Spatial mapping takes time.
The experiment tested the prediction that spatial mapping takes time and asked whether time use is reflected in the overt behavior of a performing animal. The study examines this question by exploiting the expected behavioral differences of control rats and rats with hippocampal formation damage induced with fimbria-fornix (FF) lesions on a spatial navigation task. Previous studies have shown that control rats use a mapping strategy, in which they use the relative positions of environmental cues to reach places in space, whereas FF rats use a cue-based strategy, in which they are guided by a single cue or their own body orientation. Therefore, control and FF rats were overtrained on a complex foraging task in which they left a burrow to retrieve eight food pellets hidden around the perimeter of a circular table. The control rats retrieved the food pellets in order of their distance from the burrow, took direct routes to the food, and made few errors, all of which suggested they used a spatial strategy. The FF rats were less likely to retrieve food as a function of its distance, took a circular path around the perimeter of the table, and made many errors, suggesting they used a cue-based strategy. Despite taking shorter routes than the FF rats, the control rats had proportionally slower response speeds. Their slow response speeds support the hypothesis that spatial mapping takes time and that mapping time is reflected in behavior. The results are discussed in relation to their relevance to spatial mapping theory, hippocampal function, and the evolution of foraging strategies.


Regions of arterial stenosis and clinical factors determining transcutaneous oxygen tension in patients with peripheral arterial disease.
Despite the clinical usefulness of transcutaneous oxygen tension (TcPO(2)) to assess the severity of limb ischemia, the factors determining TcPO(2) in patients with peripheral arterial disease (PAD) have not been fully clarified. We therefore examined the regions of arterial stenosis and clinical factors affecting lower-extremity TcPO(2). Resting TcPO(2) (REST-TcPO(2)) and postexercise TcPO(2) (Ex-TcPO(2)) in the calf region and the dorsalis pedis were measured simultaneously in 66 patients (132 limbs) with clinically suspected PAD, in whom angiography was also performed. The peripheral arteries of the lower extremities were divided into five segments, and the impact of significant stenosis in each segment on ipsilateral TcPO(2) was evaluated by multiple regression analysis. In the calf region, significant stenosis of the proximal arteries (common-external iliac artery) revealed stronger involvement determining Ex-TcPO(2) than the peripheral segment (posterior tibial artery). In the dorsalis pedis, the peripheral segment (anterior tibial artery) more strongly determined Ex-TcPO(2) and REST-TcPO(2) than proximal segments. Age, creatinine, and diabetes were associated with REST-TcPO(2) of the calf region independent of arterial stenoses, while those of the dorsalis pedis were independently associated with age, and creatinine. In contrast, Ex-TcPO(2) in both regions was not independently associated with clinical factors, except for stenosis of the perfusing arteries. The vascular lesions affecting TcPO(2) differ between the calf region (proximal > peripheral) and the dorsalis pedis (proximal < peripheral). In addition postexercise TcPO(2) is solely determined by stenosis of the perfusing arteries, while TcPO(2) at rest is affected by multiple clinical factors.


Pseudolaric acid B inhibits T-cell mediated immune response in vivo via p38MAPK signal cascades and PPARγ activation.
Pseudolaric acid B (PAB) has been prescribed for its potent immunomodulatory effect. However, the detail of mechanism remains to be demonstrated. The purpose of this study is to further clarify the mechanism of PAB on T-cell mediated immune response in vivo. Investigations were carried to ascertain the pharmacological effect of PAB in a delayed-type hypersensitivity (DTH) mouse model of T-cell mediated immune response. Histological assessment was examined by hematoxylin and eosin staining. Affymetrix GeneChip® Mouse Genome 430 2.0 arrays were employed to evaluate the expression profile of PAB. Western blot was performed to detect p38MAPK signal cascades, including p38MAPK, ATF-2, MK2, and HSP27. Finally, TNF-α level was analyzed by ELISA, and Jurkat T cells were treated with PAB to determine its role on PPARγ activation using a reporter gene assay. The results showed that PAB (5, 10, and 20mg/kg) could lead to a marked improvement for ear swelling and inflammatory infiltrate in DTH mice dose-dependently. According to the associated biological pathways from microarray analysis, PAB resulted in the restoration of abnormal immune-related gene expression linked to MAPK and PPAR signaling pathways. Moreover, PAB inhibited the activation of p38MAPK, ATF-2, MK2, and HSP27 significantly, as well as the production of TNF-α, which was reversed by GW9662, a specific antagonist for PPARγ. In addition, treatment with PAB also increased the transcriptional activity of PPARγ in a dose-dependent manner. These results provide us with novel insights into pharmacological action of PAB as a potential immunomodulator for the treatment of immune-related diseases.


Patterns of inversion polymorphism in three species of the Drosophila melanogaster species group.
In Drosophila, chromosomal polymorphism due to paracentric inversions is very common and constitutes an adaptive character. The degree of chromosomal variability varies in different species and also in different populations of the same species. Chromosomal polymorphism in Indian natural populations of three species, D. melaonogaster, D. ananassae and D. bipectinata which belong to the melanogaster species group has been studied and the quantitative data on frequency of inversions have been reported. Behaviour of chromosome inversions has also been studied in laboratory conditions. The present review summarises the work done on inversion polymorphism in Indian populations of three species which clearly demonstrates that these three species vary in their patterns of inversion polymorphism and have evolved different mechanisms for adjustment to their environments although they belong to the same species group.


BMP signaling regulates satellite cell-dependent postnatal muscle growth.
Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here, we demonstrate that postnatal satellite cells express components of the bone morphogenetic protein (BMP) signaling machinery. Overexpression of noggin in postnatal mice (to antagonize BMP ligands), satellite cell-specific knockout of Alk3 (the gene encoding the BMP transmembrane receptor) or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth, and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and upregulated the expression of cell cycle inhibitors p21 and p57 In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell-dependent myofiber growth and the generation of the adult muscle stem cell pool.


A Kappa Opioid Receptor Agonist Blocks Bone Cancer Pain Without Altering Bone Loss, Tumor Size, or Cancer Cell Proliferation in a Mouse Model of Cancer-Induced Bone Pain.
Breast cancer metastasizes to bone, diminishing quality of life of patients because of pain, fracture, and limited mobility. Cancer-induced bone pain (CIBP) is characterized as moderate to severe ongoing pain, primarily managed by mu opioid agonists such as fentanyl. However, opioids are limited by escalating doses and serious side effects. One alternative may be kappa opioid receptor (KOR) agonists. There are few studies examining KOR efficacy on CIBP, whereas KOR agonists are efficacious in peripheral and inflammatory pain. We thus examined the effects of the KOR agonist U50,488 given twice daily across 7 days to block CIBP, tumor-induced bone loss, and tumor burden. U50,488 dose-dependently blocked tumor-induced spontaneous flinching and impaired limb use, without changing tactile hypersensitivity, and was fully reversed by the KOR antagonist nor-binaltorphimine. U50,488 treatment was higher in efficacy and duration of action at later time points. U50,488 blocked this pain without altering tumor-induced bone loss or tumor growth. Follow-up studies in human cancer cell lines confirmed that KOR agonists do not affect cancer cell proliferation. These studies suggest that KOR agonists could be a new target for cancer pain management that does not induce cancer cell proliferation or alter bone loss. This study demonstrates the efficacy of KOR agonists in the treatment of bone cancer-induced pain in mice, without changing tumor size or proliferation in cancer cell lines. This suggests that KOR agonists could be used to manage cancer pain without the drawbacks of mu opioid agonists and without worsening disease progression.


New perspectives on the face in fetal alcohol syndrome: what anthropometry tells us.
Fetal alcohol syndrome (FAS) refers to the adverse effects to the fetus from prenatal exposure to alcohol. Originally, the diagnosis of FAS was given only to those individuals that were the most severely affected. Since that time, it has become apparent that the effects of prenatal alcohol exposure are broad-based, and those individuals diagnosed with FAS represent the severe end of the continuum in their phenotypic expression. This study utilized 21 craniofacial anthropometric measurements on 100 prenatally exposed individuals to quantify the elements of the FAS facial phenotype and to extend the quantitative phenotype to individuals who exhibited less severe or incomplete manifestations of prenatal alcohol exposure.


Phytochemical composition and biological activities of native and in vitro-propagated Micromeria croatica (Pers.) Schott (Lamiaceae).
In vitro culture conditions and kinetin induced quantitative modifications in the production of the major volatile constituents in Micromeria croatica plantlets. Antimicrobial activity of methanolic extracts obtained from micropropagated and wild-growing plants was evaluated. Micromeria spp. are aromatic plants, many of which were shown to exhibit various biological effects. The present study aimed to determine the content and the composition of the essential oil of in vitro-cultured Micromeria croatica (Pers.) Schott and to evaluate the in vitro antimicrobial activity of its methanolic extract, in order to compare its phytochemical profile and biological activity with wild-growing plants. Shoots regenerated on MS medium without plant growth regulators (PGRs) or supplemented with kinetin were used for phytochemical analysis. Essential oils from both native plant material and in vitro-cultivated M. croatica plants, with a total of 44 identified constituents, were dominated by oxygenated monoterpenes. Borneol was the main component detected in wild-growing plants (25.28%) and micropropagated plants grown on PGR-free medium (20.30%). Kinetin treatment led to increased oil yield and favored the production of oxygenated monoterpenes, dominated by geranial (33.53%) and cis-p-mentha-1(7),8-dien-ol (23.69%). The percentage of total sesquiterpenoids in micropropagated plant material was considerably lower than in wild-growing plants. In vitro culture conditions and PGRs affected the production of essential oils, inducing quantitative modifications in the production of the major volatile constituents in M. croatica plantlets. The antimicrobial activity of M. croatica methanolic extracts was investigated using the broth microdilution method. Extracts obtained from in vitro cultures generally exhibited greater antibacterial potential, compared to wild-growing plants. Among six bacterial strains tested, Bacillus cereus and Staphylococcus aureus were the most sensitive microorganisms. The present study provided evidence that in vitro culture conditions might favorably affect the antimicrobial activity of M. croatica methanolic extracts.


