Enhanced sensing and conversion of ultrasonic Rayleigh waves by elastic metasurfaces.
Recent years have heralded the introduction of metasurfaces that advantageously combine the vision of sub-wavelength wave manipulation, with the design, fabrication and size advantages associated with surface excitation. An important topic within metasurfaces is the tailored rainbow trapping and selective spatial frequency separation of electromagnetic and acoustic waves using graded metasurfaces. This frequency dependent trapping and spatial frequency segregation has implications for energy concentrators and associated energy harvesting, sensing and wave filtering techniques. Different demonstrations of acoustic and electromagnetic rainbow devices have been performed, however not for deep elastic substrates that support both shear and compressional waves, together with surface Rayleigh waves; these allow not only for Rayleigh wave rainbow effects to exist but also for mode conversion from surface into shear waves. Here we demonstrate experimentally not only elastic Rayleigh wave rainbow trapping, by taking advantage of a stop-band for surface waves, but also selective mode conversion of surface Rayleigh waves to shear waves. These experiments performed at ultrasonic frequencies, in the range of 400-600 kHz, are complemented by time domain numerical simulations. The metasurfaces we design are not limited to guided ultrasonic waves and are a general phenomenon in elastic waves that can be translated across scales.


[Effect of sodium nitrite on Trichomonas vaginalis].
We have investigated the action of sodium nitrite on the growth and morphologic changes of T. vaginalis and on the treatment of subcutaneous abscess by trichomonad in mice. Sodium nitrite inhibited the growth of metronidazole-sensitive KT9 isolate and metronidazole-resistant CDC85 strain of T. vaginalis as concentration of 6 mM and 10 mM, respectively. Intraperitoneal injection of sodium nitrite (70 micrograms, 100 micrograms, 130 micrograms/g body weight) did not reduce the size of abscess produced by subcutaneous inoculation of T. vaginalis in mice. T. vaginalis, treated with sodium nitrite at concentration giving about 50% inhibition of growth, showed fissures, many vacuoles and electron-translucent zone in the cytoplasm by transmission electron microscopy. In the case of CDC85 treated with 9 mM sodium nitrite, hydrogenosomal matrical change, destruction of hydrogenosomal membrane, autophagic vacuoles, disappearance of Golgi complex and polysome were notably observed. With above results, it is assumed that sodium nitrite inhibits the growth of metronidazole-sensitive and--resistant strains of T. vaginalis and induces the morphological changes of T. vaginalis although it does not affect in reducing of abscess size by T. vaginalis in mice.


Senior Co-Housing in the Netherlands: Benefits and Drawbacks for Its Residents.
Senior co-housing communities offer an in-between solution for older people who do not want to live in an institutional setting but prefer the company of their age peers. Residents of co-housing communities live in their own apartments but undertake activities together and support one another. This paper adds to the literature by scrutinizing the benefits and drawbacks of senior co-housing, with special focus on the forms and limits of social support and the implications for the experience of loneliness. Qualitative fieldwork was conducted in eight co-housing communities in the Netherlands, consisting of document analysis, interviews, focus groups, and observations. The research shows that co-housing communities offer social contacts, social control, and instrumental and emotional support. Residents set boundaries regarding the frequency and intensity of support. The provided support partly relieves residents' adult children from caregiving duties but does not substitute formal and informal care. Due to their access to contacts and support, few residents experience social loneliness. Co-housing communities can potentially also alleviate emotional loneliness, but currently, this happens to a limited degree. The paper concludes with practical recommendations for enhancing the benefits and reducing the drawbacks of senior co-housing.


