ICI 182,780 penetrates brain and hypothalamic tissue and has functional effects in the brain after systemic dosing.
Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg.d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 alpha-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg.d) dose dependently inhibited this effect. ICI (3.0 mg/kg.d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg.d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg.d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.


Hydrolysis of lactose in skim milk by immobilized beta-galactosidase (bacillus circulans).
A novel chemical reactor, consisting of beta-galactosidase from Bacillus circulans immobilized onto a ribbed membrane made from polyvinylchloride and silica, was used to hydrolyze the lactose constituent of skim milk. Multiresponse nonlinear regression methods were employed to determine the kinetic parameters of rate expressions based on a proposed enzymatic mechanism that includes the formation of oligosaccharides. High-performance liquid chromatography (HPLC) methods were employed to monitor the concentrations of all species present in the effluent stream. For the experimental conditions used in this research, rate expressions which include the formation of trisaccharides, the inhibition effects of both the alpha and beta anomers of galactose, and the corresponding mutarotation reaction are sufficient to model the reaction network.


Gamma-amido-ATP stabilizes a high-fluorescence state of myosin subfragment 1.
On binding to myosin subfragment 1 (S1), the gamma-amido derivative of ATP (ATPgammaNH2), an isomer of adenosine 5'-[beta,gamma-imido]-triphosphate (AMPPNP), induces a larger increase in the intrinsic (tryptophan) fluorescence than is seen with ATP. A binding constant of 1.7x10(7) M(-1) was measured for ATPgammaNH2, compared to 2.1-2.4x10(7) M(-1) for AMPPNP. ATPgammaNH2 was hydrolyzed only very slowly by S1. ATPgammaNH2 appears to stabilize the 'closed' conformation of S1, and does so without cleavage of the beta-gamma phosphate bond. The dissociation of actin-S1 by ATPgammaNH2 and that of S1.ATPgammaNH2 by actin are both strikingly slow.


Impact of elective frozen vs. fresh embryo transfer strategies on cumulative live birth: Do deleterious effects still exist in normal & hyper responders?
Is freeze-all strategy effective in terms of cumulative live birth rates (CLBRs) in all patients? This retrospective single-center study analyzed the CLBRs of 2523 patients undergoing fresh or electively frozen blastocyst transfer cycles. In 1047, cycles, the fresh embryo transfer (ET) strategy was applied for the 1st ET, whereas electively frozen ET (e-FET) was performed in 1476 cycles. Female age ≤ 37 and blastocysts frozen via vitrification were included. The patients in each arm were further stratified into four subgroups according to the number of oocytes retrieved as follows: Group A: 1-5, group B: 6-10, group C: 11-15 and group D: 16-25 oocytes retrieved. The primary endpoint was the CLBR. The secondary endpoints were the ovarian hyperstimulation syndrome (OHSS) rate and the live birth rates (LBRs) following fresh ETs and e-FETs for the first transfers. The CLBR was similar between the fresh ET and e-FET arms in group A (35/76 (46.1%) vs 29/67 (43.3%), p = 0.74) and group B (165/275 (60%) vs 216/324 (66.7%), p = 0.091), whereas significantly higher rates were detected in favor of the e-FET arm within group C (328/460 (71.3%) vs 201/348 (57.8%), p<0.001) and group D (227/348 (65.2%), vs 446/625 (71.5%), p<0.001). The OHSS rate was also found to be higher in the fresh ET arm among group C (12/348 (3.4%) vs 0/460 (0%), p<0.001) and group D (38/348 (10.9%) vs 3/625 (0.5%), p<0.001) patients than e-FET arm. Perinatal and obstetrical outcomes were nonsignificantly different between fresh and e-FET arms. However, the birth weights were significantly lower for fresh ET, 3064 versus 3201 g for singletons (p<0.001). Compared with a fresh-transfer strategy, the e-FET strategy resulted in a higher CLBR among patients with >10 oocytes retrieved during stimulated cycles.


A cryptic, intergeneric cytochrome c oxidase I pseudogene in tyrant flycatchers (family: Tyrannidae).
Nuclear mitochondrial pseudogenes, or "numts", are nonfunctional copies of mitochondrial genes that have been translocated to the nuclear genome. Numts have been used to study differences in mutation rates between the nuclear and mitochondrial genomes, but have also been implicated as troublesome for phylogenetic studies and DNA-based species identification (i.e., DNA barcoding). In this study, a suspected numt discovered during a study of mitochondrial cytochrome c oxidase I (COI) diversity in North American birds was targeted and sequenced from tyrant flycatchers (family: Tyrannidae). In total, the numt was found in five taxa representing two genera. Substitution rates were compared between COI and numt sequences. None of the numt sequences harboured stop codons nor frameshift mutations, but phylogenetic analysis revealed they had accumulated more amino acid substitutions than the mitochondrial COI sequences. Mitochondrial COI appeared to be preferentially amplified in most cases, but methods for numt detection are discussed for cases like this where sequences lack obvious features for identification. Because of its persistence across a broad taxonomic lineage, this numt could form a valuable model system for studying evolution in numts. The full size of the numt and its location within the nuclear genome are yet to be determined.


Prospects of glove-box versus air-processed organic solar cells.
In the search for alternate green energy sources to offset dependence on fossil fuels, solar energy can certainly meet two needs with one deed: fulfil growing global energy demands due to its non-depletable nature and lower greenhouse gas emissions. As such, third generation thin film photovoltaic technology based organic solar cells (OSCs) can certainly play their role in providing electricity at a competing or lower cost than 1st and 2nd generation solar technologies. As OSCs are still at an early stage of research and development, much focus has been placed on improving power conversion efficiencies (PCEs) inside a controlled environment i.e. a glove-box (GB) filled with an inert gas such as N2. This was necessary until now, to control and study the local nanomorphology of the spin-coated blend films. For OSCs to compete with other solar energy technologies, OSCs should produce similar or even better morphologies in an open environment i.e. air, such that air-processed OSCs can result in similar PCEs in comparison to their GB-processed counterparts. In this review, we have compared GB- vs. air-processed OSCs from morphological and device physics aspects and underline the key features of efficient OSCs, processed in either GB or air.


Glasgow Coma Scale is unreliable for the prediction of severe head injury in elderly trauma patients.
Elderly patients comprise an ever-increasing proportion of major trauma patients. The presenting GCS in elderly patients with traumatic brain injury (TBI) may not reflect the severity of injury as accurately as it does in the younger patient population. However, GCS is often used as part of the decision tool to define the population transferred directly to a major trauma centre. The aim of this study was to explore the relationship between age and presenting GCS in patients with isolated TBI. A retrospective database review was undertaken using the Trauma Audit and Research Network database. All patients presenting to Derriford Hospital, Plymouth, between 1 January 2009 and 31 May 2014 with isolated TBI were included. Demographic, mechanistic, physiological, resource use and outcome data were collected. Abbreviated injury scale (AIS) was recorded for all patients. Patients were categorised into those older and younger than 65 years on presentation. Distribution of GCS, categorised into severe (GCS 3-8), moderate (GCS 9-12) and mild TBI (13-15), was compared between the age groups. Median GCS at each AIS level was also compared. The distribution of GCS differed between young and old patients with TBI (22.1% vs 9.8% had a GCS 3-8, respectively) despite a higher burden of anatomical injury in the elderly group. Presenting GCS was higher in the elderly at each level of AIS. The difference was more apparent in the presence of more severe injury (AIS 5). Elderly patients who have sustained isolated severe TBI may present with a higher GCS than younger patients. Triage tools using GCS may need to be modified and validated for use in elderly patients with TBI.


Cytokine mRNA quantification in duodenal mucosa from dogs with chronic enteropathies by real-time reverse transcriptase polymerase chain reaction.
The pathogenesis of inflammatory bowel disease (IBD) and antibiotic-responsive diarrhea (ARD) in dogs likely involves an interaction between the intestinal immune system and luminal bacterial or food antigens. German Shepherd Dogs (GSD) are particularly predisposed to both IBD and ARD. CD4+ T cells are important for the regulation of immune responses in the mucosa, and they exert their effects through the secretion of cytokines. The present study examined the role of cytokines in the pathogenesis of canine chronic enteropathies by quantification of mRNA encoding interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, interferon gamma, tumor necrosis factor-alpha, transforming growth factor-beta, and glyceraldehyde-3-phosphate dehydrogenase by real-time reverse transcriptase polymerase chain reaction in duodenal mucosal biopsies obtained from 39 dogs with chronic diarrhea and 18 control dogs. Contemporaneously collected biopsies were assessed for histologic changes with a 4-point grading system. No significant difference in the expression of cytokine mRNA (P > .01) was detected between dogs with and those without chronic diarrhea. Similarly, no significant differences in cytokine mRNA expression were observed between GSD and other breeds with chronic diarrhea, or between histologically normal duodenal mucosa and that with evidence of inflammatory change. Failure to detect a difference in mRNA expression does not rule out the possibility of a defect downstream at the level of translation or protein function. No conclusion can be drawn from these data as to the predominant CD4+ cell type in the pathogenesis of these canine chronic enteropathies.


Yang needle tunneling technique in creating antireflux and continent mechanisms.
A total of 7 patients underwent cystectomy due to bladder malignancy and the ileum was used for lower urinary tract reconstruction (5 underwent bladder substitutions, 1 an internal ileal reservoir and 1 ileal conduit diversion). Antireflux mechanisms were created by submucosally tunneled ureters and in 1 case the continent mechanism was created by a submucosally tunneled ileal tube. In all cases the Yang needle was used, which consists of a needle portion and a forceps portion. The selected position of the ileum for ureteral and ileal tube implantation is injected with normal saline submucosally to form a wheal. The Yang needle is introduced submucosally, guided under the wheal for a certain distance and then directed through the ileal wall. Smooth dilation of the tunnel is achieved with the dilated portion of the needle without laceration of the mucosa. The needle portion is then removed. The ureter or ileal tube is grasped by the forceps portion of the needle and brought through the tunnel to the mucosal side of the ileal plate, followed by mucosa-to-mucosa anastomosis. For all 14 ureteral implantations only 1 ureter had reflux on postoperative radiographic studies and only 1 of 4 hydroureters remained. No additional obstructive lesions or pyelonephritis was noted postoperatively. The patient whose continent mechanism is formed by the submucosal tunneled ileal tube method is continent and free of an appliance. The Yang needle tunneling technique may be a choice in the creation of antireflux and continent mechanisms.


