Safety of glucocorticoids in cancer patients treated with oncolytic adenoviruses.
Oncolytic adenoviruses are an emerging treatment option for advanced and refractory cancer. Such patients are often treated with corticosteroids to ameliorate tumor associated symptoms. Thus, it is important to evaluate whether safety is affected by immunosuppression possibly induced by corticosteroids. Concurrent low-dose cyclophosphamide, appealing for its immunomodulatory effects, could also impact safety. In a retrospective case-control study, we evaluated the effect of systemic corticosteroid use in cancer patients receiving oncolytic virotherapy. Four treatment groups were identified: (1) oncolytic adenovirus with oral glucocorticoids, (2) virus alone, (3) virus with glucocorticoids and cyclophosphamide and (4) virus with cyclophosphamide. Adverse events, neutralizing antibody titers, viral DNA in circulation and tumor responses were evaluated. The most common adverse effects were grade 1-2 fatigue, nausea, fever and abdominal pain. Common asymptomatic findings included self-limiting grade 1-3 hyponatremia and aspartate aminotransferase increase. Safety was good and no significant differences were observed between the groups. All patients had an increase in neutralizing antibody titers post-treatment, and no trends for differences between groups were observed. There were fewer post-treatment virus genomes circulating in patients receiving glucocorticoids when compared to their control groups. Overall, glucocorticoid use in cancer patients receiving oncolytic adenovirus, with or without low-dose cyclophosphamide, seems safe.


Effects of extraction and nonextraction treatment on class I and class II subjects.
This study aims to examine the profile as well as the dentoalveolar and skeletal effects of extraction or nonextraction treatment in a wide range of patients including Class I and Class II, division 1 cases. Results achieved with extraction and nonextraction modalities have also been compared. The study was performed on pretreatment and posttreatment lateral cephalograms of 87 orthodontic patients. There were no significant differences between the pretreatment values of extraction and nonextraction Class I groups, whereas SN-GoGn (degrees), maxillary incisor to A-Po (degrees), mandibular incisor to A-Po (mm), Co-Gn (mm), overjet (mm), and overbite (mm) measurements of extraction Class II group were significantly higher before the treatment. After treatment, these differences were eliminated in the Class II group; however, incisors were significantly protruded in both nonextraction groups. No other differences in profile or lip position were found between the extraction and nonextraction groups. The results of this study indicate that in successfully treated cases, whether by extraction or nonextraction, the same soft and hard tissue profile posttreatment end points were reached except for the incisor positioning, which is rather easier to anticipate than profile and soft tissue changes. The simple statement that extraction means a more retrusive or dished-in profile seems to be unacceptable. It seems that a more thorough assessment and investigation including pretreatment extent of crowding and factors related to anchorage, soft tissue thickness, and strain should be carried out.


microRNA access to the target helicases from rice.
Major classes of small RNAs include microRNAs (miRNAs) and small interfering RNAs (siRNAs). miRNAs are single-stranded RNA molecules of around 22 nucleotides in length. Most miRNAs show imperfect homology with their targets. The biogenesis mechanisms of miRNAs are different for plant and animals. Silencing of genes by miRNAs may serve as an appropriate tool to speed-up analyses of gene functions in a post-genome era. We have identified in silico a set of miRNAs that control helicase gene expression by regulating its mRNA stability and translation in rice. Our analysis revealed that several rice helicases have distinct miRNA specificities. Such analyses will be a prerequisite to refining our understanding of target selection and regulation of helicase gene expression by miRNAs in rice. Further, we discuss recent findings on miRNA gene family and its gene structure, criteria for miRNA annotation and on miRNA biogenesis that involve transcription, processing and maturation of miRNAs.


Relation of contaminants to fish intersex in riverine sport fishes.
Endocrine active compounds (EACs) are pollutants that have been recognized as an emerging and widespread threat to aquatic ecosystems globally. Intersex, the presence of female germ cells within a predominantly male gonad, is considered a biomarker of endocrine disruption caused by EACs. We measured a suite of EACs and assessed their associated impacts on fish intersex occurrence and severity in a large, regulated river system in North Carolina and South Carolina, USA. Our specific objective was to determine the relationship of contaminants in water, sediment, and fish tissue with the occurrence and severity of the intersex condition in wild, adult black bass (Micropterus), sunfish (Lepomis), and catfish (Ictaluridae) species at 11 sites located on the Yadkin-Pee Dee River. Polycyclic aromatic hydrocarbons (PAHs), ethinylestradiol (EE2), and heavy metals were the most prevalent contaminants that exceeded effect levels for the protection of aquatic organisms. Fish intersex condition was most frequently observed and most severe in black basses and was less frequently detected and less severe in sunfishes and catfishes. The occurrence of the intersex condition in fish showed site-related effects, rather than increasing longitudinal trends from upstream to downstream. Mean black bass and catfish tissue contaminant concentrations were higher than that of sunfish, likely because of the latter's lower trophic position in the food web. Principal component analysis identified waterborne PAHs as the most correlated environmental contaminant with intersex occurrence and severity in black bass and sunfish. As indicated by the intersex condition, EACs have adverse but often variable effects on the health of wild sport fishes in this river, likely due to fluctuations in EAC inputs and the dynamic nature of the riverine system. These findings enhance the understanding of the relationship between contaminants and fish health and provide information to guide ecologically comprehensive conservation and management decisions.


Development of miotic cross-tolerance between pyridostigmine and sarin vapor.
The organophosphorous nerve agent sarin (GB) and the carbamate pyridostigmine bromide (PB) both inhibit acetylcholinesterase (AChE), leading to overstimulation of muscarinic receptors. Both GB and PB produce miosis through stimulation of ocular muscarinic receptors. This study investigated 2 hypotheses: (1) that the miotic response to PB would decrease following repeated injections; and (2) that repeated administration of PB would result in tolerance to the miotic effect of GB vapor. Rats were injected intramuscularly with saline, 0.04 mg/kg, 0.5 mg/kg, or 1.4 mg/kg of PB twice daily for 8 consecutive days. After day 3, animals injected with 1.4 mg/kg PB developed miotic tolerance. Twenty-four (24) h following the final PB injection, the rats were exposed to GB vapor (4.0 mg/m(3)). A similar magnitude of miosis was observed in all groups after GB exposure. However, the rate of recovery of pupil size in animals pretreated with 0.5 and 1.4 mg/kg PB was significantly increased. Twenty (20) h following exposure to GB vapor, the pupils of animals pretreated with 1.4 mg/kg PB had recovered to 77% +/- 4% of their pre-exposure baseline, whereas the saline-injected controls had recovered to only 52% +/- 2% of their pre-exposure baseline. The increased rate of recovery does not appear to be a result of protection of pupillary muscarinic receptors by the higher doses of PB, as there was no longer PB present in the animal at the time of GB exposure. These results demonstrate the development of tolerance to the miotic effect of PB following repeated exposures, and also suggest that cross-tolerance between PB and GB occurs. However, because the magnitude of the response was not reduced, the PB pretreatment and its associated miotic cross-tolerance does not appear to diminish the effectiveness of miosis as a biomarker of acute exposure to nerve agent vapor.


Self-pulsation in fiber-coupled, on-chip microcavity lasers.
We report self-pulsation in an erbium-doped silica toroidal microcavity laser coupled to a tapered fiber and investigate the effects of pump power and taper-cavity coupling condition on the dynamic behaviors of the pulse train. The microcavity is pumped at 1444.8 nm, and lasing occurs at 1560.2 nm with a threshold of 12 microW. Experimental results are interpreted within the framework of ion-pair induced self-quenching model.


Research progress in the organic cation transporters.
The organic cation transport systems were initially recognized in studies of renal elimination. A variety of endogenous and exogenous compounds that are harmful to the body are eliminated from the kidney via glomerular filtration and/or active tubular secretion. Among those compounds are polar organic cations that require a transporter-mediated process to cross cellular membrane and be eventually excreted into the urine. The organic cation transport systems in the kidney have been recognized for several decades. Following the insight gained from the kidney, organic cation transporters (OCTs) have also been characterized in other tissues. In particular, the OCTs in the liver and in the intestine have been proposed as important determinants of drug absorption and disposition. Over the past several decades, the mechanisms of organic cation transport have been extensively characterized using in vivo models, ex vivo organ perfusions, in vitro tissue preparations and cell lines. In particular, the molecular cloning and characterization of OCTs have remarkably increased our knowledge of this important subfamily of solute carriers. In this article, we first review the molecular cloning and characterization of OCTs. We will then describe their transport mechanisms, tissue distribution and localization, and their specificity of interaction with organic cations. Regulatory mechanisms and genetic animal models will be reviewed as they provide the most important insight on this class of transporters in recent years. Finally, we will summarize genetic variation in human OCT genes and raise clinical perspectives on these important transporters.


Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11.
Recently, various approaches for controlling the embryonic stem (ES) cell microenvironment have been developed for regulating cellular fate decisions. It has been reported that the lineage specific differentiation could be affected by the size of ES cell colonies and embryoid bodies (EBs). However, much of the underlying biology has not been well elucidated. In this study, we used microengineered hydrogel microwells to direct ES cell differentiation and determined the role of WNT signaling pathway in directing the differentiation. This was accomplished by forming ES cell aggregates within microwells to form different size EBs. We determined that cardiogenesis was enhanced in larger EBs (450 microm in diameter), and in contrast, endothelial cell differentiation was increased in smaller EBs (150 microm in diameter). Furthermore, we demonstrated that the EB-size mediated differentiation was driven by differential expression of WNTs, particularly noncanonical WNT pathway, according to EB size. The higher expression of WNT5a in smaller EBs enhanced endothelial cell differentiation. In contrast, the increased expression of WNT11 enhanced cardiogenesis. This was further validated by WNT5a-siRNA transfection assay and the addition of recombinant WNT5a. Our data suggest that EB size could be an important parameter in ES cell fate specification via differential gene expression of members of the noncanonical WNT pathway. Given the size-dependent response of EBs to differentiate to endothelial and cardiac lineages, hydrogel microwell arrays could be useful for directing stem cell fates and studying ES cell differentiation in a controlled manner.