Glucose regulation of insulin gene transcription and pre-mRNA processing in human islets.
Glucose is the primary regulator of insulin granule release from pancreatic islets. In rodent islets, the role of glucose in the acute regulation of insulin gene transcription has remained unclear, primarily because the abundance and long half-life of insulin mRNA confounds analysis of transcription by traditional methods that measure steady-state mRNA levels. To investigate the nature of glucose-regulated insulin gene transcription in human islets, we first quantitated the abundance and half-lives of insulin mRNA and pre-mRNAs after addition of actinomycin D (to stop transcription). Our results indicated that intron 1-and intron 2-containing pre-mRNAs were approximately 150- and 2,000-fold less abundant, respectively, than mature mRNA. 5' intron 2-containing pre-mRNAs displayed half-lives of only approximately 60 min, whereas all other transcripts displayed more extended lifetimes. In response to elevated glucose, pre-mRNA species increased within 60 min, whereas increases in mature mRNA did not occur until 48 h, suggesting that measurement of mature mRNA species does not accurately reflect the acute transcriptional response of the insulin gene to glucose. The acute increase in pre-mRNA species was preceded by a sixfold increase in histone H4 acetylation and a twofold increase in RNA polymerase II recruitment at the insulin promoter. Taken together, our data suggest that pre-mRNA species may be a more reliable reflection of acute changes to human insulin gene transcriptional rates and that glucose acutely enhances insulin transcription by a mechanism that enhances chromatin accessibility and leads to recruitment of basal transcriptional machinery.


Real-time PyMOL visualization for Rosetta and PyRosetta.
Computational structure prediction and design of proteins and protein-protein complexes have long been inaccessible to those not directly involved in the field. A key missing component has been the ability to visualize the progress of calculations to better understand them. Rosetta is one simulation suite that would benefit from a robust real-time visualization solution. Several tools exist for the sole purpose of visualizing biomolecules; one of the most popular tools, PyMOL (Schrödinger), is a powerful, highly extensible, user friendly, and attractive package. Integrating Rosetta and PyMOL directly has many technical and logistical obstacles inhibiting usage. To circumvent these issues, we developed a novel solution based on transmitting biomolecular structure and energy information via UDP sockets. Rosetta and PyMOL run as separate processes, thereby avoiding many technical obstacles while visualizing information on-demand in real-time. When Rosetta detects changes in the structure of a protein, new coordinates are sent over a UDP network socket to a PyMOL instance running a UDP socket listener. PyMOL then interprets and displays the molecule. This implementation also allows remote execution of Rosetta. When combined with PyRosetta, this visualization solution provides an interactive environment for protein structure prediction and design.


Fluorescence sensor array for metal ion detection based on various coordination chemistries: general performance and potential application.
A sensor array containing 9 cross-reactive sensing fluorescent elements with different affinity and selectivity to 10 metal cations (Ca(2+), Mg(2+), Cd(2+), Hg(2+), Co(2+), Zn(2+), Cu(2+), Ni(2+), Al(3+), Ga(3+)) is described. The discriminatory capacity of the array was tested at different ranges of pH and at different cation concentrations using linear discriminant analysis (LDA). Qualitative identification of cations can be determined with over 96% of accuracy in a concentration range covering 3 orders of a magnitude (5-5000 microM). Quantitative analysis can be achieved with over 90% accuracy in the concentration range between 10 and 5000 microM. The array performance was also tested in identification of nine different mineral water brands utilizing their various electrolyte compositions and their Ca(2+), Mg(2+), and Zn(2+) levels. LDA cross-validation routine shows 100% correct classification for all trials. Preliminary results suggest that similar arrays could be used in testing of the consistency of the purification and manufacturing process of purified and mineral waters.


Polyglycolic acid suture in strabismus surgery.
Polyglycolic acid, synthetic, absorbable braided suture was compared to gut with respect to handling, strength, and tissue reaction in 70 strabismus procedures. This new suture material produced less tissue reaction than gut and had handling characteristics that were similar to silk. It can be used in smaller sizes than gut because of its greater strength and firm knot. Polyglycolic acid suture appears to be a useful addition to ophthalmic suture materials.


Reference gene selection in the desert plant Eremosparton songoricum.
Eremosparton songoricum (Litv.) Vass. (E. songoricum) is a rare and extremely drought-tolerant desert plant that holds promise as a model organism for the identification of genes associated with water deficit stress. Here, we cloned and evaluated the expression of eight candidate reference genes using quantitative real-time reverse transcriptase polymerase chain reactions. The expression of these candidate reference genes was analyzed in a diverse set of 20 samples including various E. songoricum plant tissues exposed to multiple environmental stresses. GeNorm analysis indicated that expression stability varied between the reference genes in the different experimental conditions, but the two most stable reference genes were sufficient for normalization in most conditions. EsEF and Esα-TUB were sufficient for various stress conditions, EsEF and EsACT were suitable for samples of differing germination stages, and EsGAPDHand EsUBQ were most stable across multiple adult tissue samples. The Es18S gene was unsuitable as a reference gene in our analysis. In addition, the expression level of the drought-stress related transcription factor EsDREB2 verified the utility of E. songoricum reference genes and indicated that no single gene was adequate for normalization on its own. This is the first systematic report on the selection of reference genes in E. songoricum, and these data will facilitate future work on gene expression in this species.