Sodium restriction in heart failure: benefit or harm?
Current guidelines vary in the recommended amount of dietary sodium intake for heart failure (HF) patients. Observational studies and the hypertension literature support the concept that sodium restriction improves HF outcomes. In contrast, several randomized controlled trials imply that dietary sodium restriction can cause harm through hypovolemia and increased neurohormonal activation. Data from hypertensive animal models and humans suggest that dietary sodium intake may need to be individually tailored based on HF severity and the physiologic response to sodium loading. Future studies must assess interactions between sodium intake, fluid intake, and diuretics to match clinical practice and improve safety. More information is needed in multiple areas, including accurate measurement of sodium intake, implementation of dietary changes in HF patients, and establishment of biomarkers that predict response to changes in sodium intake. Additional research is urgently needed to determine the true impact of the most commonly recommended self-care strategy in HF.


Proteogenomics Integrating Novel Junction Peptide Identification Strategy Discovers Three Novel Protein Isoforms of Human NHSL1 and EEF1B2.
In eukaryotes, alternative pre-mRNA splicing allows a single gene to encode different protein isoforms that function in many biological processes, and they are used as biomarkers or therapeutic targets for diseases. Although protein isoforms in the human genome are well annotated, we speculate that some low-abundance protein isoforms may still be under-annotated because most genes have a primary coding product and alternative protein isoforms tend to be under-expressed. A peptide coencoded by a novel exon and an annotated exon separated by an intron is known as a novel junction peptide. In the absence of known transcripts and homologous proteins, traditional whole-genome six-frame translation-based proteogenomics cannot identify novel junction peptides, and it cannot capture novel alternative splice sites. In this article, we first propose a strategy and tool for identifying novel junction peptides, called CJunction, which we then integrate into a proteogenomics process specifically designed for novel protein isoform discovery and apply to the analysis of a deep-coverage HeLa mass spectrometry data set with identifier PXD004452 in ProteomeXchange. We succeeded in identifying and validating three novel protein isoforms of two functionally important genes, NHSL1 (causative gene of Nance-Horan syndrome) and EEF1B2 (translation elongation factor), which validate our hypothesis. These novel protein isoforms have significant sequence differences from the annotated gene-coding products introduced by the novel N-terminal, suggesting that they may play importantly different functions.


[Estrogen-progestin contraception. Advantages of estrogen reduction].
Among the low dose oral contraceptives that is to say less than 50 mcg of ethinylestradiol per pill one must single out the pills made of a third generation progestagen (desogestrel, gestodene, norgestimate) from the others. The contraceptive efficacy (tested on the Pearl index) according to the files of government authorities visa (AMM) is equivalent for all the oral contraceptives whatever their composition (between 0 to 0.07 women year). The clinical tolerance of the low dose pills of the 3rd generation is comparable to that of the other low dose pills. Is there any advantage then in prescribing them? The most important advantage is the decrease of metabolic and vascular effects. The use of so-called third generation progestive, besides the beneficial effects an lipidic and glucidic metabolisms, has mainly enabled the decrease of the estrogen doses of progestagens. The ethinylestradiol is directly implicated in the risk of venous thrombosis: hemostasis the modifications are less important with 30 mcg than with 50, 20 than 30 mcg. Relying on theoretical arguments one could have estimated that minipills would lead to an insufficient ovarian slow down. These hypothesis are contradicted by recent studies from Falsetti and Benagiano who studied the rates of FSH and LH under minipills. This does not include the variability and the individual sensitiveness of the patients and as well the reason following which minipills would favor functional ovarian cysts, lies on the confusion made between a cyst and a 20 mm diameter follicule.(ABSTRACT TRUNCATED AT 250 WORDS)


Laser-desorption/Laser-ionization mass spectrometry of biomolecules.
Some applications of the powerful novel method of laser evaporation of intact neutral molecules into a supersonic beam and the subsequent multiphoton ionization are shown. The mass spectra of several bioorganic molecules are presented and their intrinsic features upon the multiphoton interaction are discussed. Owing to the details of desorption and multiphoton ionization these mass spectra yield, in relation to the intensity of the laser beam, in very few and structural dependent signals. In every case the molecular ion of the investigated sample is detected.


A novel framework of MOPSO-GDM in recognition of Alzheimer's EEG-based functional network.
Most patients with Alzheimer's disease (AD) have an insidious onset and frequently atypical clinical symptoms, which are considered a normal consequence of aging, making it difficult to diagnose AD medically. But then again, accurate diagnosis is critical to prevent degeneration and provide early treatment for AD patients. This study aims to establish a novel EEG-based classification framework with deep learning methods for AD recognition. First, considering the network interactions in different frequency bands (δ, θ, α, β, and γ), multiplex networks are reconstructed by the phase synchronization index (PSI) method, and fourteen topology features are extracted subsequently, forming a high-dimensional feature vector. However, in feature combination, not all features can provide effective information for recognition. Moreover, combining features by manual selection is time-consuming and laborious. Thus, a feature selection optimization algorithm called MOPSO-GDM was proposed by combining multi-objective particle swarm optimization (MOPSO) algorithm with Gaussian differential mutation (GDM) algorithm. In addition to considering the classification error rates of support vector machine, naive bayes, and discriminant analysis classifiers, our algorithm also considers distance measure as an optimization objective. Finally, this method proposed achieves an excellent classification error rate of 0.0531 (5.31%) with the feature vector size of 8, by a ten-fold cross-validation strategy. These findings show that our framework can adaptively combine the best brain network features to explore network synchronization, functional interactions, and characterize brain functional abnormalities, which can improve the recognition efficiency of diseases. While improving the classification accuracy of application algorithms, we aim to expand our understanding of the brain function of patients with neurological disorders through the analysis of brain networks.


Lifetime number of ovulatory cycles and epithelial ovarian cancer risk in African American women.
Incessant ovulation has been consistently linked to epithelial ovarian cancer (EOC). Although reproductive characteristics differ substantially by race, the association between incessant ovulation and EOC has been evaluated only in populations of predominantly white women. In the present study, we examined the association between lifetime number of ovulatory cycles (LOCs) and EOC risk among African American (AA) women. We used data from 534 cases and 722 controls enrolled in the African American Cancer Epidemiology Study. LOCs were determined using the standard method, with modifications to include episodes of irregular or missed periods. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between LOCs and EOC risk overall and by age, while adjusting for appropriate confounders. The mean number of LOCs was 378.2 ± 105.8 for cases and 346.4 ± 117.3 for controls. Women in the highest tertile of LOCs had 59% higher odds of EOC compared to women in the lowest tertile (OR = 1.59; 95% CI = 1.15-2.20). When examining this relationship by age, the positive association with EOC was stronger among women <50 years of age (OR for highest vs. lowest tertile = 2.61; 95% CI = 1.15-5.94), followed by women aged 50-60 years (OR = 2.27; 95% CI = 1.30-3.94). Yet, no association was present among women aged >60 years (OR = 0.79; 95% CI = 0.45-1.40). In a population of AA women, we observed a positive association between LOCs and EOC risk, providing further support for the hypothesis that incessant ovulation contributes to the etiology of EOC.


Muscle architecture and its relationship with lower extremity muscle strength in multiple sclerosis.
This study was planned to determine the muscle architecture (pennation angle, muscle fiber length, and muscle thickness) and its relationship to lower extremity muscle strength in patients with Multiple Sclerosis (pwMS). The muscle architecture (pennation angle, muscle fiber length, and muscle thickness) and lower extremity muscle strength were assessed in 33 pwMS [13 Relapsing-Remitting MS (RRMS), 5 Primary Progressive MS (PPMS), 5 Secondary Progressive MS (SPMS), and 11 matched healthy controls (HC)]. Muscle architecture features were assessed with ultrasonography and muscle strength were assessed with a digital hand-held dynamometer. The rectus femoris muscle thickness and pennation angle, gastrocnemius muscle thickness, and the tibialis anterior pennation angle were significantly lower in pwMS compared to HC (p < 0.05). The strength of hip flexors, hip extensors, knee extensors, foot plantar, and foot dorsi flexors were lower in pwMS. In PPMS group, muscle strength of hip flexors was lower than RRMS and SPMS groups, and muscle strength of foot dorsi flexors was lower than RRMS (p < 0.05). In pwMS, positive correlations were found, between knee flexor strength and biceps femoris pennation angle. Also knee extensor strength and rectus femoris fiber length and muscle thickness were correlated positively (p < 0.05). According to our results the muscle architecture is affected in MS. The determination of architectural changes of lower extremity muscles may guide the arrangement of optimal strength exercises in functional rehabilitation programs.ClinicalTrials: NCT03766698.


In vivo stabilization of preinitiation complexes by formaldehyde cross-linking.
Translation initiation starts with the formation of the 43S preinitiation complex (PIC) consisting of several soluble factors, including the ternary complex (TC; elF2-GTP-Met-tRNA(i)(Met)), which associate with the small ribosomal subunit. In the next step, mRNA is recruited to form the 48S PIC and the entire machinery starts scanning the 5' untranslated region of the mRNA until the AUG start codon is encountered. The most widely used method to separate 40S and 60S ribosomal subunits from soluble factors, monosomes and polysomes, is sucrose density centrifugation (SDC). Since PICs are intrinsically unstable complexes that cannot withstand the forces imposed by SDC, a stabilization agent must be employed to detect the association of factors with the 40S subunit after SDC. This was initially achieved by adding heparin (a highly sulfated glycosaminoglycan) directly to the breaking buffer of cells treated with cycloheximide (a translation elongation inhibitor). However, the mechanism of stabilization is not understood and, moreover, there are indications that the use of heparin may lead to artifactual factor associations that do not reflect the factor occupancy of the 43S/48S PICs in the cell at the time of lysis. Therefore, we developed an alternative method for PIC stabilization using formaldehyde (HCHO) to cross-link factors associated with 40S ribosomal subunits in vivo before the disruption of the yeast cells. Results obtained using HCHO stabilization strongly indicate that the factors detected on the 43S/48S PIC after SDC approximate a real-time in vivo "snapshot" of the 43S/48S PIC composition. In this chapter, we will present the protocol for HCHO cross-linking in detail and demonstrate the difference between heparin and HCHO stabilization procedures. In addition, different conditions for displaying the polysome profile or PIC analysis by SDC, used to address different questions, will be outlined.