Knowledge, perceptions and behaviours regarding dietary management of adults living with phenylketonuria.
Lifelong dietary treatment remains the mainstay for many with phenylketonuria (PKU); however, adherence is known to reduce with age. It remains unclear whether knowledge and perceptions of the PKU diet amongst adults with PKU influence dietary behaviours. A nationwide questionnaire survey was performed to investigate the knowledge and perceptions, and associated diet behaviours of adults with PKU in the UK. The survey was sent to adults with PKU under the care of the host hospital and members of the National Society of PKU. One hundred and thirty-seven respondents (n = 78 females, 56.9%) completed the survey with a mean age of 34 years and 4 months (16-65 years). Sixty (43.8%) respondents had always followed a PKU diet, 39 (28.5%) returned to diet and 35 (25.5%) were off diet. Overall mean ± SD knowledge score was 75.2% ± 13.4%, with significantly higher scores for knowledge of PKU (80.7% ± 16.2%) compared to knowledge specifically of the PKU diet (72.6% ± 14.5%, p < 0.001). Knowledge was associated with dietary adherence. Respondents who always followed a PKU diet had similar knowledge to those who returned to diet, whereas respondents off diet had significantly lower scores. Perception of the diet was not a predictor of dietary adherence, with the exception of whether patients had concerns for their long-term health when on diet or felt well when not following a diet. The present study highlights the importance of ongoing dietetic input in building knowledge and skills for dietary management. Further research is needed to understand the motivators and beliefs that influence dietary adherence.


MicroRNA-449a reduces cell survival and enhances cisplatin-induced cytotoxicity via downregulation of NOTCH1 in ovarian cancer cells.
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. Platinum-based chemotherapy is the first-line treatment for the advanced ovarian cancer, but resistance to cisplatin remains a major obstacle to successful treatment. MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in disease processes, including the development of drug resistance. In this study, we found miR-449a were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. The overexpression of miR-449a increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis. The luciferase assay confirmed that miR-449a functioned through suppressing NOTCH1 directly. Concordantly, BALB/c nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-449a mimics exhibited enhanced cisplatin sensitivity in vivo. Taken together, these results suggest that the ectopic expression of miR-449a may be a promising therapeutic strategy for the management of cisplatin resistance in ovarian cancer.


A linear optical modulator with high FM sensitivity.
By using KDP inside a short laser cavity, a large linear frequency deviation has been achieved with a moderate modulation voltage, i.e., +/-44 Mc/s for +/-110 V. The modulation bandwidth is to 10 Mc/s, the modulation power is 2.5 W, and the optical output power is 0.4 mW (single mode, single frequency) at 6328 A. The piezoelectric resonances which occur at modulation frequencies in the 80 kc/s to 2 Mc/s range have been nearly eliminated by clamping the KDP in a rigid, but highly damped, mount. As a result, the change in FM sensitivity at the fundamental resonance, at 83 kc/s is only +/-5%. Noise loading tests, which simulate 2400 telephone channels, indicate that the FM distortion is negligible. Square wave tests verify that the distortion is indeed small by showing that the input pulses are reproduced faithfully at the output.


Dysregulation of LXR responsive genes contribute to ichthyosis in trichothiodystrophy.
Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterised by brittle hairs and various systemic symptoms, including photosensitivity and ichthyosis. While photosensitivity could result from DNA repair defects, other TTD clinical features might be due to deficiencies in certain molecular processes. The aim of this study was to understand the pathophysiological mechanism of ichthyosis in TTD, focused on the transcriptional dysregulation. TTD mouse skin tissue and keratinocytes were pathologically and physiologically examined to identify the alteration of lipid homeostasis in TTD with ichtyosis. Gene expression of certain lipid transporter was assessed in fibroblasts derived from TTD patients and TTD mouse keratinocytes. Histopathology and electron microscopy revealed abnormal lipid composition in TTD mice skin. In addition to abnormal cholesterol dynamics, TTD mouse keratinocytes exhibit impaired expression of Liver X receptor (LXR) responsive genes, including Abca12, a key regulator of Harlequin ichthyosis, and Abcg1 that is involved in the cholesterol transport process in the epidermis. Strikingly, dysregulation of LXR responsive genes has been only observed in cells isolated from TTD patients who developed ichthyosis. Our results suggest that the altered expression of the LXR-responsive genes contribute to the pathophysiology of ichthyosis in TTD. These findings provide a new drug discovery target for TTD.


Tankyrase modulates insulin sensitivity in skeletal muscle cells by regulating the stability of GLUT4 vesicle proteins.
Tankyrase 1 and 2, members of the poly(ADP-ribose) polymerase family, have previously been shown to play a role in insulin-mediated glucose uptake in adipocytes. However, their precise mechanism of action, and their role in insulin action in other cell types, such as myocytes, remains elusive. Treatment of differentiated L6 myotubes with the small molecule tankyrase inhibitor XAV939 resulted in insulin resistance as determined by impaired insulin-stimulated glucose uptake. Proteomic analysis of XAV939-treated myotubes identified down-regulation of several glucose transporter GLUT4 storage vesicle (GSV) proteins including RAB10, VAMP8, SORT1, and GLUT4. A similar effect was observed following knockdown of tankyrase 1 in L6 myotubes. Inhibition of the proteasome using MG132 rescued GSV protein levels as well as insulin-stimulated glucose uptake in XAV939-treated L6 myotubes. These studies reveal an important role for tankyrase in maintaining the stability of key GLUT4 regulatory proteins that in turn plays a role in regulating cellular insulin sensitivity.


Human endonuclease V is a ribonuclease specific for inosine-containing RNA.
Deamination of DNA bases can create missense mutations predisposing humans to cancer and also interfere with other basic molecular genetic processes; this deamination generates deoxyinosine from deoxyadenosine. In Escherichia coli, the highly conserved endonuclease V is involved in alternative excision repair that removes deoxyinosine from DNA. However, its exact activities and roles in humans are unknown. Here we characterize the FLJ35220 protein, the human homologue of E. coli endonuclease V, hEndoV as a ribonuclease specific for inosine-containing RNA. hEndoV preferentially binds to RNA and efficiently hydrolyses the second phosphodiester bond located 3' to the inosine in unpaired inosine-containing ssRNA regions in dsRNA. It localizes to the cytoplasm in cells. The ribonuclease activity is promoted by Tudor staphylococcal nuclease and detected on inosine-containing dsRNA created by the action of adenosine deaminases acting on RNA. These results demonstrate that hEndoV controls the fate of inosine-containing RNA in humans.


A comparison between different ways to assess demands-abilities fit in higher education: Empirical results and recommendations for research practice.
Researchers studying person-environment fit can choose between various measurement approaches. Even though these measures are distinctly different, they often get used interchangeably, which makes interpreting the results of person-environment fit studies difficult. In the present article, we contrast the most commonly used measurement approaches for person-environment fit in higher education and compare them in terms of explained variance. We obtained data on the fit as well as subjective and objective study-related outcomes of N = 595 university students. We analyzed the fit between the demands of the study program and the abilities of the student, using the algebraic, squared and absolute difference score, response surface analysis (RSA), and direct fit as measurement approaches. Our results indicate that RSA explains the most variance for objective outcomes, and that direct fit explains the most variance for subjective outcomes. We hope that this contribution will help researchers distinguish the different measurement approaches of demands-abilities fit (and ultimately person-environment fit) and use them accordingly.


Transmembrane helix and topology prediction using hierarchical SVM classifiers and an alternating geometric scoring function.
A key class of membrane proteins contains one or more transmembrane (TM) helices, traversing the membrane lipid bilayer. Various properties such as the length, arrangement and topology or orientation of TM helices, are closely related to a protein's functions. Although a range of methods have been developed to predict TM helices and their topologies, no single method consistently outperforms the others. In addition, topology prediction has much lower accuracy than helix prediction, and thus requires continuous improvements. We develop a method based on support vector machines (SVM) in a hierarchical framework to predict TM helices first, followed by their topology. By partitioning the prediction problem into two steps, specific input features can be selected and integrated in each step. We also propose a novel scoring function for topology models based on membrane protein folding process. When benchmarked against other methods in terms of performance, our approach achieves the highest scores at 86% in helix prediction (Q(2)) and 91% in topology prediction (TOPO) for the high-resolution data set, resulting in an improvement of 6% and 14% in their respective categories over the second best method. Furthermore, we demonstrate the ability of our method to discriminate between membrane and non-membrane proteins, with higher than 99% in accuracy. When tested on a small set of newly solved structures of membrane proteins, our method overcomes some of the difficulties in predicting TM helices by incorporating multiple biological input features.


Chimeras on a ring of oscillator populations.
Chimeras occur in networks of coupled oscillators and are characterized by coexisting groups of synchronous oscillators and asynchronous oscillators. We consider a network formed from N equal-sized populations at equally spaced points around a ring. We use the Ott/Antonsen ansatz to derive coupled ordinary differential equations governing the level of synchrony within each population and describe chimeras using a self-consistency argument. For N=2 and 3, our results are compared with previously known ones. We obtain new results for the cases of 4,5,…,12 populations and a numerically based conjecture resulting from the behavior of larger numbers of populations. We find macroscopic chaos when more than five populations are considered, but conjecture that this behavior vanishes as the number of populations is increased.


Recurrence of Hypophysitis After Immune Checkpoint Inhibitor Rechallenge.
Immune checkpoint inhibitor (ICI)-induced hypophysitis is an immune-mediated pituitary inflammation that tends to cause long-term pituitary deficiency. Management of ICI-induced hypophysitis includes corticosteroids for acute inflammation and long-term hormone replacement due to irreversible pituitary cell damage. We report a case of recurrent hypophysitis following ICI rechallenge for metastatic melanoma. A 33-year-old woman with recurrent metastatic melanoma with adrenal, pelvic, and inguinal metastases developed recurrent hypophysitis during treatment with ipilimumab and nivolumab which recurred with rechallenge >5 years later. In both cases, headache was the most notable symptom and brain MRI showed pituitary enlargement and edema without evidence of metastases. Central adrenal insufficiency and symptoms caused by mass effect were treated with acute high-dose corticosteroids and long-term replacement corticosteroids. Based on recurrence and failure of symptomatic treatment with continued steroid treatment, ICI was discontinued. This case illustrates that hypophysitis may recur with ICI rechallenge, challenging traditional assumptions that chronic, irreversible irAEs are unlikely to recur or flare. The regenerative potential of pituitary cells after ICI-induced damage or additional damage to previously unaffected cells may be more conceivable than previously realized. Additional research on the potential for recurrent ICI-induced endocrinopathies are needed.