Elevated Behavioral Economic Demand for Alcohol in a Community Sample of Heavy Drinking Smokers.
Cigarette smokers are more likely to consume alcohol at higher levels and experience poorer response to treatment for alcohol problems than are nonsmokers. One previous study in university students suggests that a potential reason for the high overlap between alcohol and tobacco use is that concurrent smoking is associated with overvaluation of alcohol, as reflected in elevated behavioral economic demand. The present study sought to extend these initial findings in a community sample with heavier levels of alcohol and tobacco use. Participants were 111 non-treatment-seeking heavy drinkers(defined as 18+/14+ drinks per week for men/women) from a larger study on alcohol pharmacotherapy mechanisms. Forty-nine participants (44%) reported regular smoking (≥5 cigarettes/day). Participants completed a hypothetical alcohol purchase task assessing alcohol consumption at escalating levels of price. Covariates included demographics, drinking quantity, alcohol use disorder severity, depression, and delay discounting. In covariate-adjusted models, smokers reported significantly higher maximum alcohol expenditures (Omax) and breakpoint price (first price suppressing consumption to zero) compared with nonsmokers. Elevated alcohol demand correlated with drinking quantity and severity in the entire sample, but not with smoking frequency or nicotine dependence among smokers only. This study offers further evidence of increased reinforcing value of alcohol among smokers in a sample of heavy drinkers from the community. Clinical implications and potential mechanisms underlying this relationship are discussed.


Membrane estrogen receptor-enriched GH(3)/B6 cells have an enhanced non-genomic response to estrogen.
We immunoselected GH(3)/B6 cells for a membrane estrogen receptor (mER) using antibodies generated against the rat intracellular ER (iER). Immunocytochemistry with anti-ER antibodies revealed bright fluorescence distributed in patches over the surface of mER-enriched cells, while cells immuno-depleted for mER showed only low-level membrane immunofluorescence. Quantitation via digital image analysis confirmed that immunoenriched populations show increases in both stained cell numbers and intensity of staining. Short-term culturing with serum reversibly decreased the intensity of immunostaining in mER-enriched cells to immuno-depleted cell levels. The mER-enriched populations initially contained ∼85% immunopositive cells in defined medium, but when cultured continuously with serum gradually decline to ∼22% immunopositive cells by 10 weeks. Cells enriched for mER showed a significant increase in rapid (after 2 or 5 min) prolactin release when treated with 17β-estradiol, while mER-depleted cells lacked this response. Immunoprecipitabie membrane proteins isolated from mER-enriched cells were 60,000, 74,000 and ∼ 200,000 MW, compared to an iER size of 67,000. Therefore, the presence and level of an mER that is antigenically related to iER is correlated with the ability of GH(3)/B6 cells to mediate a rapid action of estrogen.


Assessing inpatients' satisfaction with hospital care: should we prefer evaluation or satisfaction ratings?
Inpatients' satisfaction with hospital care is often assessed by questionnaire. From a psychometrical standpoint, this method has drawbacks, however. We further investigated which item response format would maximise desirable outcomes regarding characteristics of the sample obtained (response rate and representativeness) and psychometric properties of the instrument (e.g. missing items responses, variance, validity) as an initial study into this question was indecisive. Subjects were 1184 discharged inpatients, of which 728 patients (62%) responded. They filled out a 55-item satisfaction questionnaire, addressing 12 aspects of care, using either a 10-point Evaluation scale ranging from "very poor" to "excellent" (E10) or a 5-point Satisfaction scale ranging from "dissatisfied" to "very satisfied" (S5). Both E10 and S5 showed good psychometric properties, but S5 yielded a better score distribution. Other results also favoured S5, but differences were small. In conclusion, different response formats do not yield widely different results. Thus, in choosing between them, convenience could be a decisive factor.


