Collateral Circulation and Outcome in Atherosclerotic Versus Cardioembolic Cerebral Large Vessel Occlusion.
Background and Purpose- Due to chronic hypoperfusion, cervical atherosclerosis may promote cerebral collateral circulation. We hypothesized that patients with ischemic stroke due to cervical carotid atherosclerosis have a more extensive collateral circulation and better outcomes than patients with cardioembolism. We tested this hypothesis in a population of patients who underwent endovascular treatment for large vessel occlusion. Methods- From the MR-CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), we selected consecutive adult endovascular treatment patients (March 2014 to June 2016) with acute ischemic stroke due to anterior circulation large vessel occlusion and compared patients with cervical carotid artery stenosis >50% to those with cardioembolic etiology. The primary outcome was collateral score, graded on a 4-point scale. Secondary outcomes included the modified Rankin Scale (mRS) score and mortality at 90 days. We performed multivariable regression analyses and adjusted for potential confounders. Results- Of 1627 patients in the Registry, 190 patients with cervical carotid atherosclerosis and 476 with cardioembolism were included. Patients with cervical carotid atherosclerosis were younger (median 69 versus 76 years, P<0.001), more often male (67% versus 47%, P<0.001), more often had an internal carotid artery terminus occlusion (33% versus 18%, P<0.001), and a lower prestroke mRS (mRS score, 0-2; 96% versus 85%, P<0.001), than patients with cardioembolism. Stroke due to cervical carotid atherosclerosis was associated with higher collateral score (adjusted common odds ratio, 1.67 [95% CI, 1.17-2.39]) and lower median mRS at 90 days (adjusted common odds ratio, 1.45 [95% CI, 1.03-2.05]) compared with cardioembolic stroke. There was no statistically significant difference in proportion of mRS 0-2 (aOR, 1.36 [95% CI, 0.90-2.07]) or mortality at 90 days (aOR, 0.80 [95% CI, 0.48-1.34]). Conclusions- Patients with stroke due to cervical carotid atherosclerosis had a more extensive cerebral collateral circulation and a slightly better median mRS at 90 days than patients with cardioembolic stroke.


Dynamical proxies of North Atlantic predictability and extremes.
Atmospheric flows are characterized by chaotic dynamics and recurring large-scale patterns. These two characteristics point to the existence of an atmospheric attractor defined by Lorenz as: "the collection of all states that the system can assume or approach again and again, as opposed to those that it will ultimately avoid". The average dimension D of the attractor corresponds to the number of degrees of freedom sufficient to describe the atmospheric circulation. However, obtaining reliable estimates of D has proved challenging. Moreover, D does not provide information on transient atmospheric motions, such as those leading to weather extremes. Using recent developments in dynamical systems theory, we show that such motions can be classified through instantaneous rather than average properties of the attractor. The instantaneous properties are uniquely determined by instantaneous dimension and stability. Their extreme values correspond to specific atmospheric patterns, and match extreme weather occurrences. We further show the existence of a significant correlation between the time series of instantaneous stability and dimension and the mean spread of sea-level pressure fields in an operational ensemble weather forecast at lead times of over two weeks. Instantaneous properties of the attractor therefore provide an efficient way of evaluating and informing operational weather forecasts.


[Vitamin supply of premature infants with intracranial birth injuries fed in different ways].
A total of 136 premature infants with intracranial birth trauma were studied during the first 2 months of life for vitamin B, C, A and carotinoid supply with regard to their body mass at birth and type of feeding. Premature children with different patterns of birth trauma showed low supply with thiamine, riboflavin, niacin and vitamin A in the presence of breast feeding. Combined feeding raised the supply of the children under observation with thiamine and riboflavin. The data obtained attest to the necessity of further study in this direction with the purpose of developing pathogenetically validated schemes for vitamin therapy of premature children.


Supervised automatic interpretation of technical documents: when interruption is a time saver.
The present study examined human-computer interactions in which the operator has to detect errors made by software designed to automatically recognize technical documents. The goal was to assess the effect of user-initiated interruptions of the recognition process to correct these errors. Participants were asked to check the interpretations, either with or without the possibility of interrupting the process. Results showed that interruptions can improve efficiency by decreasing task duration, especially in the post-recognition verification phase. Interruptions provide an opportunity to correct errors during rather than after the recognition process, which is easier because it requires fewer cognitive resources.


Beyond the individual: An improved telecom fraud detection approach based on latent synergy graph learning.
The development of telecom technology not only facilitates social interactions but also inevitably provides the breeding ground for telecom fraud crimes. However, telecom fraud detection is a challenging task as fraudsters tend to commit co-fraud and disguise themselves within the mass of benign ones. Previous approaches work by unearthing differences in calling sequential patterns between independent fraudsters, but they may ignore synergic fraud patterns and oversimplify fraudulent behaviors. Fortunately, graph-like data formed by traceable telecom interaction provides opportunities for graph neural network (GNN)-based telecom fraud detection methods. Therefore, we develop a latent synergy graph (LSG) learning-based telecom fraud detector, named LSG-FD, to model both sequential and interactive fraudulent behaviors. Specifically, LSG-FD introduces (1) a multi-view LSG extractor to reconstruct synergy relationship-oriented graphs from the meta-interaction graph based on second-order proximity assumption; (2) an LSTM-based calling behavior encoder to capture the sequential patterns from the perspective of local individuals; (3) a dual-channel based graph learning module to alleviate the disassortativity issue (caused by the camouflages of fraudsters) by incorporating the dual-channel frequency filters and the learnable controller to adaptively aggregate high- and low-frequency information from their neighbors; (4) an imbalance-resistant model trainer to remedy the graph imbalance issue by developing a label-aware sampler. Experiment results on the telecom fraud dataset and another two widely used fraud datasets have verified the effectiveness of our model.


Low milk supply and the pediatrician.
Human milk is the optimal food for human infants, and provides many diverse and well described benefits for both mother and infant. Low milk supply, whether perceived or actual, is one of the most common reasons why mothers stop breastfeeding. Breastfeeding mothers often seek out the guidance and support of their pediatrician in evaluating and resolving milk production concerns. Recent evidence supports the importance of breastfeeding for maternal and child health in both developing and developed countries. Lack of knowledge regarding optimal breastfeeding management accounts for the large majority of low milk supply concerns, but there is emerging evidence that impaired glucose tolerance may contribute to intrinsic low milk supply. Breastfeeding mother-infant dyads should be followed closely until lactation is well established and the infant is gaining well. Further research is needed to understand the physiologic contributors to low milk supply and to guide evidence-based interventions to optimize maternal success in reaching breastfeeding goals, particularly for women of poorer metabolic health.


Cost-effectiveness analysis of pre-ART HIV drug resistance testing in Kenyan women.
The prevalence of pre-treatment drug resistance (PDR) to non-nucleoside reverse-transcriptase inhibitor (NNRTI) agents is increasing in sub-Saharan Africa, which may decrease the effectiveness of efavirenz-based antiretroviral therapy (ART) programs. However, due to recent safety concerns, there has been hesitancy to replace efavirenz-based ART with dolutegravir in women of reproductive potential. Our objective was to evaluate whether PDR testing for women not initiating dolutegravir-based ART would be a cost-effective strategy to address the challenges posed by PDR. We developed an HIV drug resistance model that simulates the emergence and transmission of resistance mutations, calibrated to the Kenyan epidemic. We modeled three care strategies for PDR testing among women not initiating dolutegravir-based ART: no PDR testing, PDR testing with a low-cost point mutation assay, known as oligonucleotide ligation assay (OLA), and PDR testing with consensus sequencing. Using a health sector perspective, this model was used to evaluate the health outcomes, lifetime costs, and cost-effectiveness under each strategy over a 15-year time horizon starting in 2019. OLA and CS PDR testing were projected to have incremental cost-effectiveness ratios (ICER) of $10,741/QALY gained and $134,396/QALY gained, respectively, which are not cost-effective by national income standards. Viral suppression rates among women at 12 months after ART initiation were 87·8%, 89·0%, and 89·3% with no testing, OLA testing, and CS testing, respectively. PDR testing with OLA and CS were associated with a 0.5% and 0.6% reduction in incidence rate compared to no PDR testing. Initial PDR prevalence among women was 13.1% in 2019. By 2034, this prevalence was 17·6%, 17·4%, and 17·3% with no testing, OLA testing, and CS testing, respectively. PDR testing for women is unlikely to be cost-effective in Kenya whether one uses a low-cost assay, such as OLA, or consensus sequencing. National Institutes of Health, Gilead Sciences.


SARS-CoV-2 Antibody Response among Women Infected during Pregnancy.
Novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus has been declared a pandemic by the World Health Organization as of March 11, 2020. Pregnant women naturally have a reduced immune system due to immunological changes and decreased lung capacity due to respiratory adaptations, making them more susceptible to coronavirus complications. Within the Mount Sinai Health system, more than 15,000 deliveries are performed annually. We began to care for pregnant women with known COVID-19 infections in late March of 2020. In early April 2020, a policy was implemented to perform universal COVID-19 testing for all women planning to deliver within the Mount Sinai Health system. We examined the antibody response of postpartum women who delivered at Mount Sinai Hospital with a SARS-CoV-2 infection between the study intervals during March 15, 2020, through April 30, 2020. This was a prospective observational study examining the immune response of pregnant women who delivered at Mount Sinai Hospital with a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Women with a SARS-CoV-2 infection were contacted via phone to discuss participation in the study. Patients who consented were scheduled for a phlebotomy visit to assess their antibody titer levels to COVID-19. The COVID-19 enzyme-linked immunosorbent assay (ELISA) immunoglobulin (Ig)-G antibody test was used to evaluate the patients' antibody titers. The assay detects IgG antibodies for the detection of IgG seroconversion in patients following a known recent SARS-CoV-2 infection. A total of 120 patients were identified with a documented SARS-CoV-2 infection who delivered within the prespecified time frame. Of those patients, 25 women agreed to participate and were included. Of them, 64.00% were Caucasian with a mean age of 35 years. The mean body mass index (BMI) was 30 kg/m2 and the majority of patients had commercial insurance (88.00%). The majority of women were asymptomatic for COVID-19 at the time of admission (80.00%) and the average gestational age of delivery and diagnosis of COVID-19 was 39 weeks' gestation. The later the gestational age at the time of diagnosis, the lower the antibody titer response. When examining the interval from diagnosis to antibody titer analysis, patients with the highest titers (2,880) tended to have a shorter interval between their COVID-19 diagnosis and the time at which the titer level was drawn. Patients with symptoms on admission had similar antibody titer levels when compared with women who were asymptomatic. The antibody response among women infected with COVID-19 during pregnancy appears to be greater when the patients are diagnosed at an earlier gestational age. · COVID-19 antibody status appears to be greater when diagnosed at an earlier gestational age.. · Asymptomatic and symptomatic pregnant women had similar antibody responses.. · Patients with the highest titers tended to have a shorter interval between their COVID-19 diagnoses..