Tetrahydrobiopterin (BH4) Supplementation Prevents the Cardiorenal Effects of Diabetes in Mice by Reducing Oxidative Stress, Inflammation and Fibrosis.
Background: The effects of diabetes on the cardiovascular system as well as in the kidney are profound, which include hypertrophy and fibrosis. Diabetes also induces oxidative stress, at least in part due to the uncoupling of nitric oxide synthase (NOS); this is a shift in NO production toward superoxide production due to reduced levels of the NOS cofactor tetrahydrobiopterin (BH4). With this in mind, we tested the hypothesis that BH4 supplementation may prevent the development of diabetic cardiomyopathy and nephropathy. Methods: Diabetes was induced in Balb/c mice with streptozotocin. Then, diabetic mice were divided into two groups: one group provided with BH4 (sapropterin) in drinking water (daily doses of 15 mg/kg/day, during eight weeks) and the other that received only water. A third group of normoglycemic mice that received only water were used as the control. Results: Cardiac levels of BH4 were increased in mice treated with BH4 (p = 0.0019). Diabetes induced cardiac hypertrophy, which was prevented in the group that received BH4 (p < 0.05). In addition, hypertrophy was evaluated as cardiomyocyte cross-sectional area. This was reduced in diabetic mice that received BH4 (p = 0.0012). Diabetes induced cardiac interstitial fibrosis that was reduced in mice that received BH4 treatment (p < 0.05). We also evaluated in the kidney the impact of BH4 treatment on glomerular morphology. Diabetes induced glomerular hypertrophy compared with normoglycemic mice and was prevented by BH4 treatment. In addition, diabetic mice presented glomerular fibrosis, which was prevented in mice that received BH4. Conclusions: These results suggest that chronic treatment with BH4 in mice ameliorates the cardiorenal effects of diabetes,, probably by restoring the nitroso−redox balance. This offers a possible new alternative to explore a BH4-based treatment for the organ damage caused by diabetes.


ULYSSES: An Efficient and Easy to Use Semiempirical Library for C+.
We introduce ULYSSES, a user-friendly and robust C++ library for semiempirical quantum chemical calculations. In its current version, ULYSSES is equipped with a large set of different semiempirical models, most of which are based on the Neglect of Diatomic Differential Overlap (NDDO) approximation. Empirical corrections for dispersion and hydrogen bonding are available for most methods, so that higher quality is achieved in the calculation of energies of nonbonded complexes. The library is furthermore equipped with geometry optimization, as well as modules for calculating molecular properties of general interest. Ideal gas thermodynamics is available and allows single structure as well as conformer (multistructure) averaged properties to be calculated. We offer the possibility to use several vibrational partition functions according to the nature of interactions being studied: for covalent systems, the traditional harmonic oscillator approximation is available; for nonbonded complexes, we systematically extended the partition function proposed by Grimme for all thermodynamic functions. The library is also capable of running Born-Oppenheimer molecular dynamics.


Suicide attempts by agricultural chemicals.
Forty three patients (42%) used agricultural chemicals as a method of suicide over nine and a half years (from Oct. 1981 to March 1991), and most cases were reported in June (agricultural activity) and December (year's end). The highest prevalence was inpatients in their fifties (34.9%). 58.1% of these patients who committed suicide were farmers or had no fixed occupation. Main precipitating factor was difficulties in interpersonal relationships (30.9%), and the largest number of patients (25.6%) were diagnosed as having manic-depressive psychosis, depressed type.


Clinical prediction scores and the utility of time to blood culture positivity in stratifying the risk of infective endocarditis in Staphylococcus aureus bacteraemia.
Infective endocarditis (IE) complicates up to a quarter of Staphylococcus aureus bacteraemia (SAB) cases. Risk scores predict IE complicating SAB but have undergone limited external validation, especially in community-acquired infections and those who use IV drugs. Addition of the time to positive culture (TTP) may provide incremental risk prognostication. To externally validate risk scores for predicting IE in SAB and assess the incremental value of TTP. The modified Duke score was calculated for adults hospitalized with SAB at a major tertiary institution. All patients underwent echocardiography. Sensitivity and specificity of the risk scores for predicting IE were calculated, and the incremental value of TTP was assessed. One hundred and six cases were analysed and 18 (17%) met definite IE criteria. The optimal TTP to predict IE was 11.5 h (sensitivity 88.9%; specificity 71.6%). The sensitivity of VIRSTA and PREDICT (Predicting risk of endocarditis using a clinical tool) were similar (94.4% for both) and higher than POSITIVE (Prediction Of Staphylococcus aureus Infective endocarditis Time to positivity, IV drug use, Vascular phenomena, pre-Existing heart condition; 77.8%). The receiver-operator characteristic AUCs were VIRSTA 0.83, PREDICT 0.75, POSITIVE 0.89 and TTP 0.85. Adding TTP to VIRSTA (i.e. VIRSTA+) resulted in the highest AUC (0.90), sensitivity (100%) and negative predictive value (100%), albeit with a low specificity (33%). The VIRSTA and POSITIVE scores were the strongest predictors for IE complicating SAB. The addition of TTP to VIRSTA (VIRSTA+) significantly improved discriminatory value and may be safely used to rationalize echocardiography strategies.


[Adsorbent effect of activated carbon on small molecular uremic toxin and its influence factors].
To analyze the adsorbent effect of activated carbon on uremic toxin and its influence factors. Uremic toxins (urea, creatinine and uric acid) were dissolved in the distilled water to obtain uremic toxic solution. Activated carbon was added to the solution, and the concentrations of uremic toxins were measured at different time spots. To determine the influence factors, some possible related materials, such as bile, amino acid, Ringer's, solution of glucose, HCl or NaOH respectively were added simultaneously. The concentrations of toxins in uremic toxic solution decreased 5 min after adding the activated carbon. The concentration of urea was the lowest at 30 min, but it increased after 50 min; while the concentrations of creatinine and uric acid reached the lowest level from 10 to 30 min after adding the activated carbon, and maintained at the same level after that. The bile, amino acid, electrolyte, glucose and pH value did not influence the adsorption of uric acid significantly, but they influenced the adsorption of urea and creatinine. Bile and amino acid influenced the concentration of urea remarkably, following glucose, NaOH and HCl. The effect of pH 2.0 solution on the creatinine concentration was the most significant, following glucose. Activated carbon has adsorptive effect on uremic toxins, but its adsorptive effect decreases as time goes on. Bile, glucose, amino acid, NaOH and HCl can affect the adsorptive effect of activated carbon on uremic toxins to some extent.


[Airway management in intensive care units in Rhineland-Palatinate : Evolution over five years].
Securing the airway in severely ill patients is associated with a high rate of complications. So far, no information exists about the equipment readily available for airway management in German intensive care units (ICUs). It is also unknown if the range of material has improved over time. In the present trial the availability of equipment for airway management in ICUs in Rhineland-Palatinate was evaluated at two different times. Using a structured questionnaire, all ICUs in the state were contacted in the years 2010 and 2015. The availability of different types of equipment for airway management, as well as the presence of a training program for airway management, was evaluated. For 2010 data from 64 ICUs were evaluated and for 2015 data sets from 63 ICUs were collected. In 2010 indirect laryngoscopes were available in eight ICUs; in 2015 these devices were directly accessible in 43 units (p < 0.0001). Extraglottic devices were available in all but one ICU in 2010 and all ICUs in 2015. Equipment for emergency surgical airway procedures was available in nearly every ICU (n = 60). The availability of capnography increased significantly from 2010 (n = 12) to 2015 (n = 56; p < 0.0001). In 2010 and 2015, frequent training with a focus on airway management was performed in 23 and 32 units, respectively (p > 0.05). Most ICUs in Rhineland-Palatinate have a broad range of equipment for airway management available, and the range has significantly improved over the time period evaluated. The availability of indirect laryngoscopes and capnometers improved significantly. However, it is remarkable that in some ICU's there is still a lack of equipment for advanced airway management.


Looking at the big picture: understanding how the oviduct's dialogue with gametes and the embryo shapes reproductive success.
The oviduct is a tubular organ comprising three distinct anatomical regions (the infundibulum, the ampulla and the isthmus) connecting the ovary and the uterus. Oviductal function is regulated by ovarian hormones, gametes, and embryo-derived factors, for optimally facilitating key reproductive events. A cross- talk is established between the oviduct and the gametes and embryo and this dialogue shapes the microenvironment in which gamete transport, fertilization, and early embryonic development occur. This review aims to address each participant in this conversation in a holistic manner by delineating several advances in the field within the greater context of understanding how oviduct-gamete and oviduct-embryo dialogue shape reproductive success and furthermore how this knowledge can be applied in vitro.


Application of Structural Retinal Biomarkers to Detect Cognitive Impairment in a Primary Care Setting.
Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimer's disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD. This study examines the predictive ability of structural retinal biomarkers in detecting cognitive impairment in a primary care setting. Participants were recruited from Alzheimer's Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging, and fundus imaging was performed. Data were examined on n = 91 participants. The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer, and the inferior quadrant of the macular retinal nerve fiber layer. The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD.


Impact of pregnancy on underlying renal disease.
Normal pregnancy involves marked renal vasodilation and large increases in glomerular filtration rate (GFR). Studies in rats reveal that the gestational renal vasodilation is achieved by parallel reductions in tone in afferent and efferent arterioles so GFR rises without a change in glomerular blood pressure. There is some evidence from animal studies that increased renal generation of nitric oxide (NO) may be involved. Although chronic renal vasodilation has been implicated in causing progression of renal disease in nonpregnant states by glomerular hypertension, there are no long-term deleterious effects of pregnancies on the kidney when maternal renal function is normal because glomerular blood pressure remains normal. When maternal renal function is compromised before conception, there are no long-term adverse effects on renal function in most types of renal disease, providing that the GFR is well maintained before conception. When serum creatinine exceeds approximately 1.4 mg/dL, pregnancy may accelerate the renal disease increases and when serum creatinine >2 mg/dL, the chances are greater than 1 in 3 that pregnancy will hasten the progression of the renal disease. The available animal studies suggest that glomerular hypertension does not occur despite diverse injuries. Thus, the mechanisms of the adverse interaction between pregnancy and underlying renal disease remain unknown.