Self-employment in joinery: an occupational risk facor?
Only a few studies have analyzed the health of self-employed workers. This cross-sectional study is the first to compare health status among craftsmen joiners and paid joiners. Clinical and paraclinical data for self-employed craftsmen and employees were collected by occupational health doctors according to a standardized protocol and compared. Health data and professional status relationships were analyzed by logistic regression. A total of 171 craftsmen and 196 paid workers were included. Craftsmen had more dermatologic pathologies (odds ratio (OR) = 2.67, p < 0.05), ear/nose/throat symptoms (OR = 3.38, p < 0.001), pulmonary symptoms (OR = 2.46, p < 0.05), musculoskeletal symptoms (OR = 3.09, p < 0.001), and abnormal audiogram (OR = 3.50, p < 0.001). The FEV1 was significantly lower among craftsmen (p < 0.01), independently of tobacco smoke exposure. This survey high-lights a high morbidity rate among self-employed craftsmen, suggesting that among woodworkers, professional status can be a risk factor for health. The preventive medical system for craftsmen has to be rethought to guarantee better safety for this population.


Occurrence of copper acclimation in the least killifish Heterandria formosa, and associated biochemical and physiological mechanisms.
We investigated the occurrence of copper acclimation in the least killifish, Heterandria formosa using both lethal and sublethal endpoints. We also investigated potential mechanisms underlying the observed acclimation. To assess the occurrence of acclimation, fish were exposed to either a background Cu level or to 15 μg/L Cu for seven days and subsequently exposed to a lethal Cu level (150 μg/L Cu). During the latter exposure, fish were monitored for survival till all fish had died, and (during the first 8h of this exposure) for changes in whole-body Na levels and lipid peroxidation (LPO). During the high-level Cu exposure, fish pre-exposed to copper had a significantly longer time-to-death than did the control fish. Similarly, neither whole-body Na nor LPO changed in the Cu-pre-exposed fish during the 8h of the exposure to 150 μg/L Cu - while both decreased significantly in the control fish. Thus, acclimation was evident for both time-to-death and the sublethal endpoints. These results also indicate that Cu toxicity may involve both Na loss and LPO, and that Cu-acclimation may be brought about by prevention of these effects. Our follow-up study on potential mechanisms underlying this copper acclimation used a similar pre-exposure/exposure design. Fish were subsampled at the end of the 7-day acclimation period - just before the commencement of high-level Cu exposure (T), after 4h of this Cu exposure (T), and again after 8h of this Cu exposure (T). Whole-body Cu accumulation, Na/K-ATPase activity, metallothionein levels, and catalase activity were quantified for these time points. While Cu levels were higher in the Cu-pre-exposed fish than in the control fish at T, net Cu accumulation was faster in the control fish than in the Cu-pre-exposed fish during the subsequent high-level Cu exposure. Consequently, changes in Cu accumulation dynamics may play a role in the resistance. Metallothionein induction may also play a role in the observed acclimation, as Cu-acclimated fish had a significantly higher metallothionein concentration compared to the control fish. There was no evidence of involvement of Na/K-ATPase in the acclimation, as the activity of this enzyme remained lower in the pre-exposed fish than in the control fish throughout both Cu exposure periods. There was limited evidence that a reduced loss of catalase activity plays a role in the acclimation; catalase activity did not differ after the pre-exposure period but was significantly higher in Cu-acclimated fish than in the control fish at T.


A novel distending laryngoscope: implications in transoral surgery.
The objective is to describe an innovative laryngoscope developed to improve visualization, provide greater exposure, and enhance precision and success during transoral procedures. A retrospective review of 170 patients who underwent transoral surgery with a new distending laryngoscope was conducted. We compared and contrasted our exposure within the oropharynx, hypopharynx, and larynx using the laryngoscope with that of currently available instrumentation. Specific mechanical dimensions of the laryngoscope along with the provided working field were calculated. Experience with the new laryngoscope afforded improved exposure over currently available instrumentation. This laryngoscope was manufactured using design elements from the Steiner, Weerda, and Lindholm laryngoscopes, including an anteriorly curved distal tip, distending capability, and lateral wings to protect against tongue herniation. The panoramic view was increased allowing for wider exposure of the supraglottis and pharynx. This design provided enhanced transoral visibility and working room for improved bimanual instrumentation. Direct laryngoscopic technique and instrumentation have continued to evolve. Over the last two decades, there has been a significant movement towards minimally invasive transoral surgical techniques fueling innovative concepts and advancement in laryngoscopic design and application. We present our experience with an innovative laryngoscope allowing for improved visualization, greater exposure, and enhanced proficiency with transoral technique.


