewing gum product. Different parameters of the drug release testing apparatus described in the Ph. Eur. and Pharmeuropa were evaluated. Drug release data indicate that the parameters, chewing distance, chewing frequency and twisting motion, affect the drug release. Higher drug release was observed when the frequency was changed from 40 chews/min to 60 chews/min for apparatus A and B, as was the case for the twisting motion when changed from 20º to 40º for apparatus B. As far as the chewing distance is concerned, the release rate was in the following order; apparatus A: 0.3 mm > 0.5 mm > 0.7 mm; apparatus B: 1.4 mm > 1.6 mm > 1.8 mm. A suitable apparatus set-up for in vitro release testing was identified. The method will be useful for the establishment of in vitro in vivo correlations (IVIVC) for medicated chewing gums. Interchangeability of the apparatus for a product is not generally recommended without prior knowledge of the performance of the product, as the construction and principle of operation for the apparatus differ considerably.


Altered trophoblast proliferation is insufficient to account for placental dysfunction in Egfr null embryos.
Homozygosity for the Egfr(tm1Mag) null allele in mice leads to genetic background dependent placental abnormalities and embryonic lethality. Molecular mechanisms or genetic modifiers that differentiate strains with surviving versus non-surviving Egfr nullizygous embryos have yet to be identified. Egfr transcripts in wildtype placenta were quantified by ribonuclease protection assay (RPA) and the lowest level of Egfr mRNA expression was found to coincide with Egfr(tm1Mag) homozygous lethality. Immunohistochemical analysis of ERBB family receptors, ERBB2, ERBB3, and ERBB4, showed similar expression between Egfr wildtype and null placentas indicating that Egfr null trophoblast do not up-regulate these receptors to compensate for EGFR deficiency. Significantly fewer numbers of bromodeoxyuridine (BrdU) positive trophoblast were observed in Egfr nullizygous placentas and Cdc25a and Myc, genes associated with proliferation, were significantly down-regulated in null placentas. However, strains with both mild and severe placental phenotypes exhibit reduced proliferation suggesting that this defect alone does not account for strain-specific embryonic lethality. Consistent with this hypothesis, intercrosses generating mice null for cell cycle checkpoint genes (Trp53, Rb1, Cdkn1a, Cdkn1b or Cdkn2c) in combination with Egfr deficiency did not increase survival of Egfr nullizygous embryos. Since complete development of the spongiotrophoblast compartment is not required for survival of Egfr nullizygous embryos, reduction of this layer that is commonly observed in Egfr nullizygous placentas likely accounts for the decrease in proliferation.


Opioid overdose crises during the COVID-19 pandemic: implication of health disparities.
Recent data suggest a disproportionate impact of opioid overdoses on Black Americans. The study aims to describe emergency department (ED) visits at a Southern, urban ED pertaining to opioid overdose and associated health disparities. Patients presenting to the ED at the University of Alabama at Birmingham Hospital with opioid overdoses from January 1 to October 31, 2019, and from January 1 to October 31, 2020, were identified from electronic medical records. The total number of opioid overdose visits increased 9.7% (556 to 611) between January and October 2020 compared with 2019. Among patients who presented with opioid overdose, the mean ages were 50.3 years and 48.3 years, in 2019 and 2020, respectively. In both 2019 and 2020, more Blacks than whites were treated for opioid overdose in the ED (284 vs. 258 in 2019, and 306 vs. 271 in 2020) although 28 patients did not record their race in 2020. Consistently, more overdose deaths were observed in Blacks than in whites in 2020. More individuals seeking opioid overdose treatment were single in both years. The study reported a greater number of visits for opioid overdoses from January to October of 2020 in an ED of a southeastern region, as well as higher overdose deaths in Blacks. Our findings highlight the importance of substance use treatment, harm reduction, and overdose prevention efforts that should be immediately present to reduce opioid overdose, especially for vulnerable populations in the South, i.e., Black community, and individuals experiencing singlehood.


Automated framework for intraretinal cystoid macular edema segmentation in three-dimensional optical coherence tomography images with macular hole.
Cystoid macular edema (CME) and macular hole (MH) are the leading causes for visual loss in retinal diseases. The volume of the CMEs can be an accurate predictor for visual prognosis. This paper presents an automatic method to segment the CMEs from the abnormal retina with coexistence of MH in three-dimensional-optical coherence tomography images. The proposed framework consists of preprocessing and CMEs segmentation. The preprocessing part includes denoising, intraretinal layers segmentation and flattening, and MH and vessel silhouettes exclusion. In the CMEs segmentation, a three-step strategy is applied. First, an AdaBoost classifier trained with 57 features is employed to generate the initialization results. Second, an automated shape-constrained graph cut algorithm is applied to obtain the refined results. Finally, cyst area information is used to remove false positives (FPs). The method was evaluated on 19 eyes with coexistence of CMEs and MH from 18 subjects. The true positive volume fraction, FP volume fraction, dice similarity coefficient, and accuracy rate for CMEs segmentation were 81.0%±7.8%, 0.80%±0.63%, 80.9%±5.7%, and 99.7%±0.1%, respectively.


Visual Analysis and Inhibitor Screening of Leucine Aminopeptidase, a Key Virulence Factor for Pathogenic Bacteria-Associated Infection.
Leucine aminopeptidase (LAP) is a hydrolase for the hydrolysis of peptides or proteins containing a leucine residue at the N-terminal. It is also known to be a key virulence factor for the pathogenic abilities of various pathogens causing infectious diseases, which indicated a new insight into the diagnosis and therapy of pathogenic infections. A new fluorescent probe (S)-2-amino-N-(4-(((6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl)oxy)methyl)phenyl)-4-methylpentanamide (DDBL) containing DDAO as the fluorophore and leucine as the recognition group was developed for LAP. By real-time visual sensing of LAP, six bacteria with LAP expression were identified efficiently from human feces, as well as by sensitive visual analysis using native-PAGE specially stained with DDBL. Furthermore, a high throughput screening system established with DDBL was applied to identify a natural inhibitor (3-acetyl-11-keto-β-boswellic acid, AKBA), which could attenuate mouse sepsis induced by Staphylococcus aureus. Therefore, the visual sensing of LAP by DDBL suggested the application for target bacteria identification and LAP homolog analysis as well as potential inhibitor expounding for treatment of bacterial infections.


Differences and Similarities between Perpetrators of Ethnic and Non-Ethnicity-Based Victimization.
Immigrant and minority youth are at risk of ethnic victimization. Despite an increasing number of studies that aim to understand the consequences of such negativity, relatively little attention has been paid to understanding who the perpetrators of ethnic victimization are. To address this gap in knowledge, the present study examined whether youth who victimize their peers due to their ethnic background are also those who engage in non-ethnicity-based victimization. The study also investigated the underlying factors, i.e., impulsivity, empathy, moral disengagement, and attitudes toward immigrants, that are common or specific to groups of youth. The sample included 949 adolescents residing in Sweden (Mage = 13.11, SD = 0.41; range: 12-15; 46% girls). Cluster analysis revealed four distinct groups of adolescents, based on their reports of ethnic and non-ethnicity-based victimization: (1) low on both forms of victimization, (2) high on ethnic victimization only, (3) high on non-ethnicity-based victimization only, and (4) high on both forms of victimization. The results showed that being morally disengaged is a common denominator of ethnic and non-ethnicity-based victimizers. Difficulties in regulating impulses and lack of perspective-taking skills trigger youth's engagement in non-ethnicity-based victimization. Lack of empathic concerns and low levels of positive attitudes toward immigrants are the bases of ethnic victimization. Together, these findings suggest that the precursors of ethnic and non-ethnicity-based victimization have similarities as well as differences, which require further attention in developing programs aimed at preventing different forms of peer victimization.


Chronic Pulmonary Blastomycosis Mimicking Pulmonary Tuberculosis.
Blastomyces dermatitidis is a dimorphic fungus endemic to the Mississippi River valley. We describe a rare case of chronic pulmonary blastomycosis complicated by large pulmonary cavitation in a young service member who was misdiagnosed with active pulmonary tuberculosis. A 25-year-old active duty male presented to his primary care provider with complaints of hemoptysis, fatigue, weight loss, and fever. Computed tomography chest with contrast identified a large cavitary lesion in the right upper lobe (RUL). The patient was admitted to an outside hospital and he underwent bronchoscopy with transbronchial biopsies and bronchoalveolar lavage of the RUL. Histology and cultures were unremarkable however; Histoplasma serum antigen was positive. The patient was empirically treated for active pulmonary tuberculosis and soon discharged. He returned for medical evaluation 3 mo later with continued hemoptysis. Repeat bronchoscopy with transbronchial biopsies of the RUL cavity grew Blastomyces dermatitidis. The patient's symptoms resolved and chest imaging significantly improved with initiation of itraconazole. Chronic pulmonary blastomycosis can present with a constellation of symptoms that may be indistinguishable from chronic pulmonary histoplasmosis, pulmonary tuberculosis, or lung cancer. Knowledge of endemic diseases and a thorough travel history should be an integral part of a military physician's infectious disease evaluation.