Uptake of cadmium and zinc by the alga Chlorella vulgaris: part 1. Individual ion species.
The ability of algae and bacteria to accumulate heavy metals from the surrounding environment is a widely recognized phenomenon that has a number of important implications. This work reports on the development of a quantitative model that addresses the basic mechanisms inherent in many uptake processes. The model postulates two mechanisms: an initial rapid metal ion uptake due to attachment onto the cell wall followed by a relatively slow uptake due to membrane transport of the metal into the cell. The mathematical model has been tested using the alga Chlorella vulgaris in the presence of cadmium and zinc in solution under various experimental conditions.


Long-term follow-up of two patients with retained intraosseous sternal needles.
Sternal intraosseous devices are widely used in both civilian and military trauma when vascular access is difficult to establish. We discuss a rare complication of intraosseous needle insertion in two patients where the needle tip remained in the sternum after the device had been removed. Neither patient had evidence of any complication of the retained intraosseous needle tip after >6 years of follow-up.


Radiation dose of cone beam CT combined with shape sensing robotic assisted bronchoscopy for the evaluation of pulmonary lesions: an observational single center study.
Shape sensing robotic-assisted bronchoscopy (ssRAB) combined with radial endobronchial ultrasound (r-EBUS) and cone beam computed tomography (CBCT) is a newer diagnostic modality for the evaluation of pulmonary lesions. There is limited data describing the radiation dose of CBCT combined with ssRAB. The purpose of this study was to describe the technical factors associated with the use of CBCT combined with ssRAB to biopsy pulmonary lesions. We conducted a single center, prospective observational study of patients undergoing ssRAB combined with fixed CBCT for the pulmonary lesion biopsy. We report our patient demographics, and pulmonary lesion and procedure characteristics. A total of 241 ssRAB procedures were performed to biopsy 269 pulmonary lesions. The mean lesion size was measured in the following dimensions: anteroposterior (18.0±8.8 mm), transverse (17.2±10.5 mm), and craniocaudal (17.7±10.2 mm). A mean of 1.5±0.7 (median: 1, range: 1-4) CBCT spins were performed. The mean total fluoroscopy time (FT) was 5.6±2.9 minutes. The mean radiation dose of cumulative air kerma (CAK) was 63.5±46.7 mGy and the mean cumulative dose area product (DAP) was 22.6±16.0 Gy·cm2. Diagnostic yield calculated based on results at index bronchoscopy was 85.9%. There was a low rate of complications with 8 pneumothoraces (3.3%), 5 (2.1%) of which required chest tube placement. We describe the use of ssRAB combined with CBCT to biopsy pulmonary lesions as a safe diagnostic modality with relatively low radiation dose that is potentially comparable to other image guided sampling modalities. Bronchoscopists should be cognizant of the radiation use during the procedure for both patient and staff safety.


Bilingualism alters infants' cortical organization for attentional orienting mechanisms.
A bilingual environment is associated with changes in the brain's structure and function. Some suggest that bilingualism also improves higher-cognitive functions in infants as young as 6-months, yet whether this effect is associated with changes in the infant brain remains unknown. In the present study, we measured brain activity using functional near-infrared spectroscopy in monolingual- and bilingual-raised 6- and 10-month-old infants. Infants completed an orienting attention task, in which a cue was presented prior to an object appearing on the same (Valid) or opposite (Invalid) side of a display. Task performance did not differ between the groups but neural activity did. At 6-months, both groups showed greater activity for Valid (> Invalid) trials in frontal regions (left hemisphere for bilinguals, right hemisphere for monolinguals). At 10-months, bilinguals showed greater activity for Invalid (> Valid) trials in bilateral frontal regions, while monolinguals showed greater brain activity for Valid (> Invalid) trials in left frontal regions. Bilinguals' brain activity trended with their parents' reporting of dual-language mixing when speaking to their child. These findings are the first to indicate how early (dual) language experience can alter the cortical organization underlying broader, non-linguistic cognitive functions during the first year of life.


Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient.
Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.


Management of interstitial ectopic pregnancies with a combined intra-amniotic and systemic approach.
Approximately 2% of all pregnancies are ectopic; of these, 4% are interstitial or cervical. There exists no clear consensus as to whether surgical or medical management is superior. We present three cases of advanced nonfallopian tube ectopic pregnancies from 6 to 8 weeks of gestation. Our first two cases were managed with a combined intrafetal, intra-amniotic and systemic approach using methotrexate and potassium chloride, whereas our third case was managed with an intra-amniotic approach alone. Our combined approach cases were successful, with resolution of human chorionic gonadotropin in 50 and 34 days, whereas our single approach case re-presented with bleeding requiring uterine artery embolization and operative removal of products of conception. Patients presenting with advanced interstitial or cervical pregnancies who are clinically stable can be offered medical management with a combined approach.


Heart Rate Estimation from Facial Image Sequences of a Dual-Modality RGB-NIR Camera.
This paper presents an RGB-NIR (Near Infrared) dual-modality technique to analyze the remote photoplethysmogram (rPPG) signal and hence estimate the heart rate (in beats per minute), from a facial image sequence. Our main innovative contribution is the introduction of several denoising techniques such as Modified Amplitude Selective Filtering (MASF), Wavelet Decomposition (WD), and Robust Principal Component Analysis (RPCA), which take advantage of RGB and NIR band characteristics to uncover the rPPG signals effectively through this Independent Component Analysis (ICA)-based algorithm. Two datasets, of which one is the public PURE dataset and the other is the CCUHR dataset built with a popular Intel RealSense D435 RGB-D camera, are adopted in our experiments. Facial video sequences in the two datasets are diverse in nature with normal brightness, under-illumination (i.e., dark), and facial motion. Experimental results show that the proposed method has reached competitive accuracies among the state-of-the-art methods even at a shorter video length. For example, our method achieves MAE = 4.45 bpm (beats per minute) and RMSE = 6.18 bpm for RGB-NIR videos of 10 and 20 s in the CCUHR dataset and MAE = 3.24 bpm and RMSE = 4.1 bpm for RGB videos of 60-s in the PURE dataset. Our system has the advantages of accessible and affordable hardware, simple and fast computations, and wide realistic applications.


Pore size and volume effects on the incorporation of polymer into macro- and mesoporous zirconium titanium oxide membranes.
Macro- and mesoporous hybrid materials have applications in the fields of drug delivery, catalysis, biosensing, and separations. The pore size requirements must be well-understood to maximize the performance (e.g., load capacity and accessibility) of such materials. Hybrid materials were prepared by coating five distinct macroporous commercial membranes with zirconium titanium oxide through sol-gel chemistry. Calcination of these templated materials produced oxide membranes which had a suite of macropore and mesopore architectures, pore volumes, and surface areas. These differences in physical properties were used to conduct a fundamental study on the relationship between the pore size and volume and the polymer incorporation. Metal oxide membranes were postsynthetically modified with poly(ethyleneimine) (PEI) ranging in molecular weight from 1300 to 1 000 000 Da (1.2-11 nm in hydrodynamic diameter). The incorporation of the polymer from a 9 wt % solution at pH 10 was highly dependent on the pore size and pore volume. As the surface area increased, loading capacity decreased, indicating that much of the increased internal surface, due to small pore diameters (< or = 8 nm), was inaccessible to the macromolecules. Exclusion of PEI from small mesopores was apparent even for the lowest molecular weight polymer. A high maximum loading of 1.25 mg m(-2) of 600 000-1 000 000 Da PEI was achieved in the metal oxide with the largest minimum mesopore diameter. Thus, mesopore diameter and pore volume must be considered when designing a mesoporous solid support.


Characterization of emerging GII.g/GII.12 noroviruses from a gastroenteritis outbreak in the United States in 2010.
Norovirus is a major cause of acute gastroenteritis in humans. A norovirus outbreak occurred in Ohio in January 2010. Stool and saliva samples were obtained from six infected individuals. The full-length genomes of two representative strains (HS206 and HS210) were characterized. They belonged to GII.12 in the capsid but GII.g in the RNA polymerase region. Interestingly, an immunocompetent 2-year-old male shed virus for up to 30 days, as detected by real-time reverse transcription (RT)-PCR. Histo-blood group antigen (HBGA) typing of saliva showed that the norovirus strains infected various types of secretor-positive individuals (types A, B, and O). The viruslike particles of strain HS206 did not bind substantially to A/B/O antigens by synthetic HBGA binding, hemagglutination, or saliva binding assays. These results suggest that infection by this strain may not be A/B/O antigen dependent or that in vitro binding patterns do not always accurately reflect in vivo HBGA usage. This is different from the HBGA binding pattern of the previously reported GII.12/Aichi76 strain. Structural analysis of the predicted capsid of these GII.12 strains revealed two amino acid mismatches located near the HBGA binding sites. Four gnotobiotic pigs were inoculated orally with HS206 (6 × 10(10) genomic equivalents [GE]/pig). Virus shedding began at postinoculation days (PID) 1 to 3 and continued up to PID 16 (1 × 10(5) to 2 × 10(7) GE/ml). Gastroenteritis cases caused by GII.12 noroviruses have been recently reported worldwide. We observed that this emerging GII.12 norovirus infected humans regardless of A/B/O blood type. The infection of pigs by strain HS206 suggests that interspecies transmission of this strain is possible under experimental conditions.


Comparison of Supine and Prone Methods of Leg Length Inequality Assessment.
The primary objective of the current study was to determine the reliability between methods of supine and prone leg length inequality (LLI) assessment. The secondary objective was to determine if the degree of examiner confidence affected the degree of intermethod agreement. Two experienced doctors of chiropractic assessed 43 participants for LLI, one using a prone and the other a supine method. They stated whether they were confident or not confident in their findings. Kappa values for intermethod agreement were 0.16 for the full data set; 0.00 for the n = 20 subgroup with both examiners confident; 0.24 for the n = 18 subgroup with 1 examiner confident; and 0.55 for the n = 5 subgroup with neither examiner confident. Supine and prone measures exhibited slight agreement for the full data set, but no agreement when both examiners were confident. The moderate agreement with both examiners not confident may be an artifact of small sample size. This study found that supine and prone assessments for leg length inequality were not in agreement. Positioning the patient in the prone position may increase, decrease, reverse, or offset the observed LLI that is seen in the supine position.