Similarities and differences between the subgenomic and minus-strand promoters of an RNA plant virus.
Promoter regions required for minus-strand and subgenomic RNA synthesis have been mapped for several plus-strand RNA viruses. In general, the two types of promoters do not share structural features even though they are recognized by the same viral polymerase. The minus-strand promoter of Alfalfa mosaic virus (AMV), a plant virus of the family Bromoviridae, consists of a triloop hairpin (hpE) which is attached to a 3' tRNA-like structure (TLS). In contrast, the AMV subgenomic promoter consists of a single triloop hairpin that bears no sequence homology with hpE. Here we show that hpE, when detached from its TLS, can function as a subgenomic promoter in vitro and can replace the authentic subgenomic promoter in the live virus. Thus, the AMV subgenomic and minus-strand promoters are basically the same, but the minus-strand promoter is linked to a 3' TLS to force the polymerase to initiate at the very 3'end.


A.C.F.S. Neoplasm survey of the foot--1975: A continuing study.
This continuing investigation, now in its third year, is being conducted to record statistics on tumors that affect the foot. The study was undertaken to increase the diagnostic information on the various types of tumors in order to assist the pediatric surgeon in the differential diagnosis and surgical management of tumors of the foot. The study is very important to the profession, and it is important for all foot surgeons to participate.


The evaluation of the OMOM capsule endoscopy with similar pictures elimination mode.
The reading of capsule endoscopy (CE) is time-consuming. Thus, several time-saving features have been added to the CE software by different CE companies. However, the similar pictures elimination mode in the OMOM capsule endoscopy software has not been evaluated yet. Our aim is to evaluate the sensitivity and specificity of the similar pictures elimination mode. We retrospectively studied 200 consecutive capsule endoscopy procedures in Nanfang Hospital between April 2012 and July 2012, among which 52 cases were excluded for poor bowel preparation, failure to reach the colon or data missing. All images of the small-bowel were re-evaluated with four different reading modes (conventional mode and three levels of similar pictures elimination mode) by four experienced endoscopists. Then, the reading time, the number of detected lesions, κ value, sensitivity and specificity were compared between 4 methods. The mean reading time with levels I to III, respectively, was significantly shorter than with conventional mode (P<0.001, conventional mode 33.25min, level I 24.90min, level II 20.54min, level III 14.96min). The sensitivity between conventional mode and level I were similar (93.8% vs. 87.7%, P=0.073), while the sensitivity of levels II and III was significantly lower than conventional mode (77.8% vs. 93.8%, 70% vs. 93.8%, respectively). The specificity between all 4 modes were similar (100% for conventional mode, 98.5% for levels I to III). Level I reading mode was as efficient as the conventional mode and less time-consuming. Its sensitivity and specificity were similar compared with the conventional mode.


Inhibitory effects of ciprofloxacin and sparfloxacin on DNA gyrase purified from fluoroquinolone-resistant strains of methicillin-resistant Staphylococcus aureus.
The activities of new quinolones against 140 strains of methicillin-resistant Staphylococcus aureus were determined. From the relationship between the MICs of sparfloxacin and ciprofloxacin, fluoroquinolone-resistant S. aureus 6171 (MIC of sparfloxacin, 200 micrograms/ml; MIC of ciprofloxacin, 100 micrograms/ml) and fluoroquinolone-susceptible S. aureus FDA 209-P were selected for purification of the subunit A and B proteins of their DNA gyrases. The supercoiling activities of reconstituted ArBr (r, resistant) (from strain 6171) and ArBs (s, susceptible) gyrases were 40-fold more resistant to new quinolones than those of AsBs from FDA 209-P and AsBr gyrases. The 50% inhibitory doses of ciprofloxacin and sparfloxacin for AmBm (from mutant 19) and AmBs (m, moderately resistant) gyrases were 15- to 27-fold higher than those for AsBs and AsBm gyrases. These findings indicate that one of the resistance mechanisms of S. aureus against fluoroquinolones is a modification of the gyrase subunit A protein.


Sequence and molecular characterization of a multicopy invasion plasmid antigen gene, ipaH, of Shigella flexneri.
A lambda gt11 expression library of Tn5-tagged invasion plasmid pWR110 (from Shigella flexneri serotype 5, strain M90T-W) contained a set of recombinants encoding a 60-kilodalton protein (designated IpaH) recognized by rabbit antisera raised against S. flexneri invasion plasmid antigens (J. M. Buysse, C. K. Stover, E. V. Oaks, M. M. Venkatesan, and D. J. Kopecko, J. Bacteriol. 169:2561-2569, 1987). Southern blot analysis of wild-type S. flexneri serotype 5 invasion plasmid DNA (pWR100) digested with various combinations of five restriction enzymes and hybridized with defined ipaH probes showed complex hybridization patterns resulting from multiple copies of the ipaH gene on pWR100. DNA sequence analysis of a 2.9-kilobase (kb) EcoRI fragment directing IpaH antigen synthesis in plasmid recombinant pWR390 revealed an open reading frame coding for a 532-amino-acid protein (60.8 kilodaltons); this size matched well with the estimated size of IpaH determined by Western blot analysis of M90T-W cells and maxicell analysis of Escherichia coli HB101(pWR390) transformants. Examination of the amino acid sequence of IpaH revealed a hydrophilic protein with six evenly spaced 14-residue (L-X2-L-P-X-L-P-X2-L-X2-L) repeat motifs in the amino-terminal end of the molecule. Southern blot analysis of HindIII-digested pWR100 DNA probed with defined segments of the pWR390 2.9-kb insert demonstrated that the multiple band hybridization pattern resulted from repeats of a significant portion of the ipaH structural gene in five distinct HindIII fragments (9.8, 7.8, 4.5, 2.5, and 1.4 kb). Affinity-purified IpaH antibody, used to monitor the expression of the antigen in M90T-W cells grown at 30 and 37 degrees C, showed that IpaH synthesis was not regulated by growth temperature.


A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients.
We previously reported a randomized phase II clinical trial combining a poxvirus-based vaccine encoding prostate-specific antigen (PSA) with radiotherapy in patients with localized prostate cancer. Here, we investigate whether vaccination against PSA induced immune responses to additional tumor-associated antigens and how this influenced clinical outcome. Pretreatment and posttreatment serum samples from patients treated with vaccine + external beam radiation therapy (EBRT) versus EBRT alone were evaluated by Western blot and serologic screening of a prostate cancer cDNA expression library (SEREX) to assess the development of treatment-associated autoantibody responses. Western blotting revealed treatment-associated autoantibody responses in 15 of 33 (45.5%) patients treated with vaccine + EBRT versus 1 of 8 (12.5%) treated with EBRT alone. SEREX screening identified 18 antigens, which were assembled on an antigen array with 16 previously identified antigens. Antigen array screening revealed that 7 of 33 patients (21.2%) treated with vaccine + EBRT showed a vaccine-associated autoantibody response to four ubiquitously expressed self-antigens: DIRC2, NDUFS1, MRFAP1, and MATN2. These responses were not seen in patients treated with EBRT alone, or other control groups. Patients with autoantibody responses to this panel of antigens had a trend toward decreased biochemical-free survival. Vaccine + EBRT induced antigen spreading in a large proportion of patients. A subset of patients developed autoantibodies to a panel of four self-antigens and showed a trend toward inferior outcomes. Thus, cancer vaccines directed against tumor-specific antigens can trigger autoantibody responses to self-proteins, which may influence the efficacy of vaccination.


Preparation and characterization of influenza virus cores.
Lipid-free influenza virus cores have been obtained by a three step procedure consisting of (a) treatment with proteolytic enzyme, (b) fixation with formaldehyde and (c) delipidization with saponin or deoxycholate. Several reagents proved efficient in removing the virus lipids as judged by morphological features and increased buoyant density, but only cores prepared by means of sodium deoxycholate have been characterized closely. Ultrathin sections revealed round bodies (about 65 nm in diam.) delineated by a single dense track and with an internal structure very similar to that of the complete virus particles. They contained both the nucleoprotein and the M-protein and no lipids. It is proposed to call the limiting structure which appears (3 to 4 nm thick in ultrathin sections) the core shell.


How 3D scaffolds with different mechanical properties affect the activity of neuronal networks in in vitro models.
Three-dimensionality has been proven extensively to be critical in the development of a reliable model for different anatomical compartments and for many diseases. Currently, we can produce implantable structures that help in the regeneration of different tissues such as bone and heart. Different is the situation when we consider the neuronal compartment. As it is still difficult to understand exactly how the brain computes, to conceive how the complex chain of neuronal events can generate conscious behavior, a comprehensive and workable model of neuronal tissue still has to be found. In this perspective, in the present work, we developed and compared different 3D scaffolds to understand the effects produced by the mechanical and material properties of four different scaffolds on a 3D neuronal network. To help in preclinical testing procedure, the scalability and ease-of-use of the different approaches were also taken into consideration.Clinical Relevance- By comparing different 3D scaffolds for the creation of neuronal constructs, the results in this paper move towards understanding the best strategy to develop functional 3D neuronal units for reliable pre-clinical studies.