[Sequence analysis of norovirus CHN02/LZ35666 from Lanzhou city of China based on RdRp and VP1 genes].
Sequence analysis of a new norovirus (NV) isolated from Lanzou city of China was performed based on partial sequence of RNA dependent RNA polymerase (RdRp) and complete capsid protein (VP1) gene. The isolated strain CHN02/LZ35666 shared high sequence homology with GII-4 NVs. Nucleotide homologies of RdRp region and encoded capsid protein region were 90.4% -- 98.6% and 89.8% -- 95.7% , respectively, while amino acid homology of capsid protein region was 94.4% -- 97.4%. The analysis of GDD motif in RdRp region indicated this GDD motif of Lanzhou strain differed from those of the GII-4 predominant epidemic strains. Lanzhou strain formed an independent branch in GII-4 cluster in the phylogenetic tree based on nucleotide sequence of RdRp region and amino acid sequence of capsid protein. Sequence alignment revealed a mutation at the fourth key site of the receptor-binding interface in the strains isolated after 2002 compared with those of previous strains suggesting a possible change of binding pattern to HBGAs receptors.


So-called nasal glioma.
Nasal glioma is heterotopic brain tissue which usually presents as a tumor around the nose of children and infants. We have encountered two cases of nasal glioma during the past nine years at Hokkaido University Hospital. One showed a tumor in the subcutis of the nasal bridge and the other a polypoid mass arising in the soft palate. Both consisted of proliferation of fibrillary spindle cells consistent with fibrillary astrocytes divided by fibrovascular septa. This was reminiscent of "gliosis" of the central nervous system. Occasional protoplasmic astrocytes were present in both and, in addition, one case showed neuronal cells and choroid plexus. The glial nature of the lesion was confirmed by the presence of glial fibrillary acidic protein demonstrated by the immunoperoxidase method. Nasal glioma is not neoplastic contrary to its name and is considered heterotopic brain tissue which was displaced during fetal development by similar pathogenetic mechanisms of sincipital and basal encephalocele, although its communication to the brain was lost.


Plants' Response to Abiotic Stress: Mechanisms and Strategies.
Abiotic stress is the adverse effect of any abiotic factor on a plant in a given environment, impacting plants' growth and development. These stress factors, such as drought, salinity, and extreme temperatures, are often interrelated or in conjunction with each other. Plants have evolved mechanisms to sense these environmental challenges and make adjustments to their growth in order to survive and reproduce. In this review, we summarized recent studies on plant stress sensing and its regulatory mechanism, emphasizing signal transduction and regulation at multiple levels. Then we presented several strategies to improve plant growth under stress based on current progress. Finally, we discussed the implications of research on plant response to abiotic stresses for high-yielding crops and agricultural sustainability. Studying stress signaling and regulation is critical to understand abiotic stress responses in plants to generate stress-resistant crops and improve agricultural sustainability.


Oxygen speciation in upgraded fast pyrolysis bio-oils by comprehensive two-dimensional gas chromatography.
Biomass fast pyrolysis is considered as a promising route to produce liquid for the transportation field from a renewable resource. However, the derived bio-oils are mainly oxygenated (45-50%w/w O on a wet basis) and contain almost no hydrocarbons. Therefore, upgrading is necessary to obtain a liquid with lower oxygen content and characterization of oxygenated compounds in these products is essential to assist conversion reactions. For this purpose, comprehensive two-dimensional gas chromatography (GC × GC) can be investigated. Oxygen speciation in such matrices is hampered by the large diversity of oxygenated families and the complexity of the hydrocarbon matrix. Moreover, response factors must be taken into account for oxygenate quantification as the Flame Ionisation Detector (FID) response varies when a molecule contains heteroatoms. To conclude, no distillation cuts were accessible and the analysis had to cover a large range of boiling points (30-630 °C). To take up this analytical challenge, a thorough optimization approach was developed. In fact, four GC × GC column sets were investigated to separate oxygenated compounds from the hydrocarbon matrix. Both model mixtures and the upgraded biomass flash pyrolysis oil were injected using GC × GC-FID to reach a suitable chromatographic separation. The advantages and drawbacks of each column combination for oxygen speciation in upgraded bio-oils are highlighted in this study. Among the four sets, an original polar × semi-polar column combination was selected and enabled the identification by GC × GC-ToF/MS of more than 40 compounds belonging to eight chemical families: ketones, furans, alcohols, phenols, carboxylic acids, guaiacols, anisols, and esters. For quantification purpose, the GC × GC-FID chromatogram was divided into more than 60 blobs corresponding to the previously identified analyte and hydrocarbon zones. A database associating each blob to a molecule and its specific response factor (determined by standards injection at different concentrations) was created. A detailed molecular quantification by GC × GC-FID was therefore accessible after integration of the corrected normalized areas. This paper aims to present a detail level in terms of characterization of oxygenated compounds in upgraded bio-oils which to our knowledge has never been reached so far. It is based on an original column set selection and an extremely accurate quantification procedure.


Meaning of ureter dilatation during ultrasonography in infants for evaluating vesicoureteral reflux.
To investigate the meaning of ureter dilatation during ultrasonography (US) in infants for evaluating vesicoureteral reflux (VUR). We retrospectively reviewed abdominal US images of infants who were diagnosed with urinary tract infection (UTI group) or only hydronephrosis without UTI (control group). Hydronephrosis (graded 0-4) and ureter dilatation (present or absent) were evaluated on each side with US. Voiding cystourethrography (VCUG) within 3 months time interval with US was also reviewed and VUR was graded (0-5) on each side. Hydronephrosis, ureter dilatation, and VUR were then compared between the two groups. Four hundred and three infants (142 in the UTI group and 261 in the control group) were included and VCUG was performed in 129 infants (68 in UTI and 61 in control groups). VUR grades were not different between the two groups (p=0.252). Hydronephrosis grade was not related to VUR in either group (p>0.05). However, ureter dilatation had a significant relationship with VUR in the UTI group (p=0.015), even among patients with a high-grade VUR (p=0.005). Whereas, ureter dilatation was not associated with VUR in the control group (p=0.744). The relationship between ureter dilatation and VUR was different between the two groups for both all grades (p=0.014) and high-grade (p=0.004) VUR. Ureter dilatation had 66.7% sensitivity, 80.3% specificity, and 79.4% accuracy for evaluating high-grade VUR in the UTI group. Ureter dilatation on US can be a helpful finding for detecting VUR in infants with UTI, but not infants without UTI.


Does Native Vitamin D Supplementation Have Pleiotropic Effects in Patients with End-Stage Kidney Disease? A Systematic Review of Randomized Trials.
Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker C-reactive protein. Included trials were heterogeneous with regards to outcomes, and the majority studied small participant populations with a relatively short follow-up. We conclude that vitamin D supplementation corrects vitamin D deficiency and is safe and well-tolerated in humans with ESKD. However, it is not clear from clinical trials conducted to date that a causal pathway exists between 25(OH)D and pleiotropic effects that is responsive to vitamin D treatment.


Association between enhancement patterns and parameters of contrast-enhanced ultrasound and microvessel distribution in breast cancer.
The aim of the present study was to evaluate the association between enhancement patterns and parameters in contrast-enhanced ultrasonography (CEUS) and microvessel distribution and histological prognostic tumor characteristics of breast cancer. Between September 2011 and April 2013, 109 breast lesions were prospectively analyzed, which were classified into Breast Imaging Reporting and Data System class 4-5 by conventional ultrasound. Before core-needle biopsy, CEUS examination was performed. Different enhancement patterns (homogeneous, peripheral and regional enhancement) were evaluated. Following CEUS, biopsies were performed at the same body positions under guidance of ultrasound. Parameters (wash-in time, peak intensity, time to peak, area under the time-intensity curve, ascending slope) of CEUS at corresponding puncture sites were recorded. Microvessel density (MVD) and pathological prognostic factors, including histological grade, lymph node status, tumor-node-metastasis stage, estrogen and progesterone receptor status, Ki-67 proliferative index and human epidermal growth factor receptor 2 overexpression, were determined. Mann-Whitney U test, Spearman's rank-correlation test and independent-samples t-tests were used for evaluation. Core-needle biopsy or surgical resection specimens of 99 malignant breast lesions were included in the present study. Of the 99 malignant lesions, 44 lesions exhibited homogeneous enhancement, 43 exhibited peripheral enhancement and 12 exhibited regional enhancement. Lesions with peripheral enhancement exhibited a higher peripheral/central ratio of MVD compared with lesions with homogeneous enhancement (P<0.001). Peak intensity and ascending slope ratios of tumor periphery/center were correlated with the corresponding MVD ratios (P=0.017 and P=0.016, respectively). MVD ratio was positively correlated with histological grade (P=0.003). In conclusion, the enhancement patterns and parameters of CEUS may not only reflect the microvessel distribution but also indirectly indicate the histological grade of breast cancer.


At the vanguard of quality patient care.
Don Berwick is a leader in health policy and improvement. He co-founded the Institute for Healthcare Improvement, ran the US Medicaid and Medicare programmes in the early part of Barack Obama's presidency, and was a leading figure in the extension of health insurance to people who struggled to afford it.


Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.
A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG. There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2. Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management. This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.


Fragile visual short-term memory is an object-based and location-specific store.
Fragile visual short-term memory (FM) is a recently discovered form of visual short-term memory. Evidence suggests that it provides rich and high-capacity storage, like iconic memory, yet it exists, without interference, almost as long as visual working memory. In the present study, we sought to unveil the functional underpinnings of this memory storage. We found that FM is only completely erased when the new visual scene appears at the same location and consists of the same objects as the to-be-recalled information. This result has two important implications: First, it shows that FM is an object- and location-specific store, and second, it suggests that FM might be used in everyday life when the presentation of visual information is appropriately designed.


Postural sway of patients with vestibular disorders during optic flow.
Patients with vestibular orders often complain of sensitivity to moving visual environments, leading to dizziness and imbalance. This study investigated standing postural sway of healthy adults and patients with vestibular disorders in response to optic flow in the central field. Visual conditions of varying properties were presented monocularly with a 60 degrees viewing field. The conditions included: eye open-no flow, eye closed, sinusoidal expansions/contractions at 0.3 Hz, a constant flow giving the appearance of tunnel, and a vertically translating checkerboard. Postural sway, defined in this study as movement of the center of pressure, was recorded using a force platform during presentation of the visual stimuli. Patients with vestibular disorders were found to have a significantly higher magnitude of postural sway than control subjects while viewing central optic flow stimuli. Sinusoidally expanding and contracting optic flow induced postural sway at the stimulus frequency in both the patients and controls; patients, however, had a much larger increase in sway at frequencies near the stimulus frequency. These results suggest that postural control in patients with vestibular disorders is particularly affected by optic flow stimuli to the central region of the visual field.


Clinicopathological analysis of HOXD4 expression in diffuse gliomas and its correlation with IDH mutations and 1p/19q co-deletion.
HOX (homologous box) is known as the dominant gene of vertebrate growth and cell differentiation. Abnormal expression of HOX gene in various tumors has attracted the attention of scholars. As a component of HOX clusters, HOXD4 plays a controversial role in the tumorigenesis of central nervous system. The data demonstrated that and the results demonstrated that HOXD4 was overexpressed in glioma tissues compared to that of normal brain tissues. patients with high HOXD4 expression had a significant shorter survival than those with low HOXD4 expression in total glioma cohort (p<0.001), WHO Grade II cohort (p=0.003) and Grade III cohort (p<0.001), but not in Grade IV cohort when OS (overall survival) was analyzed (p=0.216). The findings were confirmed by the large-scale omics data analysis including lower-grade glioma (LGG) and glioblastoma multiforme (GBM) in TCGA (the cancer genome atlas) and CGGA (Chinese glioma genome atlas). Moreover, it was revealed that the expression of HOXD4 have a significant impact on the OS of Grade IV glioma with IDH wild-type and 1p/19q intact according to TCGA data. Clinicopathological analysis of HOXD4 expression in 453 glioma patients was performed in the current study. Expression of HOXD4 was evaluated by qPCR and immunohistochemical (IHC) staining. Univariate and multivariate analysis were conducted to investigate the prognostic role of HOXD4 in glioma patients. Expression of HOXD4 was closely related to the clinical outcomes of patients with gliomas, and HOXD4 may be a potential prognostic biomarker of gliomas.


Influenza Vaccine Effectiveness in Children at the Emergency Department during the 2018-2019 Season: the First Season School-aged Children Were Included in the Korean Influenza National Immunization Program.
For the 2018-2019 season, the national influenza immunization program expanded to cover children aged from 6 months to 12 years in Korea. This study aimed to analyze vaccine effectiveness (VE) against influenza in children visiting the pediatric emergency room at a tertiary hospital during the 2018-2019 season. Patients tested for influenza antigens from October 1st 2018 to May 31st 2019 at the pediatric emergency room of Samsung Medical Center were included. Patients' influenza antigen test results, influenza vaccination history, and underlying medical conditions were reviewed retrospectively. VE was estimated from the test-negative design study. Among the 2,901 visits with influenza test results 1,692 visits of 1,417 patients were included for analysis. Among these 1,417 patients, 285 (20.1%) were positive (influenza A, n = 211, 74.0%; influenza B, n = 74, 26.0%). The VE in all patients was 36.4% (95% confidence interval [CI], 13.9 to 53.1). The VE for influenza A was 37.6% (95% CI, 12.6 to 55.5) and VE for influenza B was 24.0% (?38.5 to 58.3). The VE in the age group 6 months to 12 years was significant with a value of 35.6% (95% CI, 10.5 to 53.7); it was not statistically significant in the age group 13 to 18 years. In a multivariate logistic regression model, patients who received an influenza vaccination were less likely to get influenza infection (OR, 0.6; 95% CI, 0.4 to 0.8; P = 0.001), with significant confounding factors such as age group 13 to 18 years (OR, 0.5; 95% CI, 0.3 to 0.8; P = 0.003) and underlying hematology-oncology disease (OR, 0.3; 95% CI, 0.1 to 0.6; P = 0.002). We report moderate effectiveness of influenza vaccination in previously healthy children aged from 6 months to 12 years in the 2018-2019 season.


Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM.


Disparities of age-based cancer-specific survival improvement with various clinicopathologic characteristics for kidney cancer.
Whether or not age is a predictor of kidney cancer survival is currently unknown but debated. It is also unknown whether improved kidney cancer survival is associated with age with particular clinicopathologic characteristics. The aim of this study was to evaluate kidney cancer survival in four age-based subgroups of patients by analyzing the Surveillance, Epidemiology, and End Results-registered database. Age-based survival disparity by sex, race, marital status, year of diagnosis, pathological grade, histological type, and stage was measured. The impact of age and further parameters on disease specific mortality was evaluated by multivariate Cox proportional hazards regression analyses. Results showed that 8-year cancer-specific survival was 79.6% in those aged ≤49 years, 70.6% in those aged 50-64 years, 65.3% in those aged 65-74 years, and 56.0% in those aged 75-84 years. These differences were significant as judged by a univariate log-rank test (P<0.001) and multivariate Cox regression (P<0.001). Age-based survival improvement was most obvious in patients diagnosed from 2005 to 2009 and with the following clinicopathologic characteristics: female, white race, low pathological grade, and localized stage. There was no obvious disparity of age-based survival improvement with regard to marital status or histologic type. No age-based survival improvement was observed in patients of the black race, pathological grade IV, or distant stage (P=0.05, P=0.07, and P=0.07, respectively). These data suggest that age is an independent prognostic factor for survival in patients with kidney cancer and that age-based survival improvement is associated with particular clinicopathologic characteristics.


Detection of renal masses: sensitivities and specificities of excretory urography/linear tomography, US, and CT.
A prospective blinded study of 201 patients was performed to determine the relative sensitivities and specificities of excretory urography/linear tomography (EU/LT) and ultrasound (US) for the diagnosis of renal parenchymal masses. Computed tomography (CT) was used as a standard. EU/LT permitted detection of 10% of CT-confirmed masses (cystic or solid) less than 1 cm, 21% of lesions greater than or equal to 1 cm but less than 2 cm, 52% of lesions greater than or equal to 2 cm but less than 3 cm, and 85% of lesions 3 cm or more in diameter. US permitted detection of 26% of CT-confirmed lesions less than 1 cm, 60% of lesions greater than or equal to 1 cm but less than 2 cm, 82% of lesions greater than or equal to 2 cm but less than 3 cm, and 85% of lesions 3 cm or more in size. The results confirm the relative insensitivity of EU/LT for masses less than 3 cm in diameter and of US for masses less than 2 cm. Further, they suggest that CT may have a role not only in evaluation of cases in which the urographic or sonographic results are questionable or positive, but also in confirmation of apparently negative urographic findings when clinical suspicion of a lesion is high.


Raman investigation of stable and metastable states of 4-octyl-4'-cyanobiphenyl confined in porous silica matrices.
We study the polymorphism of solid phases of 4-octyl-4(')-cyanobiphenyl (8CB) by Raman spectroscopy. For bulk 8CB, the Raman spectrum of the CN stretch is featured by a single peak, which shifts abruptly at the smectic-A-crystal transition. In confinement, the CN peak splits both at high and low temperatures. In the isotropic and liquid crystal phases, the signature of the liquid crystal bulk (LC) coexists with another peak that is assigned to LC molecules interacting with the matrice interface. We find correlations between the volumic fractions of interfacial liquid and the texture of the matrices. At low temperatures, we assign the splitting of the CN peak to the coexistence of different metastable solid phases. For strong confinements, the temperature dependence of the CN stretching frequency extends to that of the liquid, which suggests the existence of frozen-in smecticlike solid phases. We discuss the structure of these metastable solid phases in the light of neutron diffraction measurements. We also report on the peculiar analogy between the effect of quenched disorder due to the porous matrices and the effect of thermal quenching.