Stress assessment using hair cortisol of kangaroos affected by the lumpy jaw disease.
The aim of this study was to objectively assess stress of kangaroos affected by lumpy jaw disease (LJD) using plasma and hair cortisol concentrations. The plasma and hair samples were collected from kangaroos with LJD and healthy controls. Collected hair samples were extracted with methanol after washing with isopropanol, following which they were processed with the cortisol enzyme immunoassay kit. The plasma cortisol concentration of LJD animals tended to be higher than that of the control. Ventral hair cortisol, but not dorsal hair, of LJD animals was significantly higher than that of the control. In conclusion, stress in kangaroos infected with LJD could be assessed by measuring ventral hair cortisol.


Jargon: A barrier in case history taking? - A cross-sectional survey among dental students and staff.
The use of jargon has become very common in the healthcare field, especially in medical/dental records. Although the use of standard medical jargon can be seen as professional, efficient shorthand, a lack of awareness regarding the standard medical abbreviations and incessant and overzealous use of slang among the healthcare professionals can act as a barrier to effective communication and understanding among patients and peers. The aim of this study was to assess the acceptance and use of jargon in case history taking among clinical dental students and dental teaching faculty members of dental colleges in Ernakulam and Idukki districts of Kerala. A cross-sectional questionnaire-based survey was carried out, consisting of 15 questions, to assess the objectives of the study. The study was conducted among clinical dental undergraduate students, house surgeons, postgraduate students and teaching faculty members of five dental colleges in Ernakulam and Idukki districts, Kerala. The results were expressed as a number and percentage of response for each question and Chi-squared test was used for inferential statistical analysis. All the 549 respondents used jargon in case history taking. Approximately 22.4% of the respondents admitted that they always used jargon and 55.8% admitted of using jargon only when there was a lack of time. The majority of the respondents (71.4%) learned the jargon from their colleagues. Approximately 50% of the respondents admitted use of jargon in a history section and about 32% of the respondents in all the sections of case history taking. Approximately 74% were of the opinion that abbreviations should be permitted in case history taking. This study showed widespread use of jargon/abbreviations in case history taking among the respondents. There is a lack of knowledge regarding standard medical abbreviations. Although the majority of the respondents were comfortable with the use of jargon, the majority of the postgraduates and faculty members felt the use of jargon should be stopped.


Hereditary Ovarian Cancer and Risk Reduction.
Mutations in BRCA1 and BRCA2 account for hereditary breast and ovarian cancer syndrome in a majority of families and 14% of epithelial ovarian cancer cases. Despite next-generation sequencing, other identified genes (Lynch Syndrome, RAD51C, RAD51D, and BRIP1) account for only a small proportion of cases. The risk of ovarian cancer by age 70 is approximately 40% for BRCA1 and 18% for BRCA2. Most of these cancers are high-grade serous cancers that predominantly arise in the fimbriae of the fallopian tube. Ovarian screening does not improve outcomes, so women at high risk are recommended to undergo risk-reducing salpingo-oophorectomy around the age of 40, followed by hormone replacement therapy (HRT). Specimens should be carefully examined for occult malignancy. Mutation carriers may benefit from newly developed poly ADP ribose polymerase inhibitors. Genetic testing should only be performed after careful counseling, particularly if testing involves the testing of panels of genes that may identify unsuspected disease predisposition or confusing variants of uncertain significance.


SRC family kinase inhibition through a new pyrazolo[3,4-d]pyrimidine derivative as a feasible approach for glioblastoma treatment.
Glioblastoma (GB) is the most common and aggressive primary tumor of the central nervous system. The current standard of care for GB consists of surgical resection, followed by radiotherapy combined with temozolomide chemotherapy. However, despite this intensive treatment, the prognosis remains extremely poor. Therefore, more effective therapies are urgently required. Recent studies indicate that SRC family kinases (SFKs) could represent promising molecular targets for GB therapy. Here, we challenged four GB cell lines with a new selective pyrazolo[3,4-d]pyrimidine derivative SFK inhibitor, called SI221. This compound exerted a significant cytotoxic effect on GB cells, without significantly affecting non-tumor cells (primary human skin fibroblasts), as evaluated by MTS assay. We also observed that SI221 was more effective than the well-known SFK inhibitor PP2 in GB cells. Notably, despite the high intrinsic resistance to apoptosis of GB cells, SI221 was able to induce this cell death process in all the GB cell lines, as observed through cytofluorimetric analysis and caspase-3 assay. SI221 also exerted a long-term inhibition of GB cell growth and was able to reduce GB cell migration, as shown by clonogenic assay and scratch test, respectively. Moreover, through in vitro pharmacokinetic assays, SI221 proved to have a high metabolic stability and a good potential to cross the blood brain barrier, which is an essential requirement for a drug intended to treat brain tumors. Therefore, despite the need of developing strategies to improve SI221 solubility, our results suggest a potential application of this selective SFK inhibitor in GB therapy.


Comparison of computational methods for the evaluation of learning potential in schizophrenia.
Learning potential (LP) refers to the ability to improve cognitive performance as a result of training. It is typically assessed by test-train-test administrations of a task, wherein changes in pre-post performance are an index of LP. In schizophrenia research, LP has been suggested as a mediator of the relationship between static neurocognition and functional outcome. While a number of studies do indicate that LP assessment improves prediction of functioning beyond standard administrations of the same task, multiple approaches of computing LP indices have been used in this work. Multiple psychometric issues have been raised with respect to computation of change scores, but have not been widely recognized in LP assessment. To address this issue, the current study aimed to evaluate the test-retest reliability, interrelatedness, construct, and criterion validity of several conventional indices of LP, obtained from a test-train-test version of a list-learning task administered to 43 individuals with chronic schizophrenia. Overall, test-retest and intercorrelation coefficients indicated variable reliability and convergence across methods. While LP indices generally correlated more highly with independent measures of neurocognition and community functioning than pretraining list learning scores, coefficients were comparably small. Recommendations and measurement issues inherent to the LP construct are discussed.


Consumption of curcumin elevates fecal immunoglobulin A, an index of intestinal immune function, in rats fed a high-fat diet.
This study was conducted to elucidate the effects of dietary polyphenols on intestinal immunoglobulin A (IgA) response and mucin levels in rats fed a high-fat diet. In experiment 1, rats were fed a high-fat diet with or without several polyphenols including curcumin, rutin, D(+)-catechin, ellagic acid and quercetin at the level of 0.5%. Among the polyphenols examined, consumption of curcumin markedly elevated the level of IgA in feces and colon contents. In experiment 2, rats were fed a high-fat diet or a low-fat diet with or without 0.5% curcumin. Fecal level of IgA was higher in the high-fat diet group than in the low-fat diet group. In the rats fed the high-fat diet, dietary curcumin elevated fecal IgA, but not in those fed the low-fat diet. These results imply a novel effect of curcumin on intestinal IgA in animals fed a high-fat diet.


Regulation of apoptosis in the endocardial cushions of the developing chick heart.
During the early stages of heart development, there are two main foci of cell death: outflow tract (OT) and atrioventricular (AV) endocardial cushions. These tissues contribute to the septa and valves of the mature heart and receive cell populations from neural crest (NC) cell migration and epicardial cell invasion. We examined embryonic chick hearts for expression, in the cushions, of bcl-2 family members, caspase-9, and the caspase substrate poly(ADP-ribose) polymerase. Antiapoptotic bcl-2 is expressed heavily in the OT and AV regions throughout embryonic days (ED) 4-7, with a decrease in levels at ED 4 and 5 in OT and AV cushions, respectively. Proapoptotic bax predominantly associated with the prongs of the NC-derived aorticopulmonary (AP) septum but was expressed throughout the AV cushions. Proapoptotic bak also associated with the prongs of the AP septum in the OT, while protein levels were upregulated at ED 4-5 and 4-6 in OT and AV cushions, respectively. Bid expression showed a similar time course. We found the 10-kDa cleavage fragment of active caspase-9 at ED 4-8 and 5-8 in OT and AV cushions, respectively, and the 24-kDa cleavage fragment of poly(ADP-ribose) polymerase throughout ED 3-8 and 7-8 in OT and AV cushions, respectively. Caspase-3 cleavage occurred throughout the time period examined. Using cushion cell cultures, we found that inhibitors of caspases-3 and -9 and a universal caspase inhibitor significantly reduced apoptosis, as did retroviral overexpression of bcl-2 using an RCAS expression vector. Premigratory NC cells were fluorescently labeled in vivo with 1,1-didodecyl-3,3,3',3'-tetramethylindocarbocyanine. Subsequent nuclear staining of cushion cells with 4,6-diamidino-2-phenylindole revealed the presence of apoptotic nuclei in the NC cells in the OT cushions and in the prongs of the AP septum. These results demonstrate a developmentally regulated role for the bcl-2 and the caspase families of molecules in the endocardial cushions of the developing heart and lend support to the possibility that some of the dying cells in the cushions are derived from the NC.


Effect of pyrithiamine treatment on potassium ion fluxes in rat cortical slices.
The effect of thiamine deficiency on energy-requiring processes in brain tissue was studied by comparing cortical slices prepared from control and pyrithiamine-treated rats. Veratridine was used to stimulate energy metabolism by opening voltage-sensitive sodium channels resulting in enhanced Na+/K+ pumping; subsequent tetrodotoxin addition closed the sodium channels. Pyrithiamine-treated slices showed both lower basal and veratridine-stimulated respiration rates compared to control slices. K+ was released from the tissue upon addition of veratridine and was taken up again upon addition of tetrodotoxin. The movement of K+ was monitored directly with a K+-sensitive electrode as well as by measuring the rubidium diffusion potential. There was no difference between control and pyrithiamine-treated slices in K+ fluxes in response to veratridine and tetrodotoxin. The extent of reuptake of K+ upon tetrodotoxin addition was inversely related to the extracellular Ca2+ concentration and to the incubation temperature. Veratridine resulted in a marked decrease in tissue levels of ATP and creatine phosphate; these levels remained quite low upon tetrodotoxin addition. Despite the different respiration rates, control and pyrithiamine-treated slices showed the same ATP and creatine phosphate levels in response to veratridine and tetrodotoxin.


