Persistent activity of moxidectin pour-on and injectable against sucking and biting louse infestations of cattle.
To evaluate the persistent activity of pour-on and injectable moxidectin against natural challenge by sucking (predominantly Linognathus vituli) and chewing (Bovicola bovis) cattle lice, 96 mixed-breed calves that had been treated to remove all lice were blocked by body weight and randomly allocated to three treatments: untreated control, moxidectin at 500 microg/kg by topical application and moxidectin at 200 microg/kg by subcutaneous injection. Twelve pens were blocked into groups of four and randomly allocated to four challenge times: 14, 21, 28 and 35 days post-treatment. Treatment groups were assigned to challenge pens randomly. Two donor calves, with demonstrated infestations of both sucking and chewing lice, were introduced into each pen containing eight principal calves at the start of each challenge time. Donors remained in the challenge pen for 7 days. Principal calves were examined for lice, 7, 14, 21 and 28 days after donor removal using a standardized hair-parting technique. Moxidectin injectable prevented re-infestation with L. vituli for up to 42 days, but did not provide persistent activity against B. bovis longer than 35 days post-treatment. Moxidectin pour-on demonstrated persistent activity against both B. bovis and L. vituli for 42 days.


Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma.
The single- and multiple-dose absorption characteristics of a new sustained-release theophylline preparation, which has been formulated for once per day dosing in adults, were investigated in children aged 8 to 14 years. Four single doses were studied, each dose separated by 1 week. During steady state the preparation was given once daily in the morning for 1 week, and serum theophylline concentration was determined through two dosing intervals (48 hours). The product showed excellent sustained-release characteristics and consistent absorption profiles, which were not affected to any clinically important extent by the intake of various meals. After single doses, only 77% to 91% of the product was absorbed during the first 28 hours after dosing. However, bioavailability was complete both after single doses and during steady state. Eight of 14 children had steady-state fluctuations in serum theophylline levels of less than 90% when given doses once daily. Steady-state day-to-day variations in serum theophylline profiles were small in all patients except one, in whom differences up to 33 mumol/L (6 micrograms/mL) were seen (8 hours after dosing). We conclude that this formulation is completely absorbed at a sufficiently slow and consistent rate to permit acceptable fluctuations in absorption with once daily dosing for many, but not all, patients. However, it should not be used in very young children until bioavailability has been studied in this age group.


Catalytic site-selective substrate processing within a tubular nanoreactor.
Chemists have long sought the ability to modify molecules precisely when presented with several sites of similar reactivity. We reasoned that the confinement of substrates within nanostructures might permit site-selective reactions unachievable in bulk solution, even with sophisticated reagents. In particular, the stretching and alignment of polymers within nanotubes might allow site-specific cleavage or modification. To explore this proposition, macromolecular disulfide substrates were elongated within members of a collection of tubular protein nanoreactors, which contained cysteine residues positioned at different locations along the length of each tube. For each nanoreactor, we defined the reactive location by using a set of polymer substrates (site-selectivity) and which of the two sulfur atoms was attacked (regioselectivity), and found that disulfide interchange occurs with atomic precision. Our strategy has potential for the selective processing of a wide variety of biomacromolecules, and the chemistry and substrates might be generalized yet further by using alternative nanotubes.


Identification of a novel secreted protease from Pseudomonas aeruginosa that causes corneal erosions.
The purpose of this study was to identify a new Pseudomonas protease and determine its possible role in keratitis. Concentrated culture supernatants of the Pseudomonas aeruginosa strains PA103 and ATCC 19660 were analyzed by zymography. P. aeruginosa small protease (PASP) was purified from strain PA103, and modified elastase B (LasB) was purified from strain ATCC 19660. SDS-PAGE and Western blot analysis were performed on purified PASP and modified LasB. PASP was further analyzed by mass spectrometry and amino-terminal sequencing. The Pasp gene was cloned and expressed, affinity-purified in denatured form from inclusion bodies, and refolded by removal of the denaturant. Purified recombinant PASP was analyzed by zymography for protease activity. PASP and heat-inactivated PASP were injected into rabbit corneas, and the corneas were monitored for erosions caused by protease activity. Each strain produced a protease with a molecular mass of 80 kDa on zymograms. LasB antiserum identified the ATCC 19660 protease as modified LasB. Mass spectrometry defined the PA103 protease as having a molecular mass of 18.5 kDa. Amino-terminal sequencing and analysis of the P. aeruginosa genome sequence determined that the PA103 Pasp gene sequence was >99% identical with the PA0423 sequence of strain PAO1. Recombinant PASP was proteolytic, with a zymogram mass of 50 kDa. PASP purified from PA103 produced extensive corneal epithelial erosions, whereas heat-inactivated PASP produced no erosions. PASP is a protease that has not been previously identified. It causes corneal epithelial erosions, indicating its likely activity as a virulence-promoting factor in Pseudomonas keratitis.


Reframing video gaming and internet use addiction: empirical cross-national comparison of heavy use over time and addiction scales among young users.
Evidence-based and reliable measures of addictive disorders are needed in general population-based assessments. One study suggested that heavy use over time (UOT) should be used instead of self-reported addiction scales (AS). This study compared UOT and AS regarding video gaming and internet use empirically, using associations with comorbid factors. Cross-sectional data from the 2011 French Survey on Health and Consumption on Call-up and Preparation for Defence-Day (ESCAPAD), cross-sectional data from the 2012 Swiss firstname.lastname@example.com study and two waves of longitudinal data (2010-13) of the Swiss Longitudinal Cohort Study on Substance Use Risk Factors (C-SURF). Three representative samples from the general population of French and Swiss adolescents and young Swiss men, aged approximately 17, 14 and 20 years, respectively. ESCAPAD: n =22 945 (47.4% men); email@example.com: n =3049 (50% men); C-SURF: n =4813 (baseline + follow-up, 100% men). We assessed video gaming/internet UOT ESCAPAD and firstname.lastname@example.com: number of hours spent online per week, C-SURF: latent score of time spent gaming/using internet] and AS (ESCAPAD: Problematic Internet Use Questionnaire, email@example.com: Internet Addiction Test, C-SURF: Gaming AS). Comorbidities were assessed with health outcomes (ESCAPAD: physical health evaluation with a single item, suicidal thoughts, and appointment with a psychiatrist; firstname.lastname@example.com: WHO-5 and somatic health problems; C-SURF: Short Form 12 (SF-12 Health Survey) and Major Depression Inventory (MDI). UOT and AS were correlated moderately (ESCAPAD: r = 0.40, email@example.com: r = 0.53 and C-SURF: r = 0.51). Associations of AS with comorbidity factors were higher than those of UOT in cross-sectional (AS: .005 ≤ |b| ≤ 2.500, UOT: 0.001 ≤ |b| ≤ 1.000) and longitudinal analyses (AS: 0.093 ≤ |b| ≤ 1.079, UOT: 0.020 ≤ |b| ≤ 0.329). The results were similar across gender in ESCAPAD and firstname.lastname@example.com (men: AS: 0.006 ≤ |b| ≤ 0.211, UOT: 0.001 ≤ |b| ≤ 0.061; women: AS: 0.004 ≤ |b| ≤ 0.155, UOT: 0.001 ≤ |b| ≤ 0.094). The measurement of heavy use over time captures part of addictive video gaming/internet use without overlapping to a large extent with the results of measuring by self-reported addiction scales (AS). Measuring addictive video gaming/internet use via self-reported addiction scales relates more strongly to comorbidity factors than heavy use over time.


Ultrasonographic Imaging of the Fetal Pyloric Sphincter.
In this study, we hypothesized that the pyloric sphincter can be directly visualized by ultrasonography in the prenatal period. This study was designed as a cross-section. Single, healthy pregnancies between 18 and 22 weeks of gestation who applied to the Perinatology outpatient clinic for second-level ultrasonography were included in the study. In addition to the demographic characteristics of the participants, fetal pyloric mucosa, fetal pyloric sphincter length, and fetal pyloric sphincter thickness were measured by ultrasonography. Intrarater variability was calculated. A total of 93 eligible patients were evaluated in the study. The mean age of the participants was 27.25 ± 6.23, and the gestational age was 21.18 ± 0.98. Pylorus imaging and measurements were possible in all fetuses that were in the optimal position. Mean pyloric sphincter length (mm) was 5.32 ± 0.93, pyloric sphincter thickness (mm) was 2.13 ± 0.44, and sphincter muscle thickness (mm) was 1.05 ± 0.24. The pyloric sphincter can be easily visualized on a second-trimester ultrasound scan when the appropriate technique is used. This may make an additional contribution to the diagnosis of fetal gastrointestinal tract pathologies.


Association between ultra-processed foods consumption and the risk of hypertension: An umbrella review of systematic reviews.
Several systematic reviews (SRs) have investigated the association between ultra-processed foods (UPFs) and the risk of hypertension in various populations. However, the quality of the evidence remains unclear. This umbrella review was thus conducted to fill this gap. We searched for SRs with and without meta-analyses comparing high UPF versus low UPF consumption on the risk of hypertension in the Cochrane Library, Embase, PubMed, and Web of Science from inception to August 2022. This study was registered in PROSPERO (No. CRD42022352934). The A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) tool and the Preferred Reporting Item for Systematic Review and Meta-analysis 2009 (PRISMA 2009) statement were used to evaluate the methodological and reporting quality of the included SRs. Stata 15/SE was used to reanalyse the data using the random-effects model, and the risk of bias of observational studies from included SRs was reassessed using the Newcastle-Ottawa Scale (NOS) tool. The certainty of the evidence body was assessed using the GRADE recommendation. Seven SRs were included in the umbrella review. Among them, nine observational studies (5 cross-sectional and 4 cohort studies), whose available data were resynthesised using meta-analysis. The methodological and reporting quality of the included SRs were relatively poor. The meta-analysis results revealed suggestive evidence of an association between high UPF consumption and the incidence of hypertension (odds ratio: 1.23, 95% confidence interval: 1.11 to 1.37, p < 0.001, 95% prediction interval: 0.92 to 1.64, critically low certainty) compared to low UPF consumption. High UPF consumption is associated with an increased risk of hypertension. However, well-conducted SRs, including high-quality prospective cohort studies, are needed to further verify these findings.