Synthesis of (Ca,Nd)TiO3 powders by complex polymerization, Rietveld refinement and optical properties.
Neodymium calcium titanate, (Ca(0.99)Nd(0.01))TiO(3) powders were synthesized by the complex polymerization method and heat treated at different temperatures for 2 h under air atmosphere. The structural evolution of these powders as a function of heat treatment temperature was analyzed by X-ray diffraction (XRD) and micro-Raman (MR) spectroscopy. The optical properties were investigated by Ultraviolet-visible (UV-vis) absorption spectroscopy and Photoluminescence (PL) measurements. XRD patterns, Rietveld refinement and MR spectra indicated that the powders heated treated at 750 degrees C for 2 h present an orthorhombic structure without secondary phases. UV-vis measurements suggested the presence of intermediary energy in disordered (Ca(0.99)Nd(0.01))TiO(3) powders. Broad and narrow bands were observed in the PL spectra of these powders when excited with 350 nm wavelength. The broad bands were associated to the structural defects and/or p-d electronic transitions while, the narrow bands were ascribed to f-f transitions arising from Nd(3+) ions.


Histogram array and convolutional neural network of DWI for differentiating pancreatic ductal adenocarcinomas from solid pseudopapillary neoplasms and neuroendocrine neoplasms.
This study aimed to investigate the diagnostic performance of the histogram array and convolutional neural network (CNN) based on diffusion-weighted imaging (DWI) with multiple b-values under magnetic resonance imaging (MRI) to distinguish pancreatic ductal adenocarcinomas (PDACs) from solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine neoplasms (PNENs). This retrospective study consisted of patients diagnosed with PDACs (n = 132), PNENs (n = 45) and SPNs (n = 54). All patients underwent 3.0-T MRI including DWI with 10 b values. The regions of interest (ROIs) of pancreatic tumor were manually drawn using ITK-SNAP software, which included entire tumor at DWI (b = 1500 s/m2). The histogram array was obtained through the ROIs from multiple b-value data. PyTorch (version 1.11) was used to construct a CNN classifier to categorize the histogram array into PDACs, PNENs or SPNs. The area under the curves (AUCs) of the histogram array and the CNN model for differentiating PDACs from PNENs and SPNs were 0.896, 0.846, and 0.839 in the training, validation and testing cohorts, respectively. The accuracy, sensitivity and specificity were 90.22%, 96.23%, and 82.05% in the training cohort, 84.78%, 96.15%, and 70.0% in the validation cohort, and 81.72%, 90.57%, and 70.0% in the testing cohort. The performance of CNN with AUC of 0.865 for this differentiation was significantly higher than that of f with AUC = 0.755 (P = 0.0057) and α with AUC = 0.776 (P = 0.0278) in all patients. The histogram array and CNN based on DWI data with multiple b-values using MRI provided an accurate diagnostic performance to differentiate PDACs from PNENs and SPNs.


Systematic domain deletion analysis of the major sporulation kinase in Bacillus subtilis.
To characterize the role of the three PAS domains in KinA, the major sporulation kinase in Bacillus subtilis, we constructed a series of systematic PAS domain deletion mutants and analyzed their activities using an IPTG (isopropyl-beta-d-thiogalactopyranoside)-inducible artificial sporulation induction system, which we have developed recently. The results showed that any one of the three PAS domains is sufficient to maintain the kinase activity and trigger sporulation, if not fully then at least partially, when the protein levels increase beyond a certain level.


Pituitary microadenomas: a PET study.
Twenty cases of surgically verified pituitary microadenoma (17 with Cushing disease and three with acromegaly) were studied with positron emission tomography (PET) with use of fluorine-18-2-fluorodeoxyglucose (FDG). The diagnostic results were compared with those of other modalities, namely, computed tomography (CT), magnetic resonance (MR) imaging, and, in the cases of Cushing disease, simultaneous bilateral inferior petrosal sinus sampling (SIPS). The PET results showed 12 positive readings and one questionable reading, compared with seven positive readings and one questionable reading for CT (18 cases studied) and 13 positive and two questionable MR imaging readings. PET complemented MR imaging, in the sense that five of the positive PET readings were negative or questionable at MR imaging. PET studies of 20 healthy control subjects showed no false-positive cases, whereas other studies of healthy subjects with contrast material-enhanced CT and MR imaging have yielded, respectively, 20% and 15% positive readings, with findings suggestive of silent or occult adenomas.


Factors predicting the severity of dengue in patients with warning signs in Rio de Janeiro, Brazil (1986-2012).
Since 1981, >12 million cases of dengue have been reported in Brazil. Early prediction of severe dengue with no warning signs is crucial to avoid progression to severe dengue. Here we aimed to identify early markers of dengue severity and characterize dengue infection in patients in Rio de Janeiro. We evaluated early severity markers, serotypes, infection status, number of days of illness and viral loads associated with dengue fever in patients from Rio de Janeiro, Brazil through an observational retrospective study (1986-2012). We compared dengue without warning signs and dengue with warning signs/severe dengue (DWWS/SD). Infection status was classified by enzyme-linked immunosorbent assay and viraemia was quantified by quantitative real-time reverse transcription polymerase chain reaction. The presence of DWWS/ SD was significantly associated with younger age; patients 13-19 y of age had a significantly greater chance of presenting warning signs. Dengue virus type 3 (DENV3) was more likely to induce DWWS/SD, which was more frequent on days 4-5 of illness. DENV3, 4-5 d of illness and 13-19 y of age were early biomarkers of dengue severity. To our knowledge, this was the first study to analyse the characteristics of dengue severity in the state of Rio de Janeiro over 27 y of epidemics since the introduction of DENV.


High Admission Glucose Is Associated With Poor Outcome After Endovascular Treatment for Ischemic Stroke.
High-serum glucose on admission is a predictor of poor outcome after stroke. We assessed the association between glucose concentrations and clinical outcomes in patients who underwent endovascular treatment. From the MR CLEAN Registry, we selected consecutive adult patients with a large vessel occlusion of the anterior circulation who underwent endovascular treatment and for whom admission glucose levels were available. We assessed the association between admission glucose and the modified Rankin Scale score at 90 days, symptomatic intracranial hemorrhage and successful reperfusion rates. Hyperglycemia was defined as admission glucose ≥7.8 mmol/L. We evaluated the association between glucose and modified Rankin Scale using multivariable ordinal logistic regression and assessed whether successful reperfusion (extended Thrombolysis in Cerebral Infarction 2b-3) modified this association. Of 3637 patients in the MR CLEAN Registry, 2908 were included. Median admission glucose concentration was 6.8 mmol/L (interquartile range, 5.9-8.1) and 882 patients (30%) had hyperglycemia. Hyperglycemia on admission was associated with a shift toward worse functional outcome (median modified Rankin Scale score 4 versus 3; adjusted common odds ratio, 1.69 [95% CI, 1.44-1.99]), increased mortality (40% versus 23%; adjusted odds ratio, 1.95 [95% CI, 1.60-2.38]), and an increased risk of symptomatic intracranial hemorrhage (9% versus 5%; adjusted odds ratio, 1.94 [95% CI, 1.41-2.66]) compared with nonhyperglycemic patients. The association between admission glucose levels and poor outcome (modified Rankin Scale score 3-6) was J-shaped. Hyperglycemia was not associated with the rate of successful reperfusion nor did successful reperfusion modify the association between glucose and functional outcome. Increased admission glucose is associated with poor functional outcome and an increased risk of symptomatic intracranial hemorrhage after endovascular treatment.


Selective oxidative stress in brain areas of neonate rats exposed to 2,4-Dichlorophenoxyacetic acid through mother's milk.
2,4-Dichlorophenoxyacetic acid (2,4-D) induced disparate alterations on enzymatic activities of the defensive mechanism and/or modifications of the reactive oxygen species levels in specific neonate rat brain regions. The midbrain, striatum, and prefrontal cortex were the areas where the alterations were more remarkable and with similar tendency. The hippocampus did not suffer many alterations, and the hypothalamus was the area where no changes were observed. The current results suggest that the developing brain areas have different susceptibilities to the adverse effect of the herbicide, especially those areas related to the dopaminergic system, and that oxidative stress is one 2,4-D mechanism of toxicity.


Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice.
Imatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear. To assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage. Quantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method. Exposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected. This study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens.


Physical Capacity and Activity in Patients With Idiopathic Normal Pressure Hydrocephalus.
Most patients with idiopathic normal pressure hydrocephalus (iNPH) improve gait after surgery. However, knowledge on physical capacity and activity after shunt surgery is limited. One of the aims of this study was to evaluate the effect of shunt surgery in patients with iNPH on short-distance walking, functional exercise capacity, functional strength, and variables of activity and sleep, 3 and 6 months postoperatively. Another aim was to evaluate the effect of a physical exercise program. Additionally, we studied how changes in short-distance walking were correlated with functional exercise capacity and voluntary walking. In total, 127 patients were consecutively included and randomized to the exercise group (n = 62) or the control group (n = 65). Participants in the exercise group underwent the supervision of a 12-week exercise program. All patients were assessed before surgery, at 3 and 6 months postoperatively with the 10-m walk test (10MWT), the 6-min walk test (6MWT), 30-s chair stand test (30sCST), and with the actigraphic recordings of activity variables measured for a total of 24 h/day for at least 3 days. All patients improved at 3 months postoperatively in the 10MWT (p < 0.001), 6MWT (p < 0.001), and 30sCST (p < 0.001). These results were maintained after 6 months. Actigraphic recordings for voluntary walking (steps per minute) were improved and nighttime sleep (%) increased after 6 months (p = 0.01, p = 0.04). There were no significant differences between the exercise group and the control group, except for the postoperative change in the proportion of daytime sleep after 3 months, which was slightly more reduced compared to baseline in the exercise group (p = 0.04). Changes after 3 months in the 10MWT and 6MWT were moderately correlated (ρ= -0.49, p = 0.01) whereas the correlation between the 10MWT and voluntary walking was weak (ρ = -0.34, p = 0.01). Shunt surgery improved short-distance walking, functional exercise capacity, functional strength, and voluntary walking. An exercise program did not affect these outcomes. Short-distance walking was weakly correlated with voluntary walking, indicating improved physical capacity does not directly translate to increased physical activity. Further research should address how interventions should be tailored to promote physical activity after shunt surgery. clinicaltrials.gov, Id: NCT02659111.