Evaluation of the Additive Effect of Domperidone on Patients with Refractory Gastroesophageal Reflux Disease; A Randomized Double Blind Clinical Trial.
BACKGROUND Gastroesophageal reflux disease (GERD) is a common problem with annoying symptoms. It is associated with negative impact on quality of life. Prokinetic agents may be used in combination with acid suppression agents as an adjunctive in patients with GERD refractory to proton pump inhibitors (PPI) therapy, rather than as sole treatment. This study aimed to evaluate the efficacy of combination of PPI with domperidone (a prokinetic agent) compared with PPI alone in the treatment of patients with refractory GERD. METHODS This study was a double blind clinical trial on 29 patients with GERD refractory to PPI during the period of one month. By randomization, the patients were divided into two groups. Group A was treated by pantoprazole 40 mg twice daily and domperidone three times a day for a month, while group B was treated by pantoprazole 40 mg twice daily and placebo three times a day. In this study endoscopy was performed to evaluate the prevalence of erosive esophagitis, non-erosive reflux, and hiatal hernia. Manometry was conducted to study the prevalence of dysmotility. GERD symptom questionnaires including the Gastrointestinal Symptom Rating Scale (GSRS), Carlson Dennett, and the Medical Outcomes Study Short Form-36 health survey (SF36) were used before and after treatment for screening GERD and assessing treatment response. RESULTS There were 17 (58.62%) women and 12 (41.37%) men. The prevalence of erosive esophagitis and non-erosive reflux, was 10.34% and 89.66%, respectively. There was a significant difference comparing reflux symptoms before and after treatment between the two groups according to reflux and Carlson Dennett questionnaires. At the end of the study, symptoms of reflux significantly improved by treatment. Although, the quality of life questionnaire scores improved by treatment, there was no statistically significant difference in response to treatment between the two groups. CONCLUSION In this research, we showed that adding domperidone to PPI could not make any improvement in patients with refractory reflux regarding the quality of life and improving the symptoms.


[The driving force in the thinking of Norbert Elias. An attempt at psychoanalytic interpretation].
The theory of civilization proposed by the eminent sociologist Norbert Elias, who died in 1990, has its roots in Freud's theory of culture. Elias always denied the importance of personal factors in connection with his work, but as has been demonstrated in connection with artists such as Leonardo da Vinci and indeed Freud himself, this does not make it any the less legitimate to go in search of those infantile/unconscious motifs and affective sources powering Elias' prodigious scholarly creativity and informing his work, in however sublimated a form. Proceeding from the observation that successful scholarly or artistic production represents a synthesis of the forces of id, ego and super-ego, i.e. of affect, knowledge and conscience, the author demonstrates that concerns of central moment to Elias' thinking--commitment and non-involvement, establishment and outsider, the restraining of aggression in the civilizational process, interdependence of individuals--are partly the product of early experiences which Elias was able to turn to fruitful account in his work.


Phyletic hot spots for B chromosomes in angiosperms.
We determined whether supernumerary B chromosomes were nonrandomly distributed among major angiosperm lineages and among lineages within families, as well as the identity of lineages with unusually high B-chromosome frequencies (hot spots). The incidence of B chromosomes for each taxon was gathered from databases showing species with and without these chromosomes (among species with known chromosome numbers). Heterogeneity was found at all ranks above the species level. About 8% of monocots had B chromosomes versus 3% for eudicots; they were rare in nonmonocot basal angiosperms. Significant heterogeneity in B-chromosome frequency occurred among related orders, families within orders, and major taxa within families. There were many B-chromosome hot spots, including Liliales and Commelinales at the order level. At the family level, there was a trend suggesting that B-chromosome frequencies are positively correlated with genome size.


Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells.
Withaferin A (WA), a naturally occurring steroidal lactone, directly binds to Hsp90 and leads to the degradation of Hsp90 client protein. The purpose of this study is to investigate the structure activity relationship (SAR) of withanolides for their inhibition of Hsp90 and anti-proliferative activities in pancreatic cancer cells. In pancreatic cancer Panc-1 cells, withaferin A (WA) and its four analogues withanolide E (WE), 4-hydroxywithanolide E (HWE), 3-aziridinylwithaferin A (AzWA) inhibited cell proliferation with IC50 ranged from 1.0 to 2.8 μM. WA, WE, HWE, and AzWA also induced caspase-3 activity by 21-, 6-, 11- and 15-fold, respectively, in Panc-1 cells, while withaperuvin (WP) did not show any activity. Our data showed that WA, WE, HWE, and AzWA, but not WP, all directly bound to Hsp90 and induced Hsp90 aggregation,hence inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins Akt and Cdk4 through proteasome-dependent pathway in pancreatic cancer cells. However, only WA, HWE and AzWA disrupted Hsp90-Cdc37 complexes but not WE and WP. SAR study suggested that the C-5(6)-epoxy functional group contributes considerably for withanolide to bind to Hsp90, inhibit Hsp90 chaperone activity, and result in Hsp90 client protein depletion. Meanwhile, the hydroxyl group at C-4 of ring A may enhance withanolide to inhibit Hsp90 activity and disrupt Hsp90-Cdc37 interaction. These SAR data provide possible mechanisms of anti-proliferative action of withanolides.


Mechanical dilatation of the cervix at non-labour caesarean section for reducing postoperative morbidity.
During non-labour caesarean, some obstetricians routinely dilate the cervix from above--using finger, sponge forceps or other instruments because they believe that the cervix of women without labour pain is undilated and may cause obstruction of blood or lochia drainage. However, mechanical cervical dilatation using sponge forceps or a finger during caesarean section may result in contamination by vaginal micro-organisms during dilatation, and increase the risk of infection or cervical trauma. To determine the effects of mechanical dilatation of the cervix during elective/non-labour caesarean section on postoperative morbidity. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2011). All randomised or quasi-randomised controlled trials comparing intraoperative cervical dilatation using a finger, sponge forceps or other instrument during non-labour caesarean section versus no mechanical dilatation. Two review authors independently assessed studies for inclusion, assessed the risk of bias of each included study and extracted data. We included three trials with a total of 735 women undergoing elective caesarean section. Of these women, 338 underwent intraoperative cervical dilatation with a double-gloved index digit inserted into the cervical canal to dilate, and 397 did not undergo intraoperative cervical dilatation. Three included trials had moderate-to-high risk of bias. None of the three trials reported our primary outcome of postpartum haemorrhage. In one study of 400 women, blood loss was significantly lower in the cervical dilatation group compared with the no dilatation group (mean difference (MD) -48.49 ml, 95% confidence interval (CI) -88.75 to -8.23). The incidence of febrile morbidity and haemoglobin concentrations in the postoperative period in women undergoing intraoperative cervical dilatation was not significantly different from those who did not receive cervical dilatation (risk ratio (RR) 1.07, 95% CI 0.52 to 2.21 (three trials, 735 women) and MD -0.05 g/dl, 95% CI -0.17 to 0.06 (two trials, 552 women), respectively. There were no significant differences in wound infection, change of haemoglobin level, hematocrit level at postoperative period, endometritis, infectious morbidity, or urinary tract infection. There was a significant difference in operative time, which was reduced in cervical dilatation group (MD -1.84 mins, 95% CI -2.21 to -1.47 (one study, 400 women), but this is of doubtful clinical significance. There was insufficient evidence of mechanical dilatation of the cervix at non-labour caesarean section for reducing postoperative morbidity. Further randomised controlled trials with adequate methodological quality comparing intraoperative cervical dilatation using a finger, sponge forceps or other instrument during non-labour caesarean section versus no mechanical dilatation for reducing postoperative morbidity are needed.


Medulloblastoma stem cells: modeling tumor heterogeneity.
Brain tumors represent the leading cause of childhood cancer mortality, with medulloblastoma (MB) being the most frequent malignant tumor. In this review we discuss the morphological and molecular heterogeneity of this malignant childhood brain tumor and how this key feature has implicated the presence of a MB stem cell. We focus on evidence from cerebellar development, histopathological and molecular subtypes of MB, the recent identification of brain tumor-initiating cells (BTICs, also referred to as MB stem cells), and the current limitations in studying the interplay between MB stem cells and tumor heterogeneity.


Air pollution and respiratory health among children with asthmatic or cough symptoms.
During the winter of 1994, the association between daily changes in air pollution and in the respiratory health of children 7 to 12 yr of age were studied in Kuopio, Finland. Seventy-four children with asthmatic symptoms and 95 children with cough only, living either in urban or suburban areas, were followed for 3 mo. During the study period, the mean daily concentration of particulate air pollution (PM10) was 18 micrograms/m3 in the urban area and 13 micrograms/m3 in the suburban area. Lagged concentrations of PM10, black smoke, and NO2 were significantly associated with declines in morning peak expiratory flow (PEF) among asthmatic children. The regression coefficient (x10) for a 2-d lag of PM10 was -0.911 (SE, 0.386) in the urban and -1.05 (0.596), in the suburban area. Among children with cough only, PM10, black smoke, and NO2 were not significantly associated with PEF. In the urban area, there was a significant association between SO2 and morning and evening PEF and incidence of upper respiratory symptoms among children who cough only. No other associations between air pollution and evening PEF or respiratory symptoms were observed. This study suggests that particulate air pollution is associated with respiratory health, especially among children with asthmatic symptoms.


Drugging cell cycle kinases in cancer therapy.
Cell cycle kinases are comprised of cyclin-dependent kinases (Cdks), non-Cdk kinases such as Plk-1 and Aurora and checkpoint proteins such as Chk1 and Chk2. Though ubiquitous to dividing cells, many cell cycle kinases are amplified or over-expressed in malignancy and are potential targets for anti-cancer therapies. Cdk inhibiting drugs (such as flavopiridol, UCN-01, E7070, R-Roscovitine and BMS-387032) have shown preclinical and clinical anticancer activity. However, many of these agents are promiscuous and undiscerning, targeting other non-cell cycle kinases and affecting normal cells, thereby causing significant toxicity. To overcome this, a new generation of Cdk inhibitors are in development with greater target specificity, as well as others that inhibit non-Cdk cell cycle kinases, both directly and indirectly. The outcome of early clinical trials involving these agents is awaited, but these certainly represent a promising new area of anticancer drug development.


Resection of stenotic trachea: a case presentation.
Tracheal stenosis is usually a complication of prolonged mechanical ventilation. If the narrowing is severe it will greatly obstruct the air flow. Resection of the damaged trachea is a life saving procedure. The anesthetic management of the resection of an "ice cream cone narrowing" of the trachea (3 mm diameter) 4 cm above the carina is reported. A forced vital capacity loop (expiration-inspiration) of air flow versus volume revealed preoperatively little difference in the flow during the forced (F-V) and resting ventilation (Vt), thus confirming a diagnosis of severe upper airway obstruction. A total obstruction of the air flow was encountered during the skeletonization of the trachea and the surgeon was allowed to work for not more than 60 seconds at a time. Perfect cooperation between the surgeon and the anesthetsia team is necessary for the successful completion of this type of surgery.