Genetic evaluation of intellectual disabilities.
All children with an intellectual disability (mental retardation) or global developmental delay should have a comprehensive evaluation to establish the etiology of the disability. A specific etiologic diagnosis offers the opportunity to discuss treatment, prognosis, and genetic recurrence risk. A diagnosis also avoids unnecessary testing and can lead to opportunities for improved health and functional outcomes. The key elements of the diagnostic evaluation are the medical and developmental history, 3-generation family history, dysmorphologic examination, neurologic examination, and judicious use of the laboratory and neuroimaging. All published guidelines for the evaluation of children with intellectual disability acknowledge that there is a substantial percentage of patients who are undiagnosed after a comprehensive evaluation and who deserve ongoing follow-up for the purpose of establishing a diagnosis. Recently, studies of the clinical application of array comparative genomic hybridization (aCGH) to individuals with intellectual disability indicate that this approach provides a diagnosis in as much as 10% of patients and that this technique is replacing the use of fluorescent in situ hybridization for subtelomere imbalances now used for such patients when the standard karyotype is normal. The literature suggests that history and examination by an expert clinician will lead to a diagnosis in 2 of 3 patients in whom a diagnosis is made. Laboratory studies alone, including neuroimaging, provide a diagnosis in the remaining one third. The approach to the evaluation of the patient in whom an etiologic diagnosis is not suspected after the history and physical examinations includes a standard karyotype, Fragile X molecular genetic testing, aCGH, and neuroimaging, based on the evidence to date. One can expect rapid changes in the microarray technology in the near future.


Multi-interfacial engineering in the hierarchical self-assembled micro-nano dielectric aerogel for wide-band absorption and low infrared emissivity.
Radar-infrared (IR) compatible stealth can satisfy the characteristics of excellent electromagnetic wave attenuation property and low infrared emissivity. However, concurrently satisfying these demands is still a great challenge at present. Herein, multi-interfacial engineering strategy was proposed for the preparation of radar-IR compatible stealth materials. ZnO has a high electron binding energy and a large band gap at room temperature, and doping with sulphide can increase the concentration of unconstrained carriers. Therefore, bimetallic sulphide aerogels loaded with ZnO were prepared by means of carbonization and vulcanization, combined with freeze-drying method. When the filling ratio is 20 %, an absorption bandwidth (fe) of 6.62 GHz at a matching thickness of 2.0 mm and a reduction in IR emissivity from 0.920 to 0.539 in the 8-14 μm band are achieved. This work provides a guidance to design and synthesize high-performance absorbers by multi-interfacial engineering for IR-radar compatible stealth application.


Occurrence of an anthropogenic gadolinium anomaly in river and coastal waters of southern France.
This study reports a pronounced positive Gd anomaly in a small river and in the largest French Mediterranean lagoon. Along the studied catchment, this anomaly is also present in the effluents of the municipal sewage treatment plants, suggesting an anthropogenic origin for the Gd excess. The anomaly corresponds to a distinct increase of Gd concentrations (up to 19 pmol/l) in the river and around 5.4 pmol/l in the lagoon. The excess flux of Gd is compatible with the medical use of water soluble Gd complexes as contrasting agent in magnetic resonance imaging.


Activity and expression of the vanilloid receptor 1 (TRPV1) is altered by long-term diabetes in epineurial arterioles of the rat sciatic nerve.
Epineurial arterioles of the sciatic nerve are innervated by sensory nerves containing calcitonin gene-related peptide (CGRP). We postulated that treating these resistance vessels with capsaicin would cause the release of endogenous CGRP and vascular relaxation. Videomicroscopy was used to examine the effect of capsaicin and neuropeptides on vascular reactivity of epineurial arterioles from control and streptozotocin-induced diabetic rats. Using immunohistochemistry, we examined expression of neuropeptide Y (NPY) and vanilloid receptor 1 in epineurial arterioles. Instead of relaxation, capsaicin was found to cause a concentration-dependent vasoconstriction in epineurial arterioles. The effect of capsaicin was transient, refractory, blocked by capsazepine and duplicated by resiniferatoxin. When examining potential candidates for the mediation of capsaicin-induced constriction, we found that vasopressin (VP), NPY, serotonin (5HT) and endothelin (ET), but not neurokinin A or substance P, caused a concentration-dependent vasoconstriction of epineurial arterioles. Epineurial arterioles express NPY and receptor antagonists to NPY significantly decreased capsaicin-induced vasoconstriction. In long-term diabetic rats, vasoconstriction to capsaicin was significantly attenuated. However, long-term diabetes did not impair vasoconstriction of epineurial arterioles to exogenous VP, NPY, 5HT or ET. Examining the expression of vanilloid receptor 1 in epineurial arterioles from control and long-term diabetic rats, we found that immunoreactivity for vanilloid receptor 1 was decreased by diabetes. These studies suggest that long-term diabetes causes vascular dysfunction in epineurial arterioles of the sciatic nerve that includes a decrease in capsaicin-induced vasoconstriction that is likely due to a decrease in the expression of vanilloid receptor 1.


Apoptosis and the loss of chondrocyte survival signals contribute to articular cartilage degradation in osteoarthritis.
Apoptotic death of articular chondrocytes has been implicated in the pathogenesis of osteoarthritis (OA). Apoptotic pathways in chondrocytes are multi-faceted, although some cascades appear to play a greater in vivo role than others. Various catabolic processes are linked to apoptosis in OA cartilage, contributing to the reduction in cartilage integrity. Recent studies suggest that beta1-integrin mediated cell-matrix interactions provide survival signals for chondrocytes. The loss of such interactions and the inability to respond to IGF-1 stimulation may be partly responsible for the hypocellularity and matrix degradation that characterises OA. Here we have reviewed the literature in this area of cartilage cell biology in an effort to consolidate the existing information into a plausible hypothesis regarding the involvement of apoptosis in the pathogenesis of OA. Understanding of the interactions that promote chondrocyte apoptosis and cartilage hypocellularity is essential for developing appropriately targeted therapies for inhibition of chondrocyte apoptosis and the treatment of OA.


Completion of the natural groups of ergot alkaloids: syntheses and pharmacological profiles of beta-ergosine and beta-ergoptine.
The syntheses and pharmacological potencies of beta-ergosine and beta-ergoptine, the missing links in the natural groups of ergot peptide alkaloids are described.


Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer.
High EREG and AREG expression, and left-sided primary tumours are associated with superior efficacy of anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (CRC), but a unifying explanation of these findings is lacking. RNA-seq, gene expression arrays, and DNA methylation profiling were completed on 179 CRC tumours. Results were validated using independent The Cancer Genome Atlas data sets. An independent cohort of 198 KRAS wild-type metastatic CRC tumours was tested for CpG island methylator phenotype (CIMP) status, and progression-free survival (PFS) with the first anti-EGFR regimen was retrospectively determined. EREG and AREG expression was highly inversely correlated with methylation and was inversely associated with right-sided primary tumour, BRAF mutation, and CIMP-high status. Treatment of CRC cell lines with hypomethylating agents decreased methylation and increased expression of EREG. Inferior PFS with anti-EGFR therapy was associated with CIMP-high status, BRAF mutation, NRAS mutation, and right-sided primary tumour on univariate analysis. Among known BRAF/NRAS wild-type tumours, inferior PFS remained associated with CIMP-high status (median PFS 5.6 vs 9.0 mo, P=0.023). EREG and AREG are strongly regulated by methylation, and their expression is associated with CIMP status and primary tumour site, which may explain the association of primary tumour site and EREG/AREG expression with anti-EGFR therapy efficacy.


Homeostatic changes in neuronal network oscillations in response to continuous hypoperfusion in the mouse forebrain.
Neuronal activity is highly sensitive to changes in oxygen tension. In this study, we examined the impact of hypoxic/ischemic conditions on neuronal ensemble activity patterns in the mouse brain using in vivo extracellular electrophysiological recordings from up to 8 sites in the thalamus, dorsal hippocampus, and neocortex, while cerebral hypoperfusion was induced by unilateral carotid artery occlusion. After a few minutes, the occlusion triggered a rapid change in the power of the local field oscillations. In the hippocampus, but not in the neocortex, the absolute power changes at all frequency ranges (relative to the baseline) became less pronounced with time, and no significant changes were observed 30min after the occlusion-induced hypoperfusion. We also tested whether continuous hypoperfusion induced by the occlusion for up to 1 week alters neuronal activity. In the hippocampus and the thalamus, the chronic occlusion did not lead to a reduction in the power of the local field oscillations. These results indicate that certain neuronal populations have the ability to maintain internal neurophysiological homeostasis against continuous hypoperfusion.


X-ray micro-computed tomography reveals a unique morphology in a new click-beetle (Coleoptera, Elateridae) from the Eocene Baltic amber.
Beetle fossils are a rich source of information about the palaeodiversity and evolutionary history of the order Coleoptera. Despite the increasing rate of fossil research on click-beetles (Coleoptera: Elateridae), the most diverse group in the superfamily Elateroidea, their fossil record has remained largely unstudied. This may be caused by the combination of their rather uniform external morphology and the suboptimal state of preservation and visibility in most fossil specimens. Here, we used X-ray micro-computed tomography to reconstruct the morphology of an interesting click-beetle from Eocene Baltic amber, which had some principal diagnostic characters obscured by opaque bubbles and body position. Our results suggest that the newly described Baltelater bipectinatus gen. et sp. nov. belongs to tribe Protelaterini within subfamily Lissominae. Since Protelaterini have a predominantly Gondwanan distribution, our discovery is of a great importance for the historical biogeography of the group. Very distinctive are the bipectinate antennae with 11 antennomeres and with rami beginning on antennomere IV, which are not found in any recent Elateridae. The discovery of a new click-beetle lineage from European Eocene amber sheds further light on the palaeodiversity and historical diversification of the family as well as on the composition of the extinct amber forest ecosystem.