A rapid method for the synthesis of nitrogen doped TiO2 nanoparticles for photocatalytic hydrogen generation.
A facile, fast, and economic method of doping TiO2, synthesized by conventional precipitation route with N has been developed. By this method, stable N doped TiO2 can be prepared within a short duration of time. The method adopted was to treat the TiO2 powder synthesized by simple precipitation with trioctyl amine (TOA) at 320 degrees C for 2 hours followed by calcination at 400 degrees C for 2 hours to obtain the N-doped TiO2. The sample along with NiO as co-catalyst showed significant photocatalytic activity for hydrogen generation from aqueous methanol solution under sunlight type irradiation. This synthesis method opens up a fast and easy route for doping the existing TiO2 or other wide band gap oxide semiconductors with nitrogen so that they can exhibit enhanced photocatalytic activity under solar irradiation.


A Rare Case of Calciphylaxis in an Orthotopic Liver Transplant Recipient with Acute Kidney Injury.
Calciphylaxis is a rare disease characterized by calcification of small- to medium-sized blood vessels in the dermis and subcutaneous fat, resulting in cutaneous necrosis. Although most commonly shown in patients with end-stage kidney disease, it has also been reported in patients with other diseases, including alcoholic cirrhosis and malignancies. Here, we report an unusual case of calciphylaxis in an orthotopic liver transplant recipient with acute kidney injury. The patient, a 43-year-old white female with a history of type 2 diabetes mellitus, alcoholic cirrhosis, and normal kidney function, presented with decompensated liver disease and hepatorenal syndrome; she no longer responded to medical treatment and required treatment with dialysis. Ten days after admission, she underwent liver transplant, resulting in improved liver function tests. She had acute tubular necrosis (creatinine peak: 325 μmol/L) from sustained hypotension during and after surgery, which required 4 sessions of dialysis over 2weeks. Six weeks after her transplant, she developed painful, nonulcerating, erythematous plaques over her shins and thighs. Skin biopsy of the lesions showed calciphylaxis, calcium deposits, and thrombotic vasculopathy. She also developed severe hypercalcemia (calcium level of 2.75 mmol/L) from immobility, which required treatment with a bisphosphonate and hemodialysis. The lesions improved 6 weeks later, and her renal function returned to normal. Calciphylaxis diagnosed in an orthotopic liver transplant recipient with acute kidney injury has not been previously reported. We hypothesize that her chronic inflammatory state caused down-regulation and low levels of fetuin A and protein C. She also had other risk factors, including hypoalbuminemia, obesity, systemic glucocorticoids, and alcoholic liver disease. Calciphylaxis can occur in patients with alcoholic cirrhosis and acute renal failure even after liver transplant. Further studies into the pathogenesis of this disease may help us understand why it develops in these patients and not others with the same risk factors.


Two further cases of spondyloenchondrodysplasia (SPENCD) with immune dysregulation.
Although the diagnosis of spondyloenchondrodysplasia (SPENCD) can only be made in the presence of characteristic metaphyseal and vertebral lesions, a recent report has highlighted the pleiotropic manifestations of this disorder which include significant neurological involvement and variable immune dysfunction. Here we present two patients, one of whom was born to consanguineous parents, further illustrating the remarkable clinical spectrum of this disease. Although both patients demonstrated intracranial calcification, they were discordant for the presence of mental retardation, spasticity and white matter abnormalities. And whilst one patient had features consistent with diagnoses of Sjögren syndrome, polymyositis, hypothyroidism and severe scleroderma, the other patient had clinical manifestations and an autoantibody profile of systemic lupus erythematosus. These cases further illustrate the association of SPENCD with immune dysregulation and highlight the differential diagnosis with Aicardi-Goutières syndrome and other disorders associated with the presence of intracranial calcification. Undoubtedly, identification of the underlying molecular and pathological basis of SPENCD will provide important insights into immune and skeletal regulation.


[Electromyostimulation (EMS) in cardiac patients. Will EMS training be helpful in secondary prevention?].
Current guidelines concerning the treatment of patients with chronic congestive heart failure (CHF) include ergospirometry-directed dynamic exercises on a daily basis. Several prospective, randomized trials have confirmed its positive influence on clinical symptoms and prognosis of the disease. Patients with stable coronary artery disease (CAD) can benefit from a 27% reduction of mortality, as shown in meta-analyses of several studies. By contrast, patients with CHF have traditionally been discouraged from physical activities, which may have had detrimental consequences. They became even less able to participate in daily activities that in turn hastened the disease-driven atrophies of skeletal muscles. On the other hand, well-adjusted endurance training at 50-70% of maximum oxygen uptake was shown to improve overall fitness. In a recent metaanalysis, the mortality of patients with CHF was reduced by 35% by sports, and the rate of hospitalizations dropped by 28%. It is a well-perceived clinical problem that successful treatment is not possible without intensive guidance and a close therapeutic relationship. Being left in their routine situation and circumstances, the majority of patients cannot cope with the day-to-day challenge of an independent, active lifestyle. Among the primary reasons not to sustain physical activity are mental, psychological or social barriers. The authors have begun, in a cohort of patients with CHF, a prospective pilot study to investigate the impact of, and attitude to, electromyostimulation (EMS). Unique features of this treatment include its passive nature that remains independent of mental attitude. An up to 96% increase of peak oxygen uptake at the anaerobic threshold could be shown (pre- vs. posttraining phase, VO(2at) 19.39 [+/- 5.3] ml/kg vs. 24.25 [+/- 6.34] ml/kg). The diastolic blood pressure decreased significantly. A 14% gain in muscle volume was observed, while overall body weight remained unchanged. All patients kept up the training until the conclusion of the study and found their overall fitness to be considerably improved. The results may indicate the enormous potential of EMS for the treatment of patients within the cardiologic arena, especially those with CHF.


Emerging Roles of Estrogen-Related Receptors in the Brain: Potential Interactions with Estrogen Signaling.
In addition to their well-known role in the female reproductive system, estrogens can act in the brain to regulate a wide range of behaviors and physiological functions in both sexes. Over the past few decades, genetically modified animal models have greatly increased our knowledge about the roles of estrogen receptor (ER) signaling in the brain in behavioral and physiological regulations. However, less attention has been paid to the estrogen-related receptors (ERRs), the members of orphan nuclear receptors whose sequences are homologous to ERs but lack estrogen-binding ability. While endogenous ligands of ERRs remain to be determined, they seemingly share transcriptional targets with ERs and their expression can be directly regulated by ERs through the estrogen-response element embedded within the regulatory region of the genes encoding ERRs. Despite the broad expression of ERRs in the brain, we have just begun to understand the fundamental roles they play at molecular, cellular, and circuit levels. Here, we review recent research advancement in understanding the roles of ERs and ERRs in the brain, with particular emphasis on ERRs, and discuss possible cross-talk between ERs and ERRs in behavioral and physiological regulations.


Lyme borreliosis in European children and adolescents.
Lyme borreliosis, a multi-system disease caused by infection with Borrelia burgdorferi, occurs most commonly in Europe and North America. This article reviews the vectors, epidemiology, clinical presentation, diagnosis, therapy, and pathogenesis of the disease, with particular regard to European children and adolescents.


Implementation of Plate Imaging for Demonstration of Monoclonality in Biologics Manufacturing Development.
Monoclonality of mammalian cell lines used for production of biologics is a regulatory expectation and one of the attributes assessed as part of a larger process to ensure consistent quality of the biologic. Historically, monoclonality has been demonstrated through statistics generated from limiting dilution cloning or through verified flow cytometry methods. A variety of new technologies are now on the market with the potential to offer more efficient and robust approaches to generating and documenting a clonal cell line.Here we present an industry perspective on approaches for the application of imaging and integration of that information into a regulatory submission to support a monoclonality claim. These approaches represent the views of a consortium of companies within the BioPhorum Development Group and include case studies utilising imaging technology that apply scientifically sound approaches and efforts in demonstrating monoclonality. By highlighting both the utility of these alternative approaches and the advantages they bring over the traditional methods, as well as their adoption by industry leaders, we hope to encourage acceptance of their use within the biologics cell line development space and provide guidance for regulatory submission using these alternative approaches.LAY ABSTRACT: In the manufacture of biologics produced in mammalian cells, one recommendation by regulatory agencies to help ensure product consistency, safety, and efficacy is to produce the material from a monoclonal cell line derived from a single, progenitor cell. The process by which monoclonality is assured can be supplemented with single-well plate images of the progenitor cell. Here we highlight the utility of that imaging technology, describe approaches to verify the validity of those images, and discuss how to analyze that information to support a biologic filing application. This approach serves as an industry perspective to increased regulatory interest within the scope of monoclonality for mammalian cell culture-derived biologics.


Correlation between oxidized low-density lipoprotein and other factors in patients on peritoneal dialysis.
Oxidized low-density lipoprotein (Ox-LDL) has been related with progression of atherosclerosis. Some studies reported increased Ox-LDL levels in hemodialysis (HD) patients. The levels of Ox-LDL in peritoneal dialysis (PD) patients have not yet been clarified. We measured Ox-LDL in PD patients and investigated the related factors. We measured plasma Ox-LDL, total cholesterol (TC), triglycerides (TG), and LDL-cholesterol (LDL-c) levels in 18 PD patients (mean age: 55.5 +/- 9.8 years; mean duration of dialysis: 2.7 +/- 1.4 years) and in 24 HD patients as controls. We compared Ox-LDL levels in patients with diabetes mellitus (DM) and ischemic heart disease (IHD). And we looked at the correlation between Ox-LDL levels and adequacy of PD. Levels of Ox-LDL were significantly higher in the PD patients (2.24 +/- 1.14 ng/microgram LDL protein) than in the HD patients (1.43 +/- 0.90 ng/microgram LDL protein), and other lipids were higher in the PD patients. The Ox-LDL did not correlate with other lipids. The Ox-LDL levels of the PD patients with DM or IHD were higher than those of non DM or non IHD patients. The adequacy of PD did not correlate with Ox-LDL. Patients on PD, especially those with DM or IHD, showed elevated Ox-LDL levels. Special attention should be paid to the level of Ox-LDL and atherosclerosis in PD patients.