[Analysis of clinical characteristics and outcome of patients with very high risk primary immunoglobulin light-chain amyloidosis].
Objective: To evaluate the clinical characteristics and outcomes of very high risk patients with primary immunoglobulin light-chain amyloidosis (pAL) at a single center in China. Method: Clinical data, treatment and outcome of 205 pAL patients in Peking Union Medical College Hospital from January 2009 to February 2016 were retrospectively analyzed. A 'very high risk' group includes patients with Mayo 2004 stage Ⅲb and Mayo 2012 stage 4. Results: Of 205 patients, 34 (16.6%) were defined as very high risk pAL patients. The median age at diagnosis was 57 (20-84) years, and 22 patients (64.7%) were male. All 34 patients were diagnosed with cardiac involvement, multi-organ involvement was observed in 15 patients (44.1%) , and 27 (81.8%) had New York Heart Association Class Ⅲ or Ⅳ. Median values of serum cTnI, NT-proBNP, and free light chains difference were 0.25 μg/L, 11 733 ng/L, and 403 mg/L, respectively. Eight (24.2%) had more than 10% plasma cell on the bone marrow aspirate. Sixteen (47.1%) patients received bortezomib based chemotherapy and overall hematologic response rate was 58.3%. Median overall survival (OS) was 4 months. The estimated OS at 3, 6, 12, and 24 months was 51.3%, 44.0%, 35.2%, and 29.6%, respectively. Fourteen (41.2%) patients died within 3 months after the diagnosis. The estimated 1-year survival rate for the patients who got hematologic response, without hematologic response, and palliative treatment was 90.9%, 11.1%, and 0, respectively (P<0.001) . Conclusion: Patients with very high risk pAL had very poor prognosis and the early death rate remained high. Those patients who obtained hematologic remission would have significantly better outcomes.


The role and regulatory mechanism of FSCN1 in breast tumorigenesis and progression.
FSCN1, an actin-bundling protein, is highly expressed in almost all metastatic tumors and is associated with the poor prognosis. In breast cancer FSCN1 is highly expressed in basal-like and triple negative subgroups. There is significant progress in understanding the role of fascin in breast cancer. Studies on FSCN1 in recent years have revealed that FSCN1 not only promotes tumor migration, invasion, metastic colonization, cancer cell self-renewal and drug resistance, but also regulates glucose and lipid metabolism and mitochondrial remodeling in tumor cells. In this review, we focus on the structure and regulatory mechanism of FSCN1 in breast tumorigenesis and metastasis, and discuss the clinical value of FSCN1 with the aim to provide a direction for further research in this field.


Testosterone supplementation improves estrogen synthesis of buffalo (Bubalus bubalis) granulosa cells.
Granulosa cells (GCs) synthesize estrogens needed for follicular growth. However, the effects of androgen on estrogen production in buffalo GCs remain unclear. In this study, the impacts of testosterone on estrogen synthesis in buffalo GCs were examined. The results showed that testosterone that was added to cell medium at a concentration of 10-7 mol/L and applied to GCs for 48 or 72 h enhanced the estrogen synthesis of buffalo GCs. This study provides a theoretical basis for further exploration of ovarian endocrine mechanism for steroidogenesis.


Leclercia pneumoniae sp. nov., a bacterium isolated from clinical specimen in Leipzig, Germany.
Strain 49125T was isolated from an infant with pneumonia and septicaemia at the Leipzig University Hospital. Phenotypic and genomic traits were investigated. The strain's biochemical profile and its MALDI-TOF spectrogram did not differ from comparative samples of Leclercia adecarboxylata, thus far the sole member of the Leclercia species. A circular genome with a size of 4.4 Mbp and a G+C content of 55.0 mol% was reconstructed using hybrid Illumina and Nanopore sequencing. Phylogenetic analysis was based on 172 marker genes and validated using a k-mer-based search against a large genome collection including subsequent in silico DNA-DNA hybridization. Whole genome average nucleotide identity to any described species was below 95%, suggesting that strain 49125T represents a new species, for which we propose the name Leclercia pneumoniae sp. nov. with the type strain 49125T (=LMG 32245T=DSM 112336T).


Adjunctive use of inhaled nitric oxide during implantation of a left ventricular assist device.
The aim of this study was to evaluate the efficacy of inhaled nitric oxide in the prevention and reversal of pulmonary hypertension during and after left ventricular assist device implantation. Inhaled nitric oxide (20 ppm) was administered to seven consecutive patients undergoing implantation of a left ventricular assist device at the time of implantation and for the first 24 hours after operation. Withdrawal of inhaled nitric oxide at 24 hours after operation was associated with a significant rise in both the transpulmonary gradient (from 8+/-1 to 14+/-2 mm Hg, p < 0.01) and in pulmonary vascular resistance (from 110+/-19 to 196+/-32 dynes x sec x cm[-5], p < 0.01). In two patients, the rise in pulmonary vascular resistance resulted in a critical fall in left ventricular assist device flow and hemodynamic deterioration, necessitating urgent reinstitution of inhaled nitric oxide. The administration of inhaled nitric oxide at the time of left ventricular assist device implantation prevents rises in pulmonary vascular resistance that in some patients result in critical reductions in left ventricular assist device flow. We suggest that inhaled nitric oxide is a useful adjunctive treatment that should be routinely available at the time of left ventricular assist device implantation.


pH-dependent translocation of alpha-tocopherol transfer protein (alpha-TTP) between hepatic cytosol and late endosomes.
alpha-Tocopherol transfer protein (alpha-TTP), a member of the Sec14 protein family, plays an important role in transporting alpha-tocopherol, a major lipid-soluble anti-oxidant, in the cytosolic compartment of hepatocytes and is known as a product of the causative gene for familial isolated vitamin E deficiency. It has been shown that the secretion of hepatocyte alpha-tocopherol taken up with plasma lipoproteins is facilitated by alpha-TTP. To explore the mechanism of alpha-TTP mediated alpha-tocopherol secretion, we investigated drugs which may affect this secretion. We found that, in a hepatocyte cell culture system, intracellular alpha-tocopherol transport is impaired by chloroquine, an agent known for its function of elevating the pH in acidic compartments. Under chloroquine treatment, the diffuse cytosolic distribution of alpha-TTP changes to a punctate pattern. Double-staining experiments with endocytosis markers revealed that alpha-TTP accumulates transiently on the cytoplasmic surface of late endosomal membranes. This phenomenon is specific for hepatoma cell lines or primarily cultured hepatocytes. Other members of the Sec14 family, such as cellular retinaldehyde-binding protein (CRALBP) and supernatant protein factor (SPF), do not show this accumulation. Furthermore, we elucidate that the obligatory amino acid sequence for this function is located between amino acids 21 and 50, upstream of the N-terminal end of the lipid-binding domain. We hypothesize that a liver-specific target molecule for alpha-TTP exists on the late endosomal membrane surface. This transient binding may explain the mechanism of how alpha-tocopherol is transferred from late endosomes to cytosolic alpha-TTP.


Primary fascial closure in 112 infants with gastroschisis.
Primary fascial closure of gastroschisis remains controversial. Some surgeons routinely place a prosthetic silo over the exposed bowel, planning a staged closure. From August 1987 to August 2004, 129 cases of gastroschisis were treated at the Pediatric Surgical Unit, Department of Surgery, Ratchaburi Hospital. There were 61 boys and 68 girls. One hundred and seven mothers were primigravida. Associated anomalies were present in 13 patients. One hundred and twelve patients underwent primary fascial closure. The success of this technique depends on enlarging the abdominal cavity and decreasing the volume of the bowel that must be replaced in the peritoneal cavity. Thorough preoperative rectal irrigation should evacuate all meconium. Seventeen patients required staged prosthetic pouch with final closure. The duration of postoperative ileus and length of hospital stay were shorter in infants who underwent primary fascial closure. Death occurred in 15 patients with primary fascial closure (13.4%) and 6 patients with staged prosthetic closure (35.3%). The present study indicated that primary fascial closure should be the treatment of choice whenever possible.


Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis.
Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumour necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis.


Plasmin promotes keratinocyte migration and phagocytic-killing accompanied by suppression of cell proliferation which may facilitate re-epithelialization of wound beds.
Keratinocytes were shown to induce the activation of plasminogen activator resulting in the formation of plasmin and the initiation of proteolysis in vitro. Activation of surface bound plasminogen may localize protease activity in the pericellular microenvironment and play a role in inducing both a conformational change and cell locomotion. Plasmin, however, can induce non-proteolytic effects on certain cell functions in a variety of cell lineages. In the present study we examined the effects of plasmin on keratinocytes with a focus on its role in the process of re-epithelialization, which included studies of cell migration, phagocytic-killing and cell proliferation. Migration of freshly isolated human epidermal keratinocytes was analyzed utilizing the agarose gel assay in the presence of 10% human serum. Plasmin at the concentration of 25 U/I induced a 160% increase in the chemotactic migration of keratinocytes that was completely blocked by the plasmin inhibitor alpha2-antiplasmin (Serpin). In the absence of serum, plasmin also induced a reversible chemotactic migration of HaCaT keratinocytes as determined utilizing the microchemotaxis assay. Dose-response analysis showed a bi-phasic effect of plasmin with a maximum increase of 52% in keratinocyte chemotaxis at a concentration of 25 U/I. HaCaT cells on the other hand, showed no detectable in vitro chemokinesis by plasmin. Phagocytic-killing of Candida albicans by freshly isolated epidermal keratinocytes was enhanced in the presence of 25 U/I plasmin which was also reversible by the addition of Serpin. Spontaneous proliferation of HaCaT keratinocytes as determined by 3H-Thymidine uptake on the other hand, was reduced by 47 and 13% in cultures with 25 U/I plasmin for 24 and 48 h respectively, in a Serpin reversible manner. These data suggest that plasmin-induced chemotactic migration of epidermal keratinocytes is accompanied by enhanced phagocytic-killing coupled with suppression of proliferation of these cells which may facilitate re-epithelialization following skin injury.


Manganese (III/IV) μ-Oxo Dimers and Manganese (III) Monomers with Tetraaza Macrocyclic Ligands and Historically Relevant Open-Chain Ligands.
The oxygen-evolving complex (OEC) located in photosystem II (PSII) of green plants is one of the best-known examples of a manganese-containing enzyme in nature, but it is also used in a range of other biological processes. OEC models incorporate two multi-dentate nitrogen-containing ligands coordinated to a bis-μ-oxo Mn(III,IV) core. Open-chain ligands were the initial scaffold used for biomimetic studies, but their macrocyclic counterparts have proven to be particularly appropriate due to their enhanced stability. Dimer and monomer complexes with such ligands have shown to be useful for a wide range of applications, which will be reviewed herein. The purpose of this review is to state with some clarity the different spectroscopic and structural characteristics of the Mn complexes formed with tetraaza macrocyclic ligands both in solution and solid-state that allow the reader to successfully identified the species involved when dealing with similar complexes of Mn.