Final Posttreatment Occlusion in Patients With Unilateral Cleft Lip and Palate.
To evaluate final posttreatment occlusion in patients with complete unilateral cleft lip and palate (cUCLP) by comparing (1) 3 treatment centers, (2) males and females, (3) cleft and noncleft sides, (4) right- and left-sided clefts, and (5) orthodontic treatment with/without orthognathic surgery (OS). Retrospective cohort study. Blinded posttreatment dental casts of 56 patients (19.4 ± 1.4 years) with cUCLP from 3 centers in Switzerland. Occlusal assessment using the modified Huddart/Bodenham (MHB) index. Our sample comprised 35 males and 21 females, 46 with left- and 10 with right-sided clefts, of which 32 had undergone OS. The final posttreatment occlusion showed a median MHB score of 0 (interquartile range: -1.0 to 2.0) in the total sample and did not seem to depend on treatment center, sex, or OS. The MHB scores for the anterior buccal and the buccal segments were more negative on the cleft than on the noncleft side (P = .002 and P = .006, respectively). When the cleft was on the left side, the MHB score tended to be more positive in the labial (P = .046) and anterior buccal segments (P = .034). This study shows a very satisfactory final posttreatment occlusion in patients with cUCLP. The more constricted buccal occlusion on the cleft side emphasizes the attention that should be given in correcting the more medially positioned lesser maxillary segment. The influence of cleft-sidedness should be analyzed further on a sample including more patients with right-sided clefts.


Role of cortisol in patients at risk for psychosis mental state and psychopathological correlates: A systematic review.
During recent decades, much evidence has been accumulated concerning the neuroendocrine basis of schizophrenia. Recently, research has focused on stress hormones, with cortisol being the most widely researched, during the prodromal phase of psychosis. Thus, the present study aims to systematically review the evidence concerning the role of cortisol in patients at risk for psychosis mental state and its associations with psychopathological correlates. We systematically reviewed the published reports referring to both 'at clinical risk for psychosis' and 'at genetic risk for psychosis' mental state. Sixteen studies were identified. A trend towards increased cortisol levels in saliva emerged. Findings concerning cortisol levels in the blood were minimal and less consistent. The longitudinal studies, though with divergent results, hinted towards upregulation of cortisol secretion prior to psychotic conversion. Regarding cortisol's reactivity, evaluated through neuroendocrine, psychosocial and naturalistic stressors, the findings were minimal and divergent. The hypothesized relation of psychotic symptomatology with cortisol in subjects at risk for psychosis was not confirmed by the majority of the studies. On the contrary, the anxiety parameter and stress-intolerance index were both positively associated with cortisol. In conclusion, the published reports related to the evaluation of cortisol levels/function at prodrome are hitherto minimal. Although the evidence favors cortisol's participation in the pathophysiology of psychosis, the exact cause-effect sequence and the intertwining of cortisol with psychopathology are still unclear.


Complete Genome Sequence of an Avian Metapneumovirus Subtype A Strain Isolated from Chicken (Gallus gallus) in Brazil.
We report here the complete genome sequence of an avian metapneumovirus (aMPV) isolated from a tracheal tissue sample of a commercial layer flock. The complete genome sequence of aMPV-A/chicken/Brazil-SP/669/2003 was obtained using MiSeq (Illumina, Inc.) sequencing. Phylogenetic analysis of the complete genome classified the isolate as avian metapneumovirus subtype A.


Postoperative Bleeding after Thyroid Surgery: Care Instructions.
Prospective studies on the incidence, etiology, and prognosis of well-characterized patients with bleeding after thyroid surgery are lacking. Bleeding after thyroid surgery cannot be predicted or prevented even if risk factors are known in every single procedure, which enhances the im-portance of the following issues: (a) meticulous hemostasis and surgical technique; (b) coopera-tion with the anesthesiologist, i.e., controlling the Valsalva maneuver, adequate blood pressure at the end of the operation as well as at extubation phase and (c) in case of bleeding, a prompt management to guarantee a better outcome. This requires an intensive postoperative clinical monitoring of patients, ideally, in a recovery room with trained staff for at least 4-6 h. Early recognition of postoperative bleeding with immediate intervention is the key to the management of this complication.


Percutaneous treatment of lumbar intervertebral disk hernias with radiopaque gelified ethanol: a preliminary study.
Prospective clinical trial. Demonstrate the safety and efficacy of gelified ethanol in the percutaneous treatment of lumbar disk hernias. After the commercial withdrawal of Chymopapain, the need for new substances to treat intervertebral disk hernias was evident. Good results were obtained with pure ethanol, but this substance was difficult to handle. We decided to use a similar substance mixed with ethylcellulose to increase its viscosity and enhanced with radiopaque material. Two hundred seventy-six consecutive patients sent to be treated of a lumbar intervertebral disk hernia percutaneously were included in this preliminary study and treated with radiopaque gelified ethanol (RGE) and intra-articular steroids. Three groups were set, group A for patients to be treated only with RGE and groups B and C for difficult cases presenting a narrow canal, foraminal hernia, or hiperalgic sleepless hernia, treated with RGE plus another intradiscal technique, automatized percutaneous diskectomy for group B and radiofrequency nucleoplasty for group C. Very good or good results were obtained in 202 (91.4%) of the 221 patients in group A. Of the 44 patients in group B, 37 patients (84%) presented very good or good results and in 9 (82%) of the 11 patients of group C, we obtained similar results. There was no allergic complication in any of our patients. Short-term follow-up with magnetic resonance showed little or no changes in the intervertebral disk but there was discordance with clinical signs. Long-term follow-up magnetic resonance showed a dramatic reduction in hernia volume. This preliminary study shows the efficacy and inocuity of this new substance that could take over the Chymopapain therapeutic field.


Construction and analyses of human large-scale tissue specific networks.
Construction and analyses of tissue specific networks is crucial to unveil the function and organizational structure of biological systems. As a direct method to detect protein dynamics, human proteome-wide expression data provide an valuable resource to investigate the tissue specificity of proteins and interactions. By integrating protein expression data with large-scale interaction network, we constructed 30 tissue/cell specific networks in human and analyzed their properties and functions. Rather than the tissue specificity of proteins, we mainly focused on the tissue specificity of interactions to distill tissue specific networks. Through comparing our tissue specific networks with those inferred from gene expression data, we found our networks have larger scales and higher reliability. Furthermore, we investigated the similar extent of multiple tissue specific networks, which proved that tissues with similar functions tend to contain more common interactions. Finally, we found that the tissue specific networks differed from the static network in multiple topological properties. The proteins in tissue specific networks are interacting looser and the hubs play more important roles than those in the static network.


Biomarkers predicting chemotherapy response in head and neck squamous cell carcinoma: a review.
Biomarkers are increasingly being used in many cancers to select patients for oncological treatment paradigms based on their inherent genetic properties. However, in head and neck cancers, there are no personalised therapies available outside the context of a clinical trial. A number of studies suggest there are intrinsic tumour properties of head and neck cancers that affect their response to chemotherapeutic agents. This paper aimed to review their evidence base. A narrative review was conducted following a search of the PubMed database. The review identified a number of biomarkers predicting response to chemotherapy in head and neck cancers. The paper discusses these in detail, and explores where future research could be directed in order to deliver personalised therapies for patients with head and neck cancers.


Partial retro-inverso, retro, and inverso modifications of hydrazide linked bifunctional peptides for opioid and cholecystokinin (CCK) receptors.
Partially modified retro-inverso, retro, and inverso isomers of hydrazide linked bifunctional peptides were designed, synthesized, and evaluated for bioactivities at delta/mu opioid receptors and CCK-1/CCK-2 receptors. All modifications of the CCK pharmacophore moiety affected bioactivities for the CCK-1 and CCK-2 receptors (up to 180-fold increase in the binding affinity with higher selectivity) and for the delta and mu opioid receptors. The results indicate that the opioid and CCK pharmacophores in one molecule interact with each other to induce topographical changes for both pharmacophores.


Bile acid dysmetabolism in the gut-microbiota-liver axis under hepatitis C virus infection.
We recently analysed and reported the features of the micro biome under hepatitis C virus (HCV) infection, but the effect of HCV infection on bile acid (BA) metabolism in the gut-liver axis remains poorly understood. The aim of this study was to clarify the characteristics of the gut-liver axis in HCV-infected patients. The faecal BAs composition and gut microbiota from 100 chronic hepatitis C (CHC) patients were compared with those from 23 healthy individuals. For transcriptional analysis of the liver, 22 mild CHC (fibrosis stages [F] 0-2) and 42 advanced CHC (F3-4) cases were compared with 12 healthy individuals. The findings were confirmed using chimeric mice with human hepatocytes infected with HCV HCR6. Chronic hepatitis C patients, even at earlier disease stages, showed BA profiles distinct from healthy individuals, in which faecal deoxycholic acid (DCA) was significantly reduced and lithocholic acid or ursodeoxycholic acid became dominant. The decrease in faecal DCA was correlated with reduction in commensal Clostridiales and increase in oral Lactobacillales. Impaired biosynthesis of cholic acid (CA) was observed as a reduction in the transcription level of cytochrome P450 8B1 (CYP8B1), a key enzyme in CA biosynthesis. The reductions in faecal DCA and liver CYP8B1 were also observed in HCV-infected chimeric mice. Chronic hepatitis C alters the intestinal BA profile, in association with the imbalance of BA biosynthesis, which differs from the pattern in NAFLD. These imbalances appear to drive disease progression through the gut-microbiome-liver axis.