Confocal/TEM overlay microscopy: a simple method for correlating confocal and electron microscopy of cells expressing GFP/YFP fusion proteins.
Genetic manipulation allows simultaneous expression of green fluorescent protein (GFP) and its derivatives with a wide variety of cellular proteins in a variety of living systems. Epifluorescent and confocal laser scanning microscopy (confocal) localization of GFP constructs within living tissue and cell cultures has become routine, but correlation of light microscopy and high resolution transmission electron microscopy (TEM) on components within identical cells has been problematic. In this study, we describe an approach that specifically localizes the position of GFP/yellow fluorescent protein (YFP) constructs within the same cultured cell imaged in the confocal and transmission electron microscopes. We present a simplified method for delivering cell cultures expressing fluorescent fusion proteins into LR White embedding media, which allows excellent GFP/YFP detection and also high-resolution imaging in the TEM. Confocal images from 0.5-microm-thick sections are overlaid atop TEM images of the same cells collected from the next serial ultrathin section. The overlay is achieved in Adobe Photoshop by making the confocal image somewhat transparent, then carefully aligning features within the confocal image over the same features visible in the TEM image. The method requires no specialized specimen preparation equipment; specimens are taken from live cultures to embedding within 8 h, and confocal transmission overlay microscopy can be completed within a few hours.


Δ(9)-THC and N-arachidonoyl glycine regulate BV-2 microglial morphology and cytokine release plasticity: implications for signaling at GPR18.
Microglial cells are extremely plastic and undergo a variety of CNS-prompted shape changes relative to their location and current role. Signaling molecules from neurons also regulate microglial cytokine production. Neurons are known to employ the endogenous cannabinoid system to communicate with other cells of the CNS. N-arachidonoyl glycine (NAGly) and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) signaling via GPR18 has been introduced as an important new target in microglial-neuronal communication. Our hypothesis is that endogenous NAGly-GPR18 signaling regulates phenotypic shape and cytokine production in microglia, and is mimicked by Δ(9)-THC in the BV-2 microglia model system. BV-2 microglia were exposed to NAGly and Δ(9)-THC or Vh for 12 h, which resulted in significant differences in the cell morphologies expressed. Cannabidiol (CBD) was effective at antagonizing the effects of both NAGly and Δ(9)-THC. Using ELISA-based microarrays, BV-2 microglia were exposed to NAGly and Δ(9)-THC or Vh for 3 h and the presence of 40 cytokines in the culture media quantified. Production of Axl, CD40, IGF-I, OPN, and Pro-MMP-9 were significantly altered by NAGly and Δ(9)-THC, and antagonized by CBD. These data add to an emerging profile that emphasizes NAGly as a component of an endogenous system present in the CNS that tightly integrates microglial proliferation, recruitment, and adhesion with neuron-glia interactivity and tissue remodeling.


Epidural steroid injections are associated with less improvement in patients with lumbar spinal stenosis: a subgroup analysis of the Spine Patient Outcomes Research Trial.
Subgroup analysis of prospective, randomized database from the Spine Patient Outcomes Research Trial (SPORT). The hypothesis of this study was that patients who received ESI during initial treatment as part of SPORT (The Spine Patient Outcomes Research Trial) would have improved clinical outcome and a lower rate of crossover to surgery than patients who did not receive ESI. The use of epidural steroid injection (ESI) in patients with lumbar spinal stenosis is common, although there is little evidence in the literature to demonstrate its long-term benefit in the treatment of lumbar stenosis. Patients with lumbar spinal stenosis who received ESI within the first 3 months of enrollment in SPORT (ESI) were compared with patients who did not receive epidural injections during the first 3 months of the study (no-ESI). There were 69 ESI patients and 207 no-ESI patients. There were no significant differences in demographic factors, baseline clinical outcome scores, or operative details between the groups, although there was a significant increase in baseline preference for nonsurgical treatment among ESI patients (ESI 62% vs. no-ESI 33%, P < 0.001). There was an average 26-minute increase in operative time and an increased length of stay by 0.9 days among the ESI patients who ultimately underwent surgical treatment. Averaged over 4 years, there was significantly less improvement in 36-Item Short Form Health Survey (SF-36) Physical Function among surgically treated ESI patients (ESI 14.8 vs. no-ESI 22.5, P = 0.025). In addition, there was significantly less improvement among the nonsurgically treated patients in SF-36 Body Pain (ESI 7.3 vs. no-ESI 16.7, P = 0.007) and SF-36 Physical Function (ESI 5.5 vs. no-ESI 15.2, P = 0.009). Of the patients assigned to the surgical treatment group, there was a significantly increased crossover to nonsurgical treatment among patients who received an ESI (ESI 33% vs. no-ESI 11%, P = 0.012). Of the patients assigned to the nonoperative treatment group, there was a significantly increased crossover to surgical treatment in the ESI patients (ESI 58% vs. no-ESI 32%, P = 0.003). Despite equivalent baseline status, ESIs were associated with significantly less improvement at 4 years among all patients with spinal stenosis in SPORT. Furthermore, ESIs were associated with longer duration of surgery and longer hospital stay. There was no improvement in outcome with ESI whether patients were treated surgically or nonsurgically.