The important role of nontypable Streptococcus pneumoniae international clones in acute conjunctivitis.
In a recent epidemiological study in southern Israel, nontypable Streptococcus pneumoniae isolates were found to be highly associated with sporadic cases of acute conjunctivitis (AC). The purpose of the present study was to evaluate the relative importance in causing AC of the absence of capsule versus genotype properties. DNA typing by pulsed-field gel electrophoresis (PFGE) was performed on 148 nontypable organisms isolated from 3 sites: nasopharynx of healthy children, middle-ear fluid, and conjunctiva. Analysis of the PFGE patterns revealed the presence of 6 clusters; 2 clusters that included 44% of the isolates (65/148) were associated with AC, and the remaining 4 were frequently isolated from the nasopharynx. Multilocus sequence typing, performed on representative isolates of the 2 major clusters, confirmed that the organisms were pneumococci; one is a single-locus variant of sequence type (ST) 448, and the other is related to ST344. Both types appear to be members of pneumococcal lineages that have lost capsular loci. The nontypable isolates showed high rates of resistance to antimicrobial agents. Our data suggest that the absence of the capsule--along with other, yet-unidentified genetic characteristics--provide S. pneumoniae with a selective virulence advantage in conjunctivitis.


Nickel(ii) PE1CE2P pincer complexes (E = O, S) for electrocatalytic proton reduction.
Nickel(ii) chloride and thiolate complexes with iPrPE1CE2PiPr (E = O, S) pincer ligands were investigated as electrocatalysts for the hydrogen evolution reaction in CH3CN in the presence of acetic acid and trifluoroacetic acid. The bis(thiophosphinite) (S,S) chloride complex reduced protons at the lowest overpotential in comparison with the bis(phosphinite) (O,O) and mixed phosphinite-thiophosphinite (O,S) complexes. A combination of electrochemical, NMR and UV-vis spectroscopic and mass spectrometric experiments provides mechanistic insights into the catalytic cycle for proton reduction to dihydrogen.


[Restriction analysis of plasmid of the strain Streptomyces sp.27].
Plasmid pSS27 was found in streptomycete strain isolated from the soil sample in the Kyiv region. The paper deals with the data of restriction analysis of streptomycete plasmid pSS27 and its molecular weight. Plasmid pSS27 has unique restriction sites for endonucleases BglII and EcoRI, there are also the restriction sites for SalGI (3 sites), PstI (4 sites), BglI (5 sites), Bsp120I (7 sites) and SacII (11 sites). The molecular weight of plasmid DNA pSS27, being equal to 13.7 +/- 0.2 kb has been determined as a result of its restriction analysis.


Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders.
Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.


Intermittent Theta Burst Stimulation of the Prefrontal Cortex in Cocaine Use Disorder: A Pilot Study.
Transcranial Magnetic Stimulation (TMS) is earning a role in the therapeutic arsenal of cocaine use disorder (CUD). A widespread and still growing number of studies have reported beneficial use of repeated TMS (rTMS) in reduction of craving, intake and cue-induced craving in cocaine addicts. In spite of these encouraging findings, many issues are still unresolved such as brain area to be stimulated, laterality of the effects, coil geometry and stimulation protocols/parameters. Intermittent theta burst stimulation (iTBS) is a more tolerable protocol administered at lower intensities and shorter intervals than conventional rTMS protocols. Yet, its effects on cocaine craving and length of abstinence in comparison with standard high frequency (10-15 Hz) protocols have never been evaluated so far. In the present paper, we describe the effect of the bilateral iTBS of the prefrontal cortex (PFC) in a population (n = 25) of treatment-seeking cocaine addicts, in an outpatient setting, and compare them with 15 Hz stimulation of the same brain area (n = 22). The results indicate that iTBS produces effects on cocaine consumption and cocaine craving virtually superimposable to the 15 Hz rTMS group. Both treatments had low numbers of dropouts and similar side-effects, safety and tolerability profiles. While larger studies are warranted to confirm these observations, iTBS appears to be a valid approach to be considered in treatment-seeking cocaine addicts, especially in light of its brief duration (3 min) vs. 15 Hz stimulation (15 min). The use of iTBS would allow increasing the number of patients treated per day with current rTMS devices, thus reducing patient discomfort and hopefully reducing drop-out rates without compromising clinical effectiveness.


Effect of Targeted Cytokine Inhibition on Progression of Post-Traumatic Osteoarthritis Following Intra-Articular Fracture.
Intra-articular fractures (IAF) result in significant and prolonged inflammation, increasing the chances of developing post-traumatic osteoarthritis (PTOA). Interleukin-one beta (IL-1β) and Tumor Necrosis Factor-alpha (TNF-α) are key inflammatory factors shown to be involved in osteochondral degradation following IAF. As such, use of targeted biologics such as Infliximab (INX), a TNF-α inhibitor, and Anakinra (ANR), an interleukin-one (IL-1) receptor antagonist (IL1RA), may protect against PTOA by damping the inflammatory response to IAF and reducing osteochondral degradation. To test this hypothesis, IAFs were induced in the hindlimb knee joints of rats treated with INX at 10 mg/kg/day, ANR at 100 g/kg/day, or saline (vehicle control) by subcutaneous infusion for a period of two weeks and healing was evaluated at 8-weeks post injury. Serum and synovial fluid (SF) were analyzed for soluble factors. In-vivo microcomputed tomography (µCT) scans assessed bone mineral density and bone morphometry measurements. Cationic CA4+ agent assessed articular cartilage composition via ex vivo µCT. Scoring according to the Osteoarthritis Research Society International (OARSI) guidelines was performed on stained histologic tibia sections at the 56-day endpoint on a 0-6 scale. Systemically, ANR reduced many pro-inflammatory cytokines and reduced osteochondral degradation markers Cross Linked C-Telopeptide Of Type II (CTXII, p < 0.05) and tartrate-resistant acid phosphatase (TRAP, p < 0.05). ANR treatment resulted in increased chemokines; macrophage-chemotractant protein-1 (MCP-1), MPC-3, macrophage inhibitory protein 2 (MIP2) with a concomitant decrease in proinflammatory interleukin-17A (IL17A) at 14 days post-injury within the SF. Microcomputed tomography (µCT) at 56 days post-injury revealed ANR Treatment decreased epiphyseal degree of anisotropy (DA) (p < 0.05) relative to saline. No differences were found with OARSI scoring but contrast-enhanced µCT revealed a reduction in glycosaminoglycan content with ANR treatment. These findings suggest targeted cytokine inhibition, specifically IL-1 signaling, as a monotherapy has minimal utility for improving IAF healing outcomes but may have utility for promoting a more permissive inflammatory environment that would allow more potent disease modifying osteoarthritis drugs to mitigate the progression of PTOA after IAF.


Characterization of the yeast KEX1 gene product: a carboxypeptidase involved in processing secreted precursor proteins.
We have identified and partially characterized the Saccharomyces cerevisiae KEX1 gene product, Kex1p, to assess its role in processing secreted protein precursors. Anti-Kex1p antibodies identified a 113-kilodalton protein that was absent in cells in which the KEX1 gene has been disrupted and that was more abundant in cells overexpressing the KEX1 gene. Kex1p was found to be a membrane-associated glycoprotein with N-linked carbohydrate. The N-linked oligosaccharide(s) was modified in a progressive manner after synthesis, causing the glycoprotein to slowly increase in mass to 115 kilodaltons. After a Kex2p-mediated cleavage event at specific pairs of basic amino acids, alpha-factor and K1 killer toxin precursors have COOH-terminal dibasic residue extensions and require a carboxypeptidase B-like enzyme to process the precursors to maturity. A carboxypeptidase activity, with apparent specificity for basic amino acids, was detected in KEX1 cells. Disruption of the KEX1 gene abolished this activity, while overexpression of KEX1 increased it. Our results provide biochemical evidence consistent with earlier genetic work, that KEX1 encodes a serine carboxypeptidase involved in the processing of precursors to secreted mature proteins.


Hepatic cytochrome P-450-dependent metabolism and enzymatic conjugation of foreign compounds in vitamin A-deficient rats.
The temporal effects of vitamin A deficiency on hepatic cytochrome P-450-dependent and conjugation reactions were studied in the rat. Cytochrome P-450 levels and N-methyl-p-chloroaniline N-demethylase activity were significantly reduced in the deficient animals. No other changes in parameters dependent on cytochrome P-450 were observed in vitro. Decreases in hepatic cytochrome P-450 were accompanied by a prolongation in hexobarbital sleeping times in deficient animals. The p-aminobenzoic acid N-acetyltransferase activity was higher in the deficient animals at 8 weeks, but by 10 weeks the activity in fact was significantly lower as compared to controls. Activities of 'native' and UDP N-acetylglucosamine 'activated' UDP-glucuronyltransferase were reduced in vitamin A deficiency. In contrast to this general pattern of impaired drug metabolism in vitamin A deficiency, glutathione S-aryltransferase activity was markedly enhanced at all time points from 4 to 10 weeks. Activities of this enzyme were twice controls at 6 weeks, a time at which no other enzyme changes were observed.


Preparing a successful, role-specific curriculum vitae.
An internet search reveals just how many articles there are on preparing a curriculum vitae (CV). The preparation of a CV should not be regarded as a 'one-off' event, to be updated periodically. A successful CV requires thoughtful preparation to ensure it is directed towards a specific post and should consider two important perspectives. First, an understanding of what is required of the practitioner in the nursing post (demand), and second, what the nurse can offer in terms of his or her skills, experience, qualities and qualifications (supply). The demands of the post will also include meeting professional standards, such as those that have emerged following consideration of the Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry (Francis 2013). This article explores how to prepare a successful CV for a specific role, using a demand and supply perspective--where a nurse seeks to match the specific requirements of the post by summarising what he or she has to offer.