Desmoid Tumor Associated With Familial Adenomatous Polyposis: Evaluation With 64-Detector CT Enterography.
Desmoid tumors (DTs) are benign tumors which are not seen very often, and most of the radiologists and clinicians do not know the characteristics of them very well. Correct and early diagnosis of DTs is important for decreasing mortality and morbidity. Computed tomography enterography (CTE) is a new modality for small bowel imaging which combines the improved spatial and temporal resolution of multidetector computed tomography (CT) with large volumes of ingested enteric contrast material to permit evaluation of the small bowel wall and lumen and also the entire abdomen. We report a familial adenomatous polyposis (FAP) patient with localized mesentery and abdominal wall DTs. We showed the exact location of the DTs and their relation with the small bowel by CTE. In conclusion, CTE is a useful technique for DT localization, the degree of extension and invasion to local structures, presence of partial and complete small bowel obstruction, and the relationship of the tumors with vasculature and whether ischemia has occurred as a result or not.


Fish biophony in a Mediterranean submarine canyon.
Although several bioacoustics investigations have shed light on the acoustic communication of Mediterranean fish species, the occurrence of fish sounds has never been reported below -40 m depth. This study assessed the occurrence of fish sounds at greater depths by monitoring the soundscape of a Mediterranean submarine canyon (Calvi, France) thanks to a combination of Static Acoustic Monitoring (three stations, from -125 to -150 m depth, 3 km from coastline) and of hydrophone-integrated gliders (Mobile Acoustic Monitoring; from -60 to -900 m depth, 3-6 km from coastline). Biological sounds were detected in 38% of the audio files; ten sound types (for a total of more than 9.000 sounds) with characteristics corresponding to those emitted by vocal species, or known as produced by fish activities, were found. For one of these sound types, emitter identity was inferred at the genus level (Ophidion sp.). An increase of from 10 to 15 dB re 1 μPa in sea ambient noise was observed during daytime hours due to boat traffic, potentially implying an important daytime masking effect. This study shows that monitoring the underwater soundscape of Mediterranean submarine canyons can provide holistic information needed to better understand the state and the dynamics of these heterogeneous, highly diverse environments.


Selected aminoacridines as fluorescent probes in cytochemistry in general and in the detection of cancer cells in particular.
Since cellular features can be visualized by proper staining of the biologic substrate, the interactions between the biologic dye and the substrate provide the parameters for automated cell recognition. A stock of 295 acridines and 19 derivatives of anthracene were tested as possible new compounds suitable as fluorescent probes in cytochemistry. Special attention was focused on marking fixed and unfixed cancer cells exfoliated from various organs. The results confirmed observations about the strong metachromatic properties of 3-aminoacridines and 9-aminoacridines. 9-amino-4-methyl-acridine showed an exceptionally high fluorescence of basophilic cellular structures. In addition to 4-aminoacridine, many quinacrine analogues, acridines lacking amino groups, 2-aminoacridine and some benzoacridines stained lipid droplets. A great variability in staining viable nuclei was found. 3-aminoacridine was superior as a Schiff's reagent, even in comparison to acriflavine. Not only aminoacridines but also pyrazol-anthracenes showed valuable properties as fluorochromes. Some further compounds (for instance, 9-aminoacridines) were accumulated in cytoplasmic vacuoles in a manner similar to that of the acridine orange. It is hoped that some of these compounds will prove useful in marking cancer cells.


Integrating cognitive bias modification into a standard cognitive behavioural treatment package for social phobia: a randomized controlled trial.
The aim of the current study was to integrate recent developments in the retraining of attentional biases towards threat into a standard cognitive behavioural treatment package for social phobia. 134 participants (M age-32.4: 53% female) meeting DSM-IV criteria for social phobia received a 12-week cognitive behavioural treatment program. They were randomly allocated to receive on a daily basis using home practice, either an additional computerised probe procedure designed to train attentional resource allocation away from threat, or a placebo variant of this procedure. Measures included diagnostic severity, social anxiety symptoms, life interference, and depression as well as state anxiety in response to a laboratory social threat. At the end of treatment there were no significant differences between groups in attentional bias towards threat or in treatment response (all p's>0.05). Both groups showed similar and highly significant reductions in diagnostic severity, social anxiety symptoms, depression symptoms, and life interference at post-treatment that was maintained and in most cases increased at 6 month follow-up (uncontrolled effect sizes ranged from d=0.34 to d=1.90). The current results do not indicate that integration of information processing-derived attentional bias modification procedures into standard treatment packages as conducted in this study augments attentional change or enhances treatment efficacy. Further refinement of bias modification techniques, and better methods of integrating them with conventional approaches, may be needed to produce better effects.


A dihydro-β-agarofuran sesquiterpene from Maytenus boaria.
The natural compound (1S,4S,5S,6R,7R,8R,9R,10S)-6-acetoxy-4,9,10-trihydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepin-5-yl furan-3-carboxylate, C22H30O9, (I), is a β-agarofuran sesquiterpene isolated from the seeds of Maytenus boaria as part of a study of the secondary metabolites from Chilean flora. The compound presents a central structure formed by a decalin system esterified with acetate at site 1 and furan-3-carboxylate at site 9. The chirality of the skeleton can be described as 1S,4S,5S,6R,7R,8R,9R,10S, which is consistent with that suggested by NMR studies. Unlike previously reported structures of sesquiterpenes containing a pure dihydro-β-agarofuran skeleton, (I) exhibits a three-dimensional hydrogen-bonded network.


DNA polymerase alpha defect in the N syndrome.
The N syndrome is characterized by mental retardation, malformations, chromosome breakage, and development of T-cell leukemia (Opitz et al.: Proceedings of the II International Congress IASSMD pp 115-119, 1971; Hess et al.: Clinical Genetics 6:237-246, 1974b, American Journal of Medical Genetics [supplement] 3:383-388, 1987). N syndrome fibroblasts were studied to see if the high chromosome breakage rate associated with this apparently X-linked syndrome could be related to a deficiency of DNA polymerase alpha, a product of a gene localized to the X chromosome. Bleomycin, which is known to break double-stranded DNA, produced increased chromosome breakage in normal control, Fanconi anemia, and N syndrome fibroblasts. When aphidicolin was used to inhibit repair mediated by DNA polymerase alpha, both normal control and Fanconi anemia fibroblasts showed significantly more chromosome breakage than was produced by bleomycin alone, but there was no increase in the amount of breakage seen in the N syndrome fibroblasts over that seen with bleomycin alone. This suggests that the N syndrome is due to a mutation affecting the region of the X chromosome on which the gene for DNA polymerase alpha is located, and that the high risk of T-cell leukemia observed in the hemizygote is due to this DNA repair defect.


Influence of angular positioning of the prosthesis in stapes surgeries with a NiTiBond prosthesis: Investigation in cadaveric temporal bones.
In incus stapedotomy surgeries, the longitudinal direction of the piston prosthesis should ideally be perpendicular to the stapes footplate. However, in reality, some amounts of angular deviation of the prosthesis from the ideal angular position is unavoidable due to anatomical constraints and surgical conditions. This study aims to evaluate the influence of angular positioning of the prosthesis on surgical outcomes in incus stapedotomy and to provide surgical guidelines related to practical tolerance of the angular positioning. In this study, this influence was assessed with a Kurz NiTiBond prosthesis (0.4-mm diameter) and fenestra sizes of 0.5- and 0.6-mm diameter in cadaveric temporal bones (n = 7 including 2 preliminary tests). Angular position of the prosthesis relative to the footplate was modulated by rotating the stapes about the long and short axes of the footplate. At each angular position, the tympanic membrane was acoustically stimulated in the frequency range of 0.2-10 kHz, and motion of the prosthesis was measured using a Laser Doppler vibrometer (LDV). Furthermore, micro-computed tomography (micro-CT) data of the middle-ear ossicles were used for anatomical analysis of angular positioning of the prosthesis. The results showed that changes of angular position of the prosthesis relative to the stapes footplate do not cause significant changes of prosthesis motion until a certain angular position threshold, and sharply attenuate prosthesis motion when the angular position reaches the threshold. The threshold of the angular position, as the tilting angle of the prosthesis from the direction normal to the stapes footplate, was 26.9 ± 2.5° with the fenestration hole of 0.5-mm diameter and 30.6 ± 3.0° with the fenestration hole of 0.6-mm diameter (n = 5, p < 0.01 for difference between the two fenestra sizes). Analysis of the middle-ear anatomy in this study revealed that the tolerances of the angular positions of the prosthesis does not always cover possible positions of prosthesis crimping. This study suggests that if an anterior offset of the stapes head and/or the thickened footplate is suspected, efforts to locate prosthesis crimping closer to the tip of the incus and/or to make a sufficiently large fenestration hole are favorable.


Wavy regimes of film flow down a fiber.
We consider axisymmetric traveling waves propagating on the gravity-driven flow of a liquid down a vertical fiber. Our starting point is the two-equation model for the flow derived in the study by Ruyer-Quil et al. [J. Fluid Mech. 603, 431 (2008)]. The speed, amplitude, and shape of the traveling waves are obtained for a wide range of parameters by using asymptotic analysis and elements from dynamical systems theory. Four different regimes are identified corresponding to the predominance of four different physical effects: advection by the flow, azimuthal curvature, inertia, and viscous dispersion. Construction of the traveling-wave branches of solutions reveals complex transitions from one regime to another. A phase diagram of the different regimes in the parameter space is constructed.


Pleiotropic effects of UCP2-UCP3 variability on leucocyte telomere length and glucose homeostasis.
The rate of telomere-shortening has been widely reported as a marker of risk for age-related conditions and mortality in human population. Genetic, environmental and stochastic factors have been shown to influence telomere attrition. In particular oxidative stress has been reported to play an important role on the process. Uncoupling proteins (UCPs) are among the most important regulators of cellular metabolism and oxidative stress. Several authors investigated the association of UCP genetic variants with leucocyte telomere length (LTL) in both healthy and unhealthy (affected by diabetes) subjects, reporting contrasting results. We tested the influence of four SNPs falling in UCP2-UCP3 genomic region on LTL and glucose metabolism by analyzing these polymorphisms in a cohort of 457 subjects, in an age range 64-105 years. Among subjects younger than 85 years, homozygotes for the minor alleles at two UCP2 variants (rs659366-A and rs660339-T) showed shorter LTL respect to the other genotypes (pmodel = 0.024). In the same samples, AA-rs659366 genotype was found associated with lower haematological levels of Glycosylate Haemoglobyn (p = 0.012 and p = 0.022, respectively). Furthermore, rs659366-AA at UCP2 and rs15673-TT at UCP3 were correlated to diabetes in a small sub-group of patients. Results here presented suggest that UCP variability has different pleiotropic effects, by affecting both telomere length and glucose homeostasis, likely through an influence on energy metabolism and stress response.