The epidermal growth factor homology domain of the LDL receptor drives lipoprotein release through an allosteric mechanism involving H190, H562, and H586.
The low density lipoprotein (LDL) receptor (LDLR) mediates efficient endocytosis of VLDL, VLDL remnants, and LDL. As part of the endocytic process, the LDLR releases lipoproteins in endosomes. The release process correlates with an acid-dependent conformational change in the receptor from an extended, "open" state to a compact, "closed" state. The closed state has an intramolecular contact involving H190, H562, and H586. The current model for lipoprotein release holds that protonation of these histidines drives the conformational change that is associated with release. We tested the roles of H190, H562, and H586 on LDLR conformation and on lipoprotein binding, uptake, and release using variants in which the three histidines were replaced with alanine (AAA variant) or in which the histidines were replaced with charged residues that can form ionic contacts at neutral pH (DRK variant). Contrary to expectation, both the AAA and the DRK variants exhibited normal acid-dependent transitions from open to closed conformations. Despite this similarity, both the AAA and DRK mutations modulated lipoprotein release, indicating that H190, H562, and H586 act subsequent to the conformational transition. These observations also suggest that the intramolecular contact does not drive release through a competitive mechanism. In support of this possibility, mutagenesis experiments showed that beta-VLDL binding was inhibited by mutations at D203 and E208, which are exposed in the closed conformation of the LDLR. We propose that H190, H562, and H586 are part of an allosteric mechanism that drives lipoprotein release.


Alternative splice variants of the human PKR protein kinase possessing different 5'-untranslated regions: expression in untreated and interferon-treated cells and translational activity.
The double-stranded RNA-dependent protein kinase PKR is an interferon-inducible enzyme that possesses antiviral and antiproliferative activities. We examined expression of PKR transcripts in human placenta tissue and cultured human amnion U cells. Alternative exon 2 structures were identified and characterized that possess different functional activities. Cloning and sequence analyses of 5'-RACE cDNAs from human placenta established a linkage between exon 1 and three alternative exon 2 structures that constitute, together with part of exon 3, the 5'-untranslated region of the PKR mRNA. The alternative splice variants of exon 2 were designated Ex2alpha (83 nucleotides), Ex2beta (167 nucleotides), and Ex2gamma (401 nucleotides). All three exon 2 variants were present in placenta tissue. However, only the Ex2alpha and Ex2beta forms were detectable in the amnion U cell line. Nuclease protection analysis revealed that the Ex2beta form was slightly more abundant than the Ex2alpha form, in both placenta tissue and U cells. Interferon treatment of U cells increased the level of both Ex2alpha and Ex2beta RNA by approximately 5-fold. The translational activities, measured in a luciferase reporter assay, of RNA transcripts possessing the Ex2alpha and Ex2beta forms of the PKR 5'-UTR were comparable to each other and more efficient than those with the Ex2gamma form.