Structure of the chromosomal gene for granulocyte-macrophage colony stimulating factor: comparison of the mouse and human genes.
A cDNA clone that expresses granulocyte-macrophage colony stimulating factor (GM-CSF) activity in COS-7 cells has been isolated from a pcD library prepared from mRNA derived from concanavalin A-activated mouse helper T cell clones. Based on homology with the mouse GM-CSF cDNA sequence, the mouse GM-CSF gene was isolated. The human GM-CSF gene was also isolated based on homology with the human GM-CSF cDNA sequence. The nucleotide sequences determined for the genes and their flanking regions revealed that both the mouse and human GM-CSF genes are composed of three introns and four exons. The organization of the mouse and human GM-CSF genes are highly homologous and strong sequence homology between the two genes is found both in the coding and non-coding regions. A 'TATA'-like sequence was found 20-25 bp upstream from the transcription initiation site. In the 5'-flanking region, there is a highly homologous region extending 330 bp upstream of the putative TATA box. This sequence may play a role in regulation of expression of the GM-CSF gene. These structures are compared with those of different lymphokine genes and their regulatory regions.


The first neural probe integrated with light source (blue laser diode) for optical stimulation and electrical recording.
In this paper, we report a neural probe which can selectively stimulate target neurons optically through Si wet etched mirror surface and record extracellular neural signals in iridium oxide tetrodes. Consequently, the proposed approach provides to improve directional problem and achieve at least 150/m gap distance between stimulation and recording sites by wet etched mirror surface in V-groove. Also, we developed light source, blue laser diode (OSRAM Blue Laser Diode_PL 450), integration through simple jig for one-touch butt-coupling. Furthermore, optical power and impedance of iridium oxide tetrodes were measured as 200 μW on 5 mW from LD and 206.5 k Ω at 1 kHz and we demonstrated insertion test of probe in 0.5% agarose-gel successfully. We have successfully transmitted a light of 450 nm to optical fiber through the integrated LD using by butt-coupling method.


REM architecture changes in bipolar and unipolar depression.
The authors compared total night sleep measures and REM sleep architecture values for normal control subjects (N = 36), unipolar depressed patients (N = 36), and bipolar depressed patients (N = 22). The unipolar and bipolar patients had significantly greater fragmentation of REM periods than control subjects, and bipolar patients showed greater fragmentation of REM periods than unipolar patients. In both the unipolar and bipolar samples, the duration of successive REM periods was related to the total number of REM periods during sleep.


[The professional mobility of hospital nurses].
For several decades, hospitals have been faced with the voluntary departures of nurses. In parallel to this external mobility, internal mobility is also on the rise and is not always initiated by the nurse. This new mode of management has repercussions for professionals, patients as well as for the quality of care.


Comparison of the effectiveness of two mumps vaccines during an outbreak in Switzerland in 1999 and 2000: a case-cohort study.
In two recent nation-wide outbreaks of mumps in Switzerland two-thirds of young children with clinical mumps had a history of primary vaccination. On average, measles-mumps-rubella (MMR) vaccination coverage is 80%. Two types of vaccine are commonly used: Jeryl-Lynn and Rubini. The effectiveness of the latter has been questioned in several publications. The authors therefore compared Rubini to Jeryl-Lynn in a case-cohort study. The study included 111 young children with clinical mumps who had been reported to the Swiss Federal Office of Public Health (SFOPH) by primary care physicians of the Swiss Sentinel Surveillance Network (SSSN) between January 1999 and May 2000. Sentinel physicians also sampled 661 children from the same birth cohort as the cases. While we found no evidence for the effectiveness of the Rubini strain, vaccination with the Jeryl-Lynn strain was 70% effective against clinical mumps. Furthermore, children vaccinated with the Rubini strain attended primary health care more frequently with clinical mumps than those who had received Jeryl-Lynn (odds ratio: 2.4; 95% confidence interval (CI): 1.3, 4.7). Restricting the analysis to laboratory confirmed cases increased the odds ratio to 18.4 (95% CI: 2.5, 811.2). Our study confirms the low effectiveness of the Rubini strain vaccine in the field. This vaccine should therefore be considered inappropriate for the control and elimination of mumps and its use should be discontinued. As other vaccines with comparable quality and safety standards and a substantially higher effectiveness are available the MMR vaccination program in Switzerland will not be compromised if the use of Rubini is no longer recommended.


Fine mapping of the polled locus to a 1-Mb region on bovine chromosome 1q12.
The absence of horns in Bos taurus is under genetic control of the autosomal dominant polled locus which has been genetically mapped to the centromeric region of cattle Chromosome 1. Recently a 4-Mb BAC contig of this chromosomal region has been constructed. Toward positional cloning of the bovine polled locus, we identified 20 additional microsatellite markers spread over the contig map by random sequencing of bacterial artificial chromosome (BAC) subclones. A total of 26 markers were genotyped in 30 two-generation half-sib families of six different German cattle breeds segregating for the hornless phenotype including 336 informative meioses for the polled character. Our fine-mapping study involving 19 recombinant haplotypes allowed us to narrow the critical region for the bovine polled locus to a 1-Mb segment with a centromeric boundary at RP42-218J17_MS1 and a telomeric boundary at BM6438. For marker-assisted selection purposes, the first evidence of informative flanking markers helps to predict polled genotypes with a higher degree of accuracy within families until testing of the causative mutation is available.


Facilitation of tonic immobility by stimulation of the vaginal cervix in the rat.
Stimulation of the vaginal cervix with a plunger from a 1 cc syringe induced tonic immobility (i.e., blocked gross movement including the righting reflex) in response to inversion combined with brief manual restraint, in otherwise insusceptible female rats. In a second experiment, estradiol benzoate administration potentiated this effect somewhat, as measured by the latency to immobilization, although the duration of immobility was not significantly affected. Results are discussed in terms of the possible relationship between tonic immobility and lordosis, the immobile mating posture of the female rat, which is also potentiated by cervical stimulation.


Evaluation of the continuation of care between psychiatric hospitalization units and the outpatient clinics in the community.
Continuum of care between health institutions is one of the basic elements of healthcare quality. In this article we present a study that was conducted in an acute psychiatric hospitalization unit for adolescent population. The present study analyzes the perception of professionals from community psychiatric care centers on the continuum of care provided to the patients hospitalized in this unit. A self-administered and anonymous questionnaire was mailed to each of the mental health centers that refer patients to the unit. The instrument used is a self-created questionnaire, based on previous tools developed for primary healthcare institutions. The data were analyzed and action plans were defined for the improvement of those areas with a lower score. The response rate was 71.4 %. All the items have an average rate higher than 3 on a scale of 1 to 5. The items with a higher score are the possibility to exchange opinions with the professionals of the unit and the knowledge of the doctor responsible for the patient during the hospitalization. The items with a lower level of satisfaction are the referral procedure and the unit's resources. The study provides data on the perception that professionals from mental health out-patient centers have about the coordination with the Unit. This data has been found to be useful to define improvement initiatives that will improve the continuum of care.


Extraction, Preconcentration and Isolation of Flavonoids from Apocynum venetum L. Leaves Using Ionic Liquid-Based Ultrasonic-Assisted Extraction Coupled with an Aqueous Biphasic System.
Ionic liquids (ILs) are considered as green solvents, and widely applied for the extraction of various compounds. The present research focuses on the extraction of flavonoids from Apocynum venetum L. leaves by ultrasound-assisted extraction (UAE). Several major influencing factors were optimized. Then, an aqueous biphasic system (ABS) was applied for further isolation of flavonoids. The flavonoids were mainly distributed in the top phase, while impurities were extracted to the bottom phase. The parameters influencing the extraction, namely type and concentration of salt, temperature, and pH, were studied in detail. Under optimized conditions (72.43% IL extract, 28.57% (NH4)2SO4, 25 °C temperature, pH 4.5), the preconcentration factor and extraction efficiency were found to be 3.78% and 93.35%, respectively. This simple and efficient methodology is expected to see great use in the extraction and isolation of pharmaceutically active components from medicinal plant resources.


Neuroscience: Hacking development to understand sensory discrimination.
Fine sensory discrimination abilities are enabled by specific neural circuit architectures. A new study reveals how manipulating particular network parameters in the fly's memory centre, the mushroom body, alters sensory coding and discrimination.


Are diabetic physicians at a lower risk of hospitalization for coronary heart disease? A nationwide cohort study in Taiwan.
It is not uncommon for physicians to work through illness and to be reluctant to seek health care from their colleagues, which is detrimental for quality of care. This study sought to assess the risk of admission for coronary artery diseases (CADs) in diabetic physicians. A cohort of 995 diabetic physicians and 9950 age- and sex-matched controls with diabetes were identified in 2000 and were followed to the end of 2008. Over an 8-year period, 200 (20.1%) diabetic physicians and 2255 (22.7%) controls were admitted for CAD. After controlling for potential confounders, diabetic physicians experienced a reduced, but insignificantly, adjusted odds ratio (OR) of CAD admission (OR = 0.89; 95% confidence interval = 0.75-1.06). Diabetic physicians in Taiwan were not at a significantly reduced risk of CAD admission. Future studies are needed to further explore the barriers that impede diabetic physicians from appropriately managing their disease.


Factors Affecting the Circulating Levels of Oxyntomodulin in Health and After Acute Pancreatitis.
To investigate the factors associated with the circulating levels of oxyntomodulin in healthy individuals and individuals after an episode of acute pancreatitis (AP). Blood samples were collected from all participants after an overnight fast and analyzed for 28 biomarkers. Participants also underwent comprehensive body composition analysis on a 3-T magnetic resonance imaging scanner. Regression analyses were done to investigate the associations between oxyntomodulin and the studied factors. The study included 105 individuals who had a primary diagnosis of AP and 58 healthy individuals. Peptide YY (B coefficient, 0.094; 95% confidence interval [95% CI], 0.164-0.123), pancreatic polypeptide (0.048; 95% CI, 0.030-0.066), and leptin (0.394; 95% CI, 0.128-0.661) had significant associations with oxyntomodulin in healthy individuals. Peptide YY was the most prominent factor associated with oxyntomodulin, explaining 60% of its variance in health. Cholecystokinin (0.014; 95% CI, 0.010-0.018), amylin (-0.107; 95% CI, -0.192 to -0.021), and glycated hemoglobin (-0.761; 95% CI, -1.249 to -0.273) had significant associations with oxyntomodulin in individuals after AP. Cholecystokinin was the most prominent factor associated with oxyntomodulin, explaining 44% of its variance after AP. Factors affecting the circulating levels of oxyntomodulin are different in health and after AP. These insights will enable the determination of populations that benefit from oxyntomodulin therapeutics in the future.