Hypersensitive carotid sinus syndrome manifested as cough syncope.
We describe a patient with cough syncope who was found to have carotid sinus hypersensitivity with mixed cardioinhibitory and vasodepressor responses. Symptoms were ameliorated by denervation of the more hypersensitive carotid sinus. Spontaneous atypical Wenckebach cycles in this patient were caused by the combined hypersensitive cardioinhibitory and vasodepressor responses. This report stresses the importance of checking blood pressure as well as heart rate in all patients in whom carotid sinus syndrome is suspected.


Barriers and motivations to volunteers' participation in preventive vaccine trials: a systematic review.
The recruitment of volunteers in preventive vaccine trials (PVT) is a challenge, since vaccine hesitancy and debates on vaccines are combined to usual difficulties of enrollment in clinical trials. Areas covered: Current knowledge of the reasons leading to the volunteers' participation or non-participation in PVT mainly focuses on data from preventive HIV vaccine trials. A systematic PubMed search was conducted using PRISMA guidelines to identify articles or reviews that reported barriers and motivations to participation in PVT regardless of the targeted disease or population. Expert commentary: In view of the barriers and motivations reviewed here, improvements in recruitment could be made through a better explanation of the prevented disease, of the expected individual and collective benefit and of all ethical protective principles associated to the trials. Use of decision aids as well as patient and public involvement may improve given information and may enhance comprehension of participants and their participation in PVT. Further prospective and interventional studies are needed to analyze if these leads may improve acceptation level in PVT.


Virtual reality psychological intervention helps reduce preoperative anxiety in patients undergoing carotid artery stenting: a single-blind randomized controlled trial.
This study aimed to explore the effectiveness and applicability of a psychological intervention using virtual reality (VR) to reduce preoperative anxiety in patients undergoing carotid artery stenting (CAS). A total of 114 patients aged 18-86 years who were scheduled to undergo CAS were randomized to the VR and control groups. Patients in the VR group used a VR headset to view a 16-min psychological intervention video, while those in the control group used a tablet for viewing. The primary assessment instrument was the State Anxiety Inventory (S-AI), which was given 20 min before and after the intervention and 24 h after surgery. Secondary assessment tools were the Self-efficacy for Managing Chronic Disease (SEMCD-6) scale, which was completed before the intervention and 24 h after the operation, a smart bracelet to assess sleep quality, monitored in the evening before the operation, and the VR Suitability and Satisfaction Questionnaire, completed 24 h after the operation. The two groups were similar in terms of demographic information, preintervention STAI scores and preintervention SEMCD-6 scores (p > 0.05). S-AI scores were lower in both groups after the intervention and surgery, and the scores of the VR group were lower than those of the control group (p = 0.036, p = 0.014). SEMCD-6 scores post-surgery had improved in both groups, but the VR group had significantly higher scores than the control group (p = 0.005). Smart bracelet measurements showed no significant differences in postintervention sleep quality between the two groups (p = 0.540). For satisfaction, the VR group scored higher in all aspects except scheduling. A total of 47 (85.45%) patients reported having a comfortable experience, and only 5 (9.09%) experienced mild adverse effects. The use of a virtual reality psychological intervention was beneficial to reduce the anxiety of patients before CAS and improved their self-efficacy. As virtual reality devices evolve and demonstrate better comfort and safety, more comprehensive and in-depth research of the use of VR to reduce patient anxiety should be performed in the future.Clinical trial registration:https://www.chictr.org.cn/showproj.aspx?proj=186412, identifier ChiCTR2200066219.


Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.
Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutations of the SMN1 gene. SMN1 interacts with multiple proteins with functions in snRNP biogenesis, pre-mRNA splicing and presumably neural transport. SMN2, a nearly identical copy of SMN1, produces predominantly exon 7-skipped transcripts, whereas SMN1 mainly produces full-length transcripts. The SR-like splicing factor Htra2-beta1 facilitates correct splicing of SMN2 exon 7 through direct interaction with an exonic splicing enhancer within exon 7. In rare cases, siblings with identical 5q13-homologues and homozygous absence of SMN1 show variable phenotypes, suggesting that SMA is modified by other factors. By analysing nine SMA discordant families, we demonstrate that in all families unaffected siblings produce significantly higher amounts of SMN, Gemin2, Gemin3, ZPR1 and hnRNP-Q protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected siblings. Protein p53, an additional SMN-interacting protein, is not subject to an SMN-dependent regulation. Surprisingly, Htra2-beta1 is also regulated by this tissue-specific mechanism. A similar regulation was found in all type I-III SMA patients, although at a different protein level than in discordant families. Thus, our data show that reduced SMN protein levels cause a reduction in the amount of its interacting proteins and of Htra2-beta1 in both discordant and non-discordant SMA families. We provide evidence that an intrinsic SMA modifying factor acts directly on the expression of SMN, thus influencing the SMA phenotype. Further insights into the molecular pathway and the identification of SMA modifying gene(s) may help to find additional targets for a therapy approach.


Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model.
We previously demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate subtype 2 (mGlu2 ) receptors have potential synergistic interactions with the antiseizure drug levetiracetam (LEV). The present study utilizes isobolographic analysis to evaluate the combined administration of JNJ-46356479, a selective and potent mGlu2 PAM, with LEV as well as sodium valproate (VPA) and lamotrigine (LTG). The anticonvulsant efficacy of JNJ-46356479 was evaluated in the 6-Hz model of psychomotor seizures in mice. JNJ-46356479 was administered in combination with LEV using 3 fixed dose-ratio treatment groups in the mouse 6-Hz (44-mA) seizure test. The combination of JNJ-46356479 with LEV was also evaluated in the mouse corneal kindling model. The potential interactions of JNJ-46356479 with the antiseizure drugs VPA and LTG were also evaluated using fixed dose-ratio combinations. Plasma levels were obtained for analysis of potential pharmacokinetic interactions for each combination studied in the mouse 6-Hz model. JNJ-46356479 was active in the 6-Hz model at both 32-mA and 44-mA stimulus intensities (median effective dose = 2.8 and 10.2 mg/kg, respectively). Using 1:1, 1:3, and 3:1 fixed dose-ratio combinations (LEV:JNJ-46356479), coadministration was significantly more potent than predicted for additive effects, and plasma levels suggest this synergism was not due to pharmacokinetic interactions. Studies in kindled mice further demonstrate the positive pharmacodynamic interaction of LEV with JNJ-46356479. Using 1:1 dose-ratio combinations of JNJ-46356479 with either VPA or LTG, there were no significant differences observed for coadministration. These studies demonstrate a synergistic interaction of JNJ-46356479 with LEV, whereas no such effect occurred for JNJ-46356479 with either VPA or LTG. The synergy seems therefore to be specific to LEV, and the combination LEV/mGlu2 PAM has the potential to result in a rational polypharmacy approach to treat patients with refractory epilepsy, once it has been confirmed in clinical studies.


Universal spin-flip transition in itinerant antiferromagnets.
We reveal a universal spin-flip (SF) transition as a function of temperature in spin-density-wave (SDW) systems. At low temperatures the antiferromagnetic (AFM) polarization is parallel to the applied field and above a critical temperature the AFM polarization flips perpendicular to the field. This transition occurs in any SDW system and may be considered as a qualitative probe of the itinerant character of AFM in a given material. Our SF transition may provide an explanation to the long-standing puzzle of the SF transition observed in chromium and may be at the origin of the equally puzzling SDW-I to SDW-II transition in Bechgaard salts for which we make experimental predictions.


Administrative decision making: staff-patient ratios (a patient classification system for a psychiatric setting).
In this article, we have described a patient classification system in use at the C.F. Menninger Memorial Hospital. It is a type of factor evaluation, in which we use critical indicators or descriptors of care as units of measurement. Each critical indicator represents a grouping of nursing activities rather than concrete time measurement of each activity. The ten critical indicators of patient care needs and nursing activities which were identified were divided into two major categories: routine and extra. Each category was then subdivided to reflect a range or variation of care levels. This type of patient classification appears to have an advantage over other classification systems when applied to psychiatric nursing. The factor evaluations are broad enough in scope to allow inclusion of patient assessment, documentation, and use of the nursing process, while providing a measurement of psychological and psychosocial needs of the patient which are frequently absent in other classification systems that rely on task measurements or acuity levels alone. Because of its practicality it has been readily accepted by nurses working on psychiatric units, and the nurse administrator's effort to put a classification system in place has been made easier.


Non-word repetition performance in Korean-English bilingual children.
The goals of this research were (1) to compare bilingual and monolingual children on Korean non-word repetition performance, and (2) to examine the relations between non-word repetition and vocabulary skills in bilingual and monolingual children. Sixty children aged from 3-5 years participated in this study, including 30 Korean-English bilinguals and 30 Korean monolinguals. The Korean-English bilingual children were sequential bilinguals who spoke Korean at home and English at school. Children were tested on a non-word repetition task and their Korean and English vocabulary skills were measured by standardized tests. The results showed that bilingual children were significantly lower on standardized vocabulary scores (p < .01). However, there was no difference between bilinguals and monolinguals on non-word repetition performance. Correlation analyses showed a significant association between non-word repetition performance and vocabulary skills of the tested language in both groups, while the association between non-word repetition and age was significant in the monolingual group. These results demonstrated that the non-word repetition task measures general language learning ability and is a sensitive predictor of vocabulary skills in linguistically diverse children.


Linear unilateral basal cell nevus: a benign follicular hamartoma simulating multiple basal cell carcinomas.
We report a case of linear unilateral basal cell nevus (LBCN) occurring on the left lateral neck and left posterior shoulder of a 23-year-old woman. LBCN is a rare benign follicular hamartoma that must be distinguished from the more aggressive unilateral and segmental variant of nevoid basal cell carcinoma syndrome (NBCCS) and the linear variant of BCC.