Mass Spectrometric Detection of Formaldehyde-Crosslinked PBMC Proteins in Cell-Free DNA Blood Collection Tubes.
Streck tubes are commonly used to collect blood samples to preserve cell-free circulating DNA. They contain imidazolidinyl urea as a formaldehyde-releasing agent to stabilize cells. We investigated whether the released formaldehyde leads to crosslinking of intracellular proteins. Therefore, we employed a shotgun proteomics experiment on human peripheral blood mononuclear cells (PBMCs) that were isolated from blood collected in Streck tubes, EDTA tubes, EDTA tubes containing formaldehyde, or EDTA tubes containing allantoin. The identified crosslinks were validated in parallel reaction monitoring LC/MS experiments. In total, we identified and validated 45 formaldehyde crosslinks in PBMCs from Streck tubes, which were also found in PBMCs from formaldehyde-treated blood, but not in EDTA- or allantoin-treated samples. Most were derived from cytoskeletal proteins and histones, indicating the ability of Streck tubes to fix cells. In addition, we confirm a previous observation that formaldehyde crosslinking of proteins induces a +24 Da mass shift more frequently than a +12 Da shift. The crosslinking capacity of Streck tubes needs to be considered when selecting blood-collection tubes for mass-spectrometry-based proteomics or metabolomic experiments.


Cellular heterogeneity of the distal nephron and its relation to function.
The distal segments beyond the macula densa--distal convoluted tubule, connecting tubule, cortical collecting duct--display cellular heterogeneity. The four different cell types, namely the DCT cell, CNT cell, the principal cell and intercalated cell differ mainly by the pattern of membrane amplification and they reveal also qualitative differences as to some cytoplasmic proteins. Each of the four cell types adapts to chronic changes in electrolyte metabolism with structural alteration, concerning essentially the membrane area over which the active transport step of the cell proceeds, in DCT-, CNT- and P-cells the basolateral cell membrane with the Na-K-ATPase, in intercalated cells the luminal cell membrane with a H+ ATPase. Since each cell type responds only to specific conditions with changes in membrane area and associated transcellular transport activity, morphological studies can help to determine the specific role of each cell type in the regulation of renal electrolyte excretion. Such investigations demonstrated that besides mineralocorticoid hormones the transport capacity of certain cells should depend on the solute composition of tubular fluid. Thus, changes in the transport pattern specifically induced in only one segment alters also the transport patterns of segments downstream. Cellular heterogeneity seems to guarantee the optimal regulation of renal electrolyte excretion.


[Use of growth hormone genes for the diagnosis of the disease of dwarfism].
The pattern of BamHI fragments of DNA from three children suggested to suffer the isolated growth hormone deficiency type. IA was not different from normal pattern registered in blot hybridization with [32P]cDNA of the growth hormone gene. The data permits one to exclude the above mentioned disease that is characterized by the deletion of HGH-N gene. The analogous DNA restriction analysis using HindIII restriction endonuclease has shown, that neither the sick children, nor their parents carry the deletion in heterozygotic state. The study of normal polymorphism of the restriction fragments length has shown that as for as the frequency of polymorphic MspI restriction endonuclease sites A and B in the growth hormone gene cluster (0.67 and 0.75 respectively) is concerned the Russian population in Moscow is closer to Mediterranean one than to North-european.


Correlates of Sleep Duration in Early Childhood: A Systematic Review.
This systematic review aimed to summarize correlates of sleep duration in children under 5 years of age. Six electronic databases (PubMed, PsycINFO, MEDLINE, CINAHL, SPORTDiscus, and Scopus) were searched from inception to May 2019. Observational studies and intervention studies reporting cross-sectional results from baseline data were considered. Data were extracted using a predesigned form and potential correlates were categorized following a sociological framework. One-hundred and sixteen studies, representing 329,166 children, met the inclusion criteria, with a high risk of bias in 62 included studies. A total of 83 correlates of sleep duration were identified. Among the associations studied four or more times, correlates of nap duration were child's age and nighttime sleep onset/bedtime; correlates of nighttime sleep duration were household income, parent marital status, parental adiposity level, nighttime sleep duration at younger age, nighttime sleep onset/bedtime, nighttime sleep wakeup time, and frequency of current bedtime routine; correlate of total sleep duration was screen time. Young children from low-income households, single families, or having overweight parents may be at risk for short sleep duration. Promoting healthy sleep duration from an early age appears essential. Effective practices may include encouraging an earlier bedtime, limiting screen time, and establishing a regular bedtime routine. The absence of consistent evidence in the psychological, cognitive, and emotional domain as well as the physical environmental domain warrants further research.