The role of endoscopic sphenopalatine artery ligation in the management of persistent epistaxis - A 15-year single-center experience.
Managing persistent epistaxis poses a great challenge for the otolaryngologist. Despite continuous development in treatment methods, no universal guideline has been commonly adopted. Among the popular methods is endoscopic sphenopalatine artery ligation (ESPAL). This study aims to evaluate the impact of ESPAL integration on persistent epistaxis management over 15 years in a single academic center. A retrospective study including all cases who were hospitalized due to persistent epistaxis and required intervention between 2000 and 2016. From 2011, ESPAL was routinely utilized in our center, hence the study population was divided based on admission year, prior to 2011 (pre-ESPAL) and from 2011 till the end of data collection (post-ESPAL). The pre-ESPAL group included 87 interventions and the post-ESPAL group 54 interventions. Electrocautery remained the most common intervention in both periods. However, ESPAL incorporation was accompanied by a significant decline in the use of posterior nasal packing in the post-ESPAL group. The hemoglobin recovery levels and the mortality rates were significantly improved in the post-ESPAL group compared with the pre-ESPAL group despite higher comorbidity rates among the post-ESPAL patients. This study demonstrates the shifting trend in managing persistent epistaxis, and suggests that ESPAL has successfully replaced posterior nasal packing. These findings may encourage clinicians to consider ESPAL as a valuable tool in the management of persistent epistaxis.


Nosocomial spread of hepatitis B virus (HBV) in a haemodialysis unit confirmed by HBV DNA sequencing.
An outbreak of hepatitis B virus (HBV) infection in a haemodialysis unit is described. Four patients in the unit contracted subclinical HBV infection within three months. DNA sequence analysis of the S gene of HBV isolates from chronic carriers and newly infected patients in the unit aided in tracing possible transmission pathways. Three newly infected patients had received partial or complete HBV vaccination previously. HBV was rapidly cleared from all three although the anti-HBs titre had not reached 10 IU L-1 in any of them at the time of infection.


Measurement of beta-galactosyltransferase activity in cell extracts with an ELISA-based assay.
An enzyme-linked immunosorbent assay (ELISA)-based glycosyltransferase assay has been used to measure UDP-Gal:N-acetylglucosamine beta-1,4-galactosyl-transferase (EC 188.8.131.52) activity in detergent extracts of chinese hamster ovary (CHO) cells. LEC11 cells (a mutant of the CHO cell line, Pro -5), which are known to express a complex array of carbohydrate structures, were used to develop the assay for use with whole cell extracts. A detergent-solubilized preparation of the enzyme from whole cells was used to convert the substrate, lactotriglycosylceramide, to the product, neolactotetraglycosylceramide. The monoclonal antibody, 1B2, which specifically binds to the Gal beta 1-4GlcNAc epitope, was used in an ELISA to identify and quantify the product. The enzyme activity in the preparations was found to be similar to that obtained by conventional radioactive assay methods. The beta-galactosyltransferase found in LEC11 cell detergent extracts exhibited an absolute requirement for the nucleotide sugar and MnCl2. The activity of the enzyme was also strictly dependent on the presence of exogenous glycolipid acceptor. When Triton X-114 was used to solubilize the LEC11 beta-galactosyltransferase, activity was found in both the hydrophilic and the hydrophobic phases, suggesting the presence of two forms of the enzyme. The ELISA-based assay was used to compare beta-1,4-galactosyltransferase activity in detergent extracts of four CHO cell lines: Pro-5, Lec1, LEC11, and LEC12 and in detergent-solubilized microsomes from human leukemia cells. The results from this study demonstrate the utility of the ELISA-based assay for measuring glycosyltransferase activity in detergent-solubilized whole cells and microsome preparations.


The case of a city where 1 in 6 residents is a refugee: ecological factors and host community adaptation in successful resettlement.
The notable success of an upstate New York community in resettling refugees raises the question of whether multiple waves of resettlement over a 15-year period have resulted in greater accommodation to refugees. Structured interviews based on transactional models of acculturation were used along with archival data to explore ecological factors supporting a host community's behavioral flexibility and perseverance in response to the influx of refugees. Evidence suggests that socioeconomic climate, historical background/social norms, and the organizational structure of agencies involved in resettlement moderate successful inclusion of refugees into a host community in a bidirectional process.


Stereocontrol in Diels-Alder cycloaddition to unsaturated sugars: reactivities of cis-dienophiles with cyclopentadiene.
Cycloaddition of cyclopentadiene with a D-arabinose-derived cis-dienophile, methyl (Z)-4,5,6,7-tetra-O-acetyl-2,3-dideoxy-D-arabino-hept-2-enonate (2), under thermal conditions gave essentially a single norbornene adduct, isolated crystalline in 81% yield and identified by NMR spectroscopy and X-ray crystallography as methyl (5R,6S)-6-endo-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol-1-yl)bic yclo [2.2.1]-hept-2-ene-5-endo-carboxylate (3). The diene adds exclusively from the si-face of the dienophile and give only the endo product. The same sequence starting from L-arabinose gave the enantiomer (7) of 3. In contrast, a related cis-dienophile (9) having a butenolide ring reacts with cyclopentadiene from the opposite (re) face giving mainly the endo adduct (5S,6R)-6-endo-(2,3,4-tri-O-acetyl)-D-arabino-tetritol-1-yl)bicycl o [2.2.1]hept-2-ene-5-endo-carboxylic acid 1,4-lactone (10), isolated crystalline in 70% yield, whose structure was again established by NMR spectroscopy, and firmly consolidated by X-ray crystallography. The minor (11%) product was the exo(5S,6R) isomer 11. A cis-enonate 14, analogous to 2 but deoxygenated at the allylic position, showed negligible diastereofacial selectivity and reacted with cyclopentadiene to give a mixture of all four possible adducts. A 6-membered ring dienophile 16 was also subjected to the same cycloaddition for comparison with the butenolide 9; it gave principally the two endo products 17 and 19 in 31 and 38% yields, respectively, accompanied by 12% of a mixture of the two exo products (18 and 20). The quantitative distribution of cycloaddition products as a function of dienophile stereochemistry is discussed. The high degree of asymmetric induction observed, especially with the readily accessible dienophiles 2 and 7, provides a valuable route of access to enantiomerically pure tetra-C-substituted cycloalkanes.


49 Mathoura Road: Geoffrey Kaye's Center of Excellence for the Australian Society of Anaesthetists.
Geoffrey Kaye, M.B.B.S. (1903 to 1986), was a prominent Australian anesthetist, researcher, and educator who envisioned that anesthesia practice in Australia would be comparable to European and American anesthesia practice during the 1940s and 1950s. Kaye's close relationship with Francis Hoeffer McMechan, M.D., F.I.C.A. (1879 to 1939), which began when Kaye left a favorable impression on McMechan at a meeting of the Australasian Medical Congress in 1929, eventually led Kaye to establish an educational center for the Australian Society of Anaesthetists at 49 Mathoura Road, Toorak, Melbourne, Australia, in 1951. The center served as the "Scientific Headquarters" and the Australian Society of Anaesthetists' official headquarters from 1951 to 1955. Although anesthesia's recognition as a specialty was at the heart of the center, Kaye hoped that this "experiment in medical education"-equipped with a library, museum, laboratory, workshop, darkroom, and meeting space-would "bring anaesthetists of all lands together" in Australia. The lack of member participation in Kaye's center, however, led Kaye to dissolve the center by 1955. Previous research has documented the history of Kaye's center from correspondence between Kaye and influential American anesthesiologist Paul M. Wood, M.D. (1894 to 1953), from 1939 to 1955. Through letters Kaye sent to American anesthesiologist Paul M. Wood, M.D. (1894 to 1963), the authors see Kaye's detailed plans, design, and intent for the center at 49 Mathoura Road. Comparisons of Kaye's letters to Wood during the 1950s with his letters to Gwenifer Wilson, M.D., M.B.B.S. (1916 to 1988), during the 1980s illustrate a change in Kaye's perceptions regarding the failure of the center.


Effects of depolarizing stimuli on calcium homeostasis in cultured rat motoneurones.
Intracellular calcium concentrations in individual rat motoneurones in enriched primary cultures were measured by Indo-1 fluorimetry. Motoneurones in the cultures were characterized morphometrically and by cholineacetyltransferase immunocytochemistry. Depolarization of the cells with glutamic acid or veratridine increased intracellular calcium levels, which returned to baseline only slowly after removal of the depolarizing agent. The use of selective agonists (N-methyl-D-aspartic acid, AMPA, kainic acid, quisqualic acid and 1R-3S-ACPD) and antagonists (MK 801 and CNQX) showed that the excitatory amino acid-evoked responses were mediated by AMPA/kainate receptors rather than by NMDA receptors. Depolarization-evoked calcium transients in motoneurones are blocked by the neuroprotective drug riluzole Calcium transients reflected entry of calcium from without the cell, and their blockade by nitrendipine and lanthanum chloride suggested that this entry took place primarily through voltage-dependent calcium channels. These findings may be relevant for understanding the selective vulnerability of motoneurones to excitotoxicity in amyotrophic lateral sclerosis, and the therapeutic activity of riluzole in the treatment of this disease.