Establishment of Cutoff Values for Newborn Screening of Six Lysosomal Storage Disorders by Tandem Mass Spectrometry.
Lysosomal storage disorders (LSDs) are becoming increasingly important in newborn screening, and tandem mass spectrometry (MS/MS) is widely used in newborn screening for LSDs through measurement of enzymatic activities in dried blood spots (DBSs). Overall, the determination of the cutoff value is important in such screening, and different laboratories have different methods of determining this value; most do not use a fixed cutoff value but rather calculate the corresponding batch cutoff value based on each batch of experimental data. In this study, we used MS/MS to screen for LSDs and sought to find an appropriate method to establish the cutoff value for LSD screening. A total of 38,945 samples from newborn blood tablets collected from various maternity hospitals in six cities in Shandong province, including Jinan, Dezhou, Heze, Linyi, Weifang, and Zibo, were tested using a Waters Xevo TQD tandem mass spectrometer; the experimental data were analyzed with MassLynx V4.1. The laboratory used 30% of the median GLA enzyme activity and 20% of the median ABG, ASM, GALC, IDUA, and GAA enzyme activities in every test as the cutoff values for that batch of experiments. There were 254 suspicious positives in the initial screening test, including one case of Gaucher disease, one of Niemann-Pick disease, 47 of Krabbe disease, four of MPS-I, 21 of Fabry disease, and 180 of Pompe disease. After genetic screening, 11 children were diagnosed, including three with Pompe disease, three with Fabry disease, and five with Krabbe disease. In addition, the enzyme activity cutoff value of this experiment showed seasonal variation, which was initially believed to be related to the ambient temperature, such as the effect of ambient temperature on the human body or the temperature when the blood tablets dried naturally. Overall, MS/MS can be used in LSD screening, and using different cutoff values in each batch of experiments is feasible. The ambient temperature might be a reason why the enzyme activity cutoff value has seasonal variation. More samples are needed to develop a method of determining cutoff values in laboratories.


Discovery of the ichneutine genus Paroligoneurus Muesebeck (Hymenoptera: Braconidae) from the Indian subcontinent with the description of a new species from Northwest India.
The small braconid subfamily, Ichneutinae is one of the least studied groups within the Braconidae. Old world species of the widely distributed ichneutine genus, Paroligoneurus (unknown from the Neotropical region) is revised along with description of a new species, P. harishi Ranjith van Achterberg sp. nov. We reinstate the genera Anaprixia Mason and Muesebeckia Mason based on the following characters; exodont mandibles and absence of spiracles in the alternate tergites (in Anaprixia) and presence of carinae on propodeum and anterior subalar depression with carina (in Muesebeckia). Five species, Paroligoneurus cosmopterygivorus (He, 2000), P. crassicornis (He, 2000), P. flavifacialis (He, 2000), P. sinensis (He, 2000) and P. songyangensis (He, 2000) were described from the Oriental part of China are transferred from Oligoneurus to Paroligoneurus. A taxonomic key to the Old world species Paroligoneurus and a provisional checklist of extant species are provided.


Eremophilane-type sesquiterpenes from the fungus Xylaria sp. BCC 21097.
Seven new eremophilane-type sesquiterpenoids (1-5, 7, and 8) and the known mairetolide F (6) were isolated from the endophytic Xylaria sp. BCC 21097. A new furofurandione (9) was also isolated from the fungal extract. The structures of the new compounds were elucidated by analyses of NMR spectroscopic and mass spectrometry data in combination with chemical reaction studies. Eremophilanolides possessing an alpha-methylene-gamma-lactone (1-3) exhibited moderate cytotoxic activities, while related analogues bearing an endo double bond (6 and 7) were inactive.


Predictors of paraplegia with current thoracoabdominal aortic aneurysm repair.
Although the results of surgical repair of thoracoabdominal aortic aneurysm continue to improve, the incidence of paraplegia remains within a wide range depending on each institution. The purpose of this study was to find predictors of paraplegia following thoracoabdominal aortic aneurysm repair in our institute, using the current spinal cord protection strategies. From January 2007 to December 2011, 200 consecutive patients underwent thoracoabdominal aortic aneurysm repair. Of these, 24 (12%) had Crawford extent I repair, 82 (41%) had extent II, 51 (25.5%) had extent III, 10 (5%) had extent IV, and 33 (16.5%) had extent V (modified by Safi). Aortic dissection was present in 101 (50.5%) patients. Adjuncts used during the procedures included left heart bypass in all patients, cerebrospinal fluid drainage in 164 (82%), and intercostal artery reimplantation in 76 (38%). There were 20 (10%) hospital deaths including 6 (3%) within 30 days; hospital mortality was 8.8% in elective operations. Postoperative complications included paraplegia in 17 (8.5%) patients, stroke in 5 (2.5%), and acute renal failure requiring dialysis in 5 (2.5%). Logistic regression analysis revealed that significant factors for the development of paraplegia were preoperative hypotension (p = 0.005, odds ratio 18.5), intraoperative hypotension (p = 0.001, odds ratio 77.6), and an open distal anastomosis technique (p = 0.012, odds ratio 4.6). The predictors of postoperative paraplegia in our institution were perioperative hypotension and an open distal anastomosis technique. Avoidance of these risk factors might diminish the incidence of postoperative paraplegia.


Use of a Novel Device to Assess Intraoral and Intrapharyngeal Baropressure during Sound Production.
We developed a novel device that simultaneously measures oral and intrapharyngeal baropressure. The transducer has the advantage that it can be placed in any region. We determined the effect of different speech samples on baropressure in these regions. Seven healthy individuals produced speech samples comprising vowels and consonants (e.g., /aka/, /apa/, and /ash/). Two transducers were installed into the experimental plate at the incisive papillae and center of the Ah-line; a third transducer was placed in the mid-pharyngeal cavity. During each task, 3 parameters were analyzed: peak pressure, mean pressure, and the temporal relationship between sound signals and pressure changes. The mean pressure did not change during the production of a single vowel; however, the pressure transiently increased during the production of the speech samples, depending on the place of articulation. Moreover, the place of articulation affected the onset and peak timing of pressure changes. These findings indicate that pressure changes during the production of speech samples reflect the functional aspects of speech production. In particular, simultaneous pressure recordings at multiple locations would provide precise information about speech production, compared to pressure studies that used a single pressure transducer.


Urinary pCO2 as an index of collecting duct hydrogen ion secretion during chronic hypercapnia.
The rise in urinary pCO2 above blood pCO2 which occurs in response to bicarbonate loading (i.e. the urine to blood (U-B) pCO2 gradient), is used with increasing frequency as an index of collecting duct hydrogen ion secretion. We recently proposed, however, that the U-B pCO2 gradient is not an appropriate index of collecting duct hydrogen ion secretion when blood pCO2 is altered acutely. This issue was further investigated by examining the effect of chronic hypercapnia on urinary pCO2 generation. In rats exposed to chronic hypercapnia induced by breathing 10% CO2 for 3 days in an environmental chamber, acute sodium bicarbonate infusion resulted in a U-B pCO2 lower than that of normocapnic control rats (11 +/- 4.6 and 30 +/- 1.8 mm Hg, p less than 0.001). This finding could be interpreted to indicate that collecting duct hydrogen ion secretion is depressed in rats with chronic hypercapnia. The urinary pCO2 of rats with chronic hypercapnia was lower than that of the blood (54 +/- 6.0 and 86 +/- 1.2 mm Hg, p less than 0.005, respectively). In these rats, NaHCO3 infusion, while blood pCO2 was kept constant, elicited a marked rise in urine pCO2 (from 54 +/- 6.0 to 104 +/- 6.0 mm Hg, p less than 0.005) which was not significantly different from that observed in normocapnic control rats. The infusion of carbonic anhydrase resulted in a comparable fall in urine pCO2 in hypercapnic and normocapnic rats (-27 +/- 5 and -30 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)


Dental size variation in admixed Latin Americans: Effects of age, sex and genomic ancestry.
Dental size variation in modern humans has been assessed from regional to worldwide scales, especially under microevolutionary and forensic contexts. Despite this, populations of mixed continental ancestry such as contemporary Latin Americans remain unexplored. In the present study we investigated a large Latin American sample from Colombia (N = 804) and obtained buccolingual and mesiodistal diameters and three indices for maxillary and mandibular teeth (except third molars). We evaluated the correlation between 28 dental measurements (and three indices) with age, sex and genomic ancestry (estimated using genome-wide SNP data). In addition, we explored correlation patterns between dental measurements and the biological affinities, based on these measurements, between two Latin American samples (Colombians and Mexicans) and three putative parental populations: Central and South Native Americans, western Europeans and western Africans through PCA and DFA. Our results indicate that Latin Americans have high dental size diversity, overlapping the variation exhibited by the parental populations. Several dental dimensions and indices have significant correlations with sex and age. Western Europeans presented closer biological affinities with Colombians, and the European genomic ancestry exhibited the highest correlations with tooth size. Correlations between tooth measurements reveal distinct dental modules, as well as a higher integration of postcanine dentition. The effects on dental size of age, sex and genomic ancestry is of relevance for forensic, biohistorical and microevolutionary studies in Latin Americans.


Synthesis and regulation of lipoprotein lipase in the hippocampus.
Lipoprotein lipase (LPL) expression was determined in adult rat hippocampus and compared to enzyme expression in other brain regions. Hippocampus LPL mRNA levels were at least 2.5-fold higher than those detected in the cerebral cortex, cerebellum, and remaining brain regions. Enzyme mass and activity levels in the hippocampus were also increased to a similar degree. De novo synthesis of LPL in the hippocampus was confirmed by [35S]methionine-labeling of the tissue and identification of a 57 kDa protein obtained by immunoprecipitation. Addition of an excess amount of bovine LPL completely prevented the immunoprecipitation of this protein. The effect of nutritional modulations on brain LPL activity was determined after a 12-h fast. While no significant changes were observed in other regions of the brain, hippocampus LPL activity in fasted rats increased by 60% compared to the fed control group. Simultaneously, fasting reduced adipose LPL activity by 60%. Intraperitoneal injection of ACTH over a 5-day period had no effect on hippocampus LPL activity, while adipose LPL levels increased 2.3-fold and heart LPL levels decreased 1.4-fold. We conclude that LPL is synthesized, active and regulated in a tissue-specific manner in the adult rat hippocampus.