Novel attractive force between ions in quantum plasmas.
We report a new attractive force between ions that are shielded by degenerate electrons in quantum plasmas. Specifically, we show that the electric potential around an isolated ion has a hard core negative part that resembles the Lennard-Jones-type potential. Physically, the new electric potential is attributed to the consideration of the quantum statistical pressure and the quantum Bohm potential, as well as the electron exchange and electron correlations due to electron-1/2 spin within the framework of the quantum hydrodynamical description of quantum plasmas. The shape of the attractive potential is determined by the ratio between the Bohr radius and the Wigner-Seitz radius of degenerate electrons. The existence of the hard core negative potential will be responsible for the attraction of ions forming lattices and atoms or molecules, as well as for critical points and phase transitions in quantum plasmas at nanoscales.


Duodenal varices: a novel treatment and literature review.
Hemorrhage associated with duodenal varices is an uncommon but often fatal manifestation of portal hypertension. We report a case of duodenal varices, review the literature, and present a new treatment modality. A 63-year-old man presented with hematemesis and hematochezia. An upper gastrointestinal endoscopy revealed hemorrhage from the duodenal varices that was initially controlled with injections of epinephrine. However, this was only partially successful, as the patient had repeated episodes of bleeding that was not amenable to injection sclerotherapy. The patient was taken emergently to the operating room after endoscopy failed to control the hemorrhage. The bleeding was controlled with simple oversewing of the duodenal varices through a duodenotomy. Three years later the patient remains symptom free. We propose that simple oversewing of duodenal variceal veins combined with a beta-blocker is an effective treatment for duodenal variceal hemorrhage.


The association of the microcystic, elongated and fragmented (MELF) invasion pattern in endometrial carcinomas with deep myometrial invasion, lymphovascular space invasion and lymph node metastasis.
The purpose of this study was to investigate the frequency of microcystic, elongated and fragmented (MELF) pattern of invasion in endometrioid endometrial adenocarcinomas (EA) and its association with prognostic factors. Stained tissue sections from 121 cases of EA (total hysterectomy and pelvic, with or without para-aortic, lymphadenectomy specimens) were reviewed to identify cases showing MELF-type invasion. The prognostic factors of low tumour grade, deep myometrial invasion (MI), cervical stromal involvement, lymphovascular space invasion (LVSI), lymph node (LN) metastasis and advanced clinical stage were more frequently observed in MELF-positive cases (p < 0.05). Thus, MELF-positive cases had an increased frequency (28/121) of these prognostic factors, which has implications in routine clinical practice, as it signals the importance of recognising MELF pattern invasion. In univariate analysis, MELF positivity, deep MI, cervical stroma involvement and LVSI were significantly related to LN metastasis (p < 0.05). However, in multivariate analysis, only MELF pattern invasion and cervical stroma involvement were independent factors for LN metastasis. Nevertheless, further studies are needed to evaluate the clinical significance of MELF pattern of invasion in endometrial adenocarcinoma.


Detecting Molecular Rotational Dynamics Complementing the Low-Frequency Terahertz Vibrations in a Zirconium-Based Metal-Organic Framework.
We show clear experimental evidence of cooperative terahertz (THz) dynamics observed below 3 THz (∼100 cm^{-1}), for a low-symmetry Zr-based metal-organic framework structure, termed MIL-140A [ZrO(O_{2}C-C_{6}H_{4}-CO_{2})]. Utilizing a combination of high-resolution inelastic neutron scattering and synchrotron radiation far-infrared spectroscopy, we measured low-energy vibrations originating from the hindered rotations of organic linkers, whose energy barriers and detailed dynamics have been elucidated via ab initio density functional theory calculations. The complex pore architecture caused by the THz rotations has been characterized. We discovered an array of soft modes with trampolinelike motions, which could potentially be the source of anomalous mechanical phenomena such as negative thermal expansion. Our results demonstrate coordinated shear dynamics (2.47 THz), a mechanism which we have shown to destabilize the framework structure, in the exact crystallographic direction of the minimum shear modulus (G_{min}).


Potential use of dendritic cells for anti-atherosclerotic therapy.
The chronic inflammatory nature of atherosclerosis is nowadays widely accepted. Dendritic cells (DCs) are likely to play a crucial role in directing innate and adaptive immunity against altered (self-)antigens, such as oxidized low density lipoproteins (oxLDL). DCs are found in early lesions and their numbers become even higher when the lesion progresses. DCs are most abundant in areas of neovascularization where they are often found near T cells. All stages from precursors to fully mature DCs are present in human plaques. Treatment of atherosclerosis is currently based on reducing risk factors, e.g. by use of statins and beta-blockers. Some of these pharmacological agents also show anti-inflammatory properties and consequently can affect DC function. Yet, many patients remain at risk for acute coronary events, and new therapies to treat atherosclerosis are needed. One therapeutic strategy is based on isolation of patient's DCs that are then pulsed with appropriate antigen(s) ex vivo, e.g. (immunogenic components of) oxLDL or total extract of atherosclerotic plaque tissue, and returned to the blood stream. Other approaches to ensure immune protection include generation of tolerogenic DCs, or using DCs to deplete detrimental Th1 or Th17 cells. However, the future lies in direct targeting of DCs by manipulating functions of different DC subsets. Therefore, it would be useful to isolate plaque-resident DCs to be able to identify unique antigen(s) on their surface. The challenge is to selectively identify regulatory molecules and novel therapies to inhibit DC migration and function during atherogenesis, without affecting normal DC function under physiological conditions.


Hypertrophic responsiveness of cardiomyocytes to alpha- or beta-adrenoceptor stimulation requires sodium-proton-exchanger-1 (NHE-1) activation but not cellular alkalization.
The influence of the sodium-proton-exchanger-1 (NHE-1) inhibitor HOE694 on alpha- or beta-adrenoceptor mediated stimulation of protein synthesis was investigated in cultured ventricular cardiomyocytes from adult rat pre-treated with fetal calf serum to induce hypertrophic responsiveness to beta-adrenoceptor stimulation. Stimulation of alpha-adrenoceptors with phenylephrine (10 microM) in bicarbonate-free medium caused cellular alkalization (Delta pH(i): + 0.17 +/- 0.02, n = 5, P < 0.05). HOE694, an NHE-1 inhibitor, completely abolished this effect. [14C]phenylalanine incorporation into cellular protein mass increased in the presence of phenylephrine by 23+/-8%, and this effect was also abolished in the presence of HOE694. HOE694 (1 mciroM) neither influenced basal protein synthesis nor interfered with alpha-adrenoceptor mediated activation of ERK2. Phorbol myristate acetate, a direct stimulator of protein kinase C, mimicked the effect of alpha-adrenoceptor stimulation in regard to protein synthesis, but did not lead to cellular alkalization. Protein synthesis increased in the presence of isoprenaline, a beta-adrenoceptor agonist also. Again, HOE694 attenuated the stimulation of protein synthesis although isoprenaline did not cause cellular alkalization. In conclusion, the growth response to different hypertrophic stimuli, namely alpha- or beta-adrenoceptor stimulation, is attenuated in the presence of the NHE-1 inhibitor HOE694 and this inhibition is independent from cellular alkalization.


Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin treatment versus optimised oral methadone treatment in the UK.
Whilst unsupervised injectable methadone and diamorphine treatment has been part of the British treatment system for decades, the numbers receiving injectable opioid treatment (IOT) has been steadily diminishing in recent years. In contrast, there has been a recent expansion of supervised injectable diamorphine programs under trial conditions in a number of European and North American cities, although the evidence regarding the safety, efficacy and cost effectiveness of this treatment approach remains equivocal. Recent British clinical guidance indicates that IOT should be a second-line treatment for those patients in high-quality oral methadone treatment who continue to regularly inject heroin, and that treatment be initiated in newly-developed supervised injecting clinics. The Randomised Injectable Opioid Treatment Trial (RIOTT) is a multisite, prospective open-label randomised controlled trial (RCT) examining the role of treatment with injected opioids (methadone and heroin) for the management of heroin dependence in patients not responding to conventional substitution treatment. Specifically, the study examines whether efforts should be made to optimise methadone treatment for such patients (e.g. regular attendance, supervised dosing, high oral doses, access to psychosocial services), or whether such patients should be treated with injected methadone or heroin. Eligible patients (in oral substitution treatment and injecting illicit heroin on a regular basis) are randomised to one of three conditions: (1) optimized oral methadone treatment (Control group); (2) injected methadone treatment; or (3) injected heroin treatment (with access to oral methadone doses). Subjects are followed up for 6-months, with between-group comparisons on an intention-to-treat basis across a range of outcome measures. The primary outcome is the proportion of patients who discontinue regular illicit heroin use (operationalised as providing >50% urine drug screens negative for markers of illicit heroin in months 4 to 6). Secondary outcomes include measures of other drug use, injecting practices, health and psychosocial functioning, criminal activity, patient satisfaction and incremental cost effectiveness. The study aims to recruit 150 subjects, with 50 patients per group, and is to be conducted in supervised injecting clinics across England.


Guiding optical flows by photonic crystal slabs made of dielectric cylinders.
We investigate the electromagnetic propagation in two-dimensional photonic crystals, formed by parallel dielectric cylinders embedded in a uniform medium. The frequency band structure is computed using the standard plane-wave expansion method, while the propagation and scattering of the electromagnetic waves are calculated by the multiple scattering theory. It is shown that within partial band gaps, the waves tend to bend away from the forbidden directions. Such a property may render novel applications in manipulating optical flows. In addition, the relevance with the imaging by flat photonic crystal slabs will also be discussed.