[Metformin has a positive effect on disorders of carbohydrate metabolism in long-term care with low doses of prednisone].
The influence of long-term, low doses of prednison administration (< 0.3 mg/kg/day) on glucoregulation and glucose tolerance was studied in 20 female patients (15-20 yrs), including verification of possibility to correct the impairment of glucose tolerance (IGT) by metformin (M). During prednison treatment, we found typical signs of insulin resistance manifestation: HOMAIR 3.55 (5.13), blood insulin/glucose ratio 3.8 (5.84), QUICKI 0.61 (0.124). These were associated with higher Langerhans (L.) islets hormone secretion detected under basal conditions as well as after bolus of 5 g arginine chloride. However, detailed analysis of hormone secretion ratios revealed distinct signs of L. islets function impairment and subcompensation. Specifically, low ratio C peptide/proinsulin and C peptide/glucagon were characteristicaly observed. Six months of M. administration (1000 mg/day) had a beneficial effect on glucose metabolisms deviations as indicated by the following: insulin resistance decreased (HOMAIR 1.96 (1.60), insulin/glucose ratio 2.34 (1.52), QUICKI increased at 0.699 (0.238)). At the same time we found a decrease in the basal levels of insulin, proinsulin, glucagon, C peptide and amyline, and AUC proinsulin and glucagon as well. HOMAsecretion decreased from an initial value of 389 (376) to 207 (119). Judging by the new hormonal secretion ratios, the L. islets' function following M. treatment substantially improved. From the clinical point of view, it is important to note that M. was tolerated very well. No patient interrupted the follow up because of M. intolerance. IGT in the whole group normalised, in spite of the fact that no accent was put on the regime, diet including. The 90% of lactate values did not exceed 1.7 mmol/l. Based on the results, we may conclude that M. has a beneficial effect on long-term, low doses of glucocorticoid-related (induced) glucose metabolism impairment, and therefore, M. administration could be recommended, particularly in the situations with higher levels of glycosylated hemoglobin.


Effects of signaled and unsignaled alternative reinforcement on persistence and relapse in children and pigeons.
Three experiments explored the impact of different reinforcer rates for alternative behavior (DRA) on the suppression and post-DRA relapse of target behavior, and the persistence of alternative behavior. All experiments arranged baseline, intervention with extinction of target behavior concurrently with DRA, and post-treatment tests of resurgence or reinstatement, in two- or three-component multiple schedules. Experiment 1, with pigeons, arranged high or low baseline reinforcer rates; both rich and lean DRA schedules reduced target behavior to low levels. When DRA was discontinued, the magnitude of relapse depended on both baseline reinforcer rate and the rate of DRA. Experiment 2, with children exhibiting problem behaviors, arranged an intermediate baseline reinforcer rate and rich or lean signaled DRA. During treatment, both rich and lean DRA rapidly reduced problem behavior to low levels, but post-treatment relapse was generally greater in the DRA-rich than the DRA-lean component. Experiment 3, with pigeons, repeated the low-baseline condition of Experiment 1 with signaled DRA as in Experiment 2. Target behavior decreased to intermediate levels in both DRA-rich and DRA-lean components. Relapse, when it occurred, was directly related to DRA reinforcer rate as in Experiment 2. The post-treatment persistence of alternative behavior was greater in the DRA-rich component in Experiment 1, whereas it was the same or greater in the signaled-DRA-lean component in Experiments 2 and 3. Thus, infrequent signaled DRA may be optimal for effective clinical treatment.


Associations Between Anthropometric Measurements and Cardiometabolic Risk Factors in White European and South Asian Adults in the United Kingdom.
To investigate the association of 4 anthropometric measurements with cardiometabolic risk factors in a UK biethnic sample of South Asians (SAs) and white Europeans (WEs). Baseline data were collected from adults of WE and SA origin participating in the Leicester arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION-Leicester) study between August 2004 and December 2007. Overall, 6268 WE and SA adults had measures of body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio assessed between June 18, 2004, and December 4, 2007. Hypertension, dyslipidemia, and dysglycemia were established from venous blood samples using standard definitions. Crude and adjusted (covariates used were age, sex, ethnicity, smoking, and alcohol consumption) odds ratios were calculated using multivariate logistic regression. Receiver operating characteristic curves and the area under the curve were used to calculate optimal cut points for the whole cohort and for both ethnic groups. Increases in all anthropometric measurements resulted in a higher odds ratio for each of the risk factors in both the crude and adjusted models (P<.001). The adjusted odds ratios for dyslipidemia, hypertension, and dysglygemia ranged from 1.30 to 1.35, from 1.36 to 1.52, and from 1.62 to 1.75 (P<.001 for all), respectively, in WEs. The adjusted odds ratio for dyslipidemia, hypertension, and dysglygemia ranged from 1.50 to 1.65 (P<.01), from 1.40 to 1.60 (P<.01), and from 1.96 to 2.11 (P<.001 for all), respectively, in SAs. The areas under the receiver operating characteristic curves for all the anthropometric measurements had low accuracy (P<.70) for the whole cohort and when stratified by ethnicity and sex. There is insufficient evidence to recommend replacing body mass index with another anthropometric measurement for the ethnically diverse population in the United Kingdom. clinicaltrials.gov Identifier: NCT00318032.


Modelling climate change impacts on viticultural yield, phenology and stress conditions in Europe.
Viticulture is a key socio-economic sector in Europe. Owing to the strong sensitivity of grapevines to atmospheric factors, climate change may represent an important challenge for this sector. This study analyses viticultural suitability, yield, phenology, and water and nitrogen stress indices in Europe, for present climates (1980-2005) and future (2041-2070) climate change scenarios (RCP4.5 and 8.5). The STICS crop model is coupled with climate, soil and terrain databases, also taking into account CO2 physiological effects, and simulations are validated against observational data sets. A clear agreement between simulated and observed phenology, leaf area index, yield and water and nitrogen stress indices, including the spatial differences throughout Europe, is shown. The projected changes highlight an extension of the climatic suitability for grapevines up to 55°N, which may represent the emergence of new winemaking regions. Despite strong regional heterogeneity, mean phenological timings (budburst, flowering, veraison and harvest) are projected to undergo significant advancements (e.g. budburst/harvest can be >1 month earlier), with implications also in the corresponding phenophase intervals. Enhanced dryness throughout Europe is also projected, with severe water stress over several regions in southern regions (e.g. southern Iberia and Italy), locally reducing yield and leaf area. Increased atmospheric CO2 partially offsets dryness effects, promoting yield and leaf area index increases in central/northern Europe. Future biomass changes may lead to modifications in nitrogen demands, with higher stress in northern/central Europe and weaker stress in southern Europe. These findings are critical decision support systems for stakeholders from the European winemaking sector.


Integrated biomarkers in cardiomyopathies: cardiovascular magnetic resonance imaging combined with molecular and immunologic markers--a stepwise approach for diagnosis and treatment.
In an integrated approach, the authors examine the most efficient combination of noninvasive and invasive biochemical, immunologic, functional, molecular, imaging and biopsy-derived biomarkers for their applicability in the diagnosis of cardiomyopathies in general and dilated cardiomyopathy (DCM) in particular. A careful selection out of the cascade of available biomarkers will allow, in individual patients, to diagnose certain conditions of cardiomyopathies without endomyocardial biopsy, e.g., borreliosis, rickettsiosis, HIV cardiomyopathy. Viral persistence in DCM associated with inflammation will need both noninvasive (echocardiography, cardiovascular magnetic resonance) and invasive biomarkers (polymerase chain reaction for viral persistence or their exclusion in case of autoreactive myocarditis and quantitative immunohistology, both from endomyocardial biopsy).


FokI as a genetic factor of intervertebral disc degeneration: A PRISMA-compliant systematic review of overlapping meta-analyses.
The association of FokI (rs2228570), a polymorphism of the vitamin D receptor gene, with intervertebral disc degeneration (IDD) has been investigated in a multitude of studies. However, conflicting results of these studies led to emergence of several meta-analyses over the past few years. Despite the increased statistical power, these meta-analyses have failed to provide uniform and conclusive data on the relationship of FokI with IDD. The aim of this study was to present a comprehensive review based on the most up-to-date meta-analyses on the association of FokI with IDD. A comprehensive search of all major databases was conducted to identify meta-analyses investigating relation between FokI and IDD. No date or language restrictions were applied. The Jadad decision algorithm was utilized to evaluate included meta-analyses and identify the one providing the best evidence. A total of 7 meta-analyses (n = 2580 original patients), that included six to ten case control studies, analyzed the association of FokI polymorphism with IDD. The meta-analysis of the highest quality supported the notion that overall there is no statistically significant association between FokI polymorphism and IDD. However, the authors showed that Caucasians have a reduced risk of IDD and Hispanics have an increased risk of IDD in the dominant and dominant/homozygous/heterozygous models of FokI polymorphism. While currently there is no evidence of an association between FokI polymorphism and IDD in the general population, ethnic predisposition has been shown.


