Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.
Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. To determine the effectiveness, safety and tolerability of NSAIDs in achieving a reduction in menstrual blood loss (MBL) in women of reproductive years with HMB. We searched, in April 2019, the Cochrane Gynaecology and Fertility specialised register, Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, the clinical trial registries and reference lists of articles. The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their HMB. We identified 19 randomised controlled trials (RCTs) (759 women) that fulfilled the inclusion criteria for this review and two review authors independently extracted data. We estimated odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes from the data of nine trials. We described in data tables the results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data, and one trial with missing variances. One trial had no data available for analysis. As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs, but this did not appear to affect the acceptability of treatment, based on trials from 1980 to 1990. However, currently danazol is not a usual or recommended treatment for HMB. There was no clear evidence of difference between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system and the oral contraceptive pill (OCP), but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. The evidence quality ranged from low to moderate, the main limitations being risk of bias and imprecision. NSAIDs reduce HMB when compared with placebo, but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, there was no clear evidence of a difference in efficacy between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCP or the older progesterone-releasing intrauterine system.


The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system.
The objective of this study was to compare the accuracy of disease progression prediction of the molecular genetics and morphometry-based Endometrial Intraepithelial Neoplasia (EIN) and World Health Organization 1994 (WHO94) classification systems in patients with endometrial hyperplasias. A multicenter, multivariate analysis was conducted on 477 patients with endometrial hyperplasia who were required to have a 1-year minimum disease-free interval from the time of the index biopsy (1-18 years of follow-up). The results from that analysis were compared with the results from 197 patients who had < 1 year of follow-up. Twenty-four of 477 hyperplasias (5.0%) progressed to malignant disease over an average of 4 years (maximum, 10 years). According to the WHO94 classification, 16 of 123 atypical hyperplasias (13%) and 8 of 354 nonatypical hyperplasias (2.3%) progressed (hazard ratio [HR] = 7). Twenty-two of 118 EINs (19%) and 2 of 359 non-EINs (0.6%) progressed (HR = 45). EIN was prognostic within each WHO94 subcategory. Progression rates were 3% in simple hyperplasias, 22% in complex hyperplasias, 17% in simple atypical hyperplasias, and 38% in complex atypical hyperplasias with EIN, compared with progression rates of 0.0-2.0% in all hyperplasias if EIN was absent. EIN detected precancerous lesions (sensitivity, 92%) better than WHO94 atypical hyperplasias collectively (67%) or complex atypical hyperplasias alone (46%). In a Cox regression analysis, EIN was the strongest prognostic index of future endometrial carcinoma. The same was true for patients with < 1 year of follow-up (HR for EIN, atypical hyperplasia, and complex atypical hyperplasia: 58, 7, and 8, respectively). The EIN classification system predicted disease progression more accurately than the WHO94 classification and identified many women with benign changes that would have been regarded as high risk according to the WHO94 classification system.


RhoA/ROCK signaling and pleiotropic α1A-adrenergic receptor regulation of cardiac contractility.
To determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility. We reported previously that transgenic mice with cardiac-restricted α1A-AR overexpression (α1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gαq/11-coupled receptor in hypertrophy. Contractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from α1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after α1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. Hypercontractility without hypertrophy with α1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, α1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its Gαq/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the α1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective α1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without α1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. We report for the first time pleiotropic α1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.


Pharmacotherapeutic Considerations for Use of Cannabinoids to Relieve Symptoms of Nausea and Vomiting Induced by Chemotherapy.
Patients suffering from malignant diseases receive very often highly emetogenic chemotherapy as part of their treatment. With the aim of assessing the efficacy of cannabinoids in treating chemotherapy-induced nausea and vomiting (CINV), we searched the literature published until April 2020 in Medline/PubMed, Embase, the Cochrane Controlled Trials Register, and in specific web pages. Randomized clinical trials comparing cannabinoids efficacy in managing CINV with that of placebo reported absence of vomit-ing (3 trials, 168 patients) and absence of nausea and vomiting (3 trials, 288 participants). In comparison with patients receiving other antiemetics, patients receiving cannabinoids reported no nausea (5 trials, 258 participants), no vomiting (4 trials, 209 participants), and absence of both (4 trials, 414 patients). Across all trials, cannabinoids were more effective in relieving the symptoms of nausea and vomiting induced by cytotoxic therapy than placebo was and slightly better than conventional antiemetics. A retrospective review com-paring nabilone, dronabinol, delta-9-THC, and delta 8-THC with other antiemetics used to manage CINV in pediatric patients showed that these drugs could also be used as adjuvant antiemetics. Cancer patients on highly emetogenic chemotherapy but with insufficiently effective standard antiemetic therapy can be given cannabis preparations containing similar amounts of tetrahydrocannabinol and can-nabidiol, which should be received in strict compliance with the professional guidelines for the treatment of CINV.


Effective Modulation by Lacosamide on Cumulative Inhibition of INa during High-Frequency Stimulation and Recovery of INa Block during Conditioning Pulse Train.
The effects of lacosamide (LCS, Vimpat®), an anti-convulsant and analgesic, on voltage-gated Na+ current (INa) were investigated. LCS suppressed both the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa with the IC50 values of 78 and 34 μM found in GH3 cells and of 112 and 26 μM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent INa (INa(P)) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of INa(T) or INa(L) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the INa block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ's of recovery from the INa block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window INa (INa(W)) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of INa activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of INa in excitable cells.


Deficiencies with current aortic endografts.
Endovascular aortic aneurysm repair (EVAR) has currently replaced open surgical repair as the primary method for treating aneurysm disease of the abdominal aorta and common iliac artery. Current EVAR devices, despite undergoing multiple improvement iterations, continue to have relatively high secondary intervention rates. Device migration, endoleak and limb occlusion continue to be challenges not completely met by any of the current devices. Investigational devices presently in clinical trials may provide significant resolution for many of the identified endograft deficiencies.


Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial.
Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or infantile hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We aimed to report the long-term outcomes over approximately 7 years of treatment. We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which children aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia were recruited from ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; dosage adjustments were made at each visit according to changes in the patient's weight. The primary objectives of this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with one or more treatment-emergent adverse events, and skeletal manifestations associated with hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (-3 indicating severe worsening, and +3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis population). This study and extension phase are registered with ClinicalTrials.gov, number NCT01205152, and EudraCT, number 2009-009369-32. 11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores of at least +2 at year 6 (n=9; median score +2·0 [range 2·0-3·0]) and year 7 (n=7; median score +2·3 [2·0-3·0]). No patient who completed the study required respiratory support after year 4. Weight Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. The most common adverse events were pyrexia (eight [73%] of 11 patients), upper respiratory tract infection (eight [73%]), craniosynostosis (seven [64%]), and pneumonia (seven [64%]). Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness). Patients with perinatal or infantile hypophosphatasia treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor function also improved, and asfotase alfa was generally well tolerated. Alexion Pharmaceuticals, Inc.


Are dietary inequalities among Australian adults changing? a nationally representative analysis of dietary change according to socioeconomic position between 1995 and 2011-13.
Increasing inequalities in rates of obesity and chronic disease may be partly fuelled by increasing dietary inequalities, however very few nationally representative analyses of socioeconomic trends in dietary inequalities exist. The release of the 2011-13 Australian National Nutrition and Physical Activity Survey data allows investigation of change in dietary intake according to socioeconomic position (SEP) in Australia using a large, nationally representative sample, compared to the previous national survey in 1995. This study examined change in dietary intakes of energy, macronutrients, fiber, fruits and vegetables among Australian adults between 1995 and 2011-13, according to SEP. Cross-sectional data were obtained from the 1995 National Nutrition Survey, and the 2011-13 National Nutrition and Physical Activity Survey. Dietary intake data were collected via a 24-h dietary recall (n = 17,484 adults) and a dietary questionnaire (n = 15,287 adults). SEP was assessed according to educational level, equivalized household income, and area-level disadvantage. Survey-weighted linear and logistic regression models, adjusted for age, sex/gender and smoking status, examined change in dietary intakes over time. Dietary intakes remained poor across the SEP spectrum in both surveys, as evidenced by high consumption of saturated fat and total sugars, and low fiber, fruit and vegetable intakes. There was consistent evidence (i.e. according to ≥2 SEP measures) of more favorable changes in dietary intakes of carbohydrate, polyunsaturated and monounsaturated fat in higher, relative to lower SEP groups, particularly in women. Intakes of energy, total fat, saturated fat and fruit differed over time according to a single SEP measure (i.e. educational level, household income, or area-level disadvantage). There were no changes in intake of total sugars, protein, fiber or vegetables according to any SEP measures. There were few changes in dietary intakes of energy, most macronutrients, fiber, fruits and vegetables in Australian adults between 1995 and 2011-13 according to SEP. For carbohydrate, polyunsaturated and monounsaturated fat, more favorable changes in intakes occurred in higher SEP groups. Despite the persistence of suboptimal dietary intakes, limited evidence of widening dietary inequalities is positive from a public health perspective. Clinical trials registration: ACTRN12617001045303 .