Microtubule dynamics followed through cell differentiation and tissue biogenesis in C. elegans.
Microtubules (MTs) are cytoskeletal filaments essential for many processes in eukaryotic cells. Assembled of tubulin subunits, MTs are dynamic structures that undergo successive and stochastic phases of polymerization and depolymerization, a behavior called dynamic instability. Dynamic instability has been extensively studied in cultured cells and in vitro using cytoplasmic extracts or reconstituted MTs. However, how MTs behave in intact tissues and how their dynamics are affected by or affect tissue function are poorly understood. Recent advances in high-resolution live imaging have helped overcome technical limitation in order to visualize MTs in intact living organisms including Drosophila or Caenorhabditis elegans. We recently took advantage of the well-characterized development, small size and transparency of C. elegans to monitor MT dynamics throughout tissue biogenesis with high spatial and temporal resolution. Using the sex myoblast lineage that generates the egg-laying muscles from 2 mitotic precursors, we identified selective dynamics in precursor versus differentiated cells, and molecular regulation of MT dynamics changes that occur during cell differentiation. We discuss here how this approach led to novel insights into the regulation of MTs dynamics and organization in vivo.


Does usnic acid affect microtubules in human cancer cells?
Usnic acid, a lichen metabolite, is known to exert antimitotic and antiproliferative activities against normal and malignant human cells. Many chemotherapy agents exert their activities by blocking cell cycle progression, inducing cell death through apoptosis. Microtubules, protein structure involved in the segregation of chromosomes during mitosis, serve as chemotherapeutical targets due to their key role in cellular division as well as apoptosis. The aim of this work was to investigate whether usnic acid affects the formation and/or stabilisation of microtubules by visualising microtubules and determining mitotic indices after treatment. The breast cancer cell line MCF7 and the lung cancer cell line H1299 were treated with usnic acid 29 microM for 24 hours and two positive controls: vincristine (which prevents the formation of microtubules) or taxol (which stabilizes microtubules). Treatment of MCF7 and H1299 cells with usnic acid did not result in any morphological changes in microtubules or increase in the mitotic index. These results suggest that the antineoplastic activity of usnic acid is not related to alterations in the formation and/or stabilisation of microtubules.


Design, synthesis, and characterization of high-affinity, systemically-active galanin analogues with potent anticonvulsant activities.
Galanin is an endogenous neuropeptide that modulates seizures in the brain. Because this neuropeptide does not penetrate the blood-brain barrier, we designed truncated galanin analogues in which nonessential amino acid residues were replaced by cationic and/or lipoamino acid residues. The analogues prevented seizures in the 6 Hz mouse model of epilepsy following intraperitoneal administration. The most active analogue, Gal-B2 (NAX 5055), contained the -Lys-Lys-Lys(palmitoyl)-Lys-NH(2) motif and exhibited high affinity for galanin receptors (K(i) = 3.5 nM and 51.5 nM for GalR1 and GalR2, respectively), logD = 1.24, minimal helical conformation and improved metabolic stability. Structure-activity-relationship analysis suggested that cationization combined with position-specific lipidization was critical for improving the systemic activity of the analogues. Because the anticonvulsant activity of galanin is mediated by the receptors located in hippocampus and other limbic brain structures, our data suggest that these analogues penetrate into the brain. Gal-B2 may lead to development of first-in-class antiepileptic drugs.


Genotypic distribution of hepatitis B virus in the Czech Republic: a possible association with modes of transmission and clinical outcome.
The relationship between hepatitis B virus (HBV) genotype with disease or treatment outcome is beginning to be characterized. However, the link between genotype and disease transmission route has not been closely examined. We addressed this question in high-risk populations in Prague, Czech Republic. Patients with HBV infection were consecutively recruited into the study at an outpatient clinic between June 2000 and March 2001. Their serum samples were analysed for HBV S gene segments by polymerase chain reaction (PCR) test. The amplified product sequences were compared to those of known HBV genotypes. Patients were evaluated for other virus co-infections, and parenteral and sexual exposure histories. Of 57 consecutively recruited patients with evidence of HBV infection, 45 (79%) had PCR-detectable S gene sequences. Only genotypes A (n = 33; 73%) and D (n = 12; 27%) were found. There was no difference in the development of chronic infection between the two genotypes. Of nine patients co-infected with TTV, all were infected with HBV genotype A. There was a trend towards an association between number of lifetime sex partners and genotype A but not genotype D. In Prague, the number of HBV genotypes appears to be limited compared to other northern European countries, suggesting that the virus has recently spread in the high-risk populations. While a large proportion of HBV infections occur in intravenous drug users, a subset of HBV genotype A may be transmitted by sexual contact. An HBV subtype may influence modes of transmission of HBV.


[Imaging of the thoracic aorta in adults: when, how and why?].
CT, MRI and transesophageal echocardiography have become the standard of reference for evaluation of the thoracic aorta. Angiography is mainly performed as a presurgical procedure. Congenital pathologies observed during adulthood include coarctation, patent ductus arteriosus, and aberrant retroesophageal subclavian arteries. Imaging plays a major role for diagnosis and management of patients with acute aortic syndromes: intramural hematoma, dissection, penetrating ulcer and nondissecting aneurysms. Cross sectional imaging of the thoracic aortic wall allows evaluation of inflammatory diseases of the aorta or aortitis.


Acute peripartum twin-twin transfusion syndrome: incidence, risk factors, placental characteristics and neonatal outcome.
The aim of this study was to examine the incidence, placental characteristics and outcome in acute peripartum twin-twin transfusion syndrome (TTTS). All consecutive cases of monochorionic (MC) twins admitted to our center were included in the study. We excluded cases with chronic TTTS or twin anemia polycythemia sequence. Acute peripartum TTTS was defined when the inter-twin hemoglobin difference at birth was >8 g/dL. A total of 241 MC twin pregnancies were included in the study. Acute peripartum TTTS was detected in six cases (2.5%, 6/241). Vaginal delivery occurred more often in the acute peripartum TTTS group compared to the control group of uncomplicated MC pregnancies, 100% (6/6) versus 57% (135/235) (P = 0.002), respectively. Acute anemia was detected only in firstborn twins. Placental angioarchitecture in acute peripartum TTTS was similar to the placentas in the control group. The incidence of acute peripartum TTTS is low (2.5%). Birth order and mode of delivery appear to be associated with increased risk of acute peripartum TTTS.


Improved Thermoelectric Performance of p-Type Argyrodite Cu8GeSe6 via the Simultaneous Engineering of the Electronic and Phonon Transports.
Guided by the concept of "phonon-liquid electron-crystal", many n-type argyrodite compounds have been developed as candidates for thermoelectric (TE) materials. In recent years, the p-type Cu8GeSe6 (CGS) compound has attracted some attention in TEs due to the presence of very strong atomic vibrational arharmonicity inside the sublattice, which is caused by the weak bonding between Cu ions and [GeSe6]8-. However, its TE performance is still poor, with a ZT value of only 0.2 at 623 K. Therefore, in this work, we propose to engineer both the electronic and phonon transports in CGS by incorporating the species In2Te3. This strategy tunes the carrier concentration and at the same time increases the phonon scattering on the point defects (InGe, Ininterstitial, and TeSe) and randomly distributed tetrahedra ([InSe4]5- and [GeTeSe3]4-). As a result, the phase transformation at 329 K in CGS is eliminated, and the peak ZT value is enhanced from 0.27 for CGS to ∼0.92 for (Cu8SnSe6)0.9(In2Te3)0.1 at 774 K; this thus proves that the incorporation of In2Te3 in CGS is an effective way of regulating its TE performance.


[Influence of seasons on risk of flare-up of systemic lupus: retrospective study of 66 patients].
To establish the possible connection between visceral, arthro-cutaneous and biological spreading of systemic lupus (SL) and hours of sunlight. Retrospective study of 66 SL patients, consisting of 52 visceral and 14 arthro-cutaneous cases taking into account the chronological pattern of each new aggravation, based on 480 clinical records. Increased frequency in visceral aggravation was observed in the post-summer period (August-January) (n = 57), as compared with the pre-summer period (February-July) (n = 25) (RR = 1.75, P = 0.006). This post-summer visceral aggravation was correlated with cutaneous affection (RR = 4.18) and absence of previous corticotherapy (RR = 3.97). Visceral and arthro-cutaneous aggravations taken together revealed a more disturbed immune balance pattern in the post-summer period (anti-dsDNA: 30 versus 25.1 IU/L [P = 0.07]; C3: 0.83 vs 0.921 IU/L [P = 0.05]; C4: 0.146 vs 0.183 [P = 0.05]), providing evidence of greater severity. Moderate thrombopenia (50-120 10(9)/L) accompanying visceral SL with antiphospholipids (n = 33) was more frequent during the post-summer period, even in the absence of aggravation (P = 0.03). The quarterly distribution of visceral aggravations was correlated with average hours of sunlight in the preceding quarter (P = 0.01). There is a post-summer increase in the frequency and severity of visceral SL spreading correlated to cutaneous exacerbation and sunlight.


A concise review of vaccines against Mycoplasma hyopneumoniae.
Mycoplasma hyopneumoniae (Mhp) is the pathogen of Mycoplasmal pneumonia of swine (MPS), a chronic respiratory infectious discease which causes enormous losses to the swine industry worldwide. At present, vaccination is the most effective mean to prevent and reduce economic losses caused by this pathogen. Currently, MPS vaccines mainly include inactivated vaccines and attenuated live vaccines. However, these approved vaccines still have many drawbacks, and the infection of Mhp has not yet been fully elucidated. Adhesion factors of Mhp have been shown to play a direct role in the pathogen's adherence, and thus were given consideration to be included in the composition of the vaccine. This shows a good prospect due to the advantages and feasibility of genetically engineering a vaccine. In this review, we summarize the work of researchers in recent years about the development of vaccines against Mhp, and we focus on the development of genetically engineering vaccines and some novel combined vaccines.