Image Phenotyping of Spring Barley (Hordeum vulgare L.) RIL Population Under Drought: Selection of Traits and Biological Interpretation.
Image-based phenotyping is a non-invasive method that permits the dynamic evaluation of plant features during growth, which is especially important for understanding plant adaptation and temporal dynamics of responses to environmental cues such as water deficit or drought. The aim of the present study was to use high-throughput imaging in order to assess the variation and dynamics of growth and development during drought in a spring barley population and to investigate associations between traits measured in time and yield-related traits measured after harvesting. Plant material covered recombinant inbred line population derived from a cross between European and Syrian cultivars. After placing the plants on the platform (28th day after sowing), drought stress was applied for 2 weeks. Top and side cameras were used to capture images daily that covered the visible range of the light spectrum, fluorescence signals, and the near infrared spectrum. The image processing provided 376 traits that were subjected to analysis. After 32 days of image phenotyping, the plants were cultivated in the greenhouse under optimal watering conditions until ripening, when several architecture and yield-related traits were measured. The applied data analysis approach, based on the clustering of image-derived traits into groups according to time profiles of statistical and genetic parameters, permitted to select traits representative for inference from the experiment. In particular, drought effects for 27 traits related to convex hull geometry, texture, proportion of brown pixels and chlorophyll intensity were found to be highly correlated with drought effects for spike traits and thousand grain weight.


Selective pressures to maintain attachment site specificity of integrative and conjugative elements.
Integrative and conjugative elements (ICEs) are widespread mobile genetic elements that are usually found integrated in bacterial chromosomes. They are important agents of evolution and contribute to the acquisition of new traits, including antibiotic resistances. ICEs can excise from the chromosome and transfer to recipients by conjugation. Many ICEs are site-specific in that they integrate preferentially into a primary attachment site in the bacterial genome. Site-specific ICEs can also integrate into secondary locations, particularly if the primary site is absent. However, little is known about the consequences of integration of ICEs into alternative attachment sites or what drives the apparent maintenance and prevalence of the many ICEs that use a single attachment site. Using ICEBs1, a site-specific ICE from Bacillus subtilis that integrates into a tRNA gene, we found that integration into secondary sites was detrimental to both ICEBs1 and the host cell. Excision of ICEBs1 from secondary sites was impaired either partially or completely, limiting the spread of ICEBs1. Furthermore, induction of ICEBs1 gene expression caused a substantial drop in proliferation and cell viability within three hours. This drop was dependent on rolling circle replication of ICEBs1 that was unable to excise from the chromosome. Together, these detrimental effects provide selective pressure against the survival and dissemination of ICEs that have integrated into alternative sites and may explain the maintenance of site-specific integration for many ICEs.


Nails: The Window to the Nose? Update on Yellow Nail Syndrome.
Yellow nail syndrome is a rare condition characterized by typical nail alterations and variable presence of lymphedema and respiratory disease. The pathogenesis is still obscure, with most of the literature deriving from case reports and few investigations. The most reported respiratory conditions associated with yellow nail syndrome are pleural effusion and bronchiectasis, whereas association with rhinosinusitis is rarer. To describe a case of yellow nail syndrome and to provide a literature review regarding this disorder, discussing pathogenetic hypothesis, associated conditions, and therapeutic options. A 49-year-old man presented with arrested growth and alterations of his nails, without any history of previous trauma or inflammation but with a severe nasal septum deviation and a history of chronic rhinosinusitis. A diagnosis of yellow nail syndrome was made. Six months after undergoing rhinoseptoplasty and treatment with oral vitamin E, the patient's nails were cured. This case emphasizes the role of the dermatologist in detecting systemic conditions. The correct diagnosis led to complete resolution of both nail alterations and associated respiratory disorders.


Telehealth interventions for PPS.
The ongoing challenge for nurses using home telehealth in PPS will be defining and routinely redefining what works to help patients better manage themselves and their treatment and care routines. This process requires careful thought and customization of telehealth routines and interventions. In PPS there is clearly a demand that nurses document that patients have followed needed care directives to reach successful outcomes, whether or not they have followed a conventional telehealth path to get there.


Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice.
Although ursodeoxycholic acid (UDCA) has long been used for patients with chronic cholestatic liver diseases, particularly primary biliary cirrhosis, it may modulate the host immune response. This study investigated the effect of UDCA feeding on experimental hepatitis, endotoxin shock, and bacterial infection in mice. C57BL/6 mice were fed a diet supplemented with or without 0.3% (wt/vol) UDCA for 4 wk. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-γ production by liver mononuclear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it increased mortality of mice following Escherichia coli infection due to the worsening of infection. UDCA-fed mice showed suppressed serum IL-18 levels and production of IL-18 from liver Kupffer cells, which together with IL-12 potently induce IFN-γ production. However, unlike normal mice, exogenous IL-18 pretreatment did not increase the serum IFN-γ levels after E. coli, LPS, or Con-A challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC of the UDCA-fed mice but not in their whole liver tissue homogenates. Silencing GR in the liver MNC abrogated the suppressive effect of UDCA on LPS- or Con-A-induced IFN-γ production. Furthermore, RU486, a GR antagonist, restored the serum IFN-γ level in UDCA-fed mice after E. coli, LPS, or Con-A challenge. Taken together, these results suggest that IFN-γ-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18-independent manner.


Feasibility of Including Hands-On Microteaching in the Medical Faculty Development Program in India: A Mixed-Methods Study.
Background Medical faculty development programs (FDPs) often lack hands-on training in teaching skills. Microteaching, a short, focused teaching practice, could be a feasible way to bridge this gap. This study aimed to explore the feasibility of including hands-on microteaching in a medical FDP in India. Methodology This mixed-methods study involved fresh medical faculty members who never attended FDP on the basics of medical education technologies, stakeholders, and students from a recently established autonomous medical institute of national importance in India. Participants completed a pre-test survey on their teaching skills and received a hands-on microteaching session during an FDP. After the session, participants completed a post-test survey and provided feedback on the feasibility and acceptability of hands-on microteaching in the program. Program evaluation was done by application of Kirkpatrick's Model levels one, two, and three. Results According to the Kirkpatrick Model of Evaluation level one (Reaction), the participants reported improved teaching skills and greater confidence in their ability to teach after the microteaching session. They also reported that hands-on microteaching was an effective way to learn teaching skills and receive feedback. Stakeholders opined that microteaching is a very effective tool for improving teaching skills and should be a part of FDP. Evaluation at level two (Learning) shows that there was a significant improvement in the mean score of post-tests. As per level three (Behaviour Change) evaluation, the majority of the students informed that there is observable improvement in the effectiveness of teaching of faculties in the past two months, i.e., since the participation of faculty in hands-on microteaching in FDP. Conclusions Hands-on microteaching could be a feasible and effective way to enhance the teaching skills of medical faculty members in India. The study findings suggest that including hands-on microteaching in FDPs could help bridge the gap between theoretical knowledge and practical teaching skills.


Molecular and immunological characterization of novel weed pollen pan-allergens.
Pan-allergens like profilins, calcium-binding proteins (CBPs), and nonspecific lipid transfer proteins have been suggested as possible specific markers for multiple pollen sensitizations, and could be used to predict cross-sensitization/poly-sensitization to several pollen allergens. Therefore, the purification and characterization of cross-reacting allergens in pollen is an extremely important task towards correct allergy diagnosis. New pan-allergens were identified by screening a ragweed pollen cDNA library with sera of patients allergic to mugwort pollen. Resulting proteins were cloned, expressed, purified and characterized. We report complete cDNA sequences of two profilin isoforms (Amb a 8.01 and Amb a 8.02), two isoforms of a 2EF-hand CBP (Amb a 9.01 and Amb a 9.02), a new 3EF-hand CBP (Amb a 10) from ragweed pollen and a 2EF-hand CBP from mugwort (Art v 5). All these proteins were expressed in Escherichia coli, purified to homogeneity and characterized by biochemical and immunological means. The identified proteins are novel pan-allergens and can be used as diagnostic markers for polysensitization and used in component-resolved diagnosis.


[Cost-effectiveness analysis (CEA) regarding vitamin A in children aged less than 5 years-old in Colombia].
Evaluating the relative cost-effectiveness of using vitamin A in children aged less than 5-years-old regarding the reduction of events involving diarrhoea, malaria and mortality from the Colombian health-related social security system (CHSSS). A decision tree was constructed, using deaths averted as outcome. Probabilities were taken from the pertinent literature and costs from official sources. The cost-effectiveness threshold was three times greater than the per capita Colombian gross domestic product (GDP) in 2012. Probabilistic and deterministic sensitivity analyses were made and cost effectiveness acceptability curves were drawn. Providing a cohort of 100,000 children with vitamin A (as opposed to not doing so) would represent a saving regarding medical attention costs of $ 340,306,917 due to the number of events involving diarrhea (4,268) and malaria (76), having become reduced, as well as cases requiring hospitalization. A saving for the CHSSS was consistently obtained in sensitivity analysis. Providing vitamin supplements for children aged less than 5 years-old would seem to be the least costly and most effective (dominant) strategy for the CHSSS, i.e. compared to not doing so).