Sudden brief unilateral tapering tinnitus: prevalence and properties.
To systematically characterize unilateral tinnitus typically lasting less than a minute. Observational study. Outpatient clinic in a tertiary referral hospital. Study I: 62 unselected adults. Study II: 74 adults with sudden brief unilateral tapering tinnitus (SBUTT). Study I: Structured interview regarding SBUTTs and other types of tinnitus. Study II: Maintaining an SBUTT log for 4 consecutive months. Study I: Retrospective prevalence of SBUTTs. Study II: Prospective frequency and characteristics of SBUTTs. Study I: 76% of the participants recalled having at least one SBUTT in the past. There was no significant difference in the incidence of SBUTTs with respect to handedness, age, sex, the presence or absence of chronic tinnitus, whether tinnitus could be brought on by exposure to loud sounds, or whether auditory perception could be modulated with strong muscle contractions of the neck or jaw. Study II: SBUTTs mean rate was 1.2 per month (range, 0-11.5). The rate in people with chronic tinnitus was twice that of those without chronic tinnitus. Right ear SBUTTs predominated nearly 2 to 1. Pitch estimates ranged between 0.1 and 4.4 kHz; 75% of SBUTTs lasted 25 seconds or less. A quarter occurred with simultaneous ear fullness. In the 76% of adults with SBUTTs, the average rate of occurrence was about once a month. SBUTTs are twice as common for the right ear as the left. One of 4 SBUTTs occurs with ear fullness. A quarter of adults never recalled ever having an SBUTT.


Effect of immunostimulant therapy on acute viral myocarditis in an animal model.
The effect of immunostimulant therapy on acute viral myocarditis, which was induced with encephalomyocarditis virus, was investigated in 4-week-old male BALB/c mice. In vitro, peritoneal exudate cells and spleen cells from mice that were pretreated with a synthetic immunoactivating peptide, FK565 (heptanoyl-gamma-D-glutamyl-(L)-meso-diaminopimelyl-(D)-alan ine), significantly inhibited the multiplication of encephalomyocarditis virus in BALB/c 3T3 cells compared with peritoneal exudate cells and spleen cells from untreated mice (6.14 +/- 0.21 log10 plaque-forming units (pfu) per milliliter, control: 6.59 +/- 0.03, p less than 0.05; 3.55 +/- 0.23, control: 5.64 +/- 0.09, p less than 0.01, respectively), although FK565 did not inhibit viral replication directly. The mice were inoculated intraperitoneally with 100 pfu of encephalomyocarditis virus. FK565 (1 mg/kg/day), which was administered 1 day before or simultaneously with virus inoculation, effectively inhibited myocardial viral replication (2.77 +/- 0.17 log10 pfu/mg, 2.46 +/- 0.35, log10 pfu/mg, respectively, control: 3.33 +/- 0.26, p less than 0.025) and increased survival (70% and 60%, respectively, control: 20%, p less than 0.01). Histopathologic findings were scored on a scale of 0 to 4. Treatment with 1 mg/kg/day of FK565 that was started 1 day before virus inoculation was most effective in reducing the inflammatory response (1.2 +/- 0.63, control: 2.0 +/- 0.81, p less than 0.05) and myocardial necrosis (1.2 +/- 0.42, control: 2.0 +/- 1.00, p less than 0.025). The present study suggests that immunostimulant therapy improves the course of viral myocarditis during the virus-mediated phase.(ABSTRACT TRUNCATED AT 250 WORDS)


The postsynaptic density.
The postsynaptic density is a specialization of the nerve cell's submembrane cytoskeleton that is hypothesized to participate in the regulation of synaptic adhesion, transmitter receptor clustering, and modulation of receptor sensitivity. Until recently, many of the major proteins in the highly insoluble postsynaptic density fraction remained uncharacterized. Modern immunological and microsequencing methods now make it possible to define more precisely the molecular composition and function of this intriguing organelle.


Magnetic resonance elastography using an air ball-actuator.
The purpose of this study was to develop a new technique for a powerful compact MR elastography (MRE) actuator based on a pneumatic ball-vibrator. This is a compact actuator that generates powerful centrifugal force vibrations via high speed revolutions of an internal ball using compressed air. This equipment is easy to handle due to its simple principles and structure. Vibration frequency and centrifugal force are freely adjustable via air pressure changes (air flow volume), and replacement of the internal ball. In order to achieve MRI compatibility, all parts were constructed from non-ferromagnetic materials. Vibration amplitudes (displacements) were measured optically by a laser displacement sensor. From a bench test of displacement, even though the vibration frequency increased, the amount of displacement did not decrease. An essential step in MRE is the generation of mechanical waves within tissue via an actuator, and MRE sequences are synchronized to several phase offsets of vibration. In this system, the phase offset was detected by a four-channel optical-fiber sensor, and it was used as an MRI trigger signal. In an agarose gel phantom experiment, this actuator was used to make an MR elastogram. This study shows that the use of a ball actuator for MRE is feasible.


Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer.
Microsatellite instability (MSI) is characteristic of hereditary nonpolyposis colorectal cancer, and occurs in a subset (10 to 15%) of unselected colorectal cancer cases. In hereditary nonpolyposis colorectal cancer, MSI is caused by defects in five mismatch repair genes, and in sporadic cases the main cause seems to be somatic MLH1 promoter methylation. Most likely additional hereditary nonpolyposis colorectal cancer genes remain to be discovered. Genes with simple repeats in their coding region are often targets for deletions in MSI-positive tumors. Several genes (TGFbeta RII, IGFIIR, MSH3, MSH6, BAX, MBD4) with significance in tumorigenesis harbor repeats in their coding regions and are often somatically inactivated because of deletions causing frameshifts. Recently, a novel human mismatch repair gene, MLH3, was cloned and shown to be involved in mammalian mismatch repair. To evaluate the possible role of MLH3 in hereditary cancer, we performed germline single-strand conformation polymorphism-analysis for 52 patients displaying features of inherited colorectal cancer. Forty-six of these had been diagnosed with MSI-positive tumors. No germline mutations were found. Similar to MSH3 and MSH6, MLH3 harbors mononucleotide repeats, ie, (A(6))-(A(9)), in its coding region, which makes it a putative target for somatic mutations in MSI-positive tumors. To evaluate its somatic inactivation we performed a deletion search focusing on eight exonic MLH3 mononucleotide repeats in a series of 93 MSI-positive tumors. Somatic deletions were found in 8.6% of the samples, a frequency similar to one detected in neutral noncoding mononucleotide repeats. No evidence of involvement of MLH3 in MSI tumorigenesis was obtained.


Characterisation of the immune-related transcriptome in resected biliary tract cancers.
Although biliary tract cancers (BTCs) are known to have an inflammatory component, a detailed characterisation of immune-related transcripts has never been performed. In these studies, nCounter PanCancer Immune Profiling Panel was used to assess the expression of 770 immune-related transcripts in the tumour tissues (TTs) and matched adjacent tissues (ATs) of resected BTCs. Cox regression analysis and Kaplan-Meier methods were used to correlate findings with relapse-free survival (RFS). The first analysis in the TT and AT of an exploratory set (n = 22) showed deregulation of 39 transcripts associated with T-cell activation. Risk of recurrence was associated with a greater number of genes deregulated in AT in comparison to TT. Analysis in the whole set (n = 53) showed a correlation between AT cytotoxic T-lymphocyte antigen-4 (CTLA4) expression and RFS, which maintained statistical significance at multivariate analysis. CTLA4 expression correlated with forkhead box P3 (FOXP3) expression, suggesting enrichment in T regulatory cells. CTLA4 is known to act by binding to the cluster of differentiation 80 (CD80). No association was seen between AT CD80 expression and RFS. However, CD80 expression differentiated prognosis in patients who received adjuvant chemotherapy. We showed that the immunomodulatory transcriptome is deregulated in resected BTCs. Our study includes a small number of patients and does not enable to draw definitive conclusions; however, it provides useful insights into potential transcripts that may deserve further investigation in larger cohorts of patients. Nanostring data have been submitted to GEO repository: GSE90698 and GSE90699.


Quantifying the impact of climate extremes on salt mobilization and loading in non-developed, high-desert landscapes using SWAT.
Excess salt loading from watershed landscapes into river systems acts as a chemical stressor in water bodies and can have significant impacts on downstream water quality. High salinity threatens sustainable crop production globally and is especially prevalent in semi-arid and arid regions. However, relatively little research has been conducted to evaluate salt movement and loadings in natural, high-desert catchments in the face of climate change and extreme climate events. In this study, we use the watershed model SWAT and a newly developed salinity module to simulate the mass transport of 8 major salt ions, SO42-, Cl-, CO32-, HCO3-, Ca2+, Na+, Mg2+, and K+, in the soil-aquifer-stream system of the Purgatoire River Watershed (PRW) (Colorado, USA, 8935 km2) via major hydrologic pathways (surface runoff, percolation, recharge, soil lateral flow, groundwater upflux, groundwater discharge) and quantify changes in predicted salt loads with possible future increasing storm intensity. The PRW is susceptible to high salt transport due to high topographic slopes, dry climatic conditions, and sparse vegetation, and loads to the Arkansas River, a major source of irrigation water in the Arkansas River Basin. From study results we conclude that 99% of salt in the Purgatoire River originates from subsurface water pathways (soil lateral flow, groundwater flow), composed primarily of SO42-, Ca2+, and HCO3-. If intensity of large storms increases by 5% and 35%, the total salt mass exported from the watershed increases by 12% and 73%, respectively, indicating large influxes of legacy salt from the soil-aquifer system. For baseline and storm intensity scenarios, the PRW contributes significant salt loads to agricultural regions via the Arkansas River, highlighting the need for basin-wide salt management strategies to include upland desert regions. We expect these results, and associated consequences for salt management, to be similar for other upland desert catchments worldwide.


Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management.
Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma. In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents. The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality. Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described.