Modified Dual-Energy Algorithm for Calcified Plaque Removal: Evaluation in Carotid Computed Tomography Angiography and Comparison With Digital Subtraction Angiography.
Computed tomography angiography (CTA) is a valuable tool for the assessment of carotid artery stenosis. However, blooming artifacts from calcified plaques might result in an overestimation of the stenosis grade. The aim of this study was to investigate a new dual-energy computed tomography (DECT) technique with a modified 3-material decomposition algorithm for calcium removal in extracranial carotid artery stenosis. In this retrospective, institutional review board-approved study, 30 calcified carotid plaques in 22 patients (15 men; mean age, 73 ± 10 years) with clinical suspicion of stroke were included. Dual-energy computed tomography image data were obtained using second-generation dual-source CT with tube voltages at 80 and 140Sn kVp. Conventional CTA and virtual noncalcium (VNCa) images using the modified DECT algorithm were reconstructed. By assessing spectral characteristics, the modified DECT algorithm allows for a selective removal of calcium independent of blooming. Two independent and blinded readers evaluated subjective image quality, blooming artifacts, amount of (residual) calcification, and performed stenosis measurements according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Differences were tested using a pairwise sign test. Paired sample t tests with Bonferroni correction (P < 0.017) and Bland-Altman analyses were used to test for differences in carotid stenosis measurements between VNCa and conventional CTA using digital subtraction angiography (DSA) as the standard of reference. Subjective image quality was similar among conventional CTA and VNCa image data sets (P = 0.82), whereas blooming artifacts were significantly reduced in VNCa images compared with conventional CTA (P < 0.001). Residual calcifications in VNCa images were absent in 11 (37%), minor in 12 (40%), medium sized in 2 (7%), and large in 5 (17%) arteries. Stenosis measurements differed significantly between VNCa (mean NASCET stenosis: 27% ± 20%) and conventional CTA images (mean NASCET stenosis: 39% ± 16%; P < 0.001) and between conventional CTA and DSA (23% ± 16%, P < 0.001). No significant differences in stenosis measurements were observed between VNCa and DSA (P = 0.189), with narrow limits of agreement (mean difference ±1.96 standard deviations: -4.7%, -35.1%, and 25.7%). A modified 3-material decomposition DECT algorithm for calcium removal was introduced, which allows for an accurate removal of calcified carotid plaques in extracranial carotid artery disease. The algorithm might overcome the problem of overestimation of calcified stenosis due to blooming artifacts in conventional CTA.


Diet induced changes in the microbiota and cell composition of rabbit gut associated lymphoid tissue (GALT).
The gut associated lymphoid tissue (GALT) is the largest immune organ of the body. Although the gut transient and mucosa-associated microbiota have been largely studied, the microbiota that colonizes the GALT has received less attention. The gut microbiome plays an important role in competitive exclusion of pathogens and in development and maturation of immunity. Diet is a key factor affecting the microbiota composition in the digestive tract. To investigate the relation between diet, microbiota and GALT, microbial and cell composition of vermiform appendix (VA) and sacculus rotundus (SR) were studied in two groups of New Zealand white rabbits on different diets. Diet shifted the lymphoid tissue microbiota affecting the presence and/or absence of certain taxa and their abundances. Immunohistochemistry revealed that a higher fibre content diet resulted in M cell hyperplasia and an increase of recently recruited macrophages, whereas T-cell levels remained unaltered in animals on both high fibre and standard diets. These findings indicate that diet has an impact on the microbiota and cell composition of the GALT, which could act as an important microbial recognition site where interactions with beneficial bacteria can take place favouring microbiota replacement after digestive dysregulations.


Recombinant immunoglobulin A specific for influenza A virus hemagglutinin: production, functional analysis, and formation of secretory immunoglobulin A.
Secretory immunoglobulin (Ig) A (SIgA), comprised of dimeric IgA and secretory component (SC), is believed to provide a defense mechanism on the mucosal surface. Influenza A virus (IAV) hemagglutinin (HA)-specific SIgA is thought to play an important role in the prevention of IAV infection. However, the topical application of preformed IAV-specific SIgA has not been shown to prevent IAV infection. This is due to the difficulty in the production of antigen-specific IgA monoclonal antibodies (mAbs) and monoclonal SIgA. Here, a recombinant hybrid IgA (HIgA) was established that utilizes variable regions of an HA-specific mouse IgG mAb and the heavy chain constant region of a mouse IgA mAb. We expressed the dimeric HIgA in Chinese hamster ovary-K1 (CHO-K1) cells. When in vitro IAV infection of Madin-Darby canine kidney (MDCK) cells was tested, 10 times lower concentrations of HIgA were able to inhibit it as compared with an HA-specific IgG with the same variable regions. A functional hybrid secretory IgA (HSIgA) was also produced through incubation of the dimeric HIgA with recombinant mouse SC in vitro. It was demonstrated that HSIgA could be separated from the dimeric HIgA on size exclusion chromatography. This study provides a basic strategy for investigating the role of SIgA upon IAV infection on the mucosal surface.


Effect of Lactobacillus rhamnosus KY-3 and cellobiose as synbiotics on lipid metabolism in rats.
Lactobacillus rhamnosus KY-3 is a fermentative bacterium that is used for the industrial production of L-lactic acid. We have examined the effect of L. rhamnosus KY-3 and cellobiose as synbiotics on lipid metabolism in rats. Rats were fed on a 20% casein diet (C) supplemented with either 1.7% L. rhamnosus KY-3 (KY-3), 10% cellobiose (CEB), or 1.7% L. rhamnosus KY-3 and 10% cellobiose (KY-3+CEB) for 13 d. The concentrations of serum total lipids, triacylglycerol, total cholesterol, and phospholipids were significantly reduced in rats fed a KY-3+CEB diet in comparison to those on the C, KY-3 and CEB diets. There was an increase in the weight of cecal contents and a significant increase in the amount of cecal short-chain fatty acids (SCFA). The dry weight of excretion increased additively upon the simultaneous administration of L. rhamnosus KY-3 and cellobiose (KY-3 + CEB). The amount of excreted fecal bile acids did not differ among the groups in this study. These findings support the hypothesis that the promotion of cecal fermentation can lower the level of serum lipids. These results suggest that simultaneous administration of L. rhamnosus KY-3 and cellobiose as synbiotics has a beneficial effect on lipid metabolism.


Selective inhibition of responses to nerve growth factor and of microtubule-associated protein phosphorylation by activators of adenylate cyclase.
To study the influence of cAMP on cellular responses to nerve growth factor (NGF) and to use elevation of intracellular cAMP to probe the NGF mechanism, cultured PC12 pheochromocytoma cells were exposed to forskolin and cholera toxin. As in other cell types, the latter agents greatly increased PC12 cell cAMP levels. Such treatment also brought about a reversible, dose-dependent suppression of NGF-promoted regeneration of neurites. In support of the role of cAMP in this effect, regeneration blockage by forskolin was potentiated by phosphodiesterase inhibitors. When tested on NGF-stimulated initiation of process outgrowth, cholera toxin and forskolin exerted a dual effect. As in previous studies, these drugs, when applied along with NGF, significantly enhanced the initial formation of short cytoplasmic extensions. However, after approximately 3 d of NGF exposure, at which time such extensions begin to acquire the morphological and ultrastructural features of neurites, these agents suppressed process outgrowth. That is, the neurites were fewer in number, significantly less branched, and much shorter than in control cultures. Such changes also occurred when these drugs were added to cultures that had been pretreated with NGF alone. Whereas forskolin and cholera toxin affect the formation and regeneration of neurites, these drugs did not interfere with the short-latency, transient changes in surface morphology that are triggered by NGF, nor did they inhibit transcription-dependent priming. In contrast, the rapidly occurring NGF-induced phosphorylation of tyrosine hydroxylase was suppressed. Moreover, forskolin and cholera toxin rapidly and selectively blocked the NGF-promoted phosphorylation of a set of microtubule-associated proteins known as chartins. Previous observations have suggested a causal relationship between NGF-induced chartin microtubule-associated protein phosphorylation and the formation and outgrowth of neurites. This is supported by the present data and provides a possible mechanism whereby elevated cAMP may interfere with neurite growth and regeneration.


Down-regulation of the expression of PKC1 and SRB1/PSA1/VIG9, two genes involved in cell wall integrity in Saccharomyces cerevisiae, causes flocculation.
The cell wall integrity determinants PKC1 and SRB1/PSA1/VIG9 of Saccharomyces cerevisiae were expressed under the control of the tightly regulated promoter pMET3. Substitution of the cell-cycle-regulated SRB1/PSA1 native promoter with pMET3 led to faster cell growth, larger cell volumes, and a twofold reduction of the steady-state SRB1/PSA1 mRNA level. In addition, the new pattern of expression of SRB1/PSA1 resulted in a dominant flocculation phenotype at all phases of batch growth. By contrast, expression of PKC1 from pMET3 increased the flocculation capacity of cells only at stationary phase. Methionine-mediated repression of either PSA1/SRB1 or PKC1 resulted in enhanced cell clumping. Cells in which both these genes had been replaced with their respective pMET3-regulated cassettes were highly flocculent under both expression and repression conditions. These results suggest that greater exposure of flocculin on the cell surface, caused by either cell wall distortion (through depletion of Pkc1p) or aberrant regulation of mannosylation (through constitutive production of Srb1p), results in an increased flocculation ability.


CRM1 mediates nuclear-cytoplasmic shuttling of mature microRNAs.
Drosha-processed microRNAs (miRNAs) have been shown to be exported from the nucleus to the cytoplasm by Exportin 5, where they are processed a second time to generate mature miRNAs. In this work we show that miRNAs also use CRM1 for nuclear-cytoplasmic shuttling. Inhibition of CRM1 by Leptomycin B results in nuclear accumulation of miRNA guide sequences. Nuclear to cytoplasmic transport can be actively competed by synthetic small interfering RNAs, indicating that this pathway is shared by different classes of processed small RNAs. We also find that CRM1 coimmunoprecipitates with Ago-1, Ago-2, Topo2alpha, EzH2, and Mta, consistent with a role of Argonautes and small RNAs in chromatin remodeling.