Neospora caninum antibodies in wild carnivores from Spain.
Serum samples from 251 wild carnivores from different regions of Spain were tested for antibodies to Neospora caninum by the commercial competitive screening enzyme linked immunosorbent assay (c-ELISA) and confirmed by Neospora agglutination test (NAT) and/or by indirect fluorescent antibody test (IFAT). Samples with antibodies detected by at least two serological tests were considered seropositive. Antibodies to N. caninum were found in 3.2% of 95 red foxes (Vulpes vulpes); in 21.4% of 28 wolves (Canis lupus); in 12.0% of 25 Iberian lynx (Lynx pardinus); in 16.7% of 6 European wildcats (Felis silvestris); in 6.4% of 31 Eurasian badgers (Meles meles); in 21.4% of 14 stone martens (Martes foina); in 66.7% of 3 pine martens (M. martes) and in 50% of 2 polecats (Mustela putorius). Antibodies to N. caninum in common genets (Genetta genetta) and Egyptian mongooses (Herpestes ichneumon) were only observed by c-ELISA but were not confirmed by IFAT and/or NAT. No antibodies were detected in 5 Eurasian otters (Lutra lutra) by any technique. Statistically significant differences were observed among species and among geographical areas. The highest seroprevalence of N. caninum infection was observed in the Cantabric Coastal region characterized by high humidity. To our knowledge, this is the first report of antibodies to N. caninum in free ranging wild carnivores, other than wild canids, in Europe. The existence of a possible sylvatic cycle could have important implications in both sylvatic and domestic cycles since they might influence the prevalence of infection in cattle farms in those areas.


Photoacoustic and photothermal cytometry using photoswitchable proteins and nanoparticles with ultrasharp resonances.
Photoswitchable fluorescent proteins (PSFPs) with controllable spectral shifts in emission in response to light have led to breakthroughs in cell biology. Conventional photoswitching, however, is not applicable to weakly fluorescent proteins. As an alternative, photothermal (PT) and photoacoustic (PA) spectroscopy have demonstrated a tremendous potential for studying absorbing nonfluorescent proteins and nanoparticles. However, little progress has been made in the development of switchable PT and PA probes with controllable spectral shifts in absorption. Here, we introduce the concept of photothermally switchable nanoparticles (PTSNs). To prove the concept, we demonstrated fast, reversible magnetic-PT switching of conventional and gold-coated magnetic nanoparticle clusters in cancer cells in vitro and PT switching of nonlinear ultrasharp plasmonic resonances in gold nanorods molecularly targeted to circulating cells in vivo. We showed that genetically encoded PSFPs with relatively slow switching can serve as triple-modal fluorescent, PT, and PA probes under static conditions, while PTSNs with ultrafast switching may provide higher PA sensitivity in the near-infrared window of tissue transparency under dynamic flow conditions. Application of nonlinear phenomena for super-resolution spectral PT and PA cytometry, microscopy, and spectral burning beyond the diffraction and spectral limits are also proposed.


Transcriptome resources for the perennial sunflower Helianthus maximiliani obtained from ecologically divergent populations.
Next-generation sequencing (NGS) technologies provide a rapid means to generate genomic resources for species exhibiting interesting ecological and evolutionary variation but for which such resources are scant or nonexistent. In the current report, we utilize 454 pyrosequencing to obtain transcriptome information for multiple individuals and tissue types from geographically disparate and ecologically differentiated populations of the perennial sunflower species Helianthus maximiliani. A total of 850 275 raw reads were obtained averaging 355 bp in length. Reads were assembled, postprocessing, into 16 681 unique contigs with an N50 of 898 bp and a total length of 13.6 Mb. A majority (67%) of these contigs were annotated based on comparison with the Arabidopsis thaliana genome (TAIR10). Contigs were identified that exhibit high similarity to genes associated with natural variation in flowering time and freezing tolerance in other plant species and will facilitate future studies aimed at elucidating the molecular basis of clinal life history variation and adaptive differentiation in H. maximiliani. Large numbers of gene-associated simple sequence repeats (SSRs) and single-nucleotide polymorphisms (SNPs) also were identified that can be deployed in mapping and population genomic analyses.


Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates.
Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post-translational modification caused by Ca(+2) -regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue-specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan-PAD inhibitor Cl-amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS-treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl-amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug-directed intervention in neurotrauma. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up-regulation of TNFα, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage.


Factors associated with urge urinary incontinence after surgery for stress urinary incontinence.
: The objectives of the study were to estimate the severity of urge urinary incontinence (UUI) after surgery for stress incontinence and identify factors associated with symptom severity. : Four hundred thirty-eight women who underwent surgery for stress incontinence over a 10-year period completed a mailed questionnaire protocol that included validated instruments to assess lower urinary tract function and mental and physical well-being. Bivariate analysis and generalized linear models were used to identify factors associated with severity of UUI as measured by the urge incontinence domain of the Incontinence Symptom Index. : Urge urinary incontinence was experienced daily by 35.9% of patients. Factors independently associated with higher UUI severity scores were preoperative mixed urinary incontinence (P = 0.006), depression (P < 0.001), aging (P < 0.001), and longer follow-up times (P = 0.01). Pubovaginal sling (P = 0.001) and urethral vaginal suspension (P = 0.04) had higher severity scores than Tension-Free Vaginal Tape. : Daily episodes of UUI are experienced by slightly more than one third of women after surgery for stress incontinence. Identification of factors associated with UUI may help physicians to modify treatment and patient expectations.


Study on Analysis of Peripheral Biomarkers for Alzheimer's Disease Diagnosis.
Many factors are involved in Alzheimer's disease (AD) pathology including tau phosphorylation, amyloid β protein (Aβ) accumulation, lipid dysregulation, oxidative stress, and inflammation. The markers of these pathological processes in cerebral spinal fluid are used currently for AD diagnosis. However, peripheral biomarkers are the need of the hour for large population screening for AD. The main objective of the present study is to evaluate the peripheral levels of redox markers, lipid peroxidation (LPO) indicators, and pathological markers in AD patients. Blood was collected from AD patients (n = 45), controls (n = 45), and analyzed for pathological markers of AD including Aβ42 and tau, LPO, and redox indicators. Plasma Aβ42 was significantly (P < 0.001) elevated while total tau was decreased in AD compared to controls. Hydroxynonenal (HNE) and malondialdehyde (MDA) were higher (P < 0.001) in AD patients pointing the enhanced LPO in AD pathology. Receiver operating characteristic curve (ROC) analysis indicated that HNE is a better indicator of LPO compared to MDA. Plasma glutathione (GSH) level was significantly (P < 0.001) low while oxidized glutathione (GSSG) level was higher (P < 0.001) in AD patients with corresponding decrease in GSH/GSSG ratio (P < 0.001). ROC analysis indicated that GSH/GSSG ratio can be used as reliable indicator for redox imbalance in AD with a cutoff value of <8.73 (sensitivity 91.1%, specificity 97.8%). Correlation analysis revealed a positive correlation for both HNE and MDA with Aβ42 and a negative correlation with total tau. Negative correlation was observed between GSH/GSSG ratio and LPO markers. While oxidative stress has been implicated in pathology of various neurodegenerative disorders, the present study pinpoints the direct link between LPO and Aβ production in plasma of AD patients. Normally, at low amyloid concentration in body fluids, this peptide shown to function as a strong metal chelating antioxidant. However, when the Aβ production enhanced as in AD, through gain of functional transformation, Aβ evolves into prooxidant, thereby enhancing oxidative stress and LPO. Altered redox status with enhanced LPO observed in AD blood could contribute to the oxidation and S-glutathionylation proteins, which has to be addressed in future studies.


Videothoracoscopic approach to primary mediastinal pathology.
Personal results and validity of videothoracoscopic (VTS) approach to primary mediastinal diseases are analyzed. Retrospective review of personal experience. Department of Surgery, San Giuseppe Hospital, University of Milano, Italy. From September 1991 to January 1999, of a personal series of 1,653 VTS procedures, 118 regarded primary mediastinal diseases. In 47 cases, diagnostic videothoracoscopy was performed to obtain large biopsy specimens or to carry out accurate staging; in 71 cases, full resection was anticipated. The patient, intubated with a double-lumen Carlen's tube and in the lateral decubitus position, underwent videothoracoscopy. Two ports and a small anterior utility thoracotomy were completed. Thorough exploration of the mediastinum and, if possible, complete resection of the lesion were accomplished. Videothoracoscopy yielded adequate diagnosis or staging in all patients operated on for diagnostic purposes. Of 71 patients operated on with resective intent, 66 had complete thoracoscopic resection (22 stage-I thymomas, 4 thymic cysts, 21 myasthenia gravis associated with thymic hyperplasia, 19 miscellaneous tumors). Conversion was required in five cases, mostly for invasion of mediastinal structures. Complications included the following: one patient developed intraoperative bleeding controlled endoscopically, two patients experienced postoperative bleeding requiring re-thoracoscopy, and one patient had postoperative pneumonia requiring assisted ventilation. One recurrence of malignant thymoma occurred 4 years postoperatively. Videothoracoscopy can attain a leading role in obtaining large samples in lymphatic mediastinal diseases. Dysembriomas, schwannomas, simple cysts, and similar lesions can benefit from VTS removal. Total thymectomy for myasthenia gravis associated with thymic hyperplasia can be performed thoracoscopically. Further data and more extensive experience are needed.