N-cadherin and M-cadherin are sequentially expressed in myoblast populations contributing to the first and second waves of myogenesis in the trout (Oncorhynchus mykiss).
The objective of this study was to investigate the expression of two promyogenic cell surface adhesion receptors, N- and M-cadherin, in developing trout (Oncorhynchus mykiss) somite, taking account of the recent identification of a dermomyotome-like epithelium in teleosts. In situ hybridization showed that N-cadherin was expressed throughout the paraxial mesoderm and nascent somite. As the somite matured, N-cadherin expression disappeared ventrally from the sclerotome, and then mediolaterally from the differentiating slow and fast muscle cells of the embryonic myotome, to become finally restricted to the undifferentiated myogenic precursors forming the dermomyotome-like epithelium that surrounds the embryonic myotome. By contrast, M-cadherin, which was transcribed in the differentiating embryonic myotome, was never expressed in the dermomyotome-like epithelium. In late-stage trout embryos, M-cadherin transcript was only detected at the periphery of the expanding myotome, where muscle cells stemming from the N-cadherin positive dermomyotome-like epithelium differentiate. Collectively, our results support the view that, in trout embryo, N-cadherin is associated with muscle cell immaturity while M-cadherin is associated with muscle cell maturation and differentiation and this during the two successive phases of myogenesis.


Production of activins by the human endosalpinx.
Uterine tubes from 11 premenopausal and 6 postmenopausal women were collected and examined for the presence of inhibin, activin, and follistatin in the endosalpinx. Immunocytochemistry of tissue from both the isthmic and ampullary regions demonstrated clear staining for the beta(A)- and beta(B)-subunits that increased in intensity from the isthmus to the ampulla. Staining for follistatin showed a similar pattern, but no staining for the alpha-subunit was observed. Although staining for the beta(A)-subunit was seen in almost every epithelial cell, staining for the beta(B)-subunit was more variable. Western blotting showed a band with an apparent molecular mass of 28 kDa (corresponding to the activin dimer) and a band of approximately 60 kDa (corresponding to the pro-protein of activin). In situ hybridization confirmed the presence of mRNA for the beta(A)- and beta(B)-subunits in the endosalpinx. These results indicate that the endosalpinx is able to synthesize activin, not inhibin, suggesting that in premenopausal women they may have an important role in the biology of the developing embryo. The role in postmenopausal women is less certain, but could lead to the stimulation of FSH secretion by the pituitary gland or other autocrine/paracrine function within the uterine tube.


Gain of chromosome arm 1q in patients in relapse and progression of multiple myeloma.
Abnormalities of chromosome 1 are among the most frequent chromosomal aberrations in patients with multiple myeloma (MM) and are considered a poor-risk genetic feature. To define the frequency and minimal region of 1q gain, we performed immunophenotyping and fluorescence in situ hybridization, comparative genomic hybridization (CGH), and array-CGH in 30 patients in relapse and progression of MM. Gain of 1q21 was found in 15 patients (50%), and in 14 of them whole-arm gain was found. One of these 14 patients had trisomy of chromosome 1 together with whole arm 1q gain, and two others had segmental duplication together with whole arm 1q gain. Segmental duplication of 1q21.1 approximately q23.1 alone was found in one patient. These results confirmed a high frequency of 1q aberrations and revealed that the vast majority of patients with 1q aberration in relapse and progression of MM display whole arm 1q gain. Finally, we observed that 1q gain is highly associated with number of additional changes.


Research hotspots and emerging trends of deep learning applications in orthopedics: A bibliometric and visualized study.
As a research hotspot, deep learning has been continuously combined with various research fields in medicine. Recently, there is a growing amount of deep learning-based researches in orthopedics. This bibliometric analysis aimed to identify the hotspots of deep learning applications in orthopedics in recent years and infer future research trends. We screened global publication on deep learning applications in orthopedics by accessing the Web of Science Core Collection. The articles and reviews were collected without language and time restrictions. Citespace was applied to conduct the bibliometric analysis of the publications. A total of 822 articles and reviews were finally retrieved. The analysis showed that the application of deep learning in orthopedics has great prospects for development based on the annual publications. The most prolific country is the USA, followed by China. University of California San Francisco, and Skeletal Radiology are the most prolific institution and journal, respectively. LeCun Y is the most frequently cited author, and Nature has the highest impact factor in the cited journals. The current hot keywords are convolutional neural network, classification, segmentation, diagnosis, image, fracture, and osteoarthritis. The burst keywords are risk factor, identification, localization, and surgery. The timeline viewer showed two recent research directions for bone tumors and osteoporosis. Publications on deep learning applications in orthopedics have increased in recent years, with the USA being the most prolific. The current research mainly focused on classifying, diagnosing and risk predicting in osteoarthritis and fractures from medical images. Future research directions may put emphasis on reducing intraoperative risk, predicting the occurrence of postoperative complications, screening for osteoporosis, and identification and classification of bone tumors from conventional imaging.


Rectal Carriage of Extended-Spectrum-Beta-Lactamase-Producing Enterobacteriaceae in Hospitalized Patients: Selective Preenrichment Increases Yield of Screening.
This study evaluated the added value of selective preenrichment for the detection of rectal carriage of extended-spectrum-beta-lactamase-producing Enterobacteriaceae (ESBL-E). ESBL-E rectal carriage was identified in 4.8% of hospitalized patients, and 25.9% of ESBL-E rectal carriers were identified with selective preenrichment only.


Influx of extracellular Ca2+ is necessary for electrotaxis in Dictyostelium.
Intracellular free Ca2+ ([Ca2+](i)) is a pivotal signalling element in cell migration and is thought to be required for chemotaxis of Dictyostelium. Ca2+ signalling may also be important for electrotaxis. However this suggestion has been controversial. We show that electric fields direct Dictyostelium cells to migrate cathodally and increase [Ca2+](i) in Dictyostelium cells, as determined by Fluo-3 AM imaging and (45)Ca2+ uptake. Omission of extracellular Ca2+([Ca2+](e)) and incubation with EGTA abolished the electric-field-stimulated [Ca2+](i) rise and directional cell migration. This suggests a requirement for [Ca2+](e) in the electrotactic response. Deletion of iplA, a gene responsible for chemoattractant-induced [Ca2+](i) increase, had only a minor effect on the electric-field-induced [Ca2+](i) rise. Moreover, iplA-null Dictyostelium cells showed the same electrotactic response as wild-type cells. Therefore, iplA-independent Ca2+ influx is necessary for electrotactic cell migration. These results suggest that the [Ca2+](i) regulatory mechanisms induced by electric fields are different from those induced by cAMP and folic acid in Dictyostelium cells. Different roles of the iplA gene in chemoattractant-induced and electrically induced Ca2+ signalling, and different effects of [Ca2+](i) elevation on chemotaxis and electrotaxis indicate that the chemoattractant and electric cues activate distinctive initial signalling elements.


Establishing reference intervals for von Willebrand factor multimers.
von Willebrand factor (VWF) multimers (VWF:MM) methodologies are technically difficult, laborious, time consuming, non-standardized and results vary between laboratories. A new semi automated VWF:MM assay is available for routine use (Sebia). Due to lack of reference values for VWF:MM fractions, results interpretation can be challenging in some cases. The aim of this study was to determine reference intervals for low molecular weight (LMWM), intermediate molecular weight (IMWM) and high molecular weight (HMWM) multimers. By the international cooperation initiated between 4 countries (Estonia, Latvia, France, and USA) 131 samples of relatively healthy individuals were analyzed for VWF:MM (in total 51 males and 80 non-pregnant females aged 17-69 years). Reference intervals were calculated according to CLSI C28-A3 standard. The proposed reference intervals for VWF:MM were calculated for LMWM 10.4-22.5%, IMWM 22.6-37.6%, HMWM 45.6-66.6%. Age related differences were seen in IMWM and HMWM (p<0.001 and 0.038). There was no gender related difference observed. Geographically LMWM results of France were different from the other regions (p<0.05). Quantification of VWF:MM fractions, in addition to qualitative assessment of VWF:MM patterns, has the potential to aid in differential diagnosis of von Willebrand disease (VWD) subtypes. The reference values calculated in this study can be used in future research to establish clinical decision limits.


Analysis of volatile organic compounds in indoor environments using thermal desorption with comprehensive two-dimensional gas chromatography and high-resolution time-of-flight mass spectrometry.
Building-related health effects are frequently observed. Several factors have been listed as possible causes including temperature, humidity, light conditions, presence of particulate matter, and microorganisms or volatile organic compounds. To be able to link exposure to specific volatile organic compounds to building-related health effects, powerful and comprehensive analytical methods are required. For this purpose, we developed an active air sampling method that utilizes dual-bed tubes loaded with TENAX-TA and Carboxen-1000 adsorbents to sample two parallel air samples of 4 L each. For the comprehensive volatile organic compounds analysis, an automated thermal desorption comprehensive two-dimensional gas chromatography high-resolution time-of-flight mass spectrometry method was developed and used. It allowed targeted analysis of approximately 90 known volatile organic compounds with relative standard deviations below 25% for the vast majority of target volatile organic compounds. It also allowed semiquantification (no matching standards) of numerous nontarget air contaminants using the same data set. The nontarget analysis workflow included peak finding, background elimination, feature alignment, detection frequency filtering, and tentative identification. Application of the workflow to air samples from 68 indoor environments at a large hospital complex resulted in a comprehensive volatile organic compound characterization, including 178 single compounds and 13 hydrocarbon groups.