Drug selection for ambulatory procedural sedation.
Ambulatory procedural sedation is used to relieve anxiety, pain and discomfort in a broad spectrum of patients during many types of diagnostic or therapeutic procedures. This review focuses on recent comparative studies of commonly used and new drugs for adult ambulatory sedation. Midazolam and propofol are commonly used for ambulatory sedation. Their pharmacological properties offer many advantages and there is much experience with their use. Ketamine can be a useful addition to hypnotic drugs but the advantage of the use of ketofol (a mixture of propofol and ketamine) is, although often practiced, difficult to assess. Dexmedetomidine is a relatively new sedative drug and many studies suggest advantages. New findings about its effects, however, show that the hemodynamic consequences of the use of dexmedetomidine may last for several hours. New sedative drugs for procedural sedation are still being developed: remimazolam has many properties that would make it an ideal sedative and has been studied in a phase 3 study. The properties that would constitute the ideal sedative have yet to be combined in one drug. The selection of the drugs used for ambulatory sedation depends on many factors such as procedure type, patient characteristics and the expectations of patients and the healthcare provider. Because of this, the literature cannot yet provide a definitive answer to the question which drug is best selected in a specific situation.


The current status and prospect of immunotherapy in colorectal cancer.
Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers.


Efficacy and safety of 5-aminolevulinic acid in adult-onset Still's disease: A preclinical study in mice and a pilot study in humans.
The study aimed to investigate the therapeutic effects of 5-aminolevulinic acid/sodium ferrous citrate (5-ALA/SFC) on adult-onset Still's disease (AOSD), specifically focusing on arthritis and macrophage activation syndrome (MAS). We used mouse models to assess the impact of 5-ALA/SFC on collagen-induced arthritis (CIA) and MAS induced by synthetic oligonucleotides containing CpG motifs (CpG-S-ODN). Additionally, we conducted a pilot study with AOSD patients receiving prednisolone (PSL) treatment and 5-ALA/SFC administration to evaluate its efficacy and safety. The 5-ALA/SFC group exhibited significantly lower joint scores in CIA mice. In CpG-S-ODN-treated mice, 5-ALA/SFC administration led to reduced hemophagocytosis and splenomegaly. The anti-inflammatory properties of 5-ALA/SFC were attributed to the suppression of CCL4 and CXCL10 production in monocytes and the induction of M2 macrophages. AOSD patients treated with 5-ALA/SFC demonstrated successful PSL tapering without adverse events. Collectively, the administration of 5-ALA/SFC showed promising potential in ameliorating arthritis and MAS in AOSD patients.


The perioperative practitioner.
This article demonstrates how patient care can be compromised when vital patient information is not communicated to the team in the operating theatre. It challenges practitioners to consider the information required to properly care for our patients. Several members of NATN were asked to comment on this article and these are reproduced at the end.


Interventional strategies to combat muscle disuse atrophy in humans: focus on neuromuscular electrical stimulation and dietary protein.
Numerous situations, such as the recovery from illness or rehabilitation after injury, necessitate a period of muscle disuse in otherwise healthy individuals. Even a few days of immobilization or bed rest can lead to substantial loss of skeletal muscle tissue and compromise metabolic health. The decline in muscle mass is attributed largely to a decline in postabsorptive and postprandial muscle protein synthesis rates. Reintroduction of some level of muscle contraction by the application of neuromuscular electrical stimulation (NMES) can augment both postabsorptive and postprandial muscle protein synthesis rates and, as such, prevent or attenuate muscle loss during short-term disuse in various clinical populations. Whereas maintenance of habitual dietary protein consumption is a prerequisite for muscle mass maintenance, supplementing dietary protein above habitual intake levels does not prevent muscle loss during disuse in otherwise healthy humans. Combining the anabolic properties of physical activity (or surrogates) with appropriate nutritional support likely further increases the capacity to preserve skeletal muscle mass during a period of disuse. Therefore, effective interventional strategies to prevent or alleviate muscle disuse atrophy should include both exercise (mimetics) and appropriate nutritional support.


Choroidal thickness changes after diabetes type 2 and blood pressure control in a hospitalized situation.
To investigate the effect of acute diabetic control on choroidal thickness in patients with Type 2 diabetes. Seventeen eyes of 17 patients with Type 2 diabetes were included in this prospective observational study. The patients with Type 2 diabetes who were scheduled to undergo a program of intensive diabetic control underwent prototype high-penetration optical coherence tomography before and 2 weeks after the start of treatment. The choroidal thickness changes 2 weeks after the protocol of intensive diabetic control were assessed, and associated ophthalmologic and general parameters were explored. Seventeen eyes of 17 healthy volunteers were included to compare diabetic patients. The choroidal thickness also was measured in this group at baseline and after 2 weeks. And the intraobserver and interobserver reproducibility were verified using this control group. The intraobserver (intraclass coefficient, 0.992) and interobserver reproducibility (0.982) in our subfoveal choroidal thickness measurement were high. The mean subfoveal choroidal thickness after 2 weeks (226 ± 56 μm) was significantly greater than at baseline (215 ± 52 μm, P < 0.05); there was no difference between the baseline and 2-week values in the control group (baseline, 312 ± 113 vs. 2-week value, 307 ± 103 μm; P = 0.17). The changes in refractive error (P < 0.001), axial length (P < 0.01), and diastolic blood pressure (P < 0.01) were associated significantly with changes in choroidal thickness 2 weeks after the intensive control. The pretreatment body mass index (P < 0.05) and hemoglobin A1c (P < 0.005) also were associated significantly with increased choroidal thickness. Diabetic patients showed a significant increase of choroidal thickness after the intensive control. Various ophthalmologic and systemic parameters seem to affect the choroidal thickness changes. This may be related to the progression of retinopathy after acute glycemic control.


Evaluating Gamma-H2AX Expression as a Biomarker of DNA Damage after X-ray in Angiography Patients.
Coronary heart disease (CHD) is one of the most common diseases. Coronary angiography (CAG) is an important apparatus used to diagnose and treat this disease. Since angiography is performed through exposure to ionizing radiation, it can cause harmful effects induced by double-stranded breaks in DNA which is potentially life-threatening damage. The aim of the present study is to investigate phosphorylation of Histone H2AX in the location of double-stranded breaks in peripheral blood lymphocytes as an indication of biological effects of radiation on angiography. This method is based on the phosphorylation measurement of Histone (gamma-H2AX or γ-H2AX) levels on serine 139 after the formation of DNA double-strand break. 5 cc of blood samples from 24 patients undergoing angiography were taken pre- and post-radiation. Blood lymphocytes were extracted, fixed and stained with specific γ-H2AX antibodies. Finally, the percentage of phosphorylation of Histone H2AX as an indicator of double-strand break was measured by a cytometry technique. An increase was observed in all patients' percentage of phosphorylated Histone H2AX (double-stranded breaks DNA) after radiation (20.15 ± 14.18) compared to pre-exposure time (1.52 ± 0.34). Also, the mean of DNA double-strand break is shown in a linear correlation with DAP. Although induction of DNA double-strand breaks was associated with the radiation dose in patients, the effect of individual factors such as radio-sensitivity and regenerative capacity should not be ignored. In the future, if we are able to measure DNA damage response in every angiography patient, we will use it as a biomarker for the patient dose; this will promote public health. Using flow cytometers readings done automatically is possible to detect γ-H2AX in the number of blood cells, therefore, the use of this technique could play a significant role in monitoring patients.


Pneumonia due to Pseudomonas aeruginosa: part I: epidemiology, clinical diagnosis, and source.
Pseudomonas aeruginosa is an uncommon cause of community-acquired pneumonia (CAP), but a common cause of hospital-acquired pneumonia. Controversies exist for diagnostic methods and antibiotic therapy. We review the epidemiology of CAP, including that in patients with HIV and also in hospital-acquired pneumonia, including ventilator-associated pneumonia (VAP) and bronchoscope-associated pneumonia. We performed a literature review of clinical studies involving P aeruginosa pneumonia with an emphasis on treatment and prevention. Pneumonia due to P aeruginosa occurs in several distinct syndromes: (1) CAP, usually in patients with chronic lung disease; (2) hospital-acquired pneumonia, usually occurring in the ICU; and (3) bacteremic P aeruginosa pneumonia, usually in the neutropenic host. Radiologic manifestations are nonspecific. Colonization with P aeruginosa in COPD and in hospitalized patients is a well established phenomenon such that treatment based on respiratory tract cultures may lead to overtreatment. We present circumstantial evidence that the incidence of P aeruginosa has been overestimated for hospital-acquired pneumonia and reflex administration of empirical antipseudomonal antibiotic therapy may be unnecessary. A diagnostic approach with BAL and protected specimen brush using quantitative cultures for patients with VAP led to a decrease in broad-spectrum antibiotic use and improved outcome. Endotracheal aspirate cultures with quantitative counts are commonly used, but validation is lacking. An empirical approach using the Clinical Pulmonary Infection Score is a pragmatic approach that minimizes antibiotic resistance and leads to decreased mortality in patients in the ICU. The source of the P aeruginosa may be endogenous (from respiratory or GI tract colonization) or exogenous from tap water in hospital-acquired pneumonia. The latter source is amenable to preventive measures.


Photodynamic therapy using chlorophyll-a in the treatment of acne vulgaris: a randomized, single-blind, split-face study.
Chlorophyll-a is a novel photosensitizer recently tested for the treatment of acne vulgaris. We sought to evaluate the clinical efficacy and safety of chlorophyll-a photodynamic therapy used for acne treatment. Subjects with acne on both sides of the face were included. Eight treatment sessions were performed over a 4-week duration. Half of the face was irradiated using a blue and red light-emitting diode after topical application of chlorophyll-lipoid complex. The other half underwent only light-emitting diode phototherapy. The lesion counts and acne severity were assessed by a blinded examiner. Sebum secretion, safety, and histologic changes were also evaluated. In total, 24 subjects completed the study. Facial acne improved on both treated sides. On the chlorophyll-a photodynamic therapy-treated side, there were significant reductions in acne lesion counts, acne severity grades, and sebum levels compared with the side treated with light-emitting diode phototherapy alone. The side effects were tolerable in all the cases. All the subjects were of Asian descent with darker skin types, which may limit the generalizability of the study. A chlorophyll-a arm alone is absent, as is a no-treatment arm. We suggest that chlorophyll-a photodynamic therapy for the treatment of acne vulgaris can be effective and safe with minimal side effects.