Automatic document classification of biological literature.
Document classification is a wide-spread problem with many applications, from organizing search engine snippets to spam filtering. We previously described Textpresso, a text-mining system for biological literature, which marks up full text according to a shallow ontology that includes terms of biological interest. This project investigates document classification in the context of biological literature, making use of the Textpresso markup of a corpus of Caenorhabditis elegans literature. We present a two-step text categorization algorithm to classify a corpus of C. elegans papers. Our classification method first uses a support vector machine-trained classifier, followed by a novel, phrase-based clustering algorithm. This clustering step autonomously creates cluster labels that are descriptive and understandable by humans. This clustering engine performed better on a standard test-set (Reuters 21578) compared to previously published results (F-value of 0.55 vs. 0.49), while producing cluster descriptions that appear more useful. A web interface allows researchers to quickly navigate through the hierarchy and look for documents that belong to a specific concept. We have demonstrated a simple method to classify biological documents that embodies an improvement over current methods. While the classification results are currently optimized for Caenorhabditis elegans papers by human-created rules, the classification engine can be adapted to different types of documents. We have demonstrated this by presenting a web interface that allows researchers to quickly navigate through the hierarchy and look for documents that belong to a specific concept.


Retreating glacier fronts on the Antarctic Peninsula over the past half-century.
The continued retreat of ice shelves on the Antarctic Peninsula has been widely attributed to recent atmospheric warming, but there is little published work describing changes in glacier margin positions. We present trends in 244 marine glacier fronts on the peninsula and associated islands over the past 61 years. Of these glaciers, 87% have retreated and a clear boundary between mean advance and retreat has migrated progressively southward. The pattern is broadly compatible with retreat driven by atmospheric warming, but the rapidity of the migration suggests that this may not be the sole driver of glacier retreat in this region.


Interaction of GB virus C/hepatitis G virus synthetic peptides with lipid langmuir monolayers and large unilamellar vesicles.
In this paper, we aimed to continue the previous study undertaken with one segment of E1 protein belonging to the GB virus C/hepatitis G virus (GBV-C/HGV), specifically between the 53-66 amino acids and their palmitoyl derivative peptide. The sequence selection has been made on the basis of different prediction algorithms of hydrophobicity and antigenicity. Their interactions between two different in vitro membrane models, lipid Langmuir monolayers and vesicles of different lipidic composition, have been evaluated. For this purpose, different lipids, varying the charge and the unsaturations of the hydrocarbon chain 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt) (DPPG) and 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt) (DOPG), have been selected. Miscibility and peptides/lipids interactions have been analyzed on the basis of surface pressure (pi)-mean molecular area (A) isotherms, which have been recorded for pure and mixed monolayers of different composition spread at the air/water interface. Furthermore, E1(53-66) sequence and PalmE1(53-66) have been labeled with a fluorescent group, succinimidyl 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoate (NBD succinimide), in order to study their behavior in the presence of vesicles. The obtained results are consistent with the existence of electrostatic (attractive) intermolecular interactions between the two positive net charges of the peptides and the polar heads of negative-charged lipids. However, both the lipidic membrane fluidity and the palmitic chain linked to the native peptide play an important role in the balance between the electrostatic forces established at the interface and the hydrophobic ones established inside the membrane. The fluorescence assays have demonstrated that electrostatic forces clearly predominate over the hydrophobic interactions only when the native sequence is retained at the polar interface of DPPG and DOPG vesicles. However, the palmitic tail linked to the peptide helped its penetration in the hydrophobic environment of the membrane, and this process was favored by decreasing the membrane fluidity.


Changes in the acetogenic population in a mesophilic anaerobic digester in response to increasing ammonia concentration.
Changes in the acetogenic population were investigated in an experimental laboratory-scale biogas reactor (37°C) subjected to gradually elevated ammonia levels (0.8 to 6.9 g NH(4)(+)-N L(-1)). A shift from aceticlastic acetate degradation to syntrophic acetate oxidation had previously been confirmed in this reactor. In a parallel control reactor, operating at constant ammonia levels (0.65-0.90 g NH(4)(+)-N L(-1)), acetate degradation proceeded via the aceticlastic pathway throughout the operating period (660 d). The acetogenic populations in the reactors were analysed using degenerated primers designed to target the functional gene encoding a key enzyme of the acetyl-CoA pathway, 10-formyltetrahydrofolate synthetase (FTHFS). The analysis consisted of terminal restriction fragment length polymorphism (T-RFLP) analysis coupled with the construction of clone libraries, and quantitative PCR (qPCR) analysis. The T-RFLP data obtained were statistically analysed by non-metric multidimensional scaling. The most abundant FTHFS genes recovered in the clone libraries were assigned to terminal restriction fragments of the T-RFLP profile. The results of the investigation clearly indicated that increased ammonia concentration substantially influenced the putative acetogenic population structure and caused two distinct shifts of the most abundant members; however, the identity of the dominating species remains unknown, as none of the genes had been identified previously. Despite the shifts in the population, the qPCR analysis revealed a relatively stable abundance of the acetogenic population throughout the operation.


Effects of fasting on serum lipids and lipoprotein profiles in the egg-laying hen (Gallus domesticus).
The effects of a 24-h fast on serum lipids and lipoprotein profiles in commercial laying hens were investigated. Blood was analyzed at 34 and 46 weeks of age from Single Comb White Leghorn hens that had been either fed ad libitum or had been fasted for 24 h prior to collection. At 12 weeks, birds were divided into 16 biological isolation units, with 8 replicate units assigned to each treatment group. Four birds out of 10 in each unit were tagged for bleeding. Parameters evaluated included total serum cholesterol and triglycerides, mean diameters of very low density lipoproteins (VLDLs) for the 10th, 50th, and 90th percentiles of serum total VLDL, mean total population VLDL particle diameter (MPD), and percentage serum cholesterol recovered in VLDL, low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions. Fasting led to decreases in total serum cholesterol and triglycerides, and a decrease in mean serum VLDL particle diameter in the 90th population percentile. At Week 34, percentage serum cholesterol recovered from LDL was increased, whereas percentage serum cholesterol recovered from HDL was decreased due to fasting. At Week 46, MPD and percentage serum cholesterol recovered from VLDL were decreased, whereas percentage serum cholesterol recovered from HDL was increased due to fasting. It was concluded that a 24-h fast decreased serum lipids (cholesterol and triglycerides) and the size of VLDL particles in the 90th population percentile in commercial laying hens. Furthermore, bird age influenced the effects of a 24-h fast on MPD and the redistribution of serum cholesterol among VLDL, LDL, and HDL particles.


In situ cytokine immune responses in acute disseminated encephalomyelitis: insights into pathophysiologic mechanisms.
Acute disseminated encephalomyelitis (ADEM) is thought to be an autoimmune disorder of the central nervous system in which myelin is targeted. Pathological studies on closely related human diseases (eg, multiple sclerosis) and on animal models for these demyelinating disorders have suggested the involvement of cytokines. Studies on peripheral immunocytes and on cerebrospinal fluid revealed the presence of cytokine-mediated responses in ADEM. We carried out this neuroimmunopathologic exploration and report for the first time the in situ expression of "inflammatory" cytokines in ADEM. Moreover, we note a particular spatial and molecular pattern whereby tumor necrosis factor-alpha and interleukin (IL)-1beta are intensely expressed, whereas IL-6 is absent. Differential expression at different levels of the neuraxis was also noticed. Our findings suggest that these cytokines, reported to be toxic to myelin, are implicated in the molecular cascade, resulting in the neural damage. These observations might provide insights into molecular pathways involved in the immunopathogenesis of ADEM and might open new horizons in neuroimmunomodulation and anticytokine treatment.


Accuracy of family history of cancer: clinical genetic implications.
Family medical history is the cornerstone of clinical genetic diagnosis and management in cases of familial cancer. The soundness of medical decisions can be compromised if reports by the family on affected relatives are inaccurate. Although very time consuming, family medical histories are therefore routinely verified. To investigate whether such verification is clinically justified, we retrospectively analysed the accuracy of a consecutive series of 383 tumour reports from counsellees on 120 families in our clinic. We evaluated these families for the impact of verification on clinical genetic diagnosis and management. Accuracy according to cancer type showed marked variation, ranging from 93% and 89% for breast cancer and colorectal cancer, respectively, to 42% and 37% for extra-colorectal alimentary tract cancer and uterine cancer. Accuracy was related to the degree of kinship of the affected relative, but not to age and gender of the counsellee, nor to the reason for referral or personal history of cancer. Age at diagnosis and multiple primary tumours were reported accurately in 97% and 94% of cases, respectively. In six out of 120 families verification data changed clinical genetic management, in five of these the genetic risk was reduced. Although verification of all reported cancer cases in a family remains the 'gold standard' for clinical as well as research purposes, verification of reports on breast cancer can be limited without seriously compromising medical decision making. In cases where verification is impossible because medical records are unavailable, findings from studies such as ours may help in interpreting family histories.