Retinal Vessel Density and Retinal Nerve Fiber Layer Thickness: A Prospective Study of One-Year Follow-Up of Patients with Parkinson's Disease.
This study aims to compare the superficial vascular density from the macular region and the retinal nerve fiber layer (RNFL) thickness from the optic disc region between Parkinson's disease (PD) patients and controls. We enrolled 56 idiopathic PD patients, totaling 86 eyes (PD group), and 45 sex- and age-matched healthy individuals, amounting to 90 eyes (control group). All subjects underwent examination using Zeiss wide-field vascular optical coherence tomography (OCT) (Cirrus HD-OCT 5000 Carl Zeiss, Germany), with a scanning range of 3 mm × 3 mm. We divided the images into two concentric circles with diameters of 1 mm and 3 mm at the macular fovea's center. Patients with PD were evaluated during their "off" phase using the Unified Parkinson's Disease Rating Scale III (UPDRS-III) and the Hoehn-Yahr scale (H-Y scale) to assess disease severity. The PD group exhibited significantly lower RNFL thickness (106.13±12.36 μm) compared to the control group (115.95±11.37 μm, P < 0.05). Similarly, the superficial retinal vessel length density was significantly lower in the PD group (20.7 [19.62, 22.17] mm-1) than in the control group (21.79±1.16 mm-1, P < 0.05). Correlation analysis revealed a negative correlation between RNFL thickness and UPDRS III score (rs=-0.036, P=0.037), and RNFL thickness tended to decrease with increasing severity of movement disorders. However, during the 6 and 12-month follow-up of some PD patients, we observed no progressive thinning of the RNFL or decreased superficial vascular density. PD patients show retinal structural damage characterized by RNFL thinning and reduced retinal vessel length density. However, RNFL thickness did not correlate with vascular density nor did it decrease with the disease's progression.


Cementing the enemy category: arrest and imprisonment of German Jews in Nazi concentration camps, 1933-8/9.
Understandably, research has focused overwhelmingly on Jews in the camps of the Holocaust. But the nazis had been detaining Jews in concentration camps ever since 1933, at times in large numbers. Who were these prisoners? This article analyzes nazi policies that brought Jews into the concentration camps. It ventures into the inner structure and dynamics of one of the most heterogeneous groups of concentration camp inmates. By contrasting the perpetrators' objectives with the victims' experiences, this article will illuminate the role of the concentration camp as the ultimate means of pressure in the fatal process of turning a minority group into an outsider group: that is, the act of defining and marking the enemy which was the critical stage before the destruction of European Jewry. Furthermore, it will examine Jewish reactions to SS terror inside the camps.


Radiotherapy of cervical cancer.
External beam radiotherapy and brachytherapy are major treatments in the management of cervical cancer. For early-stage tumours with local risk factors, brachytherapy is a preoperative option. Postoperative radiotherapy is indicated according to histopathological criteria. For advanced local tumours, chemoradiation is the standard treatment, followed by brachytherapy boost, which is not optional. We present the update of the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for cervical cancer.


Payment of reimbursement for emergency treatment furnished by non-VA providers in non-VA facilities to certain veterans with service-connected or nonservice-connected disabilities. Final rule.
This document amends the Department of Veterans Affairs (VA) medical regulations concerning emergency hospital care and medical services provided to eligible veterans at non-VA facilities. The amendments are required by section 402 of the Veterans' Mental Health and Other Care Improvements Act of 2008. Among other things, the amendments authorize VA to pay for emergency treatment provided to a veteran at a non-VA facility up to the time the veteran can be safely transferred to a VA or other Federal facility and such facility is capable of accepting the transfer, or until such transfer was actually accepted, so long as the non-VA facility made and documented reasonable attempts to transfer the veteran to a VA or other Federal facility.


Improved pronuclear mouse embryo development over an extended pH range in Ham's F-10 medium without protein.
Pronuclear mouse embryos were cultured at four different pHs (7.17, 7.27, 7.37, and 7.50) in Ham's F-10 medium (Gibco, Grand Island, NY) alone and in Ham's F-10 medium supplemented with 10% human cord serum (v/v) to assess the effects of pH and serum on preimplantation embryo development. Media used in these experiments was stored both without (old protocol) or with triple gas equilibration (new protocol). Development was assessed by the percent of embryos developing to the 2-cell stage and on to the morula and blastocyst stages. Triple gas equilibration prior to media storage improved development to the morula and blastocyst stages. Development to the 2-cell and morula stages was not adversely affected by the presence of serum, but development to the blastocyst stage was significantly higher in Ham's F-10 medium without serum at all pHs tested. In conditions without serum, percent development at all stages examined was similar over the pH range of 7.17 to 7.37, with a significant decrease in development to the morula and blastocyst stage at pH 7.50. Embryos cultured in the presence of serum demonstrated a greater decrease in the percent development to blastocyst at both the low, 7.17 and 7.27, and high, 7.50, pHs, with an apparent pH optimum at 7.37. In summary, the complex media Ham's F-10 medium supports mouse embryo development without the need for serum. Serum inhibits pronuclear embryo development to the blastocyst stage. Mouse embryo culture in the absence of serum can tolerate a pH as low as 7.17 (8.4% CO2) without any detrimental effects.


Maize microarray annotation database.
Microarray technology has matured over the past fifteen years into a cost-effective solution with established data analysis protocols for global gene expression profiling. The Agilent-016047 maize 44 K microarray was custom-designed from EST sequences, but only reporter sequences with EST accession numbers are publicly available. The following information is lacking: (a) reporter - gene model match, (b) number of reporters per gene model, (c) potential for cross hybridization, (d) sense/antisense orientation of reporters, (e) position of reporter on B73 genome sequence (for eQTL studies), and (f) functional annotations of genes represented by reporters. To address this, we developed a strategy to annotate the Agilent-016047 maize microarray, and built a publicly accessible annotation database. Genomic annotation of the 42,034 reporters on the Agilent-016047 maize microarray was based on BLASTN results of the 60-mer reporter sequences and their corresponding ESTs against the maize B73 RefGen v2 "Working Gene Set" (WGS) predicted transcripts and the genome sequence. The agreement between the EST, WGS transcript and gDNA BLASTN results were used to assign the reporters into six genomic annotation groups. These annotation groups were: (i) "annotation by sense gene model" (23,668 reporters), (ii) "annotation by antisense gene model" (4,330); (iii) "annotation by gDNA" without a WGS transcript hit (1,549); (iv) "annotation by EST", in which case the EST from which the reporter was designed, but not the reporter itself, has a WGS transcript hit (3,390); (v) "ambiguous annotation" (2,608); and (vi) "inconclusive annotation" (6,489). Functional annotations of reporters were obtained by BLASTX and Blast2GO analysis of corresponding WGS transcripts against GenBank.The annotations are available in the Maize Microarray Annotation Database http://MaizeArrayAnnot.bi.up.ac.za/, as well as through a GBrowse annotation file that can be uploaded to the MaizeGDB genome browser as a custom track.The database was used to re-annotate lists of differentially expressed genes reported in case studies of published work using the Agilent-016047 maize microarray. Up to 85% of reporters in each list could be annotated with confidence by a single gene model, however up to 10% of reporters had ambiguous annotations. Overall, more than 57% of reporters gave a measurable signal in tissues as diverse as anthers and leaves. The Maize Microarray Annotation Database will assist users of the Agilent-016047 maize microarray in (i) refining gene lists for global expression analysis, and (ii) confirming the annotation of candidate genes before functional studies.


The short metyrapone test: comparison of the plasma ACTH response to metyrapone and insulin-induced hypoglycaemia.
Plasma ACTH levels in response to metyrapone and insulin hypoglycaemia were compared in subjects with normal pituitary-adrenal function. After a single dose of 2 g of metyrapone given with a snack at midnight, the ACTH level was 468 ng/l +/- 66 )SEM) at 07.30 h the next morning (mean increment approximately nine fold over normal morning values). After insulin-hypoglycaemia the peak ACTH level was 369 ng/l +/- 31 (SEM). Peak ACTH levels greater than 200 ng/l were achieved in twenty of twenty-one (95%) subjects after metyrapone and twenty of twenty-four (83%) after insulin. No major side effects were noted after metyrapone. It is concluded that the short single-dose metyrapone test produces at least as strong and consistent a stimulus to ACTH release as the standard insulin-hypoglycaemia test in normal subjects. A direct assay of ACTH avoids misinterpretations which are inherent in a judgement based on compound S increase only. The short test has significant practical advantages over the classical metyrapone test, and provides a convenient and sensitive method of assessing the negative feedback ACTH control mechanism. It may be particularly useful in detecting minor degrees of pituitary suppression. The value of this test in clinical practice for the investigation of patients with hypothalamic-pituitary diseases in comparison to the classical tests of ACTH stimulation has yet to be demonstrated.


A clinicopathological analysis of supratentorial ependymoma, ZFTA fusion-positive: utility of immunohistochemical detection of CDKN2A alterations and characteristics of the immune microenvironment.
EPN-ZFTA is a rare brain tumor where prognostic factors remain unclear and no effective immunotherapy or chemotherapy is currently available. Therefore, this study investigated its clinicopathological features, evaluated the utility of MTAP and p16 IHC as surrogate markers of CDKN2A alterations, and characterized the immune microenvironment of EPN-ZFTA. Thirty surgically removed brain tumors, including 10 EPN-ZFTA, were subjected to IHC. MLPA was performed for CDKN2A HD in 20 ependymal tumors, including EPN-ZFTA. The 5-years OS and PFS of EPN-ZFTA were 90% and 60%, respectively. CDKN2A HD was detected in two cases of EPN-ZFTA; these cases were immunohistochemically negative for both MTAP and p16 and recurred earlier after surgery. As for the immune microenvironment of EPN-ZFTA, B7-H3, but not PD-L1, was positive in all cases of EPN-ZFTA; Iba-1-positive or CD204-positive macrophages were large, while infiltrating lymphocytes were small, in number in EPN-ZFTA. Collectively, these results indicate the potential of MTAP and p16 IHC as useful surrogate markers of CDKN2A HD in EPN-ZFTA, and tumor-associated macrophages, including the M2 type, may contribute to its immune microenvironment. Furthermore, the expression of B7-H3 in EPN-ZFTA may indicate the usefulness of B7-H3 as a target of immune checkpoint chemotherapy for EPN-ZFTA via B7-H3 pathway.