Bio-kinetics of radon ingested from drinking water.
Previous studies have identified the stomach as the most significant organ for the dose from ingested radon. An important factor in dosimetric modelling is the rate of radon loss from the stomach. In the present study, two subjects who ingested radon-rich water were measured using a NaI(Tl) detector fixed over the stomach. The counting rates for 214Pb and 214Bi peak regions were plotted as a function of time after ingestion. These data were interpreted using a compartment model that expressed biokinetics of radon and its progeny. The model was fitted to the experimental data by changing biokinetic parameters such as the rate of radon loss from the stomach. Previous models for dosimetric purposes often assumed that the half-time for radon loss from the stomach is below 20 min. The present results, however, suggest that a part of radon stayed longer in the stomach than expected in the previous models.


Layer-by-layer assembled composite films of side-functionalized poly(3-hexylthiophene) and CdSe nanocrystals: electrochemical, spectroelectrochemical and photovoltaic properties.
Regioregular poly(3-hexylthiophene) containing one diaminopyrimidine side group per ten repeat units (P3HT-co-P3(ODAP)HT) can form molecular composites with 1-(6-mercaptohexyl)thymine capped CdSe nanocrystals (CdSe(MHT)) via hydrogen bonds directed molecular recognition. Here we report complementary spectroscopic, electrochemical and spectroelectrochemical investigations of both the functionalized poly(thiophene) and its composite with the nanocrystals, the latter being fabricated using the layer-by-layer (LbL) deposition technique. UV-Vis-NIR and Raman spectroelectrochemical investigations unequivocally show that the onset of the first anodic peak in the cyclic voltammogram of the copolymer can be attributed to the oxidation of the pi-conjugated backbone in the polymer chains. For this reason, it is possible to determine the width and the position of its band gap (corresponding to the pi-pi* transition) by UV-Vis spectroscopy combined with cyclic voltammetry. These studies show that the polymer exhibits a slightly larger band gap with the HOMO level insignificantly lower in energy (by 0.03 eV) as compared to the case of regioregular poly(3-hexylthiophene) of comparable degree of polymerization. Hydrogen bond interactions of the polymer with CdSe(MHT) in the molecular composite result in a hypsochromic shift of the band corresponding to the pi-pi* transition from 504 nm to 488 nm. This can be taken as a spectroscopic manifestation of the conformational changes induced by shortening of the conjugation length. The observed spectral modifications are consistent with electrochemically determined lowering of the polymer HOMO level (from -4.91 eV in the pure polymer to -4.99 eV in the composite). Cyclic voltammetry studies supported by spectroelectrochemistry also show that the redox stability of CdSe(MHT) in the molecular composite with P3HT-co-P3(ODAP)HT is lower than that determined for stearate-capped nanocrystals. Their irreversible oxidation starts at E = +0.7 V vs. Ag/0.1 M Ag(+)i.e. at potentials by ca. 0.3 V lower than the oxidation of stearate stabilized CdSe nanocrystals of the same size. We show that-despite these modifications-the alignment of the HOMO and LUMO levels of the composite components remains appropriate for its use in hybrid solar cells, which is demonstrated by the photovoltaic effect observed for the LbL-processed composite sandwiched between two electrodes.


Descriptions of Two New Species and a New Subspecies of the Genus Ctenophthalmus (Insecta: Siphonaptera: Ctenophthalmidae) from Turkey.
Two new species and a new subspecies of fleas belonging to the genus Ctenophthalmus Kolenati (Siphonaptera: Ctenophthalmidae) were described from Turkey. Ctenophthalmus (Spalacoctenophthalmus) beyzanurae n. sp. was collected from Nannospalax leucodon Nordmann (Mammalia: Rodentia) in Tekirdağ province while Ctenophthalmus (Euctenophthalmus) kefelioglui n. sp. and Ctenophthalmus (Euctenophthalmus) teres anatolicus n. ssp. were collected from Microtus guentheri (Danford & Alston) and Apodemus uralensis (Pallas) (Mammalia: Rodentia) in the Aksaray and Kars provinces of Turkey, respectively. Detailed illustrations of new taxa described were also provided.


Crystallization in a dense suspension of self-propelled particles.
Using Brownian dynamics computer simulations, we show that a two-dimensional suspension of self-propelled ("active") colloidal particles crystallizes at sufficiently high densities. Compared to the equilibrium freezing of passive particles, the freezing density is both significantly shifted and depends on the structural or dynamical criterion employed. In nonequilibrium the transition is accompanied by pronounced structural heterogeneities. This leads to a transition region between liquid and solid in which the suspension is globally ordered but unordered liquidlike "bubbles" still persist.


[Systematic Analysis of the Roles of Trace Elements in the Prevention and Treatment of Chronic Heart Failure].
Systematic analysis of 3 728 publications on the relationship between microelement status and chronic heart failure (CHF) was carried out. Three main areas of research have been identified: 1) magnesium, electrolytes and CHF; 2) the transcriptional and antioxidant effects of zinc, selenium, copper; 3) iron-deficiency anemia and CHF. In this paper, we consider a complex of relationships between the magnesium insufficiency and CHF, the effect of magnesium on vascular tone, mitochondria, heart rhythm and the susceptibility of cardiomyocytes to adrenergic stimulation. Using magnesium orotate for the treatment of CHF is a feasible approach to compensate magnesium insufficiency in patients with CHF.


Endothelial-dependent dilation following chronic hypoxia involves TRPV4-mediated activation of endothelial BK channels.
Following chronic hypoxia (CH), the systemic vasculature exhibits blunted vasoconstriction due to endothelial-dependent hyperpolarization (EDH). Previous data demonstrate that subsequent to CH, EDH-mediated vasodilation switches from a reliance on SKca and IKca channels to activation of the endothelial BKca channels (eBK). The mechanism by which endothelial cell stimulation activates eBK channels following CH is not known. We hypothesized that following CH, EDH-dependent vasodilation involves a TRPV4-dependent activation of eBK channels. ACh induced concentration-dependent dilation in pressurized gracilis arteries from both normoxic and CH rats. Inhibition of TRPV4 (RN-1734) attenuated the ACh response in arteries from CH rats but had no effect in normoxic animals. In the presence of L-NNA and indomethacin, TRPV4 blockade attenuated ACh-induced vasodilation in arteries from CH rats. ACh elicited endothelial TRPV4-mediated Ca2+ events in arteries from both groups. GSK1016790A (GSK101, TRPV4 agonist) elicited vasodilation in arteries from normoxic and CH rats. In arteries from normoxic animals, TRAM-34/apamin abolished the dilation to TRPV4 activation, whereas luminal iberiotoxin had no effect. In CH rats, only administration of all three Kca channel inhibitors abolished the dilation to TRPV4 activation. Using Duolink®, we observed co-localization between Cav-1, TRPV4, and BK channels in gracilis arteries and in RAECs. Disruption of endothelial caveolae with methyl-β-cyclodextrin significantly decreased ACh-induced vasodilation in arteries from both groups. In gracilis arteries, endothelial membrane cholesterol was significantly decreased following 48 h of CH. In conclusion, CH results in a functional coupling between muscarinic receptors, TRPV4 and Kca channels in gracilis arteries.


Controversies in the use of beta blockers in heart failure.
Recent evidence from randomized controlled trials has provided compelling evidence to support the use of beta blockers in most patients with heart failure due to systolic dysfunction. There is little disagreement about the mortality benefit provided by adding beta blockers to standard therapy, which may include angiotensin-converting enzyme inhibitors, diuretics, and sometimes digoxin. A few areas are still controversial. The authors review the available literature encompassing four of those controversial areas: 1) the comparability among beta blockers; 2) the utility of beta blockers among patients with New York Heart Association class I and class IV heart failure symptoms; 3) the impact of race on the effectiveness of beta blockers; and 4) the safety and efficacy of beta blockers among patients on concomitant therapy with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or spironolactone.


Computed tomography of the temporomandibular joint.
We present a pictorial review of the spectrum of temporomandibular joint (TMJ) pathology diagnosed with CT. Although MRI is the modality of choice for most TMJ pathology, CT is useful when MRI is contraindicated or not accessible. With attention to technique and viewing conditions, CT is capable of showing internal disc derangement, arthritis, neoplasms and non-TMJ regional pathology at a relatively low radiation dose.


[Familial presentation of microdeletion and inverted microduplication with array-CGH].
INTRODUCTION. Over the years the field of genetics has advanced significantly. Following the polymerase chain reaction and mass sequencing techniques, the array-CGH technique (comparative genomic hybridization) has helped to improve genetic procedures. A resolution of up to 200 kb is currently being accomplished in the human genome. CASE REPORTS. We report the case of two sisters with delays in developmental milestones and a characteristic phenotype with normal results from initial studies of the karyotype and subtelomeric regions. Array-CGH was later used to detect a deletion and duplication that were different in each of the sisters, this being the result of a balanced paternal translocation. In the two cases, despite being the result of the same translocation, the genetic and phenotype expression were different. CONCLUSIONS. The precision achieved by means of array-CGH is making it possible to establish a correlation between minimum gains or losses of the genome and the clinical features. Chromosome 3 codes for genes that play a fundamental role in neurological development (contactins, neurotransmitter modulator proteins, etc.) and chromosome 10 codes for proteins involved in apoptosis and proteins regulating transcription. In the literature there have been reports of chromosome 3 deletion syndrome and monosomy 10. Likewise, there are also descriptions of rearrangements between these chromosomes in individuals from the same family. Nevertheless, we describe two cases of a family with a micro-deletion and an inverted microduplication, detected by means of array-CGH, that have not been reported to date. This technique can provide a diagnostic and prognostic approximation as regards development and offer genetic counselling.