[Comparison of event-related potentials components characteristics obtained during stimulation of symbolical and alphabetic matrixes used in brain-computer interface paradigm].
In order to create a brain-computer interface (BCI) on the basis of paradigm P300 (the so-called Farwell-Donchin paradigm, FD) with a symbolical matrix used as stimuli, there were compared characteristics of event-related potentials (ERP) obtained from stimulation both by symbolical and alphabetical matrixes. The matrixes contained 6 x 6 signs (cyrillic letters or symbols-pictograms). Nine healthy adults were examined in 18 experiments during which 28 channel EEG were recorded while matrixes of two types (containing either cyrillic letters or symbols-pictograms) were used for stimulation. The obtained ERP data, i.e. amplitudes and peak latencies of the following components of ERP: N1, P3 with sub-components P3a and P3b, N4 were compared and analized for different types of the stimulation matrixes. Similar changes in amplitude or peak latency received from 7 or more out of 9 examinees were taken into consideration, matching the criteria of significance. It was discovered that for components P3a, P3b and N4 the amplitudes of ERP in response to a symbolic matrix were bigger than to a letter matrix, the opposite being true for component N1. Latent periods of ERP components were shorter for a symbolic matrix than for a letter matrix in case of components N1 and P3a, and longer in case of P3b and N4. In order to find out which zones of the brain react to stimulation the most, there was conducted a pair t-test (series of pair t-tests) to analize the topography of variety of ERP responses to different types of stimuli, and, through comparing the amplitudes of ERP components, a topographical map detailing the variety of responses to the different types of matrixes was obtained. The data about the differences were analized separately for each of 28 channels, then the (absolute magnitude t-test) were summed up algebraically for all the nine examinees. Thus, it was shown, for amplitudes of all the tested ERP components in the case of pair "significant-insignificant letters", the topography of the t-test is represented by two separate areas with distinct lateralization. In the case of pair "significant-insignificant symbols", the field of maximum responses streanch in croas direction. In the case of pair "significant letters-significant symbols" the topography is elaboratly orgenised.


The association of enzymatic and non-enzymatic antioxidant defense parameters with inflammatory markers in patients with exudative form of age-related macular degeneration.
There are evidence that oxidative stress and inflammation are involved in the pathogenesis of the age-related macular degeneration (AMD). The aim of this study was to analyze the antioxidant defense parameters and inflammatory markers in patients with exudative form of AMD (eAMD), their mutual correlations and association with the specific forms of AMD. The cross-sectional study, included 75 patients with the eAMD, 31 patients with the early form, and 87 aged-matched control subjects. Significantly lower SOD, TAS and albumin values and higher GR, CRP and IL-6 were found in the eAMD compared to the early form (p<0.05). Significant negative correlations were found between GPx and fibrinogen (r = -0.254), TAS and IL-6 (r = -0.999) and positive correlations between uric acid and CRP (r = 0.292), IL-6 and uric acid (r = 0.398) in the eAMD. A significant association of CRP (OR: 1.16, 95% CI: 1.03-1.32, p = 0.018), fibrinogen (OR: 2.21, 95% CI: 1.14-4.85, p = 0.021), TAS (OR: 7.45, 95% CI: 3.97-14.35, p = 0.0001), albumin (OR: 1.25, 95% CI: 1.11-1.41, p = 0.0001) and uric acid (OR: 1.006, 95% CI: 1.00-1.02, p = 0.003) was found with the eAMD. In conclusion it may be suggested, there is a significant impairment of antioxidant and inflammatory parameter levels in eAMD patients. In addition, significant association exists between the tested inflammatory markers and antioxidant parameters with late-eAMD.


Preserving global land and water resources through the replacement of livestock feed crops with agricultural by-products.
While animal-source foods contribute to 16% of the global food supply and are an important protein source in human diets, their production uses a disproportionately large fraction of agricultural land and water resources. Therefore, a global comprehensive understanding of the extent to which livestock production competes directly or indirectly with food crops is needed. Here we use an agro-hydrological model combined with crop-specific yield data to investigate to what extent the replacement of some substitutable feed crops with available agricultural by-products would spare agricultural land and water resources that could be reallocated to other uses, including food crop production. We show that replacing 11-16% of energy-rich feed crops (that is, cereals and cassava) with agricultural by-products would allow for the saving of approximately 15.4-27.8 Mha of land, and 3-19.6 km3 and 74.2-137.8 km3 of blue and green water, respectively, for the growth of other food crops, thus providing a suitable strategy to reduce unsustainable use of natural resources both locally or through virtual land and water trade.


Can axillary and supraclavicular radiotherapy be avoided after breast-conserving surgery and axillary dissection in women with multiple involved axillary nodes? Experience at the European Institute of Oncology.
Although some guidelines recommend adjuvant radiotherapy (RT) to the axilla and supraclavicular nodes if 4 or more axillary nodes are involved, the current practice at our Institute is not to irradiate the axilla but to perform complete axillary dissection in which all 3 Berg levels are removed. We performed a retrospective analysis of patients with 4 or more axillary nodes involved and sufficient follow-up to provide indications as to whether our current treatment is adequate. We retrospectively analyzed 287 T1-T3 patients with a median follow-up of 5 years and 4 or more involved nodes treated by quadrantectomy and breast RT but no axillary RT; supraclavicular RT was given only when prognostic factors were unfavorable. A total of 170 (59.2%) patients did not receive supraclavicular RT, while 117 (40.8%) patients received supraclavicular irradiation. No patient received axillary RT. After a median follow-up of 5 years (range, 4-105 months), 4.7% had died and 13.5% had developed distant metastases in the no supraclavicular RT group, compared to 12.0% dead (P = 0.028 log rank) and 24.8% (P = 0.201 log rank) in the supraclavicular RT group. No patients with supraclavicular RT developed supraclavicular metastases compared to 4 in the no supraclavicular RT group. There were no axillary recurrences. Complete axillary dissection appears adequate treatment in patients with 4 or more involved nodes. The low breast recurrence rate also suggests that breast conservation is adequate treatment in such patients. Supraclavicular RT appears to reduce the number of supraclavicular metastases but confers no survival advantage. Although a small number of cases were examined in this retrospective single-center series, all received highly uniform treatment.


Rethinking the neurophysiological concept of cortical myoclonus.
Cortical myoclonus is thought to result from abnormal electrical discharges arising in the sensorimotor cortex. Given the ease of recording of cortical discharges, electrophysiological features of cortical myoclonus have been better characterized than those of subcortical forms, and electrophysiological criteria for cortical myoclonus have been proposed. These include the presence of giant somatosensory evoked potentials, enhanced long-latency reflexes, electroencephalographic discharges time-locked to individual myoclonic jerks and significant cortico-muscular connectivity. Other features that are assumed to support the cortical origin of myoclonus are short-duration electromyographic bursts, the presence of both positive and negative myoclonus and cranial-caudal progression of the jerks. While these criteria are widely used in clinical practice and research settings, their application can be difficult in practice and, as a result, they are fulfilled only by a minority of patients. In this review we reappraise the evidence that led to the definition of the electrophysiological criteria of cortical myoclonus, highlighting possible methodological incongruencies and misconceptions. We believe that, at present, the diagnostic accuracy of cortical myoclonus can be increased only by combining observations from multiple tests, according to their pathophysiological rationale; nevertheless, larger studies are needed to standardise the methods, to resolve methodological issues, to establish the diagnostic criteria sensitivity and specificity and to develop further methods that might be useful to clarify the pathophysiology of myoclonus.


Fast and pervasive transcriptomic resilience and acclimation of extremely heat-tolerant coral holobionts from the northern Red Sea.
Corals from the northern Red Sea and Gulf of Aqaba exhibit extreme thermal tolerance. To examine the underlying gene expression dynamics, we exposed Stylophora pistillata from the Gulf of Aqaba to short-term (hours) and long-term (weeks) heat stress with peak seawater temperatures ranging from their maximum monthly mean of 27 °C (baseline) to 29.5 °C, 32 °C, and 34.5 °C. Corals were sampled at the end of the heat stress as well as after a recovery period at baseline temperature. Changes in coral host and symbiotic algal gene expression were determined via RNA-sequencing (RNA-Seq). Shifts in coral microbiome composition were detected by complementary DNA (cDNA)-based 16S ribosomal RNA (rRNA) gene sequencing. In all experiments up to 32 °C, RNA-Seq revealed fast and pervasive changes in gene expression, primarily in the coral host, followed by a return to baseline gene expression for the majority of coral (>94%) and algal (>71%) genes during recovery. At 34.5 °C, large differences in gene expression were observed with minimal recovery, high coral mortality, and a microbiome dominated by opportunistic bacteria (including Vibrio species), indicating that a lethal temperature threshold had been crossed. Our results show that the S. pistillata holobiont can mount a rapid and pervasive gene expression response contingent on the amplitude and duration of the thermal stress. We propose that the transcriptomic resilience and transcriptomic acclimation observed are key to the extraordinary thermal tolerance of this holobiont and, by inference, of other northern Red Sea coral holobionts, up to seawater temperatures of at least 32 °C, that is, 5 °C above their current maximum monthly mean.