Vancomycin does not affect the enzymatic activities of purified VanSA.
VanS is a membrane-bound sensor histidine kinase responsible for sensing vancomycin and activating transcription of vancomycin-resistance genes. In the presence of vancomycin, VanS phosphorylates the transcription factor VanR, converting it to its transcriptionally active form. In the absence of vancomycin, VanS dephosphorylates VanR, thereby maintaining it in a transcriptionally inactive state. To date, the mechanistic details of how vancomycin modulates VanS activity have remained elusive. We have therefore studied these details in an in vitro system, using the full-length VanS and VanR proteins responsible for type-A vancomycin resistance in enterococci. Both detergent- and amphipol-solubilized VanSA display all the enzymatic activities expected for a sensor histidine kinase, with amphipol reconstitution providing a marked boost in overall activity relative to detergent solubilization. A putative constitutively activated VanSA mutant (T168K) was constructed and purified, and was found to exhibit the expected reduction in phosphatase activity, providing confidence that detergent-solubilized VanSA behaves in a physiologically relevant manner. In both detergent and amphipol solutions, VanSA's enzymatic activities were found to be insensitive to vancomycin, even at levels many times higher than the antibiotic's minimum inhibitory concentration. This result argues against direct activation of VanSA via formation of a binary antibiotic-kinase complex, suggesting instead that either additional factors are required to form a functional signaling complex, or that activation does not require direct interaction with the antibiotic.


Evaluation of Kras gene mutation and copy number gain in non-small cell lung cancer.
Recent studies for the characterization of the lung cancer genome have suggested that Kras gene was frequently amplified and correlated with activating mutations of Kras, which occur in approximately 5 to 10% of Japanese lung cancers. We analyzed Kras mutation and Kras copy number in 172 Japanese non-small cell lung cancer (NSCLC) cases and their relation to the survival of patients. We also studied using fluorescence in situ hybridization to provide direct evidence of Kras amplification in 40 clinical specimens. In 172 NSCLC cases, increased Kras copy number existed in 19 (11.0%) cases. Increased Kras gene copy number was correlated with Kras mutation. Nevertheless, Kras gene copy number gain was not correlated with gender, pathological subtypes, stages, and smoking status. Increased Kras copy number was not associated with overall survival in these 172 cases; however, patients with increased Kras copy number and Kras mutant had significantly worse prognosis, when compared with patients with Kras wild type and Kras not increased. From the fluorescence in situ hybridization analysis, Kras polysomy or amplified patients showed significantly worse prognosis, when compared with Kras disomy patients. Kras mutation plus increased copy number was a predictor of poor clinical outcome in patients with NSCLC.


[Use of recombinant human TSH for stimulation of iodine radioisotope uptake in metastases of thyroid cancer during therapy with 131I].
The diagnostics with the use of recombinant human TSH for the follow-up of differentiated thyroid carcinoma (DTC) has been already approved. In more than 400 diagnostic scans, rhTSH proved to be effective in promoting 131I uptake in thyroid remnants and DTC metastases in patients receiving suppressive doses of thyroxine. However, information about its application in radioiodine treatment of DTC are scarce, especially with respect to patients with metastatic disease. In this review we have described our own results obtained during rhTSH aided radioiodine treatment of 42 patients with advanced DTC with reference to current literature data about diagnostic and therapeutic application of rhTSH.


Joint volumetric extraction and enhancement of vasculature from low-SNR 3-D fluorescence microscopy images.
To simultaneously overcome the challenges imposed by the nature of optical imaging characterized by a range of artifacts including space-varying signal to noise ratio (SNR), scattered light, and non-uniform illumination, we developed a novel method that segments the 3-D vasculature directly from original fluorescence microscopy images eliminating the need for employing pre- and post-processing steps such as noise removal and segmentation refinement as used with the majority of segmentation techniques. Our method comprises two initialization and constrained recovery and enhancement stages. The initialization approach is fully automated using features derived from bi-scale statistical measures and produces seed points robust to non-uniform illumination, low SNR, and local structural variations. This algorithm achieves the goal of segmentation via design of an iterative approach that extracts the structure through voting of feature vectors formed by distance, local intensity gradient, and median measures. Qualitative and quantitative analysis of the experimental results obtained from synthetic and real data prove the effcacy of this method in comparison to the state-of-the-art enhancing-segmenting methods. The algorithmic simplicity, freedom from having a priori probabilistic information about the noise, and structural definition gives this algorithm a wide potential range of applications where i.e. structural complexity significantly complicates the segmentation problem.


Progress of Large-Scale Synthesis and Electronic Device Application of Two-Dimensional Transition Metal Dichalcogenides.
The recent exploration of semiconducting two-dimensional (2D) transition metal dichalcogenides (TMDs) with atomic thickness has taken both the scientific and technological communities by storm. Extensively investigated TMD that are accessible by large-scale synthetic methods materials are remarkably stable, such as MoS2 and WSe2 . They allow superior gate control due to their 2D nature and favorable electronic transport properties, thus suggesting a bright future for digital and RF electronics. In this review, the latest developments in the controlled synthesis of large scale TMDs are firstly introduced by discussing various approaches. The major obstacles that must be overcome to achieve wafer-scale, uniform, and high-quality TMD films for practical electronic applications are included. Advances in the electronic transport studies of TMDs are presented, such as doping, contact engineering, and mobility improvement, which contribute to overall device performance. A perspective and a look at the future for this field is provided in closing.


Effect of chondroitin sulfate proteoglycans on neuronal cell adhesion, spreading and neurite growth in culture.
As one major component of extracellular matrix (ECM) in the central nervous system, chondroitin sulfate proteoglycans (CSPGs) have long been known as inhibitors enriched in the glial scar that prevent axon regeneration after injury. Although many studies have shown that CSPGs inhibited neurite outgrowth in vitro using different types of neurons, the mechanism by which CSPGs inhibit axonal growth remains poorly understood. Using cerebellar granule neuron (CGN) culture, in this study, we evaluated the effects of different concentrations of both immobilized and soluble CSPGs on neuronal growth, including cell adhesion, spreading and neurite growth. Neurite length decreased while CSPGs concentration arised, meanwhile, a decrease in cell density accompanied by an increase in cell aggregates formation was observed. Soluble CSPGs also showed an inhibition on neurite outgrowth, but it required a higher concentration to induce cell aggregates formation than coated CSPGs. We also found that growth cone size was significantly reduced on CSPGs and neuronal cell spreading was restrained by CSPGs, attributing to an inhibition on lamellipodial extension. The effect of CSPGs on neuron adhesion was further evidenced by interference reflection microscopy (IRM) which directly demonstrated that both CGNs and cerebral cortical neurons were more loosely adherent to a CSPG substrate. These data demonstrate that CSPGs have an effect on cell adhesion and spreading in addition to neurite outgrowth.


Breastfeeding Positioning and Attachment among Postnatal Mothers: A Mixed Methods Study in a Tertiary Care Hospital in Puducherry, South India.
Proper positioning and attachment play a key role in exclusive breastfeeding. Whereas incorrect breastfeeding techniques lead to poor milk transfer and early discontinuation of breastfeeding. 1. To assess the breastfeeding techniques among postnatal mothers and to identify the factors associated with improper positioning and poor attachment. 2. To prioritize the action points to improve the poor breastfeeding practices according to the viewpoint of the staff nurses. A hospital-based mixed-methods study was carried out in Puducherry for 6 months. In quantitative phase, 99 postnatal mothers were interviewed consecutively and breastfeeding techniques were observed based on Baby Friendly Hospital Initiative and Integrated Management of Neonatal and Childhood Illness guidelines. In qualitative phase, 45 staff nurses ranked the action points to improve the poor breastfeeding practices. Bivariate and multivariate analyses were employed. Mean rank and Kendalls' Concordance Coefficient were calculated for the ranked data. About 28.3% and 27.3% of mothers demonstrated improper positioning and poor attachment, respectively. Young mothers, housewives, <10 days old infants, and failure to receive breastfeeding counseling were associated with poor breastfeeding techniques. Poster displays, healthcare workers' training, targeted counseling, and assistance were the priority action points suggested by the staff nurses. Maternal age, maternal occupation, infants' age, and breastfeeding counseling influenced breastfeeding techniques. The prioritized action points need to be implemented to achieve the level of Baby Friendly Hospital.


Insulin-like growth factor-1 receptor activation inhibits oxidized LDL-induced cytochrome C release and apoptosis via the phosphatidylinositol 3 kinase/Akt signaling pathway.
We have shown previously that oxidized LDL decreases insulin-like growth factor-1 (IGF-1) and IGF-1 receptor expression in vascular smooth muscle cells and that IGF-1 and IGF-1 receptor expression are reduced in the deep intima of early atherosclerotic lesions. Because oxidized LDL is potentially important for the depletion of vascular smooth muscle cells contributing to plaque destabilization, we studied the role of IGF-1 in oxidized LDL-induced apoptosis. We provide evidence that oxidized LDL-induced apoptosis is caused by decreased mitochondrial membrane potential and increased cytochrome C release in human aortic vascular smooth muscle cells. Overexpression of the IGF-1 receptor by using an adenovirus completely abrogated these effects. The antiapoptotic function of the IGF-1 receptor was associated with increased Akt kinase activity and increased expression of phosphorylated Bad. Moreover, a dominant-negative p85 phosphatidylinositol 3-kinase adenovirus blocked the capacity of the IGF-1 receptor to prevent oxidized LDL-induced apoptosis. Our data demonstrate that IGF-1 receptor activation inhibits oxidized LDL-induced cytochrome C release and apoptosis through the phosphatidylinositol 3-kinase/Akt signaling pathway and suggest that genetic or pharmacological activation of the IGF-1 receptor may be a useful strategy to stabilize atherosclerotic plaques.


[Role of prostaglandin E2 in the modulation of renal water transport].
Prostaglandin E2 (PGE2), a bioactive lipid mediator, is one of the most important locally acting factors involved in a variety of physiological and pathophysiological processes. PGE2 binds with four EP receptors (EP1-4) to activate G protein-coupled receptor signaling responses. Recent functional and molecular studies have revealed that PGE2 plays an essential role in regulation of renal fluid transport via a variety of mechanisms. The water balance mainly depends on the regulation of aquaporin-2 (AQP2) by arginine vasopressin (AVP) in renal collecting duct principal cells. In recent years, increasing evidence suggests that PGE2 plays an important role in renal water reabsorption in the collecting ducts. In this paper, we reviewed the role of PGE2 and its receptors in the regulation of water reabsorption in the kidney, which may provide a new therapeutic strategy for many diseases especially nephrogenic diabetes insipidus.