European Conference on Health Economics.
The biennial European Conference on Health Economics was held in Finland this year, at the Finlandia Hall in the centre of Helsinki. The European conferences rotate among European countries and fall between the biennial world congresses organized by the International Health Economics Association (iHEA). A record attendance of approximately 800 delegates from 50 countries around the world were present at the Helsinki conference. The theme of the conference was 'Connecting Health and Economics'. All major topics of health economics were covered in the sessions. For the first time, social care economics was included in the agenda of the European Conference as a session of its own.


Specialized peptide transport system in Escherichia coli.
Trileucine is utilized as a source of leucine for growth of strains of Escherichia coli K-12 that are deficient in the oligopeptide transport system (Opp). Trithreonine is toxic to E. coli K-12. Opp- mutants of E. coli K-12 retain complete sensitivity to this tripeptide. Moreover, E. coli W, which is resistant to trithreonine, can utlize this tripeptide as a threonine source and this capability is fully maintained in E. coli W (Opp-). A spontaneous trithreonine-resistant mutant of E. coli K-12 (Opp-) has been isolated that has an impaired growth response to trileucine and is resistant to trithreonine. Trileucine competes with the uptake of trithreonine as measured by its ability to relieve trithreonine toxicity in E. coli K-12. It is concluded that trileucine as well as trithreonine are transported into E. coli K-12 or W by a common uptake system that is distinct from the Opp system. Trimethionine can act as a competitor of trileucine or trithreonine-supported growth and as an antagonist of trithreonine toxicity in Opp- mutants. It is concluded that trimethionine is recognized by the trileucine-trithreonine transport system. Trithreonine, trimethionine, and trileucine are also transported by the Opp system, as they all relieve triornithine toxicity towards E. coli W and compete with tetralysine utilization as lysine source for growth of a lysine auxotroph of this strain.


Carbon irradiation overcomes glioma radioresistance by eradicating stem cells and forming an antiangiogenic and immunopermissive niche.
Tumor radioresistance leading to local therapy failure remains a major obstacle for successful treatment of high-grade glioma. We hypothesized that distinct radiobiological features of particle therapy with carbon ions may circumvent glioma radioresistance. We demonstrate that carbon irradiation (CIR) efficiently eradicates radioresistant patient-derived glioma stem cells (GSCs), leading to growth inhibition and prolonged survival. The impact of CIR at the tumor-stroma interface was further investigated in 2 syngeneic mouse and 2 orthotopic GSC xenograft models. Intriguingly, tumor regressions and long-term local controls were observed at doses greater than or equal to 15-Gy CIR. Fractionated CIR further prolonged survival. The enhanced relative biological effectiveness of CIR in vivo was attributed to its potent antiangiogenic effects and eradication of radioresistant hypoxic tumor cells. Blockade of the HIF1-α/stromal cell-derived factor 1/CXCR4 axis by CIR reduced the recruitment of microglia and myeloid-derived suppressor cells (CD11b+Gr1+). Consequently, CIR abrogated M2-like immune polarization and enhanced the influx of CD8+ cells, generating an immunopermissive niche. We report that radiotherapy with carbon ions could surmount several central glioma resistance mechanisms by eradicating hypoxic and stem cell-like tumor cells, as well as modulating the glioma niche toward an antiangiogenic and less immunosuppressive state. Conclusively, potentially novel rationales for CIR in conquering glioma radioresistance are provided.


Hierarchical Micro/Nano Structures by Combined Self-Organized Dewetting and Photopatterning of Photoresist Thin Films.
Photoresists are the materials of choice for micro/nanopatterning and device fabrication but are rarely used as a self-assembly material. We report for the first time a novel interplay of self-assembly and photolithography for fabrication of hierarchical and ordered micro/nano structures. We create self-organized structures by the intensified dewetting of unstable thin (∼10 nm to 1 μm) photoresist films by annealing them in an optimal solvent and nonsolvent liquid mixture that allows spontaneous dewetting to form micro/nano smooth dome-like structures. The density, size (∼100 nm to millimeters), and curvature/contact angle of the dome/droplet structures are controlled by the film thickness, composition of the dewetting liquid, and time of annealing. Ordered dewetted structures are obtained simply by creating spatial variation of viscosity by ultraviolet exposure or by photopatterning before dewetting. Further, the structures thus fabricated are readily photopatterned again on the finer length scales after dewetting. We illustrate the approach by fabricating several three-dimensional structures of varying complexity with secondary and tertiary features.


Locating Order-Disorder Phase Transition in a Cardiac System.
To prevent sudden cardiac death, predicting where in the cardiac system an order-disorder phase transition into ventricular fibrillation begins is as important as when it begins. We present a computationally efficient, information-theoretic approach to predicting the locations of the wavebreaks. Such wavebreaks initiate fibrillation in a cardiac system where the order-disorder behavior is controlled by a single driving component, mimicking electrical misfiring from the pulmonary veins or from the Purkinje fibers. Communication analysis between the driving component and each component of the system reveals that channel capacity, mutual information and transfer entropy can locate the wavebreaks. This approach is applicable to interventional therapies to prevent sudden death, and to a wide range of systems to mitigate or prevent imminent phase transitions.


Rapid killing of bed bugs (Cimex lectularius L.) on surfaces using heat: application to luggage.
The resistance of bed bugs (Cimex lectularius L.) to chemical insecticides has motivated the development of non-chemical control methods such as heat treatment. However, because bed bugs tend to hide in cracks or crevices, their behavior incidentally generates a thermally insulated microenvironment for themselves. Bed bugs located on the outer surface of luggage are less insulated and potentially more vulnerable to brief heat treatment. Soft-sided suitcases with adult male bed bugs on the outside were exposed to an air temperature of 70-75 °C. It took 6 min to kill all of the bed bugs, even those that had concealed themselves under zipper flaps or decorative piping. During heating, only one bed bug (out of 250 in total) moved into the luggage (through a closed zipper). Over long periods of time (24 h) at room temperature, adult male bed bugs on the exterior of luggage only infrequently moved inside; only 3% (5/170) had moved inside during 24 h. Brief exterior heat treatment of luggage is a promising way to reduce the spread of bed bugs being transported on the outer surface of luggage. This treatment will not kill bed bugs inside the luggage, but could be a component of integrated management for this pest. © 2016 Society of Chemical Industry.


Porcelain gallbladder: ultrasound and CT appearance.
Nine patients with calcification of the gallbladder wall (porcelain gallbladder) were analyzed by ultrasound and the appearance correlated with the CT, radiographic, clinical, and surgical findings. Three distinct patterns were identified: (a) a hyperechoic semilunar structure with acoustic shadowing posteriorly, simulating a stone-filled gallbladder devoid of bile, which was seen in 5 patients; (b) a biconvex , curvilinear echogenic structure with variable acoustic shadowing, seen in all 3 patients with carcinoma of the gallbladder; and (c) an irregular clump of echoes with posterior acoustic shadowing, seen in 1 patient. Potential pitfalls in the diagnosis of gallbladder calcification are presented, and the association between calcification and cancer is emphasized.


Noise-induced effective oscillation in oil-water membrane oscillator.
Noise-induced oscillation (NIO) was investigated in a model of an oil-water membrane oscillator. First, we analyzed an unexcitable region and an excitable region of the system by proposing a critical threshold of NIO appearance and found a linearlike relation between the critical threshold and noise intensity. Then the phenomenon of noise-induced coherence resonance was investigated by calculating the signal-to-noise ratio. Furthermore, it was found that an optimal noise intensity range could most improve the appearance of effective oscillation (EO). The presence of EO regions made the stochastic model show EO at a more extended region than the deterministic description.


Hypoxic bone marrow mesenchymal stem cell-derived exosomal lncRNA XIST attenuates lipopolysaccharide-induced acute lung injury via the miR-455-3p/Claudin-4 axis.
Mesenchymal stem cell-derived exosomes and long non-coding RNAs (lncRNAs) have been identified to play a role in acute lung injury (ALI). In this study, we investigated whether exosomal lncRNAs could regulate ALI and the underlying mechanisms. Bone marrow mesenchymal stem cells (BM-MSCs) were pretreated with hypoxia or normoxia, and exosomes were subsequently extracted from normoxic BM-MSCs (Nor-exos) and hypoxic BM-MSCs (Hypo-exos). A rat model of ALI was established via an airway perfusion of lipopolysaccharide (LPS). Exosomes were administered via the tail vein to evaluate the in vivo effect of exosomes in ALI. LPS-exposed RLE-6TN cells were incubated with exosomes to explore their in vitro effect in ALI. A luciferase reporter assay was used to evaluate the interaction between lncRNA XIST and miR-455-3p, as well as miR-455-3p and Claudin-4. We found that the exosomes attenuated LPS-induced ALI and Hypo-Exos exerted a greater therapeutic effect compared with Nor-exos both in vitro and in vivo. Moreover, an abundance of lncRNA XIST was observed in Hypo-exos compared with Nor-exos. Mechanistically, LncRNA XIST functioned as a miR-455-3p sponge and targeted Claudin-4 in ALI. Our results provide novel insight into the role of exosomal lncRNA XIST for the treatment of ALI. Thus, hypoxic pretreatment may represent an effective method for improving the therapeutic effects of exosomes.