A comparison of the burden and resultant risk associated with occupational falls from a height and on the same level in Australia.
Occupational falls are one of the leading causes of occupational injury and death internationally. This study described the nature of occupational falls following an analysis of workers compensation data in Western Australia. Frequencies, proportions and incidence rates were calculated following mechanism, gender, age and industry stratification. The natures of injury and bodily locations affected were compared between mechanisms of fall. Industry incidence rates were ranked and their corresponding proportions reported. Cost and lost time were described and risk scores for each burden type (incapacity, cost and lost time) were calculated and compared between fall mechanisms. Of all occupational falls, the proportion, incidence rates and risk scores of falls on same level were consistently greater compared to falls from a height. Gender, age and industry groups that appear to be at highest risk vary with the measure used and mechanism of incident. This study translates epidemiological information into a risk score that can aid in prioritisation. Practitioner Summary: This paper presents an in-depth analysis of Worker's Compensation claims for falls in Western Australia. Calculated proportion, incidence rates and formulated risk scores for falls on the level were consistently greater compared to falls from a height. Limitations associated with the analysis of large-scale data-sets are described.


The contingency symmetry bias (affirming the consequent fallacy) as a prerequisite for word learning: A comparative study of pre-linguistic human infants and chimpanzees.
Humans are known to possess an "affirming the consequent fallacy," which assumes that a learned contingency holds true even when the order is reversed. In contrast, non-human animals do not fall for this fallacy, as they do not have the contingency symmetry bias. Importantly, language is founded on the symmetrical relationship between symbols and referents, and the contingency symmetry bias plays a key role in word learning. A critical problem for the ontogenesis of language is whether the contingency symmetry bias has been acquired through the experience of word learning or if it is present before infants begin word learning. Using a habituation switch paradigm, 8-month-old human infants and adult chimpanzees were familiarized with two object-then-movement sequences, whereby Object A (or B) was always paired with Movement A (or B). At test, the order of the contingency was reversed. The infants showed surprise when observing the violation of the object-movement pairings in the reversed sequence (Experiment 1). In contrast, despite the chimpanzees being able to detect the violation of the pairings in the original direction (Experiment 2a), they did not discriminate the learned and novel pairings when the order of the contingency was reversed (Experiment 2b). The results suggest that the contingency symmetry bias is a uniquely human cognitive bias, one which plays a critical role for language acquisition ontogenetically. This contingency symmetry bias likely gives humans a great advantage, by enabling them to rapidly expand their knowledge without direct training and making them strikingly different from other animal species. (250 words).


Radioimmunological and immunohistochemical study of carcinoembryonic antigen in pleomorphic adenoma and mucoepidermoid carcinoma of the salivary glands.
The aim of the present study was the evaluation of CEA-radio-immunoassay and CEA-immunohistochemistry in the management of pleomorphic adenoma and mucoepidermoid carcinoma of salivary glands. 23 pleomorphic adenomas, 9 mucoepidermoid carcinomas, and 7 normal salivary glands were examined. CEA-concentration in serum and saliva were assayed before and after surgery. Polyclonal CEA antibody was used for immunohistochemical CEA detection in the tumor tissue and in the normal salivary glands. The mean CEA concentrations were found to be 14.94 ng/ml in the serum and 216.67 ng/ml in the saliva of patients with mucoepidermoid carcinoma. These values were considerably higher compared to healthy controls (188.64 ng/ml in saliva) and in patients with pleomorphic adenoma - 7.65 ng/ml in serum and 189.35 ng/ml in saliva (P < 0.001). A correlation was found between high CEA concentration in the saliva and the intensity of CEA expression in the tumour tissue. An increased synthesis and secretion of CEA was determined by the prevalence of tubular structures, a high proliferative activity in pleomorphic adenoma, and its malignant transformation.


Influence of surface temperature on the mechanism of atomic layer deposition of aluminum oxide using an oxygen plasma and ozone.
We have examined the role of substrate temperature on the surface reaction mechanisms during the atomic layer deposition (ALD) of Al(2)O(3) from trimethyl aluminum (TMA) in combination with an O(2) plasma and O(3) over a substrate temperature range of 70-200 °C. The ligand-exchange reactions were investigated using in situ attenuated total reflection Fourier transform infrared spectroscopy. Consistent with our previous work on ALD of Al(2)O(3) from an O(2) plasma and O(3) [Rai, V. R.; Vandalon, V.; Agarwal, S. Langmuir 2010, 26, 13732], both -OH groups and carbonates were the chemisorption sites for TMA over the entire temperature range explored. The concentration of surface -CH(3) groups after the TMA cycle was, however, strongly dependent on the surface temperature and the type of oxidizer, which in turn influenced the corresponding growth per cycle. The combustion of surface -CH(3) ligands was not complete at 70 °C during O(3) exposure, indicating that an O(2) plasma is a relatively stronger oxidizing agent. Further, in O(3)-assisted ALD, the ratio of mono- and bidentate carbonates on the surface after O(3) exposure was dependent on the substrate temperature.


Stabilization of TiO2 nanoparticles in complex medium through a pH adjustment protocol.
Preparing TiO(2) nanoparticle (NP) suspensions displaying well-defined and reproducible dispersion state is a key feature to perform relevant toxicity experiments for environmental, animal, or human concerns. Relying on the evolution of surface charge with pH, and interactions between nanoparticles in their medium, we developed an optimized dispersion protocol involving a pH adjustment before addition of bovine serum albumin (BSA). It yielded highly dispersed and stable concentrated stock suspensions of TiO(2) NP at pH 7. It was designed for four kinds of manufactured TiO(2) nanomaterials and can be extended to a wide range of TiO(2) NP. The suspensions studied here were characterized by small-angle X-ray scattering (SAXS), using a model quantitatively describing fractal aggregates. Results were correlated with dynamic light scattering (DLS) measurements. Moreover, the stability in a typical biological medium was assessed by diluting stock suspensions in Luria-Bertani (LB) medium. It resulted in highly dispersed and stable working suspensions. No sedimentation, followed by in situ DLS, was observed over 17 h for both the concentrated stock suspensions prepared according to the pH adjusted-BSA protocol and their dilution into LB medium.


Melanopsin and non-melanopsin expressing retinal ganglion cells innervate the hypothalamic suprachiasmatic nucleus.
Retinal input to the hypothalamic suprachiasmatic nucleus (SCN) synchronizes the SCN circadian oscillator to the external day/night cycle. Retinal ganglion cells that innervate the SCN via the retinohypothalamic tract are intrinsically light sensitive and express melanopsin. In this study, we provide data indicating that not all SCN-projecting retinal ganglion cells express melanopsin. To determine the proportion of ganglion cells afferent to the SCN that express melanopsin, ganglion cells were labeled following transsynaptic retrograde transport of a recombinant of the Bartha strain of pseudorabies virus (PRV152) constructed to express the enhanced green fluorescent protein (EGFP). PRV152 injected into the anterior chamber of the eye retrogradely infects four retinorecipient nuclei in the brain via autonomic circuits to the eye, resulting in transneuronally labeled ganglion cells in the contralateral retina 96 h after intraocular infection. In animals with large bilateral lesions of the lateral geniculate body/optic tract, ganglion cells labeled with PRV152 are retrogradely infected from only the SCN. In these animals, most PRV152-infected ganglion cells were immunoreactive for melanopsin. However, a significant percentage (10-20%) of EGFP-labeled ganglion cells did not express melanopsin. These data suggest that in addition to the intrinsically light-sensitive melanopsin-expressing ganglion cells, conventional ganglion cells also innervate the SCN. Thus, it appears that the rod/cone system of photoreceptors may provide signals to the SCN circadian system independent of intrinsically light-sensitive melanopsin ganglion cells.


Cost-effectiveness of High-performance Biomarker Tests vs Fecal Immunochemical Test for Noninvasive Colorectal Cancer Screening.
Biomarker assays could increase the accuracy of noninvasive detection of colorectal cancer (CRC); fecal immunochemical tests (FITs) are estimated to miss 27%-47% of CRCs and 70%-80% of advanced adenomas per round of screening. We investigated the conditions under which biomarker screens would be cost-effective compared with FIT screens of average-risk individuals. We used the MISCAN-Colon microsimulation model to estimate the effects of various CRC screening test characteristics on life-years gained (LYG) and; age-specific all-cause mortality was based on the 2010 Dutch life tables. Simulated CRC incidence rate and CRC stage distribution were calibrated to observed data in The Netherlands from 1999 through 2003 (before opportunities for screening). Survival rates after diagnosis of CRC at an age younger than 75 years were based on CRC relative survival data from 1985 through 2004; survival for individuals diagnosed at an age of 75 years or older was adjusted to fit the observed age-increasing mortality/incidence ratio. We modeled FIT along with hypothetical biomarker tests with different test performance levels. For each biomarker test we calculated the maximum unit cost for the test to be cost-effective compared with FIT, assuming a willingness-to-pay threshold of €50,000 ($56,000) per LYG. Biennial FIT screening of subjects 55-75 years old provided 84.9 LYG at a cost of €122,000 ($137,000) per 1000 participants. Considering a unit cost of €7 ($8) for FIT (including kit and analysis only, excluding organizational costs), a biomarker test that detects CRC with higher levels of specificity and sensitivity (100%) and advanced adenomas at a proportionally higher level of sensitivity (53%) should never exceed a cost of €51 ($57). The threshold cost could increase to more than €200 ($224) for high-performing biomarker tests in cases of limited colonoscopy capacity or higher uptake of this test. By using the MISCAN-Colon microsimulation model to estimate effects of CRC screening tests, we found that for a biomarker test with increased overall performance to be cost-effective, it should not exceed 7-fold the unit cost of FIT. This maximum would increase substantially if colonoscopy becomes more expensive or scarce, or if the new test has higher screening uptake. These values could be used to estimate the added value of new biomarkers compared with current FIT screening.