A biallelic loss-of-function variant in TMEM147 causes profound intellectual disability and spasticity.
Intellectual disability (ID), occurring in syndromic or non-syndromic forms, is the most common neurodevelopmental disorder. Although many cases are caused by single gene defects, ID is highly genetically heterogeneous. Biallelic variants in the transmembrane protein TMEM147 have recently been linked to intellectual disability with dysmorphic facial features. TMEM147 is believed to localize to the endoplasmic reticulum membrane and nuclear envelope and also involved in biogenesis of multi-pass membrane proteins. Here, we report two patients born to a consanguineous family with a novel loss-of-function variant; (NM_001242597.2:c.193-197del) in TMEM147 causing intellectual disability and spasticity. Whole exome sequencing and validating Sanger sequencing were utilized to confirm the identified causal variant. Our findings were in line with the previously described patients with TMEM147 variants manifesting intellectual disability as a major clinical sign but also featured spasticity as a phenotypic expansion. This study provides additional evidence for the pathogenicity of TMEM147 mutations in intellectual disability and expands the phenotypic and variant spectrum linked to this gene.


Investigating the associations between organophosphate flame retardants (OPFRs) and fine particles in paired indoor and outdoor air: A probabilistic prediction model for deriving OPFRs in indoor environments.
Contaminants of emerging concern such as organophosphate flame retardants (OPFRs) are associated with atmospheric fine particles (PM2.5), which pose the greatest health risk in the world. However, few surveys have explored the interaction between PM2.5 and OPFRs in residential paired indoor/outdoor environments. 11 priority OPFRs and PM2.5 were investigated across 178 paired indoor and outdoor air samples taken from 89 children's households in southern Taiwan, across cold and warm seasons. This involved exploring their associations with building characteristics, interior materials, and human activities. We developed a probabilistic predictive model for indoor OPFRs based on the indoor/outdoor (I/O) ratio of contaminants and an air quality index. The significant associations of paired indoor/outdoor OPFRs and PM2.5 were explored. The indoor level of OPFRs was greater than that of outdoor households, contrasting with PM2.5. The I/O OPFRs ratio was higher than 1 (except for TEHP, EHDPP, and TCP), which suggests that the sources of OPFRs were primarily emitted from indoors. Indoor TCEP was significantly positively associated with indoor and outdoor PM2.5. The OPFR level detected in apartments was higher than in houses due to the greater decoration, furniture and electronic devices. However, this was not the case for PM2.5. TCIPP was the dominant compound in paired indoor and outdoor air. The indoor OPFR predictive model obtained a high accuracy with an R2 value of 0.87. The material used in mattresses, the use of purifiers and heaters, and the total material area were the main influencing factors for indoor OPFRs in households. These findings could provide important evidence of the interaction between paired indoor/outdoor OPFRs and PM2.5 and interior equipment in different building types. In addition, it could prevent the potential risks posed by indoor/outdoor air pollutants and eliminate OPFR emissions through the selection of better construction and building materials.


Sexually transmissible infection testing guidelines for men who have sex with men.
Since 2002, biennial production of sexually transmissible infection testing guidelines for men who have sex with men has supported sexually transmitted infection control efforts in inner Sydney, Australia.


Androgenization in Klinefelter syndrome: Clinical spectrum from infancy through young adulthood.
Klinefelter syndrome (KS) is an uncommon chromosomal disorder in males that has a variable clinical appearance. Classic KS involves an extra X chromosome, (47, XXY), although other variations may exist, including a milder mosaic form as well as multiple extra sex chromosomes with more dramatic phenotypes. KS is underdiagnosed, especially pre-pubertally, owing to a paucity of concrete clinical signs; however, diagnostic rates increase during and after puberty, as the consequences of hypergonadotropic hypogonadism begin to manifest. Testicular failure causing decreased circulating testosterone (T) and germ cell depletion, a hallmark feature in KS, commonly begins shortly after the onset of puberty and leads to the most commonly recognized KS traits: small testes, azoospermia, gynecomastia, decreased facial and pubic hair. While many KS men maintain adequate T levels leading up to young adulthood, some may have lower T levels at an earlier age leading to varied levels of androgenization and clinical KS features. At certain critical time points, absent or decreased T may alter the development of normal male reproductive organs, external genitalia, development of secondary sexual characteristics and spermatogenesis. Testicular failure in utero may lead to ambiguous genitalia, cryptorchidism and/or hypospadias, all of which depend on fetal T production. In the neonatal period and childhood, decreased T levels during the mini-puberty of infancy may negatively impact germ cell differentiation and male neuropsychological development. Finally, decreased T during pubertal and young adulthood can lead to decreased virilization during puberty, eunuchoid skeleton and decreased spermatogenesis. Depending on the timing of the testicular failure, a reproductive window of sperm production may exist to achieve paternity for KS men. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight to the relative testicular function during these developmental time points for those with KS and contributes to variability within the syndrome.


[Secondary dislocation of primarily unnoticed fracture of the medial clavicle].
This is a case report of a 16-year-old boy with a bipolar fracture of the left clavicle. The patient crashed into a car on a moped with 40 mph. In the accident & emergency department (A&E) the patient was examined physically and by X-ray. There was no protruding bone or threatened skin. The X-ray showed a lateral clavicle fracture, but there were no clinical or radiological signs of medial fracture. The treatment was conservative. Three days later the patient was referred to A&E due to increasing pain and bone protruding of the medial clavicle. A computed tomography revealed a displaced medial and lateral clavicle fracture. The treatment was altered to operative treatment.


On the Fabrication of High-Performance Additively Manufactured Copper Winding Using Laser Powder Bed Fusion.
Due to its exceptional electrical and thermal conductivity, pure copper is frequently employed in industry as the base metal for thermal management and electromagnetic applications. The growing need for complicated and efficient motor designs has recently accelerated the development of copper additive manufacturing (AM). The present work aims to improve the power density of the copper laser powder bed fusion (Cu-LPBF) coil by increasing the slot-filling factor (SFF) and the electrical conductivity. Firstly, the dimensional limitation of Cu-LPBF fabricated parts was identified. Sample contouring and adjusting beam offset associated with optimum scan track morphology upgraded the minimum feature spacing to 80 μm. Accordingly, the printed winding's slot-filling factor increased to 79% for square wire and 63% for round wire. A maximum electrical conductivity of 87% (IACS) was achieved by heat treatment (HT). The electrical impedance of full-size Cu-LPBF coils, newly reported in this study, was measured and compared with solid wire. It can reflect the performance of Cu-LPBF coils (power factor) in high-frequency applications. Furthermore, surface quality benefited from either sample contouring and HT, where the side surface roughness was lowered by 45% and an additional reduction of 25% after HT.


Early changes of platelet‑lymphocyte ratio correlate with neoadjuvant chemotherapy response and predict pathological complete response in breast cancer.
Markers with inflammatory properties, such as the ratio of neutrophils to lymphocytes and the platelet-to-lymphocyte ratio (PLR), have been documented as potential indicators for predicting pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT) in cases of breast cancer. However, whether early changes of PLR (ΔPLR) during NACT can predict pCR has not been reported. A total of 257 breast cancer patients who underwent NACT were retrospectively analyzed. PLR was calculated by evaluating the complete blood cell counts prior to NACT and following two cycles of NACT. The analysis focused on the association between changes in PLR and the response to chemotherapy, as well as the association with pCR. Patients who stayed in or changed to the low PLR level subgroup after two cycles of NACT exhibited a superior response to chemotherapy, in contrast to those who stayed in or changed to the high PLR level subgroup. Of the 257 patients, 75 (29.1%) achieved a pCR after NACT. In the multivariate analysis, there was a significant association between ΔPLR and pCR, whereas pre-treatment and post-treatment PLR did not show any significant association. In multivariate analysis, patients who had a ΔPLR <0 had a notably higher rate of pCR compared with patients with a ΔPLR ≥0. It was concluded that ΔPLR, rather than pre-treatment or post-treatment PLR, is associated with pCR. This suggested that the early changes of PLR after two cycles of NACT might serve as a more accurate predictor for chemotherapy response and pCR in breast cancer.


ATP in current biotechnology: regulation, applications and perspectives.
Adenosine tri-phosphate (ATP), the most important energy source for metabolic reactions and pathways, plays a vital role in the growth of industrial strain and the production of target metabolites. In this review, current advances in manipulating ATP in industrial strains, including altering NADH availability, and regulating NADH oxidation pathway, oxygen supply, proton gradient, the electron transfer chain activity and the F(0)F(1)-ATPase activity, are summarized and discussed. By applying these strategies, optimal product concentrations, yields and productivity in industrial biotechnology have been achieved. Furthermore, the mechanisms by which ATP extends the substrate utilization spectra and enhances the ability to challenge harsh environmental stress have been elucidated. Finally, three critical issues related to ATP manipulation have been addressed.


Modelling framework to evaluate societal effects of ecosystem management.
The ecosystem effects of different management options can be predicted through models that simulate the ecosystem functioning under different management scenarios. Optimal management strategies are searched by simulating different management (and other, such as climate) scenarios and finding the management measures that produce desirable results. The desirability of results is often defined through the attainment of policy objectives such as good environmental/ecological status. However, this often does not account for societal consequences of the environmental status even though the consequences can be different for different stakeholder groups. In this work we introduce a method to evaluate management alternatives in the light of the experiential value of stakeholder groups, using a case study in the Baltic Sea. We use an Ecopath with Ecosim model to simulate the ecosystem responses to management and climate scenarios, and the results are judged based on objectives defined based on a stakeholder questionnaire on what aspects of the ecosystem they value or detest. The ecosystem responses and the stakeholder values are combined in a Bayesian decision support model to illustrate which management options bring the highest benefits to stakeholders, and whether different stakeholder groups benefit from different management choices. In the case study, the more moderate climate scenario and strict fisheries and nutrient loading management brought the highest benefits to all stakeholders. The method can be used to evaluate and compare the effects of different management alternatives to various stakeholder groups, if their preferences are known.


Flow cytometry derived DNA content of the primary lesions of advanced germ cell tumours.
We currently lack good prognostic indicators for patients with advanced disseminated germ cell tumours (GCT). An analysis of archival tumour samples of forty-nine patients with advanced GCT for flow cytometry derived DNA content suggests an inverse relationship between tumour proliferative activity and patient survival. The great majority of patients with advanced GCT have aneuploid tumour subpopulations. This analysis suggests that the survival of patients with advanced GCT may depend in part on kinetic variables present in the primary tumour.