Cholesterol-enriched membrane microdomains are required for inducing host cell cytoskeleton rearrangements in response to attaching-effacing Escherichia coli.
The diarrheal pathogens enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain CL56 and enteropathogenic Escherichia coli (EPEC) O127:H6 strain E2348/69 adhere intimately to epithelial cells through attaching-effacing lesions, which are characterized by rearrangements of the host cytoskeleton, intimate adherence, and destruction of microvilli. These cytoskeletal responses require activation of host signal transduction pathways. Lipid rafts are signaling microdomains enriched in sphingolipid and cholesterol in the plasma membrane. The effect of perturbing plasma membrane cholesterol on bacterial intimate adherence was assessed. Infection of both HEp-2 cells and primary skin fibroblasts with strains CL56 and E2348/69 caused characteristic rearrangements of the cytoskeleton at sites of bacterial adhesion. CL56- and E2348/69-induced cytoskeletal rearrangements were inhibited following cholesterol depletion. Addition of exogenous cholesterol to depleted HEp-2 cells restored cholesterol levels and rescued bacterially induced alpha-actinin mobilization. Quantitative bacterial adherence assays showed that EPEC adherence to HEp-2 cells was dramatically reduced following cholesterol depletion, whereas the adherence of EHEC remained high. Cytoskeletal rearrangements on skin fibroblasts obtained from children with Niemann-Pick type C disease were markedly reduced. These findings indicate that host membrane cholesterol contained in lipid rafts is necessary for the cytoskeletal rearrangements following infection with attaching-effacing Escherichia coli. Differences in initial adherence indicate divergent roles for host membrane cholesterol in the pathogenesis of EHEC and EPEC infections.


[Persistent organic contaminants in food : Exposure, hazard potential, and health assessment].
Environmental emissions of organic contaminants are caused by man-made and natural combustion processes, industrial production facilities, and the release from products. Food represents the main source of human exposure for some of these compounds. This is the case for three groups of persistent organic contaminants: (1) per- and polyfluoroalkyl substances (PFAS), (2) polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and for (3) polycyclic aromatic hydrocarbons (PAHs). The issues regarding PCDD/F emissions were already recognized as a problem in the 1970s and have since then been effectively regulated; the impact of PFAS as global anthropogenic environmental contaminants was identified much later.A system of toxicity equivalency factors (TEF system) was established for the assessment of the toxic potency of a mixed exposure to PCDD/F and certain PCBs. For the health assessment and regulation of PAHs and PFAS, no such system has been implemented so far. For PFAS, a re-evaluation of the present tolerable daily intake values (TDI values) is currently being discussed, as new insights into toxicology and epidemiology have been gained.The persistence in the environment of the compound groups discussed here leads to entry into the food chain over long periods of time, even if access into the environment is minimized. This requires a long-term continuation of the monitoring of food stuffs and forward-looking risk assessment approaches and regulatory measures.


Pulsed field ablation of superior vena cava in paroxysmal atrial fibrillation: a case report.
Paroxysmal atrial fibrillation originates most commonly in the pulmonary veins. However, the superior vena cava has proved to be arrhythmogenic in some cases. Pulsed field ablation, an emerging ablation technology, selectively affects myocardial tissue. Herein, we present a case of paroxysmal atrial fibrillation in a 64-year-old man who was admitted to our hospital for pulsed field ablation. The tachycardia was recurrent despite four successful pulmonary vein isolations. The superior vena cava was determined to be involved in arrhythmogenesis. The atrial fibrillation terminated immediately after the pulsed field ablation discharge at the superior vena cava.


Evaluation of the "Pipeline" for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research.
Cocaine use disorder is a persistent public health problem for which no widely effective medications exist. Self-administration procedures, which have shown good predictive validity in estimating the abuse potential of drugs, have been used in rodent, nonhuman primate, and human laboratory studies to screen putative medications. This review assessed the effectiveness of the medications development process regarding pharmacotherapies for cocaine use disorder. The primary objective was to determine whether data from animal and human laboratory self-administration studies predicted the results of clinical trials. In addition, the concordance between laboratory studies in animals and humans was assessed. More than 100 blinded, randomized, fully placebo-controlled studies of putative medications for cocaine use disorder were identified. Of the 64 drugs tested in these trials, only 10 had been examined in both human and well-controlled animal laboratory studies. Within all three stages, few studies had been conducted for each drug and when multiple studies had been conducted conclusions were sometimes contradictory. Overall, however, there was good concordance between animal and human laboratory results when the former assessed chronic drug treatment. Although only seven of the ten reviewed drugs showed fully concordant results across all three types of studies reviewed, the analysis revealed several subject-related, procedural, and environmental factors that differ between the laboratory and clinical trial settings that help explain the disagreement for other drugs. The review closes with several recommendations to enhance translation and communication across stages of the medications development process that will ultimately speed the progress toward effective pharmacotherapeutic strategies for cocaine use disorder.


Unmet needs and relationship challenges of head and neck cancer patients and their spouses.
In head and neck cancer (HNC), couple-based interventions may be useful for facilitating treatment completion, patient rehabilitation, and improving both partners' quality of life. With the goal of identifying targets for future interventions, we conducted a qualitative study to understand patient and spouse unmet needs and relationship challenges during curative radiotherapy for HNC. Semistructured interviews were conducted with six HNC patients (83% male) and six spouses (83% female) within 6 months of completing treatment. Interviews were audiotaped and transcribed using grounded theory analysis. Patients and spouses identified several unmet needs including better preparation regarding the severity of physical side effects, a clearer timeline for recovery, and strategies for dealing with their own and each other's emotional reactions. Caregiver's unmet needs included balancing competing roles/responsibilities, making time for self-care, and finding effective strategies for encouraging patient's self-care. Eighty-three percent of spouses and all patients reported increased conflict during treatment. Other relationship challenges included changes in intimacy and social/leisure activities. Findings suggest that couple-based interventions that emphasize the importance of managing physical and psychological symptoms through the regular practice of self-care routines may be beneficial for both patients and spouses. Likewise, programs that teach spouses ways to effectively motivate and encourage patients' self-care may help minimize conflict and help couples navigate HNC treatment and recovery together as a team.


Infantile Anorexia and Co-parenting: A Pilot Study on Mother-Father-Child Triadic Interactions during Feeding and Play.
Infantile Anorexia (IA), defined by the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood Revised (DC: 0-3R, Zero To Three, 2005), occurs when the child (a) refuses to eat adequate amounts of food for at least 1 month, and shows growth deficiency, (b) does not communicate hunger and lacks interest in food, and (c) the child's food refusal does not follow a traumatic event and is not due to an underlying medical illness. IA usually emerges during the transition to self-feeding, when the child issues of autonomy are played out daily in the feeding situation. Studies evidence that the feeding interactions between children with IA and their mothers are characterized by low reciprocity, greater interactional conflict and negative affects (Chatoor et al., 2000; Ammaniti et al., 2010, 2012). Moreover, these studies pointed out that maternal depression and eating disorders are frequently associated with IA (Cooper et al., 2004; Ammaniti et al., 2010; Lucarelli et al., 2013). To date, research has focused almost exclusively on the mother-child dyad, while fathers' involvement, co-parental and family interactions are poorly studied. The current study is a pilot research that investigated mother-father-child triadic interactions, during feeding and play, in families with children diagnosed with IA, in comparison to families with normally developing children. Until now, at the study participated N = 10 families (five with a child with IA diagnosis and five with lack of child's IA diagnosis, matched for child's age and gender). The parents-child triadic interactions were assessed in feeding and play contexts using the Lausanne Trilogue Play (Fivaz-Depeursinge and Corboz-Warnery, 1999), adapted to observe father-mother-infant primary triangle in the feeding context, compared to the play context (Lucarelli et al., 2012). Families of the IA-group showed difficulties in expressing and sharing pleasure and positive affects, and in structuring a predictable and flexible context. Children showed little autonomy and difficulty in being actively engaged and tune with parents. Dysfunctional family interactions are a critical issue for IA that affects co-parental and family subsystems, stressing the importance of an articulated diagnostic assessment in order to target effective treatment approaches.


One-step synthesis of N-doped metal/biochar composite using NH3-ambiance pyrolysis for efficient degradation and mineralization of Methylene Blue.
A series of new biochar-supported composite based on the combination of biochar and metallic nanoparticles (NPs) were produced through single-step pyrolysis of FeCl3-Ti(OBu)4 laden agar biomass under NH3 environment. The physiochemical properties of composites were characterized thoroughly. It has found that heating temperature and N-doping through NH3-ambiance pyrolysis significantly influence the visible-light sensitivity and bandgap energy of composites. The catalytic activities of composites were measured by degradation of Methylene Blue (MB) in the presence or absence of H2O2 and visible-light irradiation. Our best catalyst (N-TiO2-Fe3O4-biochar) exhibits rapid and high MB removal competency (99.99%) via synergism of adsorption, photodegradation, and Fenton-like reaction. Continuous production of O2- and OH radicles performs MB degradation and mineralization, confirmed by scavenging experiments and degradation product analysis. The local trap state Ti3+, Fe3O4, and N-carbon of the catalyst acted as active sites. It has suggested that the Ti3+ and N-doped dense carbon layer improve charge separation and shuttle that prolonged photo-Fenton like reaction. Moreover, the catalyst is highly stable, collectible, and recyclable up to 5 cycles with high MB degradation efficiency. This work provides a new insight into the synthesis of highly visible-light sensitized biochar-supported photocatalyst through NH3-ambiance pyrolysis of NPs-laden biomass.