Renal hemodynamics in Otsuka Long-Evans Tokushima fatty rat, a model rat of spontaneous non-insulin-dependent diabetes mellitus with obesity.
Renal hemodynamic features in obese non-insulin-dependent diabetic rats remain unknown. We investigated renal hemodynamic and morphologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at the age of 5 and 10 months compared with age-matched lean nondiabetic control rats (LETO). OLETF rats showed obesity compared with age-matched LETO rats. Hyperglycemia was mild in 5-month-old OLETF rats and moderate in 10-month-old OLETF rats. The absolute value for glomerular filtration rate (GFR) was significantly higher in OLETF rats than in age-matched LETO rats at the age of 5 and 10 months. Ten-month-old OLETF rats had significantly higher absolute values for renal plasma flow (RPF) than age-matched LETO rats but not 5-month-old OLETF rats. Stepwise multiple regression analysis revealed that body weight was a powerful determinant of GFR and RPF. When factored for body weight, no difference in GFR was demonstrated between 5-month-old OLETF and LETO rats, whereas 10-month-old OLETF rats still had significantly higher GFR and RPF than age-matched LETO rats. Renal hypertrophy was demonstrated in both 5- and 10-month-old OLETF rats even when factored for body weight. Glomerular volume was significantly increased in 10-month-old OLETF rats, but the ratio of glomerular volume to body weight was not different among the groups. Both absolute value for glomerular capillary length free from mesangial area and the value factored for glomerular area were significantly longer in OLETF rats than in age-matched LETO rats. Mesangial matrix expansion was remarkable in 10-month-old OLETF rats, and the glomerular sclerosis index was significantly higher in 10-month-old OLETF rats than in age-matched LETO rats. Stepwise multiple regression analysis revealed that body weight, hemoglobin A1c, and hypertriglyceridemia were powerful determinants for kidney weight and glomerular volume. These data suggest that renal hyperfiltration and hypertrophy observed in 10-month-old OLETF rats are related to diabetic metabolic disorders and that obesity-related conditions may be involved in the renal hemodynamic and morphologic features in OLETF rats.


Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort.
DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Västerbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.


BET 1: Everything in graduation: arterial/end-tidal CO2 gradient and the diagnosis of pulmonary embolism.
A short cut review was carried out to establish the diagnostic characteristics of alveolar dead space fraction (AVDSf) in the diagnosis of pulmonary embolism (PE). This is calculated from the arterial and end-tidal CO2 Three papers were selected to answer the clinical question. The author, study type, relevant outcomes, results and weaknesses are tabulated. It is concluded that there is good evidence to support the use of AVDSf within a clinical prediction model to exclude a PE in patients when there is a low pretest probability. However, the specificity is not sufficient to support it as a 'rule in' test.


Thumb digital neuropathy caused by splinting.
Healthcare professionals are currently faced with a great variety of splints and splinting materials. Choices range from prefabricated products to custom splints made on-site from plaster, orthoplast, or fiberglass. In addition to providing immobilization to maintain a particular posture, a splint must protect important soft tissues. Patients with hand or wrist injuries often receive a prefabricated metal cock-up wrist splint in emergency departments. Complications from splints are not uncommon but are infrequently reported. We report a case in which a metal wrist cock-up splint caused compression of the thumb ulnar digital nerve. Preventive measures for such complication are included.


[Assessment of the severity of grave cranio-cerebral injury and its outcome according to the state of energy metabolism in the brain].
A dynamic study of the arteriovenous oxygen and lactic acid content difference, as well as a study of the CSF content of the lactic acid in patients with a severe craniocerebral trauma permitted to evaluate the severity of the pathological process and the results of its treatment. A growing production of lactic acid by the brain and its progressive accumulation in the CSF to a high level as 45-50 mg%, and a sharp dissociation between the increasing lactate level in the CSF and its growing concentration in the venous blood flowing from the brain is a prognostic sign of an unfavourable course and outcome of the disease.


Efflux transporter breast cancer resistance protein dominantly expresses on the membrane of red blood cells, hinders partitioning of its substrates into the cells, and alters drug-drug interaction profiles.
1. Red blood cell (RBC) partitioning is important in determining pharmacokinetic and pharmacodynamic properties of a compound; however, active transport across RBC membranes is not well understood, particularly without transporter-related cell membrane proteomics data. 2. In this study, we quantified breast cancer resistance protein (BCRP/Bcrp) and MDR1/P-glycoprotein (P-gp) protein expression in RBCs from humans, monkeys, dogs, rats and mice using nanoLC/MS/MS, and evaluated their effect on RBC partitioning and plasma exposure of their substrates. BCRP-specific substrate Cpd-1 and MDR1-specific substrate Cpd-2 were characterized using Caco-2 Transwell® system and then administered to Bcrp or P-gp knockout mice. 3. The quantification revealed BCRP/Bcrp but not MDR1/P-gp to be highly expressed on RBC membranes. The knockout mouse study indicated BCRP/Bcrp pumps the substrate out of RBCs, lowering its partitioning and thus preventing binding to intracellular targets. This result was supported by a Cpd-1 and Bcrp inhibitor ML753286 drug-drug interaction (DDI) study in mice. Because of enhanced partitioning of Cpd-1 into RBCs after BCRP/Bcrp inhibition, Cpd-1 plasma concentration changed much less extent with genetic or chemical knockout of Bcrp albeit marked blood concentration increase, suggesting less DDI effect. 4. This finding is fundamentally meaningful to RBC partitioning, pharmacokinetics and DDI studies of BCRP-specific substrates.


Evaluation of ankylosing spondylitis quality of life (EASi-QoL): reliability and validity of a new patient-reported outcome measure.
There is currently no universally accepted measure of quality of life in ankylosing spondylitis (AS). Our objective was to develop and evaluate a patient-reported outcome measure of quality of life in AS, EASi-QoL. We used patient interviews, a literature review, and completion of an individualized measure of AS quality of life during clinic-based and pilot surveys to derive questionnaire content. Classical and modern psychometrics were then used to evaluate the questionnaire using data from a large UK-based postal survey of 1000 patients with AS. Data analysis from the interviews and clinic-based and postal surveys produced a 57-item self-completed questionnaire. Fifteen items were removed as a result of patient interviews and the pilot survey. In total, 612 (64.0%) patients responded to the main postal survey. After assessment of data quality, confirmatory factor analysis, and Rasch analysis, 20 items were found to contribute to 4 domains of AS-related quality of life: physical function, disease activity, emotional well-being, and social participation. Item-total correlations ranged from 0.66 to 0.84. Cronbach's alpha and test-retest reliability estimates were 0.88-0.92 and 0.88-0.93, respectively. Confirmed hypothesized correlations with the AS Quality of Life questionnaire, the Bath AS Disease Activity Index, Bath AS Functional Index, SF-36, EQ-5D, and the Hospital Anxiety and Depression Scale were evidence for the construct validity of the EASi-QoL. The EASi-QoL has good evidence of data quality, internal reliability, test-retest reliability, and content and construct validity, and should be considered for use with patients in routine practice settings and in evaluative studies including clinical trials. Measurement responsiveness and minimal important change are currently being assessed.


[Aortic Valve Regurgitation with Dove-coo Murmur: Report of Two Cases].
We performed aortic valve replacement in 2 patients with aortic regurgitation (AR) in whom a "dovecoo" murmur was heard. Here we discuss the valve shape and the origin of the heart murmur. In the 1st patient, echocardiography revealed prolapse of the right coronary valve cusp toward the left ventricular outflow tract during the diastolic phase and fibrillation of the valve leaflet due to the AR jet. In the 2nd patient, surgical findings revealed thickening of the middle part of the leaflet of the right coronary cusp, which caused prolapse of the right coronary valve cusp toward the left ventricle. We hereby report 2 rare cases of "dove-coo" murmur in which the cause of the murmur was morphologically confirmed by echocardiography in one case and by surgical findings in the other case.


Novel Bending and Helical Extensile/Contractile Pneumatic Artificial Muscles Inspired by Elephant Trunk.
Pneumatic artificial muscles (PAMs) are an extensively investigated type of soft actuator. However, the PAM motions have been limited somewhat to uniaxial contraction and extension, restraining the development of PAMs. Given the current strong interest in soft robotics, PAMs have been gaining renewed attention due to their excellent compliance and ease of fabrication. Herein, under the inspiration of the elephant trunk, a family of bending and helical extensile PAMs (HE-PAMs)/helical contractile PAMs (HC-PAMs) was proposed and analyzed. Through both experiment and analysis, a model of generalized bending behavior of PAMs was built and developed to investigate the properties of axial, bending, and helical PAMs in the same theoretical framework. The topological equivalence and bifurcation were found in the analysis and utilized to explain the behaviors of these different PAMs. Meanwhile, a coupled constant curvature and torsion kinematics model was proposed to depict the motion of PAMs more accurately and conveniently. Moreover, a soft tandem manipulator consisting of bending and helical PAMs was proposed to demonstrate their attractive potential.