[Chemical constituents from Paris mairei].
Twelve compounds were isolated from the rhizome of Paris mairei Lévl by silica gel, Sephadex LH-20 and ODS col-umn chromatographies. The structure elucidation was accomplished by ESI-MS and NMR methods. These compounds were identified as lupeol(1), lup-20(29) -ene-3β-yl octacosanoate(2), palmitic acid(3), glyceryl α-mono-palmitate(4), α-spinasterol(5), diosgenin (6), (25R) diosgenin-3-O-α-L-rhamnopyranosyl (1--> 4) -α-L-rhamnopyranosyl (1 --> 4) - [α-L-rhamnopyranosyl(1 --> 2)] -β-D-glucopyranoside(7), pennogenin(8), pennogenin-3-O-β-D-glucopyranosyl(1 -->3) - [α-L-rhamnopyranosyl(1 --> 2)] -β-D-glucopyranoside(9), flazin(10), calonysterone(11), and isorhamnetin-3-O-β-gentiobioside(12). Compounds 1-5,10-11 were isolated from the genus Paris for the first time, and all compounds were isolated from this plant for the first time.


Outcomes of head and neck cancer surgery in the geriatric population based on case volume at academic centers.
Evaluate the impact of case volume and other variables on cost and mortality after head and neck oncologic surgery in the geriatric population. Cross-sectional study. The Vizient database was accessed for data on geriatric patients (age ≥65 years) who underwent surgery for head and neck cancers (excluding thyroid and skin cancer) at full member academic medical centers between 2009 and 2012. Multivariate, linear regression analyses, χ2 tests, and analysis of variance were applied to evaluate significant associations between hospital case volume and independent variables including cost, cost index, mortality, mortality index, length of stay, length of stay index, and readmission rates. A total of 4,544 patients were included. Total length of stay was 6.72 days in high-volume hospitals, compared to 8.12 days and 7.91 days in moderate- and low-volume hospitals, respectively (P = .0144). Frequency of intensive care unit stays was 36.5% in high-volume hospitals, compared to 42.19% and 40.29% in moderate- and low-volume hospitals, respectively (P = .0048). Mortality (0.78%) and average cost per case ($21,834) was lower, but nonsignificant in high-volume hospitals. Using multiple regression analysis, major severity of disease was positively associated with complication rate (P < .0001) and length of stay (P = .0481). After controlling for other factors, high-volume academic medical centers have a lower intensive care unit stay, but no difference in mortality or average cost per case when compared to low-volume hospitals. 2b. Laryngoscope, 127:2539-2544, 2017.


Dynamically Bioresponsive DNA Hydrogel Incorporated with Dual-Functional Stem Cells from Apical Papilla-Derived Exosomes Promotes Diabetic Bone Regeneration.
The regeneration of bone defects in patients with diabetes mellitus (DM) is remarkably impaired by hyperglycemia and over-expressed proinflammatory cytokines, proteinases (such as matrix metalloproteinases, MMPs), etc. In view of the fact that exosomes represent a promising nanomaterial, herein, we reported the excellent capacity of stem cells from apical papilla-derived exosomes (SCAP-Exo) to facilitate angiogenesis and osteogenesis whether in normal or diabetic conditions in vitro. Then, a bioresponsive polyethylene glycol (PEG)/DNA hybrid hydrogel was developed to support a controllable release of SCAP-Exo for diabetic bone defects. This system could be triggered by the elevated pathological cue (MMP-9) in response to the dynamic diabetic microenvironment. It was further confirmed that the administration of the injectable SCAP-Exo-loaded PEG/DNA hybrid hydrogel into the mandibular bone defect of diabetic rats demonstrated a great therapeutic effect on promoting vascularized bone regeneration. In addition, the miRNA sequencing suggested that the mechanism of dual-functional SCAP-Exo might be related to highly expressed miRNA-126-5p and miRNA-150-5p. Consequently, our study provides valuable insights into the design of promising bioresponsive exosome-delivery systems to improve bone regeneration in diabetic patients.


Floristic evolution in an agroforestry system cultivation in Southern Brazil.
Bracatinga (Mimosa scabrella Bentham) is an important pioneer tree species in Ombrophylous Mixed Forest of Brazil and is widely used as an energy source. In traditional agroforestry systems, regeneration is induced by fire, then pure and dense stands known as bracatinga stands (bracatingais) are formed. In the first year, annual crops are intercalated with the seedlings. At that time the seedlings are thinned, then the stands remain at a fallow period and cut at seven years old. The species is very important mainly for small landowners. We studied the understory species that occur naturally during the succession over several years in order to manage them rationally in the future and maintain the natural vegetation over time. Three to 20 year-old Bracatinga stands were sampled between 1998 and 2011. All tree species with diameter at breast height (DBH) ≥ 5 cm were measured.The floristic evolution was assessed with respect to Sociability Index, the Shannon Diversity Index and the Pielou Evenness Index. Graphs of rank/abundance over different age groups were evaluated using the Kolmogorov-Smirnov test. We identified 153 species dispersed throughout the understory and tend to become aggregated over time.


Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma.
Hepatic resection is the only curative treatment for large hepatocellular carcinoma (HCC). Sequential, preoperative, selective transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE) allow feasible and safe major hepatic resections to be performed in HCC patients with chronic liver disease. Retrospective cohort study. University hospital. Seventeen HCC patients who underwent preoperative PVE following selective TACE for planned major hepatic resections were enrolled. The indications for PVE were determined using the volumetric ratio of the future remnant liver parenchyma and the indocyanine green retention ratio at 15 minutes. Preoperative TACE and PVE. Tumor characteristics and blood test results before and after TACE and PVE, changes in the volumes of the liver segments after PVE, the feasibility of major hepatic resections, and short- and long-term patient prognoses. The liver function test results transiently worsened after TACE and PVE but returned to baseline levels within 1 (after TACE) or 2 (after PVE) weeks. Within 2 weeks after PVE, 22% +/- 4% hypertrophy of the nonembolized segments was obtained; subsequent major hepatic resections were feasible in 16 patients. Four minor complications (25%) were experienced postoperatively; however, liver failure did not occur. The 5-year overall and disease-free survival rates after curative resection were 55.6% and 46.7%, respectively. Sequential TACE and PVE contribute to both the broadening of surgical indications and the safety of major hepatic resections performed in HCC patients with damaged livers. The long-term outcome of this treatment strategy is satisfactory.


Incidence, clinical characteristics, and long-term prognosis of travel-associated pulmonary embolism.
Prolonged air travel is considered a risk factor for pulmonary embolism (PE). The clinical characteristics as well as the long-term prognosis of patients suffering from travel-associated PE ('economy-class syndrome', ECS) remain largely unknown. Owing to its proximity, our hospital is the primary referral centre for Frankfurt Airport, Europe's third-largest airport. The goal of our study was to follow-up all patients with ECS, who were admitted to our hospital between 1997 and 2006. We systematically reviewed all medical charts from patients presenting with acute PE to our emergency room or intensive care unit (ICU) and performed a telephone follow-up on patients discharged alive. Together with the data provided from the statistics department of Fraport Inc., the operating company of the Frankfurt International Airport, we were also able to put the medical data in context with the corresponding number of passengers and flight distances. A total of 257 patients with acute PE were admitted to our emergency and ICU between 1997 and 2006. Out of these, 62 patients suffered from ECS (45 flight-associated PE and 17 from other travel-associated PE). ECS patients were prone to more haemodynamic relevant acute events, reflected by a higher rate of initial cardiopulmonary resuscitation (4.8% vs. 1.5%; P = 0.153) and higher percentage of massive PE (8% vs. 3%; P = 0.064). Nevertheless, intrahospital mortality was similar in both groups (ECS 4.8%, others 4.1%; P = 0.730). Interestingly, the long-term outcome of ECS patients was excellent (Kaplan-Meier analysis; P log-rank: 0.008 vs. other entities). In general, ECS was a rare event (one event/5 million passengers), where long-haul flights over 5000 km lead to a 17-fold risk increase compared with shorter flights. Travel-associated PE was a common cause of PE in our hospital, with patients showing excellent long-term prognosis after discharge. The risk of ECS is rather low and strictly dependent on the flight distance.


Subunit-specific regulation of NMDA receptor endocytosis.
At excitatory synapses, both NMDA and AMPA receptors are localized to the postsynaptic density (PSD). However, unlike AMPA receptors, synaptic NMDA receptors are stable components of the PSD. Even so, surface-expressed NMDA receptors undergo endocytosis, which is more robust early in development and declines during synaptic development. We investigated the subunit-specific contributions to NMDA receptor endocytosis, specifically defining the endocytic motifs and endocytic pathways preferred by the NR2A and NR2B subunits. We find that NR2A and NR2B have distinct endocytic motifs encoded in their distal C termini and that these interact with clathrin adaptor complexes with differing affinities. We also find that NR2A and NR2B sort into different intracellular pathways after endocytosis, with NR2B preferentially trafficking through recycling endosomes. In mature cultures, we find that NR2B undergoes more robust endocytosis than NR2A, consistent with previous studies showing that NR2A is more highly expressed at stable synaptic sites. Our findings demonstrate fundamental differences between NR2A and NR2B that help clarify developmental changes in NMDA receptor trafficking and surface expression.


Turning a practice into a science: reconceptualizing postwar medical practice.
In recent years, many editorials in leading North American medical journals have argued that medical practice is seriously flawed. Ofter, decision-support techniques are mentioned as a potential solution to this problem. I argue that these recent calls embody a specific reconceptualization of medical practice and its problems. Within the postwar medical literature, divergent discourses on the virtues and troubles of postwar medical practice can be found. Through a focus on medical editorials, I demonstrate the existence of several different notions of the 'scientific nature' of medical action. Comparing the more recent of these images to those dominating earlier medical journals, one main shift is apparent. While, earlier, medical action was often described as an artful application of scientific knowledge, only mildly tainted by external, social problems, recent conceptualizations often locate both the scientific nature of medicine and the causes of its problems in the physician's brain. Even within this new discourse, however, scientific rationality does not always speak with the same voice, as reflected in the existence of different decision-support techniques. I argue that these different techniques, which are presented as solutions to the flaws of medical practice, lay at the root of the development of the cognitivist image(s) in the first place.