Visible-Light Driven TiO₂ Photocatalyst Coated with Graphene Quantum Dots of Tunable Nitrogen Doping.
Nitrogen doped graphene quantum dots (NGQDs) were successfully prepared via a hydrothermal method using citric acid and urea as the carbon and nitrogen precursors, respectively. Due to different post-treatment processes, the obtained NGQDs with different surface modifications exhibited blue light emission, while their visible-light absorption was obviously different. To further understand the roles of nitrogen dopants and N-containing surface groups of NGQDs in the photocatalytic performance, their corresponding composites with TiO₂ were utilized to degrade RhB solutions under visible-light irradiation. A series of characterization and photocatalytic performance tests were carried out, which demonstrated that NGQDs play a significant role in enhancing visible-light driven photocatalytic activity and the carrier separation process. The enhanced photocatalytic activity of the NGQDs/TiO₂ composites can possibly be attributed to an enhanced visible light absorption ability, and an improved separation and transfer rate of photogenerated carriers.


Hybrid Targeted/Untargeted Screening Method for the Determination of Wildfire and Water-Soluble Organic Tracers in Ice Cores and Snow.
Wildfires can influence the earth's radiative forcing through the emission of biomass-burning aerosols. To better constrain the impacts of wildfires on climate and understand their evolution under future climate scenarios, reconstructing their chemical nature, assessing their past variability, and evaluating their influence on the atmospheric composition are essential. Ice cores are unique to perform such reconstructions representing archives not only of past biomass-burning events but also of concurrent climate and environmental changes. Here, we present a novel methodology for the quantification of five biomass-burning proxies (syringic acid, vanillic acid, vanillin, syringaldehyde, and p-hydroxybenzoic acid) and one biogenic emission proxy (pinic acid) using solid phase extraction (SPE) and ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry. This method was also optimized for untargeted screening analysis to gain a broader knowledge about the chemical composition of organic aerosols in ice and snow samples. The method provides low detection limits (0.003-0.012 ng g-1), high recoveries (74 ± 10%), and excellent reproducibility, allowing the quantification of the six proxies and the identification of 313 different molecules, mainly constituted by carbon, hydrogen, and oxygen. The effectiveness of two different sample storage strategies, i.e., re-freezing of previously molten ice samples and freezing of previously loaded SPE cartridges, was also assessed, showing that the latter approach provides more reproducible results.


The pathogenesis and virulence of enterovirus-D68 infection.
In 2014, enterovirus D68 (EV-D68) emerged causing outbreaks of severe respiratory disease in children worldwide. In a subset of patients, EV-D68 infection was associated with the development of central nervous system (CNS) complications, including acute flaccid myelitis (AFM). Since then, the number of reported outbreaks has risen biennially, which emphasizes the need to unravel the systemic pathogenesis in humans. We present here a comprehensive review on the different stages of the pathogenesis of EV-D68 infection - infection in the respiratory tract, systemic dissemination and infection of the CNS - based on observations in humans as well as experimental in vitro and in vivo studies. This review highlights the knowledge gaps on the mechanisms of systemic dissemination, routes of entry into the CNS and mechanisms to induce AFM or other CNS complications, as well as the role of virus and host factors in the pathogenesis of EV-D68.


Immunohistochemical estimation of cell cycle entry and phase distribution in astrocytomas: applications in diagnostic neuropathology.
An immunohistochemical method for assessing cell cycle phase distribution in neurosurgical biopsies would enable such data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in glial neoplasms, without the requirement for flow cytometric analysis. Paraffin-embedded sections of intracerebral gliomas (n = 48), consisting of diffuse astrocytoma (n = 9), anaplastic astrocytoma (n = 8) and glioblastoma (n = 31), were analysed by immunohistochemistry using markers of cell cycle entry, Mcm-2 and Ki67, and putative markers of cell cycle phase, cyclins D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis). Double labelling confocal microscopy confirmed that the phase markers were infrequently coexpressed. Cell cycle estimations by immunohistochemistry were corroborated by flow cytometric analysis. There was a significant increase in Mcm-2 (P < 0.0001), Ki67 (P < 0.0001), cyclin A (P < 0.0001) and cyclin B1 (P = 0.002) expression with increasing grade from diffuse astrocytoma through anaplastic astrocytoma to glioblastoma, suggesting that any of these four markers has potential as a marker of tumour grade. In a subset of glioblastomas (n = 16) for which accurate clinical follow-up data were available, there was a suggestion that the cyclin A:Mcm-2 labelling fraction might predict a relatively favourable response to radical radiotherapy. These provisional findings, however, require confirmation by a larger study. We conclude that it is feasible to obtain detailed cell cycle data by immunohistochemical analysis of tissue biopsies. Such information may facilitate tumour grading and may enable information of prognostic value to be obtained in the routine diagnostic laboratory.


A Tunable Ionic Diode Based on a Biomimetic Structure-Tailorable Nanochannel.
A tunable ionic diode is presented that is based on biomimetic structure-tailorable nanochannels, with precise ion-transport characteristics from ohmic behavior to bidirectional rectification as well as gating properties. The forward/reverse directions of the ionic diode and the degree of rectification can be well-regulated by combining the patterned surface charge and the sophisticated structure. This system creates an ideal platform for precise transportation of ions and molecules, and potential applications in analytical sciences are anticipated.


UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis.
The UVB component of the solar spectrum induces DNA lesions that, in the absence of error-free DNA repair, may give rise during DNA replication to mutations in caretaker and gatekeeper genes. The DNA repair genes are the best candidates for caretaker genes as exemplified by the human hereditary xeroderma pigmentosum (XP) syndrome. Cultured XP cells are hypermutable after UVB irradiation. This increased mutation frequency is also found in gatekeeper genes, which govern signalling pathways implicated in the control of cellular proliferation, differentiation and survival of human epidermal keratinocytes. We describe and discuss the role of mutated gatekeeper genes in five specific signalling pathways which have been implicated in skin carcinogenesis. The pathways we focus on in this review are: (i) P16(INK4A)-CDK4/6-RB; (ii) P14(ARF)-HDM2-P53; (iii) Sonic hedgehog (SHH)/GLI; (iv) WNT/beta-catenin; and (v) Bone Morphogenetic Protein (BMP)/SMAD. 70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs). In XP cancers, the typically UVB-induced CC to TT tandem transitions represent approximately 60% of total mutations compared to 10-15% in skin tumours from DNA repair-proficient patients. Acquired activation of the pathways described herein can alter proliferation and differentiation of keratinocytes, allowing a damaged cell to replicate and give rise to mutated daughter cells, then eventually to the development of the carcinogenic process following clonal selection.


Dilemmas in the interpretation of diagnostic accuracy studies on presurgical workup for epilepsy surgery.
We conducted a systematic review to determine which noninvasive technologies should be used in the workup for epilepsy surgery to identify structural or functional abnormalities to help locate the site of seizure onset. The review focused on patients where there was insufficient confidence, in either the decision to go to surgery or the site at which surgery should be conducted, after the initial clinical examination. The majority of the studies identified were single-gate diagnostic accuracy studies; none were randomized controlled trials, and only one reported the effect of the test results on the decision making process. It became apparent that the data derived from diagnostic accuracy studies could not be used to answer the review question. This article focuses on the methods used to extract data from the diagnostic accuracy studies, the difficulties interpreting the resulting data, why such studies are not an appropriate study design in this setting, and how the evidence-base can be improved.


[BCL-2/IgH translocation in peripheral blood cells of healthy Chinese individuals of Han nationality located in Zhejiang area].
To investigate the relationship between the frequency of BCL-2/IgH rearrangement in peripheral blood cells of healthy Chinese individuals of Han nationality located in Zhejiang area and the low incidence of follicular lymphoma (FL). Nested-PCR and direct DNA sequencing were used to detect the Bcl-2/IgH rearrangement in peripheral blood cells of 196 healthy individuals. DNA sequences involved were then searched and aligned in NCBI database to confine the broken points in major breakpoint region and the IgH segments involved. First, in this sample the frequency of BCL-2/IgH translocation in Chinese individuals of Han nationality located in Zhejiang area is 9.66%, being much lower than that in North America and Europe countries. Second, the breakpoints tend to fall into 3 clusters: 3055, 3116 and 3165 bp. Usage of J6 segment is most common. Third, There are different subclones of BCL-2/IgH rearrangements in the same individual. The low frequency of BCL-2/IgH translocation in healthy Chinese individuals of Han nationality located in Zhejiang area may be one of the reasons for the difference in the incidence of FL between China and Western countries.


Temporal and spatial properties of arterial pulsation measurement using pressure sensor array.
Conventionally, a pulse taking platform is based on a single sensor, which initiates a feasible method of quantitative pulse diagnosis. The aim of this paper is to implement a pulse taking platform with a tactile array sensor. Three-dimensional wrist pulse signals are constructed, and the length, width, ascending slope, and descending slope are defined following the surface of the wrist pulse. And the pressure waveform of the wrist pulse obtained through proposed pulse-taking platform has the same performance as the single sensor. Finally, the results of a paired samples t-test reveal that the repeatability of the proposal platform is consistent with clinical experience. On the other hand, the results of ANOVA indicate that differences exist among different pulse taking depths, and this result is consistent with clinical experience in traditional Chinese medicine pulse diagnosis (TCMPD). Hence, the proposed pulse taking platform with an array sensor is feasible for quantification in TCMPD.


Nontargeted Screening Method for Illegal Additives Based on Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometry.
Identification of illegal additives in complex matrixes is important in the food safety field. In this study a nontargeted screening strategy was developed to find illegal additives based on ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). First, an analytical method for possible illegal additives in complex matrixes was established including fast sample pretreatment, accurate UHPLC separation, and HRMS detection. Second, efficient data processing and differential analysis workflow were suggested and applied to find potential risk compounds. Third, structure elucidation of risk compounds was performed by (1) searching online databases [Metlin and the Human Metabolome Database (HMDB)] and an in-house database which was established at the above-defined conditions of UHPLC-HRMS analysis and contains information on retention time, mass spectra (MS), and tandem mass spectra (MS/MS) of 475 illegal additives, (2) analyzing fragment ions, and (3) referring to fragmentation rules. Fish was taken as an example to show the usefulness of the nontargeted screening strategy, and six additives were found in suspected fish samples. Quantitative analysis was further carried out to determine the contents of these compounds. The satisfactory application of this strategy in fish samples means that it can also be used in the screening of illegal additives in other kinds of food samples.