[Lafora disease. A new case of confirmation of diagnosis on molecular genetic studies].
Lafora s disease is a type of progressive myoclonic epilepsy with bad prognosis. Until now diagnosis was based on finding characteristic intracytoplasmatic polyglucosan bodies in biopsies of sweat secreting cells in the skin. Recently the gene responsible has been discovered. This permits firm diagnosis and screening of carriers. We present the case of a child diagnosed on molecular genetic studies. A 12 year old boy with a clinical history of three febrile seizures at the age of one year but no other abnormalities, presented a seizure of visual disorder with secondary generalization. There was no family history of seizures. Following a period of normality he had further seizures (clonic, visual and generalized myoclonic). The EEG showed generalized spike and wave activity, which was more marked after stimulation by light and became progressively worse. Neuroimaging studies were normal. In spite of treatment there was a progressive increase in visual and generalized myoclonic seizures together with deterioration of cognitive function and ataxia. Histological studies of the sweat glands showed homogeneous nodular deposits of intracytoplasmatic PAS+. Molecular studies of the EPM2A gene linked to chromosome 6q24 showed the presence of two mutations on the 1 and 4 exons. We describe a 12 year old patient with all the clinical features of Lafora type progressive myoclonic epilepsy in whom characteristic cytoplasmic bodies were found in the sweat gland biopsy. Molecular genetic studies of the EPM2A gene confirmed diagnosis of the disorder.


Unidirectional Emission of a Site-Controlled Single Quantum Dot from a Pyramidal Structure.
Emission control of a quantum emitter made of semiconductor materials is of significance in various optical applications. Specifically, the realization of efficient quantum emitters is important because typical semiconductor quantum dots are associated with low extraction efficiency levels due to their high refractive index contrast. Here, we report bright and unidirectional emission from a site-controlled InGaN quantum dot formed on the apex of a silver-coated GaN nanopyramidal structure. We show that the majority of the extracted light from the quantum dot is guided toward the bottom of the pyramid with high directionality. We also demonstrate that nanopyramid structures can be detached from a substrate, thus demonstrating great potential of this structure in various applications. To clarify the directional radiation, the far-field radiation pattern is measured using Fourier microscopy. This scheme will pave the way toward the realization of a bright and unidirectional quantum emitter along with easy fabrication and large-area reproducibility.


Use of the Internet by parents of middle school students: internet rules, risky behaviours and online concerns.
Using the Internet is a daily occurrence for parents and children in today's world. Although they use the Internet differently, many individuals may face online hazards that they may be ill equipped to deal with. To better understand Internet use and online behaviours, a study was conducted with 227 parents of early adolescent (ages 11 to 14 years) middle school students (grades 6, 7 and 8). Four important findings emerged: (1) parents are using the Internet like their children but have different online behaviours; (2) parents have Internet use rules at home; (3) parents are participating in risky Internet behaviours (electronic aggression, intentional online harassment and communication with online strangers); and (4) parents are concerned about their child's online safety, specifically about the exposure to sexually explicit materials and online strangers, but the majority of parents do not know where to report negative or unsafe Internet experiences. Nurses, clinicians, healthcare providers and other professionals can and do provide comprehensive care to families by identifying needs and areas of knowledge deficit. By asking Internet use questions, nurses and other professionals are able to develop plans of care for all family members that will promote Internet safety and healthy lifestyle choices.


Preparing children for international travel: need for training and pediatric-focused research.
The International Society of Travel Medicine (ISTM) Pediatric Interest Group (PedIG) was created in 2010. We studied the group's professional characteristics and practice patterns to identify clinical areas requiring further training and research related to pediatric international travel. PedIG members were emailed a two-part online questionnaire in September 2011, which comprised questions about professional and practice details, followed by a survey regarding decisions on nine patient scenarios that represent common pediatric pre-travel health challenges. Ninety-three (34%) of 273 members completed the survey. Most were physicians (80%) having a primary specialization in pediatrics (55%) and family medicine (19%). About a third (37%) had acquired the ISTM Certificate in Travel Health (CTH); 14 and 11% chose not to provide malaria chemoprophylaxis for a 2-month-old infant and a 13-year-old child traveling to West Africa, respectively. Azithromycin for empiric treatment of travelers' diarrhea in a 2-year-old traveler to Thailand and Mexico was suggested by 74 and 58%, respectively, while the use of acetazolamide for a 2-month old infant traveling to a high-altitude destination was rarely (13%) chosen. In vaccine-focused scenarios, 71, 69, 21, and 10% would prescribe the meningococcal vaccine for a 6-month-old traveler to Burkina Faso, Japanese encephalitis vaccine to a 10-year-old traveler to Cambodia, hepatitis A vaccine to a 6-month-old traveler to El Salvador, and the typhoid vaccine to a 1-year-old traveler to India, respectively. Members of the PedIG have diverse professional and practice backgrounds. Lack of awareness of established guidelines may place international pediatric travelers at risk for travel-associated morbidity. Strategies are needed to facilitate education and support research in pediatric travel medicine to formulate evidence-based guidelines wherever they are currently missing.


Pressure natriuresis in salt-sensitive and salt-resistant Sabra rats.
Salt-resistant (SBN/y) and salt-sensitive (SBH/y) Sabra rats are a useful model of salt-sensitive hypertension with incompletely explored renal mechanisms. We investigated their pressure-natriuresis curves, with and without deoxycorticosterone acetate (DOCA)-salt treatment. To differentiate between extrinsic neural and hormonal mechanisms and intrinsic renal influences, we performed experiments with neural denervation, adrenalectomy, and infusions of vasopressin, norepinephrine, 17-hydroxycorticosterone, and aldosterone as well as without these maneuvers. In untreated SBN/y without controlled neural and circulating hormonal factors, urine flow and sodium excretion increased from 32 to 95 microL/min per gram kidney weight (gkwt) and from 4 to 17 mumol/min per gkwt, respectively, as renal perfusion pressure was increased from 85 to 146 mm Hg. Renal blood flow and glomerular filtration rate were autoregulated and averaged 7.5 and 1.2 mL/min per gkwt. In untreated SBN/y with controlled neural and circulating factors, pressure-diuresis and -natriuresis curves were shifted toward the right, and renal blood flow and glomerular filtration rate ranged between 4.2 and 9.1 or 1 and 1.3 mL/min per gkwt as perfusion pressure was increased from 99 to 164 mm Hg. In both protocols, values in SBH/y did not differ. DOCA-salt increased blood pressure in SBH/y. In SBH/y without controlled neural and hormonal factors, pressure-diuresis and -natriuresis curves were shifted approximately 20 mm Hg toward the right. Fractional sodium and water excretion curves, renal blood flow, and glomerular filtration rate were shifted rightward in parallel. On the other hand, SBH/y with DOCA-salt and controlled neural and hormonal factors had lower sodium and water excretion rates only at the renal perfusion pressure of 150 mm Hg as well as decreased renal blood flow and glomerular filtration rate compared with DOCA-salt SBN/y. These data suggest that both extrinsic and intrinsic factors are responsible for reduced sodium and water excretory capacity in DOCA-salt SBH/y; however, the extrinsic factors may be more important.


Continuous glucose monitoring targets in type 1 diabetes pregnancy: every 5% time in range matters.
With randomised trial data confirming that continuous glucose monitoring (CGM) is associated with improvements in maternal glucose control and neonatal health outcomes, CGM is increasingly used in antenatal care. Across pregnancy, the ambition is to increase the CGM time in range (TIR), while reducing time above range (TAR), time below range (TBR) and glycaemic variability measures. Pregnant women with type 1 diabetes currently spend, on average, 50% (12 h), 55% (13 h) and 60% (14 h) in the target range of 3.5-7.8 mmol/l (63-140 mg/dl) during the first, second and third trimesters, respectively. Hyperglycaemia, as measured by TAR, reduces from 40% (10 h) to 33% (8 h) during the first to third trimester. A TIR of >70% (16 h, 48 min) and a TAR of <25% (6 h) is achieved only in the final weeks of pregnancy. CGM TBR data are particularly sensor dependent, but regardless of the threshold used for individual patients, spending ≥4% of time (1 h) below 3.5 mmol/l or ≥1% of time (15 min) below 3.0 mmol/l is not recommended. While maternal hyperglycaemia is a well-established risk factor for obstetric and neonatal complications, CGM-based risk factors are emerging. A 5% lower TIR and 5% higher TAR during the second and third trimesters is associated with increased risk of large for gestational age infants, neonatal hypoglycaemia and neonatal intensive care unit admissions. For optimal neonatal outcomes, women and clinicians should aim for a TIR of >70% (16 h, 48 min) and a TAR of <25% (6 h), from as early as possible during pregnancy.


Selective inhibition of human solute carrier transporters by multikinase inhibitors.
Solute carrier (SLC) transporters regulate the cellular influx and disposition of endogenous and xenobiotic compounds, including anticancer agents such as the multikinase inhibitors (MKIs). Recent evidence suggests that MKIs may also inhibit SLC-dependent transport of coadministered drugs, although present information on the relative susceptibilities of multiple SLC transporters is limited. This study evaluated 18 MKI drugs and metabolites as inhibitors of prototypic substrate uptake by 13 SLC transporters that were overexpressed in human embryonic kidney cells. Organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 2B1, organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) were inhibited by most MKIs, whereas substrate uptake by OATP1B1, OAT1, 2, and 4, OCT2 and 3, and organic zwitterion/cation transporter 1 (OCTN1) was less susceptible to inhibition; OCTN2 was also inhibited by cediranib. In further studies, IC50 values were determined for the most effective MKIs, and erlotinib and cediranib were found to be potent competitive inhibitors of OATP2B1 (Ki = 41 nM) and OATP1A2 (Ki = 33 nM), respectively. From predictive approaches, several MKI-SLC interactions were found to be of potential in vivo significance.