Exploration of the regulatory mechanisms of regeneration, anti-oxidation, anti-aging and the immune response at the post-molt stage of Eriocheir sinensis.
Eriocheir sinensis is widely appreciated by the surrounding population due to its culinary delicacy and rich nutrients. The E. sinensis breeding industry is very prosperous and molting is one of the important growth characteristics. Research on the regulation of molting in E. sinensis is still in the initial stages. There is currently no relevant information on the regulatory mechanisms of heart development following molting. Comparative transcriptome analysis was used to study developmental regulation mechanisms in the heart of E. sinensis at the post-molt and inter-molt stages. The results indicated that many regulatory pathways and genes involved in regeneration, anti-oxidation, anti-aging and the immune response were significantly upregulated after molting in E. sinensis. Aside from cardiac development, the differentially expressed genes (DEGs) were relevant to myocardial movement and neuronal signal transduction. DEGs were also related to the regulation of glutathione homeostasis and biological rhythms in regard to anti-oxidation and anti-aging, and to the regulation of immune cell development and the immune response. This study provides a theoretical framework for understanding the regulation of molting in E. sinensis and in other economically important crustaceans.


[Cellular culture of osteoblasts and fibroblasts on porous calcium-phosphate bone substitutes].
Calcium phosphate ceramics are synthetic bone substitutes able to fill in bone destruction as a support of the bone growth. This work consisted in an in vitro assessment of osteoblasts and fibroblasts cultures on macroporous calcium-phosphate bone substitutes to analyze the interaction between cells and bone substitute. The macroporous ceramic was composed of 70% hydroxyapatite and 30% tri-calcium phosphate with known mechanical and physico-chemical properties. Three compounds were processed with different size of macropore and with or without microporosity on their surface. Cells were seeded on discs measuring 10 mm in diameter and 2 mm in thickness. Cellular viability was evaluated by the MTT test for every stage of observation. An histological study to observe the invasion in the depth of discs was performed. Scanning electron microscopy was used to analyze the cellular comportment in contact with the surface of substitutes. An exponential cellular growth was effective on each substitute with the two cellular types. Cells spread on the surface of the compounds covering macropores and colonized the depth of the discs. A size of macropore of 300 microm or more seemed to support this invasion. 15 microm sized interconnections appeared to be effective to allow cell migration between macropores. The cell proliferation was similar on substitutes with or without microporosity. Biomaterials currently used as bone substitute are more or less osteoconductive but they have no osteoinductive property. A hybrid association of calcium-phosphate ceramic with osteogenic cells should promote the development of a calcium phosphate compound with osteoinductive capacity.


Emojis in public health and how they might be used for hand hygiene and infection prevention and control.
Emojis are frequently used picture characters known as possible surrogates for non-verbal aspects of behavior. Considering the ability of emojis to enhance and facilitate communication, there has been a growing interest in studying their effects in scientific and health-related topics over the past few years. Infection prevention and control (IPC) is a field of medicine that is directly associated with specific behaviors. These include hand hygiene, which is the cornerstone of the prevention of healthcare-associated infections, and essential in stemming the spread of antimicrobial resistance. This paper aims to provide an overview of how emojis have been used in the medical and public health literature and proposes their possible use in IPC and hand hygiene to put forth a vision for the future research.


Functional Status Following Pulmonary Rehabilitation: Responders and Non-Responders.
The 6 min walking test (6MWT) has been largely studied. Less is, however, known about responders and non-responders to pulmonary rehabilitation (PR) in other meaningful activities. We explored responders and non-responders and the predictors of response to PR in the 1 min sit-to-stand test (1 min STS) and the 6MWT and compared both measures in classifying responders. An observational study was conducted with 121 people with chronic obstructive pulmonary disease (COPD). The functional status was assessed before and after PR. Baseline differences between responders and non-responders were tested with Mann-Whitney U, chi-square, or Fisher exact tests. Predictors were explored with binary logistic regressions. Agreement between both measures was assessed with chi-square, Cohen's kappa, and McNemar tests. There were 54.5% and 57.0% of responders in the 1 min STS and the 6MWT, respectively. The proportion of responders was significantly different (p = 0.048), with a small agreement between the measures (kappa = 0.180; p = 0.048). The baseline 6MWT was the only significant predictor of response in the 6MWT (OR = 0.995; pseudo-r2 = 0.117; p < 0.001). No significant predictors were found for the 1 min STS. A large number of non-responders in terms of functional status exist. The 1 min STS and the 6MWT should not be used interchangeably. Future studies should explore the added benefit of personalizing PR to this outcome and investigate other potential predictors.


The effect of posterior sagittal anorectoplasty and its variants on lower urinary tract function in children with anorectal malformations.
The effect of posterior sagittal anorectoplasty (PSARP) and its variants on lower urinary tract function was investigated urodynamically in 32 patients with anorectal malformations. In 27 patients urodynamic evaluation was performed before and after surgery and in 4 it was done postoperatively only. One child was clinically assessed with no postoperative urodynamic study. Minor postoperative changes in the specific preoperative urodynamic pattern were observed in 4 cases but the changes did not seem to be related to surgery. In 3 boys with rectourethral fistulas detrusor failure consistent with autonomic denervation was noted postoperatively. Standard posterior sagittal anorectoplasty was performed in 1 of the 3 boys and posterior sagittal anorectoplasty combined with additional transabdominal procedures was done in the other 2. In general our findings suggest that posterior sagittal anorectoplasty and its variants do not affect lower urinary tract function unless these surgical techniques are combined with major transabdominal procedures and extensive retrovesical dissection.


Ionic currents and firing patterns of mammalian vagal motoneurons in vitro.
The electrophysiological properties of guinea-pig dorsal vagal motoneurons were studied in an in vitro slice preparation. Antidromic, orthodromic and direct stimulation of the neurons demonstrated that the action potential is comprised of several distinct components: a fast initial spike followed by afterdepolarization and an early and a late afterhyperpolarizations. The fast initial spike and the early afterhyperpolarization were blocked by tetrodotoxin and tetraethylammonium ions, respectively. The afterdepolarization (present on the falling phase of the spike) and the late afterhyperpolarization were blocked by the addition of ions known to block calcium conductance (CdCl2, CoCl2 or MnCl2), indicating close association between these two potentials. Prolonged outward current injection through the recording electrode produced two different firing patterns, depending on the initial level of the membrane potential. From resting potential (usually -60 mV) the firing pattern was characterized by a short train of action potentials appearing shortly after the onset of the depolarization step. By contrast, when the depolarization was delivered from a hyperpolarized membrane potential level, a short train of repetitive firing appeared after an initial delay of 300-400 ms. The membrane current responsible for this initial reduction in excitability was studied by means of a single-electrode voltage-clamp technique. The magnitude, direction and kinetics of such current flow are consistent with the presence of early potassium current (IA), partly inactive at the resting potential. Synaptic activation of vagal motoneurons could be obtained by electrical stimulation of the tissue surrounding the vagal nucleus or by direct activation of the vagal nerve. Perivagal stimulation generated excitatory and inhibitory synaptic potentials which could be reversed by shifting the membrane potential. Vagal nerve stimulation, in addition to the antidromic activation of the cells, generated depolarizing responses which were unitary in nature and did not show much sensitivity to shifts in membrane potential. Perivagal and vagal nerve-evoked depolarizations could generate action potentials as well as partial dendritic spikes. We conclude that spike electroresponsiveness in vagal motoneurons is generated by voltage-dependent Na+ and Ca2+ conductances. In addition, the Ca2+-dependent current triggers a K+ conductance which is responsible for modulating the firing frequency obtained from the normal resting level.(ABSTRACT TRUNCATED AT 400 WORDS)


Plasma Exchange May Enhance Antitumor Effects by Removal of Soluble Programmed Death-Ligand 1 and Extracellular Vesicles: Preliminary Study.
The antitumor effect of antibody-drug conjugates (ADC) is the main factor in achieving cures. Although the mechanism of tumor resistance to treatment is multifaceted, tumor-derived extracellular vesicles (T-EVs) have been implicated as contributing to the attenuation of ADC therapeutic efficacy. Thus, strategies to eliminate T-EVs are highly promising for overcoming drug resistance. Here we demonstrate plasma exchange therapy to remove T-EVs, decreasing their amount in vitro by 75%. Although trastuzumab emtansine (T-DM1) treatment alone was effective in our rat tumor model, the combination therapy of T-DM1 and T-EV filtration achieved early tumor shrinkage. Our results indicate that T-EV filtration plus ADC is a promising strategy for overcoming drug resistance.


Correlated magnetic states in extended one-dimensional defects in graphene.
Ab initio calculations indicate that while the electronic states introduced by tilt grain boundaries in graphene are only partially confined to the defect core, a translational grain boundary introduces states near the Fermi level that are very strongly confined to the core of the defect, and display a ferromagnetic instability. The translational boundary lies along a graphene zigzag direction and its magnetic state is akin to that which has been theoretically predicted to occur on zigzag edges of graphene ribbons. Unlike ribbon edges, the translational grain boundary is fully immersed within the bulk of graphene, hence its magnetic state is protected from the contamination and reconstruction effects that have hampered experimental detection of the magnetic ribbon states. Moreover, our calculations suggest that charge transfer between grain boundaries and the bulk in graphene is short ranged, with charge redistribution confined to ~5 Å from the geometric center of the 1D defects.


Atypical IgM multiple myeloma with deletion of c-MAF.
IgM multiple myeloma (MM) is a rare subtype of myeloma that shares clinical and pathological features with Waldenström's macroglobulinaemia. These are two separate entities that differ both in therapy and prognosis. We report a 57-year-old male, who presented with anaemia, hypercalcaemia, acute renal failure and several vertebral fractures that clinically suggested a multiple myeloma. Further investigations revealed a serum monoclonal component of IgM lambda type and a bone marrow infiltrated by small, lymphoplasmocytic cells. IgM MM was finally diagnosed by means of both inmunophenotypic and immunohistochemistry techniques, stressing the importance of inmunophenotypic evaluation when clinical and morphological features are discordant. Fluorescence in situ hybridization (FISH) studies disclosed a particular combination of deletion 13q14, t(11;14) and monoallelic deletion C-MAF without t(14;16). The clinical evolution after a Bortezomib-containing polychemotherapy and autologous stem cell transplantation (ASCT) conditioned with busulphan and melphalan is also presented. This very uncommon case highlights the impact of immunophenotyping on the differential diagnosis between IgM MM and WM, to choose the best treatment and establish an appropriate outcome.