Standardized Asthma Admission Criteria Reduce Length of Stay in a Pediatric Emergency Department.
Asthma is the most common chronic illness in children and accounts for > 600,000 emergency department (ED) visits each year. Reducing ED length of stay (LOS) for moderate to severe asthmatics improves ED throughput and patient care for this high-risk population. The objective of this study was to determine the impact of adding standardized, respiratory score-based admission criteria to an asthma pathway on ED LOS for admitted patients, time to bed request, overall percentage of admitted asthmatics, inpatient LOS, and percentage of pediatric intensive care unit (PICU) admissions. This was a retrospective study of a quality improvement intervention. Statistical process control methodologies were used to analyze measures 15 months before and after implementation of a modified asthma pathway (June 2010 to December 2012; pathway modification September 2011). A total of 3,688 patients aged 1 through 18 years who presented to the ED with an asthma exacerbation during the study period were included. Patients were excluded if they were not eligible for the asthma pathway. Patient characteristics were similar before and after the intervention. Mean ED LOS and time to bed request for admitted asthmatics both decreased by 30 minutes. There was no change in percentage of asthma admissions (34%), mean inpatient LOS (1.4 days), or percentage of PICU admissions (2%). Standardizing care for asthma patients to include objective admission criteria early in the ED course may optimize patient care and improve ED flow.


Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders.
Prenatal viral infection has been associated with development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain structure and function in mouse offspring following late first trimester (E9) administration of influenza virus. We hypothesized that late second trimester infection (E18) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6J mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offsping of the infected mice were collected at P0, P14, P35 and P56, their brains removed and prefrontal cortex, hippocampus and cerebellum dissected and flash frozen. Microarray, qRT-PCR, DTI and MRI scanning, western blotting and neurochemical analysis were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with schizophrenia or autism including Sema3a, Trfr2 and Vldlr were found to be altered as were protein levels of Foxp2. E18 infection of C57BL6J mice with a sublethal dose of human influenza virus led to significant gene alterations in frontal, hippocampal and cerebellar cortices of developing mouse progeny. Brain imaging revealed significant atrophy in several brain areas and white matter thinning in corpus callosum. Finally, neurochemical analysis revealed significantly altered levels of serotonin (P14, P35), 5-Hydroxyindoleacetic acid (P14) and taurine (P35). We propose that maternal infection in mouse provides an heuristic animal model for studying the environmental contributions to genesis of schizophrenia and autism, two important examples of neurodevelopmental disorders.


Synthesis and surface self-assembly of [3]rotaxane-porphyrin conjugates: toward the development of a supramolecular surface tweezer for C60.
Surface immobilization of pristine C60 by supramolecular interactions is an attractive way to introduce C60 on surfaces since the pi-electron network and the electronic properties of C60 remain intact. Several hosts have been developed for surface complexation of C60. With few exceptions, the hosts reported to date are "electronically inert", limiting the potential applications of pristine C60-based devices. In this study, we present the synthesis and self-assembly of a potential tweezer-like host for C60 having a light-harvesting moiety and an electron-donating unit. More precisely, an azide-containing [3]rotaxane scaffold having ferrocene moieties as blocking group and thioctic acid as anchoring group for a gold surface has been synthesized. This [3]rotaxane has been self-assembled on gold in its protonated (NH2+) (1p) and neutral (NH) (1n) forms and characterized using electrochemistry, XPS, and contact angle measurements. The SAMs were functionalized with free-base and zinc porphyrin using copper-catalyzed 1,3-dipolar cycloaddition in optimized conditions. In combination with C60, this new host is expected to form a triad that could potentially be used as active building block in the preparation of nanostructured electrodes for photoelectrochemical application.


Prevalence and determinants of antibiotic exposure in infants: A population-derived Australian birth cohort study.
The aim of this study was to describe antibiotic exposure in Australian infants during the first year of life, focusing on antibiotic class, indication, risk factors associated with exposure and comparison with international counterparts. The Barwon Infant Study is a birth cohort study (n = 1074) with an unselected antenatal sampling frame from a large regional centre in Victoria, Australia. Longitudinal data on infection and medication were collected at 1, 3, 6, 9 and 12 months by parental questionnaire and from general practitioner and hospital records. Predictors of questionnaire non-completion were identified. A total of 660 infants with complete serial data were comprehensively examined. Antibiotic exposure was calculated as (i) antibiotic prescriptions and (ii) antibiotic days-exposed per person-year. Mean antibiotic prescription rate was 0.92 prescriptions (95% confidence interval (CI), 0.83-1.02) per person-year, with the highest rates in those aged <1 month (1.50 (95% CI, 1.09-1.91) per person-year). A total of 50.0% of infants were exposed to at least one antibiotic in their first year of life. Increasing number of siblings was associated with increased antibiotic exposure. Penicillin with extended spectrum (365 of 661 antibiotic prescriptions, 52.6%) and cephalosporins (12.0%) were the most frequently prescribed antibiotics. One fifth of antibiotics were prescribed for respiratory tract infections and bronchiolitis. Australian infants in this large population-based study are exposed to considerably more antibiotics than the majority of their international counterparts. Interventions aimed at addressing avoidable prescribing by medical practitioners and modifiable risk factors associated with antibiotic exposure may reduce antibiotic use.


Time spent on health related activity by older Australians with diabetes.
There is little information available about what people do to look after their health, or how long people spend on health activities. This study identifies key health related activities and time taken as part of self management by people with diabetes. Management planning often lacks information that this study provides that would help clinicians and patients to create manageable and do-able plans that patients can follow. Data were collected in 2010 using a national survey of people aged 50 years the National Diabetes Services Scheme. Respondents provided recall data on time used for personal health care, non-clinical health activity; and health service interactions. Data were analysed using Stata 12 and SPSS 19. While most people with diabetes spend on average less than 30 minutes a day on health-related activities (excluding exercise), the highest decile of respondents averaged over 100 minutes. Time spent increased with the number of co-existent conditions. Taking medication and sitting in waiting rooms were the most frequently reported activities. The greatest amount of time was spent on daily personal health care activities. The time demands of diabetes for older people can be substantial. Better patient engagement in self management might result from a better match in care planning between the illness demands and the patient time availability, with potential to reduce admissions for hospital care.


The Effect of Demineralization and Remineralization Cycles on the Bond Strength of Resin Composite to Enamel.
Toothwear is a growing concern, particularly in young adults. Prevention strategies remain of utmost importance and may involve the use of remineralising agents. If restorative treatment is indicated, adhesive techniques are recommended. It is unknown whether remineralising agents affect adhesion. 77 bovine incisors were subjected to simulated toothwear by erosion (0.3% citric acid) and abrasion (oscillating toothbrush). Samples were randomly arranged into 5 test and 2 control groups (n=11). Each test group had a remineralising agent applied. Subsequently, composite was bonded to each sample and subjected to shear bond testing. Shear bond strength, mode of failure and enamel surface changes were analysed. There was no statistically significant difference for bond strength between groups (p=0.262). Mode of failure was statistically significant between groups (p⟨0.0001). Qualitative analysis showed a surface layer on samples remineralised by calcium silicate and stannous fluoride. Both groups had more adhesive failures. Within the limitations of this study, it can be concluded that the remineralising agents tested do not affect shear bond strength though surface layers created on the enamel influence the mode of failure. These 'sacrificial' surface layers have the potential to protect the underlying enamel structure.


The experiences of adults with intellectual disabilities and their carers in general hospitals: a focus group study.
People with intellectual disabilities (ID) have higher levels of health needs compared with the general population, many of which are unrecognised and unmet. While there has been interest and research into the primary health provision for this group, there has been a more limited focus on addressing their care received in general hospitals. Access to health care has predominated in the literature, with less attention being paid to the experiences of people with ID as users of general hospital care. A qualitative focus group methodology was used. Eleven adults with ID, nine parents and five paid carers of adults with ID participated. The focus groups were audiotaped and transcriptions were analysed using principles of grounded theory. The analysed data highlighted key themes identified from the experiences of participants. These were the interrelated issues of feelings, particularly anxiety and fear, communication and behaviour problems; the practicalities of being in or attending hospitals, including the role played by carers; and issues around perceived discrimination and negative comments. The experiences of participants in this study concur with and add to concern expressed in recent reports and published research. Wide ranging implications are discussed for further research, wider policy development, clinical practice, local health service provision and education of health professionals.


DNA cleavage by hydroxy-salicylidene-ethylendiamine-iron complexes.
Bis(hydroxy)salen.Fe complexes were designed as self-activated chemical nucleases. The presence of a hy-droxyl group on the two salicylidene moieties serve to form a hydroquinone system cooperating with the iron redox system to facilitate spontaneous formation of free radicals. We compared the DNA binding and cleaving properties of the ortho -, meta- and para -(bishydroxy) salen.Fe complexes with that of the corresponding chelate lacking the hydroxyl groups. DNA melting temperature studies indicated that the para complex exhibits the highest affinity for DNA. In addition, this para compound was considerably more potent at cleaving supercoiled plasmid DNA than the regio-isomeric ortho - and meta -hydroxy-salen.Fe complexes, even in the absence of a reducing agent, such as dithiothreitol used to activate the metal complex. The DNA cleaving activity of the para isomer is both time and concentration dependent and the complexed iron atom is absolutely essential for the sequence uniform cleavage of DNA. From a mechanistic point of view, electron spin resonance measurements suggest that DNA contributes positively to the activation of the semi-quinone system and the production of ligand radical species responsible for subsequent strand scission in the absence of a reducing agent. The para -hydroxy-salen.Fe complex has been used for detecting sequence-specific drug-DNA interactions. Specific binding of Hoechst 33258 to AT sequences and chromomycin to GC sequences were shown. The para -bis(hydroxy)salen.Fe derivative complements the tool box of footprinting reagents which can be utilised to produce efficient cleavage of DNA.