Mutational analysis of the herpes simplex virus type 1 trans-inducing factor Vmw65.
The herpes simplex virus type 1 (HSV-1) polypeptide Vmw65 is a structural component of the virus particle and is also responsible for trans-induction of immediate early (IE) transcription. Functional domains of this polypeptide were investigated by constructing a series of 10 plasmids each with a 12 bp insertion in the gene encoding Vmw65. Plasmids were analysed for their ability to stimulate IE transcription in short term transfection assays, and the altered Vmw65 polypeptides were assayed for the ability to form an IE-specific protein-DNA complex (IEC) in vitro. A direct correlation was observed between stimulation of transcription and formation of IEC, strongly suggesting that IEC is an important intermediate in transcription activation. Plasmids were also tested for their ability to rescue the temperature-sensitive mutation in the HSV-2 assembly mutant ts2203, since marker rescue analysis indicated that this mutation maps within the gene encoding Vmw65. Five plasmids failed to rescue ts2203, thereby defining regions of Vmw65 required for virus assembly. The results show that distinct domains exist in Vmw65 for activation of transcription and assembly of virus.


Do synaesthesia and mental imagery tap into similar cross-modal processes?
Synaesthesia has previously been linked with imagery abilities, although an understanding of a causal role for mental imagery in broader synaesthetic experiences remains elusive. This can be partly attributed to our relatively poor understanding of imagery in sensory domains beyond vision. Investigations into the neural and behavioural underpinnings of mental imagery have nevertheless identified an important role for imagery in perception, particularly in mediating cross-modal interactions. However, the phenomenology of synaesthesia gives rise to the assumption that associated cross-modal interactions may be encapsulated and specific to synaesthesia. As such, evidence for a link between imagery and perception may not generalize to synaesthesia. Here, we present results that challenge this idea: first, we found enhanced somatosensory imagery evoked by visual stimuli of body parts in mirror-touch synaesthetes, relative to other synaesthetes or controls. Moreover, this enhanced imagery generalized to tactile object properties not directly linked to their synaesthetic associations. Second, we report evidence that concurrent experience evoked in grapheme-colour synaesthesia was sufficient to trigger visual-to-tactile correspondences that are common to all. Together, these findings show that enhanced mental imagery is a consistent hallmark of synaesthesia, and suggest the intriguing possibility that imagery may facilitate the cross-modal interactions that underpin synaesthesic experiences. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.


What Works When Treating Granulomatous Disease in Genetically Undefined CVID? A Systematic Review.
Granulomatous disease is reported in at least 8-20% of patients with common variable immunodeficiency (CVID). Granulomatous disease mainly affects the lungs, and is associated with significantly higher morbidity and mortality. In half of patients with granulomatous disease, extrapulmonary manifestations are found, affecting e.g. skin, liver, and lymph nodes. In literature various therapies have been reported, with varying effects on remission of granulomas and related clinical symptoms. However, consensus recommendations for optimal management of extrapulmonary granulomatous disease are lacking. To present a literature overview of the efficacy of currently described therapies for extrapulmonary granulomatous disease in CVID (CVID+EGD), compared to known treatment regimens for pulmonary granulomatous disease in CVID (CVID+PGD). The following databases were searched: Embase, Medline (Ovid), Web-of-Science Core Collection, Cochrane Central, and Google Scholar. Inclusion criteria were 1) CVID patients with granulomatous disease, 2) treatment for granulomatous disease reported, and 3) outcome of treatment reported. Patient characteristics, localization of granuloma, treatment, and association with remission of granulomatous disease were extracted from articles. We identified 64 articles presenting 95 CVID patients with granulomatous disease, wherein 117 different treatment courses were described. Steroid monotherapy was most frequently described in CVID+EGD (21 out of 53 treatment courses) and resulted in remission in 85.7% of cases. In CVID+PGD steroid monotherapy was described in 15 out of 64 treatment courses, and was associated with remission in 66.7% of cases. Infliximab was reported in CVID+EGD in six out of 53 treatment courses and was mostly used in granulomatous disease affecting the skin (four out of six cases). All patients (n = 9) treated with anti-TNF-α therapies (infliximab and etanercept) showed remission of extrapulmonary granulomatous disease. Rituximab with or without azathioprine was rarely used for CVID+EGD, but frequently used in CVID+PGD where it was associated with remission of granulomatous disease in 94.4% (17 of 18 treatment courses). Although the number of CVID+EGD patients was limited, data indicate that steroid monotherapy often results in remission, and that anti-TNF-α treatment is effective for granulomatous disease affecting the skin. Also, rituximab with or without azathioprine was mainly described in CVID+PGD, and only in few cases of CVID+EGD.


Unlearning and relearning sexuality: a qualitative exploration of The Sex Wrap, a sex education podcast.
Traditional school-based sexuality education has a myriad of problems with its successful delivery, including access to comprehensive sexuality curricula, access to trained facilitators, and community and parental fears. As an alternative form of sexuality education, The Sex Wrap podcast is released in weekly episodes of about 20-45min, providing listeners with diverse, evidence-based sexual health information. Participants in a larger mixed-methods study evaluating The Sex Wrap were invited to participate in qualitative in-depth interviews to explore their experiences with sexuality education, including The Sex Wrap , and how they relate to information received through the podcast. Seventeen interviews were conducted with listeners of The Sex Wrap , aged 20-25years old. One core category and three axial codes were identified in the interview data. The core category is: sexuality education is an ongoing process that includes learning and unlearning. The three temporally related axial codes are: (1) experiences with formal and informal sexuality education (mostly negative) drove participants to seek more information about sex, (2) participants use The Sex Wrap as a way of exploring and personalising information about sexuality, and (3) participants equipped with comprehensive sexuality education are empowered to educate their peers. This study suggests that podcast-based interventions, such as The Sex Wrap , can play a key role in young people's process of sexuality education and should be considered for incorporation into other forms of sex education.


Connective tissue progenitors: practical concepts for clinical applications.
Tissue engineering can be defined as any effort to create or induce the formation of a specific tissue in a specific location through the selection and manipulation of cells, matrices, and biologic stimuli. The biologic concepts and the biochemical and biophysical principles on which these efforts are based have become an exciting and rapidly evolving field of biomedical research. More importantly, tissue engineering is becoming a clinical reality in the practice of orthopaedic surgery, providing patients and physicians with an expanding set of practical tools for effective therapy. New and improved matrices and bioactive factors inevitably will play important roles in the evolution of orthopaedic tissue engineering. However, tissue engineering never can stray far from fundamental biologic principles, and one of these is that cells do all the work. No new tissue forms except through the activity of living cells. No bone graft, no matrix, no growth factor, no cytokine can contribute to the generation or integration of new tissue, except through the influence it has on the behavior of cells. The efficacy of all current clinical tools depends entirely on the cells in the grafted site, particularly the small subset of stem cells and progenitor cells that are capable of generating new tissue. The current authors review a series of key biologic concepts related to the rational design and selection of composites of cells and matrices in contemporary bone grafting and tissue engineering efforts. The functional paradigms of stem cell biology are reviewed, including self renewal, asymmetric and symmetric mitosis, and lineage restriction. Several potential sources for autogenous stem cells for connective tissues are discussed. Finally, a simple mathematical model is introduced as a tool for understanding the functional demands placed on stem cells and progenitors in a graft site and to provide a conceptual framework for the rational design of cell matrix composite grafts.


Size, edge, and stage of NSCLC determine the release of CYFRA 21-1 in bloodstream.
The computed tomography (CT) is the "golden standard" for the assessment of lung cancer progression due to its ability to clearly display the radiomorphologic characteristics. As lung cancer mortality is very high, more comprehensive approaches may be needed for its earlier diagnosis. The research hypothesis was to investigate the relation between the CT morphologic characteristics (size, stage, and edges) of pulmonary lesion and the extent of release of a soluble fragment of cytokeratin 19 being a part of the cytoskeleton of lung epithelial cells. This is a retrospective study including 246 pulmonary lesions being diagnosed and subsequently treated at the University Hospital Centre Zagreb, Croatia. The information about the relevant clinical, radiological, and laboratory facts was collected at the time of diagnosis in 164 NSCLC patients, 52 patients with pulmonary metastases, and 30 benign cysts. CYFRA 21-1 was determined by electrochemiluminescence immunoassay. The nonparametric statistical methods were applied. There was a positive correlation between the size and CYFRA 21-1 in NSCLC unlike metastases or cysts (p = 0.0001). The highest values of CYFRA 21-1 were seen in advanced stages of NSCLC and lesions with spiculated edges. The level of CYFRA 21-1 positively correlates with the greatest size of NSCLC measured by CT. The differences in CYFRA 21-1 according to TNM classification are significant (p = 0.0001): higher values were observed in advanced stages and with tumors having spiculated, lobulated, and poorly defined edges. The combination of CYFRA 21-1 and CT may help articulate the malignancy of pulmonary lesions.