MicroRNA-22: a Novel and Potent Biological Therapeutics in Neurological Disorders.
MicroRNAs (miRs) are regulatory RNAs with 18-25 nucleotides lengths involved in various biological processes. Some miRs, including miR-22, play an essential role in regulating neurological disorders. MiR-22 is a brain-enriched regulatory element involved in angiogenesis, energy supply, adjustment of ionic channels, and suppression of malignant cell proliferation, migration, and invasion. This article discusses the protective and therapeutic effects of miR-22 on neurological diseases and injuries, including cerebral ischemia, neurodegenerative diseases, epilepsy, and brain malignancies. We also correlated miR-22 with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), panic disorders, schizophrenia, neural tube defect (anencephaly), and traumatic brain injury. This work provides a therapeutic perspective for miR-22 as a new approach in treating neurological disorders.


Expression of common cytoplasmic antigens by epithelial cells of thymus and epidermis.
The expression of common cytoplasmic antigens by thymic epithelial cells and keratinocytes was analyzed by immunolabelling on cryostat sections of human and animal thymus and epidermis. Experimental sera to human epidermal keratin subunits of molecular weight (MW) 67 K, 63 K and 55 K were used, as well as human sera with antibodies to epidermal cytoplasmic antigens (KCA), reacting either with U-Cyt antigens expressed by cells from the upper compartment of the epidermis or with BLC antigens in cells from the basal layer. It was demonstrated that keratin subunits of MW 67 K and 63 K were detected only in the upper layers of human epidermis, whereas 55 K was present in all epidermal layers. On rabbit lip a labelling was obtained throughout the epidermis by the three immune sera. On thymus sections a cytoplasmic staining of epithelial cells was observed with the three immune sera, suggesting an antigenic similarity between cytokeratins of thymus epithelial cells and keratins of the upper layers of human epidermis. Two human sera with U-Cyt antibodies and one with BCL antibodies labelled human thymic epithelial cells but were negative with mice thymus. Ten other sera with KCA were negative on both thymus. These results show that the expression of keratins and cytoplasmic antigens, defined by human KCA, differed in immunofluorescence on normal human epidermis, rabbit lip and thymic epithelial cells. These suggests a heterogeneity among human keratinocyte cytoplasmic antigens defined by KCA and the presence in man of common antigenic constituents from keratins in epidermal cells and thymic epithelial cells.


Differential involvement of the lateral and medial divisions of the septal area on spatial learning processes as revealed by intracranial self-administration of morphine in mice.
The present study was conducted to investigate the effects of morphine self-administration into either the medial or lateral divisions of the septal region on spatial discrimination abilities in mice. To this end, BALB/c mice received a dose of 5 ng/50 nl of morphine sulfate, via a stainless steel injection cannula, inserted into either the medial septal area (MS) or the lateral septal nucleus (LS), when they are close to the end of one of the two choice arms of a Y-maze (acquisition period). In these conditions a discrimination between the reinforced arm and the neutral arm is acquired in MS as well as in LS mice. However both acquisition and subsequent extinction (vehicle only available) was more rapid in the LS group than in the MS group. Moreover, during the extinction period, numerous escape attempts from the Y-maze were observed for MS mice. When the dose of morphine was raised to 50 ng the pattern of acquisition was unchanged in the LS group. In contrast animals of the MS group learned to avoid the arm where the higher dose of morphine was delivered thus allowing us to conclude that in MS animals the drug effect became aversive at this higher dose. This possibility was directly investigated in a second experiment by closing the access to the neutral arm. Thus, for a 5-ng dose the rewarding effect of morphine was demonstrated in both MS and LS groups by the decrease of self-administration latencies which, furthermore, were notably lower than in the discrimination situation. Moreover, with the dose of 50 ng of morphine the latencies were identical for the two groups and at their lowest value thus indicating that morphine had similar appetitive effects in MS as well as in LS mice in this situation. Thus, the previously observed deficit of MS subjects, including escape attempts, disappeared when the dose of morphine was raised and the experimental context simplified. These results which demonstrate differential functional properties of these two septal divisions are discussed in terms of conflict resulting from the strongly appetitive effects of the morphine which induces, in parallel, deleterious consequences on cognitive processing in MS self-injected mice.


An image registration method for voxel-wise analysis of whole-body oncological PET-CT.
Whole-body positron emission tomography-computed tomography (PET-CT) imaging in oncology provides comprehensive information of each patient's disease status. However, image interpretation of volumetric data is a complex and time-consuming task. In this work, an image registration method targeted towards computer-aided voxel-wise analysis of whole-body PET-CT data was developed. The method used both CT images and tissue segmentation masks in parallel to spatially align images step-by-step. To evaluate its performance, a set of baseline PET-CT images of 131 classical Hodgkin lymphoma (cHL) patients and longitudinal image series of 135 head and neck cancer (HNC) patients were registered between and within subjects according to the proposed method. Results showed that major organs and anatomical structures generally were registered correctly. Whole-body inverse consistency vector and intensity magnitude errors were on average less than 5 mm and 45 Hounsfield units respectively in both registration tasks. Image registration was feasible in time and the nearly automatic pipeline enabled efficient image processing. Metabolic tumor volumes of the cHL patients and registration-derived therapy-related tissue volume change of the HNC patients mapped to template spaces confirmed proof-of-concept. In conclusion, the method established a robust point-correspondence and enabled quantitative visualization of group-wise image features on voxel level.


Dietary restriction, cell proliferation and carcinogenesis: a preliminary study.
Four groups of female Swiss Webster mice were given either laboratory chow or a purified (semi-synthetic) diet (AIN-76A) either ad libitum or at 75% of the ad libitum rate for about 30 days. Three tissues, the crypt cells of the jejunum, the dermis and the basal epithelial cells of the esophagus were investigated using [3H]thymidine labelling and by counting mitoses; four other tissues, the alveolar cells of the mammary gland, the crypt cells of the duodenum and colo-rectum, and the transitional cells of the urinary bladder were examined using [3H]thymidine labelling only. In each case dietary restriction led to a reduction of cellular proliferation assessed by these indices. The potential of the approach for the study of the effects of dietary modification on the induction of cancer is discussed.


Learning to overeat in infancy: Concurrent and prospective relationships between maternal BMI, feeding practices and child eating response among Hispanic mothers and children.
Parents play a key role in shaping children's eating behaviours and self-regulation. There is limited data on how maternal weight influences feeding practices in the first year of life. To examine the relationships between maternal BMI, feeding practices and infant eating behaviours related to self-regulation. Participants were 160 mother-infant dyads. A longitudinal design was used to examine concurrent and prospective associations between maternal 6-month postpartum BMI, mothers' feeding practices at 6 months (Infant Feeding Practices Questionnaire) and children's eating behaviours at 6 months (Baby Eating Behaviour Questionnaire) and 12 months (Child Eating Behaviour Questionnaire). Higher maternal BMI was associated positively with mothers' use of restrictive feeding practices (β = 0.036, p = 0.033), and inversely with responsivity to infant satiety cues (Spearman partial r = -0.249, p = 0.002) at 6 months. Mother's restrictive feeding practices were associated with infant food responsiveness (β = 0.157, p = 0.009) and emotional overeating (β = 0.118, p = 0.005) at 12 months. Maternal use of responsive feeding practices was associated with lower infant food responsiveness at 6 months (Spearman partial r = -0.173, p = 0.031) and lower emotional overeating at 12 months (Spearman partial r = -0.183, p = 0.022). Our findings add to studies suggesting that feeding practices can provide mechanistic pathways in the intergenerational transmission of obesity. Postpartum family-system approaches focusing on maternal health while integrating infant feeding guidance may confer benefits in improving maternal-child health.


RBM22, a Key Player of Pre-mRNA Splicing and Gene Expression Regulation, Is Altered in Cancer.
RNA-Binding Proteins (RBP) are very diverse and cover a large number of functions in the cells. This review focuses on RBM22, a gene encoding an RBP and belonging to the RNA-Binding Motif (RBM) family of genes. RBM22 presents a Zinc Finger like and a Zinc Finger domain, an RNA-Recognition Motif (RRM), and a Proline-Rich domain with a general structure suggesting a fusion of two yeast genes during evolution: Cwc2 and Ecm2. RBM22 is mainly involved in pre-mRNA splicing, playing the essential role of maintaining the conformation of the catalytic core of the spliceosome and acting as a bridge between the catalytic core and other essential protein components of the spliceosome. RBM22 is also involved in gene regulation, and is able to bind DNA, acting as a bona fide transcription factor on a large number of target genes. Undoubtedly due to its wide scope in the regulation of gene expression, RBM22 has been associated with several pathologies and, notably, with the aggressiveness of cancer cells and with the phenotype of a myelodysplastic syndrome. Mutations, enforced expression level, and haploinsufficiency of RBM22 gene are observed in those diseases. RBM22 could represent a potential therapeutic target in specific diseases, and, notably, in cancer.


Ultrasonographic finding of lung sliding in patients on mechanical ventilation with alveolar-interstitial syndrome.
To determine the visibility of pleural lung sliding in alveolar-interstitial syndrome (AIS) in patients on mechanical ventilation at two different time points, as a confirmatory ultrasonographic method for excluding pneumothorax. Fifty-two mechanically ventilated patients in the semirecumbent position in a surgical/neurosurgical intensive care unit with ultrasonographic lung 'comet tails' in three upper anterolateral intercostal spaces, indicating the presence of AIS, were scanned for lung sliding in the same three intercostal spaces with a linear 5-10 MHz transducer after starting mechanical ventilation and on weaning trials. Pneumothorax and atelectasis were excluded by chest radiograph. Absent lung sliding was found in 22.7% of intercostal spaces scanned after starting mechanical ventilation and in 21.2% of scans taken on weaning trials. The lowest invisible rate was in patients with acute heart failure and the highest in patients with acute respiratory distress syndrome. Lung sliding specificity in AIS during mechanical ventilation was 78%. Our opinion is that different levels of airway pressure between starting mechanical ventilation and weaning trials have no influence on lung sliding visibility.


The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy-a multicenter retrospective analysis.
This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort. Patients who underwent 68 Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS. Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1-4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) confirmed these results. The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology-Genitourinary.