Evaluation of Speech-Based Digital Biomarkers: Review and Recommendations.
Speech represents a promising novel biomarker by providing a window into brain health, as shown by its disruption in various neurological and psychiatric diseases. As with many novel digital biomarkers, however, rigorous evaluation is currently lacking and is required for these measures to be used effectively and safely. This paper outlines and provides examples from the literature of evaluation steps for speech-based digital biomarkers, based on the recent V3 framework (Goldsack et al., 2020). The V3 framework describes 3 components of evaluation for digital biomarkers: verification, analytical validation, and clinical validation. Verification includes assessing the quality of speech recordings and comparing the effects of hardware and recording conditions on the integrity of the recordings. Analytical validation includes checking the accuracy and reliability of data processing and computed measures, including understanding test-retest reliability, demographic variability, and comparing measures to reference standards. Clinical validity involves verifying the correspondence of a measure to clinical outcomes which can include diagnosis, disease progression, or response to treatment. For each of these sections, we provide recommendations for the types of evaluation necessary for speech-based biomarkers and review published examples. The examples in this paper focus on speech-based biomarkers, but they can be used as a template for digital biomarker development more generally.


Effectiveness of adalimumab in the treatment of scalp and nail affection in patients with moderate to severe plaque psoriasis in routine clinical practice.
Data on the effectiveness of biologics in the treatment of nail and scalp psoriasis (PSO) in a routine clinical setting are scarce. The aim of this study was therefore to evaluate the effectiveness of adalimumab in the treatment of nail and scalp psoriatic lesions in routine dermatologic practice. Five hundred one patients were analyzed in this observational study; 157 patients had nail involvement (nail PSO set; NPS) and 404 had scalp involvement (scalp PSO set; SPS). Patients treated with adalimumab were observed for up to 12 months. Outcomes were evaluated via changes in the Nail Psoriasis Severity Index (NAPSI), Psoriasis Scalp Severity Index (PSSI), Psoriasis Area and Severity Index (PASI), and QoL (using the Dermatology Life Quality Index). Eighty-four percent of the patients in the NPS and 93.8% in the SPS achieved a good clinical response upon treatment with adalimumab. Complete clearing of local symptoms was achieved by 33.3% of the patients with nail involvement and 66.7% of the patients with scalp involvement. There was also a marked improvement in QoL. Adalimumab appears to be an effective treatment for scalp and nail PSO in patients with moderate to severe plaque PSO. No new clinical concerns were established.


The role of labels and motions in infant category learning.
We investigated the impact of two highly salient transient features, labels and motions, on novel visual category learning in 10-month-old infants. In three eye-tracking experiments, infants were presented with exemplars from two novel categories either accompanied by category-specific labels, accompanied by category-specific motions, or in silence. Labels (Experiment 1) and motions (Experiment 2) were presented using a gaze-contingent design in which these transient features were triggered by infants' fixations. Gaze-contingent transient features, despite being redundant, had a strong impact on categorization. The results revealed that both labels and motions support infants' category formation. Furthermore, both labels and motions promoted similarity-focused exploration, whereas no such pattern was found when infants learned the categories in silence. Analyses of visual exploration patterns revealed that infants readily form expectations about motion properties of categories and that these expectations drive their looking behavior.


Transcription of interferon-stimulated genes is induced by adenovirus particles but is suppressed by E1A gene products.
Interferon treatment of cell cultures results in the rapid transcriptional induction of a specific set of genes. In this paper we explore the effect of cellular infection by several adenoviruses, both wild type and mutant, on the expression of these genes. Infection with adenovirus induces the transcription of the interferon-stimulated genes in the absence of any protein synthesis. In fact, the inhibition of protein synthesis during a wild-type infection produces enhanced stimulation of transcription of these genes. Experiments with viral mutants indicate the ability to specifically suppress this transcription maps to the E1A gene. In addition, the E1A gene products are capable of suppressing the specific transcriptional induction of interferon-stimulated promoters during cotransfection experiments and therefore presumably during viral infection. The dual effect of adenovirus on the expression of interferon-stimulated genes may represent an example of action and evolutionary reaction between virus and host.


Hybridization rates between lettuce (Lactuca sativa) and its wild relative (L. serriola) under field conditions.
Hybridization and introgression between crops and wild relatives may have important evolutionary and ecological consequences such as gene swamping or increased invasiveness. In the present study, we investigated hybridization under field conditions between crop lettuce (Lactuca sativa) and its wild relative prickly lettuce (L. serriola), two cross-compatible, predominantly autogamous and insect pollinated species. In 2003 and 2004, we estimated the rates of hybridization between L. sativa and L. serriola in close-to-reality field experiments carried out in two locations of Northern Switzerland. Seeds set by the experimental wild plants were collected and sown (44 352 in 2003 and 252 345 in 2004). Progeny was screened morphologically for detecting natural hybrids. Prior to the experiment, specific RAPD markers were used to confirm that morphological characters were reliable for hybrid identification. Hybridization occurred up to the maximal distance tested (40 m), and hybridization rates varied between 0 to 26%, decreasing with distance. More than 80% of the wild plants produced at least one hybrid (incidence of hybridization, IH) at 0 m and 1 m. It equaled 4 to 5% at 40 m. In sympatric crop-wild populations, cross-pollination between cultivated lettuce and its wild relative has to be seen as the rule rather than the exception for short distances.


Transfection of human topoisomerase II alpha into etoposide-resistant cells: transient increase in sensitivity followed by down-regulation of the endogenous gene.
We have investigated the possibility of overcoming the resistance of human brain tumour cells (HBT20) to etoposide by transferring the normal human topoisomerase II alpha (H-topo II) gene into these cells. H-topo II in a mammalian expression vector containing a glucocorticoid-inducible mouse mammary tumour virus (MMTV) promoter was transfected into etoposide-resistant HBT20 cells (HBT20-hTOP2MAM). HBT20 cells transfected with pMAMneo vector alone served as control cells (HBT20-MAM). These were stable transfections. Following a 2 h dexamethasone treatment, H-topo II mRNA expression, protein production, etoposide-induced DNA-protein complex formation and sensitivity to etoposide were increased in HBT20-hTOP2MAM cells compared with control HBT20-MAM cells and with HBT20-hTOP2MAM cells not treated with dexamethasone. However, mRNA and protein levels and cell sensitivity returned to baseline when incubation with dexamethasone was continued for 24 h. This decrease from the 2 h values could not be explained by a loss of the MMTV promoter response to dexamethasone. (H-topo II alpha promoter)-(chloramphenicol acetyltransferase) constructs containing regions -559-0 and -2400-0 were significantly down-regulated in HBT20-hTOP2MAM cells treated for 24 h with dexamethasone compared with dexamethasone-treated control cells. H-topo II mRNA stability after 24 h of dexamethasone treatment was not altered compared with that in control cells. Our data indicate that the exogenously produced H-topo II may have a negative-feedback effect on the endogenous topoisomerase II promoter, causing down-regulation of the endogenous gene.


Changes in morphology and cell wall structure that occur during growth of Vibrio sp. NCTC4716 in batch culture.
When grown in batch culture in various media Vibrio sp. NCTC4716 displayed a distinct sequence of morphological forms. Organisms occurred as stout, almost straight rods in exponential phase, curved rods (characteristic of Vibrio spp.) in stationary phase, and predominantly as spheres in decline phase. The spheres were formed after growth had ceased due to the depletion of the carbon/energy source. They were not viable, survival of the culture depending on the few rod forms that remained during the decline phase. The spheres seemingly arose from degradation, but not complete removal, of the peptidoglycan present in the walls. Though spheres contained less nucleic acid and low molecular weight cytoplasmic constituents than did rods, many still possessed an intact cytoplasmic membrane.


Multiple pathways involved in the biosynthesis of anandamide.
Endocannabinoids, including anandamide (arachidonoyl ethanolamide) have been implicated in the regulation of a growing number of physiological and pathological processes. Anandamide can be generated from its membrane phospholipid precursor N-arachidonoyl phosphatidylethanolamine (NAPE) through hydrolysis by a phospholipase D (NAPE-PLD). Recent evidence indicates, however, the existence of two additional, parallel pathways. One involves the sequential deacylation of NAPE by alpha,beta-hydrolase 4 (Abhd4) and the subsequent cleavage of glycerophosphate to yield anandamide, and the other one proceeds through phospholipase C-mediated hydrolysis of NAPE to yield phosphoanandamide, which is then dephosphorylated by phosphatases, including the tyrosine phosphatase PTPN22 and the inositol 5' phosphatase SHIP1. Conversion of synthetic NAPE to AEA by brain homogenates from wild-type and NAPE-PLD(-/-) mice can proceed through both the PLC/phosphatase and Abdh4 pathways, with the former being dominant at shorter (<10 min) and the latter at longer (60 min) incubations. In macrophages, the endotoxin-induced synthesis of anandamide proceeds uniquely through the phospholipase C/phosphatase pathway.


Elevated Plasma Levels of Soluble (Pro)Renin Receptor in Patients with Obstructive Sleep Apnea Syndrome in Parallel with the Disease Severity.
(Pro)renin receptor ((P)RR), a receptor for renin and prorenin, is implicated in the pathophysiology of diabetes mellitus, hypertension and their complications. Soluble (P)RR (s(P)RR) is composed of extracellular domain of (P)RR and thus exists in blood. We have reported that plasma concentrations of s(P)RR were elevated in male patients with obstructive sleep apnea syndrome (OSAS). The aim of the present study was to clarify the difference in plasma s(P)RR concentrations between male and female OSAS patients. Plasma s(P)RR concentrations were studied in 289 subjects (206 males and 83 females) consisting of 259 OSAS patients and 30 non-OSAS control subjects. The 259 OSAS patients were classified into mild (5 ≤ apnea hypopnea index (AHI) < 15 events/h), moderate (15 ≤ AHI < 30), and severe OSAS (AHI ≥ 30). Plasma s(P)RR levels were significantly elevated in all three OSAS groups compared to non-OSAS control subjects (AHI < 5) in the entire cohort and male subjects, whereas in female subjects, the significant elevation was found only in severe OSAS. Plasma s(P)RR levels were significantly correlated with AHI in both sexes, with a higher r value found in male subjects (male r = 0.413, p < 0.0001; female r = 0.263, p < 0.05). Importantly, when OSAS patients (26 males and 15 females) with AHI ≥ 20 underwent continuous positive airway pressure treatment, plasma s(P)RR levels were significantly decreased. In conclusion, plasma s(P)RR levels are elevated in both male and female OSAS patients in parallel with the disease severity.