Impella percutaneous left ventricular assist device for severe acute ischaemic mitral regurgitation as a bridge to surgery.
Ischaemic papillary muscle rupture causing acute severe mitral regurgitation (MR) has a dramatic presentation and a very high mortality. Emergent surgical repair improves outcomes, which necessitates robust preoperative stabilisation. Here we discuss a patient with cardiogenic shock with an acute severe MR that was deemed very high risk for emergent valve replacement due to haemodynamic instability and respiratory failure. A percutaneous left ventricular assist device Impella 2.5 (Abiomed, Danvers, MA) drastically improved clinical status, and the patient underwent a successful surgical mitral valve replacement soon after placement of the temporary assist device. Our case highlights that percutaneous ventricular assist devices may help to stabilise patients with severe acute ischaemic MR, and it can serve as a bridge to surgery in high risk patients.


Core verbal working-memory capacity: the limit in words retained without covert articulation.
Verbal working memory may combine phonological and conceptual units. We disentangle their contributions by extending a prior procedure (Chen & Cowan, 2005) in which items recalled from lists of previously seen word singletons and of previously learned word pairs depended on the list length in chunks. Here we show that a constant capacity of about 3 chunks holds across list lengths and list types, provided that covert phonological rehearsal is prevented. What remains is a core verbal working-memory capacity.


Benzotriazole: an ideal synthetic auxiliary.
Benzotriazole is a synthetic auxiliary that offers many advantages. It is inexpensive, odorless, and stable. A benzotriazole group is easily introduced, activates molecules towards numerous transformations, and can be removed easily at the end of the reaction sequence. This Concept provides some recent examples of the synthetic application of benzotriazole methodology and is intended to draw attention to the versatile applications of benzotriazole in organic chemistry.


Friend or foe? Inflammation and the foreign body response to orthopedic biomaterials.
The use of biomaterials and implants for joint replacement, fracture fixation, spinal stabilization and other orthopedic indications has revolutionized patient care by reliably decreasing pain and improving function. These surgical procedures always invoke an acute inflammatory reaction initially, that in most cases, readily subsides. Occasionally, chronic inflammation around the implant develops and persists; this results in unremitting pain and compromises function. The etiology of chronic inflammation may be specific, such as with infection, or be unknown. The histological hallmarks of chronic inflammation include activated macrophages, fibroblasts, T cell subsets, and other cells of the innate immune system. The presence of cells of the adaptive immune system usually indicates allergic reactions to metallic haptens. A foreign body reaction is composed of activated macrophages, giant cells, fibroblasts, and other cells often distributed in a characteristic histological arrangement; this reaction is usually due to particulate debris and other byproducts from the biomaterials used in the implant. Both chronic inflammation and the foreign body response have adverse biological effects on the integration of the implant with the surrounding tissues. Strategies to mitigate chronic inflammation and the foreign body response will enhance the initial incorporation and longevity of the implant, and thereby, improve long-term pain relief and overall function for the patient. The seminal research performed in the laboratory of Dr. James Anderson and co-workers has provided an inspirational and driving force for our laboratory's work on the interactions and crosstalk among cells of the mesenchymal, immune, and vascular lineages, and orthopedic biomaterials. Dr. Anderson's delineation of the fundamental biologic processes and mechanisms underlying acute and chronic inflammation, the foreign body response, resolution, and eventual functional integration of implants in different organ systems has provided researchers with a strategic approach to the use of biomaterials to improve health in numerous clinical scenarios.


Short-term outcomes following cytoreductive surgery and heated intra-peritoneal chemotherapy at Waikato.
Pseudomyxoma peritonei is a rare disease that affects 1-2 per million population per year. Treatment with cytoreductive surgery with heated intraperitoneal chemotherapy (CRS with IPC) has been well described. The purpose of this study was to look at the short-term outcomes following CRS with IPC for all such patients treated in Waikato. Records for all patients presenting to surgery for CRS with IPC were retrospectively reviewed. CRS with IPC was performed in accordance with the techniques described by Sugarbaker. Data recorded included patient characteristics, characteristics of surgical treatment and early post-operative outcomes. Sixty-eight patients underwent 72 procedures. Fourteen patients were deemed unresectable at surgery and were treated palliatively. The median age was 57 with the majority being female (59%). The median time, from the decision made for surgery to CRS with IPC, was three months. The median prior surgical score was 1 and the median peritoneal cancer index (PCI) was 19.5. The median operating time was 9.08 hours (5.43-15.20). The majority of patients (76%) had pseudomyxoma peritonei, while the remainder had a combination of other appendiceal, colorectal, ovarian, gastric and primary mesothelial primaries. The major complication rate was 24% and the 30-day mortality rate was 1.4%. The median hospital stay was 12 days. Short-term outcomes following CRS with IPC at Waikato are comparable to those published in the literature. Further follow-up is anticipated for the publication of survival and recurrence data.


HL-60-1E3, a novel phorbol diester-resistant HL-60 cell line.
The HL-60 (human promyelocytic leukemia) cell line has proved to be a useful model for the study of the expression of cellular functions and markers associated with hematopoietic differentiation. We report here the development and initial characterization of a novel, differentiation-resistant HL-60 cell line (HL-60-1E3) which was established by cloning the parent HL-60 line in the absence of mutagens or differentiation-inducing agents. HL-60-1E3 exhibits markedly reduced phorbol diester-induced expression of extracellular cytolytic activity, nonspecific esterase, phagocytosis, and surface Mo1 antigen. In addition, dimethyl sulfoxide-induced expression of both Mo1 and Mo2 is markedly reduced. However, if HL-60-1E3 is exposed to dimethyl sulfoxide, it acquires appreciable phorbol diester-triggered cytolytic activity and production of superoxide anion (O2-). Phorbol diester receptor number and dissociation constant (Kd) obtained by Scatchard analysis are not significantly different for the two cell lines. The HL-60-1E3 cell line should provide a useful adjunct to other cell lines used in the study of normal myeloid and leukemic cell differentiation, as well as the study of cytokine maturation factors and oncogene expression.


Gas Chromatography/Mass Spectrometry Metabolomics of Urine and Serum from Nonhuman Primates Exposed to Ionizing Radiation: Impacts on the Tricarboxylic Acid Cycle and Protein Metabolism.
Ionizing radiation (IR) directly damages cells and tissues or indirectly damages them through reactive free radicals that may lead to longer term adverse sequelae such as cancers, persistent inflammation, or possible death. Potential exposures include nuclear reactor accidents, improper disposal of equipment containing radioactive materials or medical errors, and terrorist attacks. Metabolomics (comprehensive analysis of compounds <1 kDa) by mass spectrometry (MS) has been proposed as a tool for high-throughput biodosimetry and rapid assessment of exposed dose and triage needed. While multiple studies have been dedicated to radiation biomarker discovery, many have utilized liquid chromatography (LC) MS platforms that may not detect particular compounds (e.g., small carboxylic acids or isomers) that complementary analytical tools, such as gas chromatography (GC) time-of-flight (TOF) MS, are ideal for. The current study uses global GC-TOF-MS metabolomics to complement previous LC-MS analyses on nonhuman primate biofluids (urine and serum) 7 days after exposure to 2, 4, 6, 7, and 10 Gy IR. Multivariate data analysis was used to visualize differences between control and IR exposed groups. Univariate analysis was used to determine a combined 26 biomarkers in urine and serum that significantly changed after exposure to IR. We found several metabolites involved in tricarboxylic acid cycle function, amino acid metabolism, and host microbiota that were not previously detected by global and targeted LC-MS studies.


Differences in the level of expression of class I major histocompatibility complex proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection.
Both positive and negative selection of immature T cells rely on engagement of their antigen-specific receptors (TCR) by peptide in association with proteins encoded in the major histocompatibility complex (MHC) protein. The decision made between these two outcomes seems to be determined by the number of TCR engaged by peptide-MHC complexes. It has been unclear how such a mechanism can be reconciled with evidence that positive and negative selection occur in different thymic compartments and are mediated by different antigen-presenting cells (APCs). In this study we demonstrate that the level of class I MHC protein is 10-fold higher on thymic dendritic cells, which mediate the negative selection of immature T cells, than on thymic epithelial cells, which mediate for positive selection. We also demonstrate that as little as a 3-fold increase in the level of a particular cognate peptide-MHC ligand is sufficient to result in negative rather than positive selection. The results suggest that quantitative differences in the level of expression of class I MHC proteins on thymic epithelial and dendritic cells contribute to the opposing roles these cells play in forming the repertoire of mature class I MHC restricted (CD8+) T cells.