Staining of proteoglycans in mouse lung alveoli. I. Ultrastructural localization of anionic sites.
In order to contrast anionic sites in mouse lung alveoli, two staining procedures were applied: (a) staining with Ruthenium Red and Alcian Blue and (b) staining with Cuprolinic Blue in a critical electrolyte concentration method. The Ruthenium Red-Alcian Blue staining procedure revealed electron-dense granules in the alveolar basement membrane. The granules were closely associated with the epithelial cell membrane and continued to stain even when the procedure was carried out at a low pH, indicating the presence of sulphate groups in the granules. After staining with Cuprolinic Blue, electron-dense filaments, also closely associated with the cell membrane, became visible in the basement membrane of type I epithelial cells. Their length depended on the MgCl2 concentration used during staining. At 0.4 M MgCl2, the length was mostly within the range 100-180 nm. Using a modified Cuprolinic Blue method, the appearance of the filaments closely resembled that of spread proteoglycan monomers with their side-chains condensed. The basement membrane of type II epithelial cells also contained filaments positive towards Cuprolinic Blue; their length, however, was smaller in comparison with those of type I epithelial cells. The filaments lay in one plane and provided the whole alveolus with an almost continuous sheet of anionic sites. Cuprolinic Blue staining also revealed filaments in the basement membrane of the capillary endothelial cells. Furthermore, Cuprolinic Blue-positive filaments (average length about 40 nm) became apparent in close contact with collagen fibrils and separated from each other according to the main banding period of the collagen fibrils (about 60 nm), indicating a specific ultrastructural interaction between these two components. Filaments connecting collagen fibrils with each other were also detected.


Thrombolysis as an adjunct to angioplasty.
Acute coronary occlusion following angioplasty is a significant cause of in-hospital morbidity and mortality. Following acute closure, several strategies can be used to reopen the artery, including redilation, adjunctive thrombolysis, or other interventional techniques. Definite indications for thrombolysis as an adjunct to angioplasty include (1) recently occluded saphenous vein grafts, patent native vessels, or saphenous grafts with abundant intracoronary thrombus; and (2) acute closure during angioplasty, which is presumably secondary to thrombus formation and resistant to redilation alone.


Formulation, stability and immunogenicity of a trivalent pneumococcal protein vaccine formulated with aluminum salt adjuvants.
We investigated the immunogenicity, stability and adsorption properties of an experimental pneumococcal vaccine composed of three protein vaccine antigens; Pneumococcal histidine triad protein D, (PhtD), Pneumococcal choline-binding protein A (PcpA) and genetically detoxified pneumolysin D1 (PlyD1) formulated with aluminum salt adjuvants. Immunogenicity studies conducted in BALB/c mice showed that antibody responses to each antigen adjuvanted with aluminum hydroxide (AH) were significantly higher than when adjuvanted with aluminum phosphate (AP) or formulated without adjuvant. Lower microenvironment pH and decreased strength of antigen adsorption significantly improved the stability of antigens. The stability of PcpA and PlyD1 assessed by RP-HPLC correlated well with the immunogenicity of these antigens in mice and showed that pretreatment of the aluminum hydroxide adjuvant with phosphate ions improved their stability. Adjuvant dose-ranging studies showed that 28 μg Al/dose to be the concentration of adjuvant resulting in optimal immunogenicity of the trivalent vaccine formulation. Taken together, the results of theses studies suggest that the type of aluminum salt, strength of adsorption and microenvironment pH have a significant impact on the immunogenicity and chemical stability of an experimental vaccine composed of the three pneumococcal protein antigens, PhtD, PcpA, and PlyD1.


Correction to: 2D SDS PAGE in Combination with Western Blotting and Mass Spectrometry Is a Robust Method for Protein Analysis with Many Applications.
This chapter was previously published as non-open access. This is updated to an open access chapter now.


An exploratory case-only analysis of gene-hazardous air pollutant interactions and the risk of childhood medulloblastoma.
There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants; however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk. We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children's Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the US EPA's 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs). There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04). This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.


Purification and characterization of a salicylate hydroxylase involved in 1-hydroxy-2-naphthoic acid hydroxylation from the naphthalene and phenanthrene-degrading bacterial strain Pseudomonas putida BS202-P1.
1-Hydroxy-2-naphthoate is formed as an intermediate in the bacterial degradation of phenanthrene. A monooxygenase which catalyzed the oxidation of 1-hydroxy-2-naphthoate to 1,2-dihydroxynaphthalene was purified from the phenanthrene- and naphthalene-degrading Pseudomonas putida strain BS202-P1. The purified protein had a molecular weight of 45 kDa and required NAD(P)H and FAD as cofactors. The purified enzyme also catalysed the oxidation of salicylate and various substituted salicylates. The comparison of the Km and Vmax values for 1-hydroxy-2-naphthoate and salicylate demonstrated a higher catalytic efficiency of the enzyme for salicylate as a substrate. A significant substrate-inhibition was detected with higher concentrations of 1-hydroxy-2-naphthoate. The aminoterminal amino acid sequence of the purified enzyme showed significant homologies to salicylate 1-monooxygenases from other Gram negative bacteria. It was therefore concluded that during the degradation of phenanthrene the conversion of 1-hydroxy-2-naphthoate to 1,2-dihydroxynaphthalene is catalysed by a salicylate 1-monooxygenase. Together with previous studies, this suggested that the enzymes of the naphthalene pathway are sufficient to catalyse also the mineralization of phenanthrene.


Postnatal growth rate and adult body weight in mammals: a new approach.
It is argued that the postnatal growth rate should be linked to maternal body weight by the exponent 0.75. This theoretically derived hypothesis is found to be consistent with published data on the growth rates of mammals in nine orders. We emphasize the importance of defining the taxonomic level and period for which postnatal growth rates are measured.


Human pluripotent stem cell-derived myogenic progenitors undergo maturation to quiescent satellite cells upon engraftment.
Human pluripotent stem cell (hPSC)-derived myogenic progenitor cell (MPC) transplantation is a promising therapeutic approach for a variety of degenerative muscle disorders. Here, using an MPC-specific fluorescent reporter system (PAX7::GFP), we demonstrate that hPSC-derived MPCs can contribute to the regeneration of myofibers in mice following local injury and in mice deficient of dystrophin (mdx). We also demonstrate that a subset of PAX7::GFP MPCs engraft within the basal lamina of regenerated myofibers, adopt a quiescent state, and contribute to regeneration upon reinjury and in mdx mouse models. This subset of PAX7::GFP MPCs undergo a maturation process and remodel their molecular characteristics to resemble those of late-stage fetal MPCs/adult satellite cells following in vivo engraftment. These in-vivo-matured PAX7::GFP MPCs retain a cell-autonomous ability to regenerate and can repopulate in the niche of secondary recipient mice, providing a proof of principle for future hPSC-based cell therapy for muscle disorders.


Electromagnetic interference and implanted cardiac devices: the nonmedical environment (part I).
The number of patients with cardiovascular implantable electronic devices (CIEDs), such as permanent pacemakers and implantable cardioverter-defibrillators, is dramatically rising due to an aging population and recent clinical trials showing benefits in mortality and morbidity. Coupled with this increase in the number of patients with CIEDs is the proliferation of technology that emits electromagnetic signals, which can potentially interfere with CIED function through electromagnetic interference (EMI). Despite continuous efforts of manufacturers to create "EMI-proof" CIEDs, adverse events from EMI still occur. Physicians caring for patients with CIEDs should be aware of potential sources of EMI and appropriate management options. This 2-part review aims to provide a contemporary overview of the current knowledge regarding risks attributable to EMI interactions from the most common nonmedical (Part I) and medical (Part II) sources.


Exostosin glycosyltransferase 1 reduces porcine reproductive and respiratory syndrome virus infection through proteasomal degradation of nsp3 and nsp5.
Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a serious threat to the swine industry worldwide. Exostosin glycosyltransferase 1 (EXT1), an enzyme involved in the biosynthesis of heparin sulfate, has also been reported to be a host factor essential for a wide variety of pathogens. However, the role of EXT1 in PRRSV infection remains uncharted. Here, we identified that PRRSV infection caused an increase of EXT1 expression. EXT1 knockdown promoted virus infection, whereas its overexpression inhibited virus infection, suggesting an inhibitory function of EXT1 to PRRSV infection. We found that EXT1 had no effects on the attachment, internalization, or release of PRRSV but did restrict viral RNA replication. EXT1 was determined to interact with viral nonstructural protein 3 (nsp3) and nsp5 via its N-terminal cytoplasmic tail and to enhance K48-linked polyubiquitination of these two nsps to promote their degradation. Furthermore, the C-terminal glycosyltransferase activity domain of EXT1 was necessary for nsp3 and nsp5 degradation. We also found that EXT2, a EXT1 homolog, interacted with EXT1 and inhibited PRRSV infection. Similarly, EXT1 effectively restricted porcine epidemic diarrhea virus and porcine enteric alphacoronavirus infection in Vero cells. Taken together, this study reveals that EXT1 may serve as a broad-spectrum host restriction factor and suggests a molecular basis for the potential development of therapeutics against PRRSV infection.


A comparative study on the two classes of heterogeneous nuclear ribonucleoprotein particles separated in metrizamide density gradient, by electrophoresis of proteins and chase experiments. Evidence for two distinct subfractions of HnRNP in mammalian nuclei.
Heterogeneous nuclear ribonucleoprotein particles (HnRNP) were separated in metrizamide density gradients, into two fractions migrating to 1.31 g ml-1 and 1.18 g ml-1, respectively. Proteins associated with each of these fractions were analysed by SDS-acrylamide gel electrophoresis. It is shown that the whole proteins extracted from these two metrizamide fractions exhibit clearly different electrophoretic patterns: 1.31 HnRNP particles contain as major polypeptide chains molecules with molecular weights ranging from 40,000 to 65,000, while major polypeptides of 1.18 HnRNP are banding in the 30,000-40,000 molecular weight region of the gels. Both fractions contain numerous other associated polypeptide chains whose molecular weights are above 65,000. A possible kinetic relationship between these two HnRNP classes was investigated in vivo by performing chase experiments. No clear evidence for a precursor-product relationship was found. Implications arising from these structural and kinetic observations, and problems relating to nuclear maturation of pre-messenger RNA, are discussed.