Sympathetic nerve blocks promote anti-inflammatory response by activating the JAK2-STAT3-mediated signaling cascade in rat myocarditis models: A novel mechanism with clinical implications.
Left stellectomy has become an important therapeutic option for patients with potentially fatal arrhythmias. However, the antiarrhythmic mechanism of left stellectomy is not well known. The cholinergic anti-inflammatory pathway (CAIP) is a complex immune mechanism that regulates peripheral inflammatory responses. The purpose of this study was to evaluate the effect of left stellectomy on CAIP using rat experimental autoimmune myocarditis (EAM) models. EAM was produced by injecting 2 mg of porcine cardiac myosin into the footpads of rats. Left stellectomy was performed before EAM induction. We evaluated the effect of left stellectomy on arrhythmic events, survival, inflammation, and CAIP in rats without and with EAM. Left stellectomy prevented arrhythmia and improved survival in EAM rats. Left stellectomy decreased the levels of tumor necrosis factor α, interleukin 6, and high mobility group box 1 (P < .05 vs EAM) in serum and heart tissues from EAM rats. In heart rate variability analysis, high-frequency peaks of the power spectrum densities, reflecting parasympathetic cardiovagal tone, were significantly decreased in EAM rats, but increased after left stellectomy. The ratios of phosphorylated STAT3/STAT3 (signal transducer and activator of transcription 3) and phosphorylated JAK2/JAK2 (Janus kinase 2) decreased in cell lysates of the spleen, liver, and heart in EAM rats. However, the same ratios significantly increased after left stellectomy. Nuclear factor κB in cell lysates of the spleen, liver, and heart increased in EAM rats, but decreased after left stellectomy. In EAM models, left stellectomy increased survival of the rats while showing antiarrhythmic effects with reduced inflammation via activation of the JAK2-STAT3-mediated signaling cascade. Our findings suggest an exciting opportunity to develop new and novel therapeutics to attenuate cardiac inflammation.


Implants in an HIV-positive patient: a case report.
Human immunodeficiency virus (HIV) causes an immune incompetence that weakens the body's defense against pathogens. It has been supposed that HIV-positive patients are more likely to develop both early and late postoperative complications, such as septicemia and poor wound healing. This has not been corroborated by more recent studies but seems to depend on the patient's level of CD4 cells and his or her general condition. As the life expectancy of HIV-positive individuals increases and the condition becomes increasingly controllable, esthetic dental treatment becomes more significant and implant-supported prostheses may be considered as an alternative to removable dentures. Except for a single case report on the immediate placement of a single-tooth implant, no reports are available on implant dentistry in HIV-positive patients. This case report concerns implant placement in the maxilla and mandible of an HIV-positive individual and complete dental and implant rehabilitation. Two years after implant placement, the prosthesis is functioning well.


High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis.
This study was designed to provide preliminary data regarding the safety and efficacy of high-dose humanized anti-IL-2 receptor (daclizumab) therapy for the treatment of active intermediate, posterior or panuveitis. Five patients were recruited into this non-randomized, prospective pilot study of high-dose intravenous induction daclizumab therapy given at doses of 8mg/kg at day 0 and 4mg/kg at day 14. Patients who did not meet a safety endpoint at the 3-week follow-up evaluation were given the option of continuing therapy with subcutaneous daclizumab at 2mg/kg every 4 weeks for 52 weeks. The primary outcome assessed was a two-step decrease in vitreous haze at day 21. Secondary outcomes evaluated included best-corrected visual acuity, retinal thickness as measured by optical coherence tomography, retinal vascular leakage assessed by fluorescein angiography, anterior chamber and vitreous cellular inflammation. Four male patients and one female patient were enrolled. Diagnoses included birdshot retinochoroidopathy (two patients), Vogt-Koyanagi-Harada's disease, bilateral idiopathic panuveitis and bilateral idiopathic intermediate uveitis. By the 4th week, four of five patients demonstrated a two-step decrease in vitreous haze. The other participant did not meet this criterion until week 20, but all five patients maintained stability in vitreous haze grade throughout their follow-up periods. At enrollment, mean visual acuity (10 eyes in 5 patients) was 69.2 ETDRS letters and following treatment was 78.2 letters (p<0.12). Anterior chamber cell, vitreous cell, and vitreous haze also improved in the majority of eyes. Adverse events were generally mild except for one episode of left-lower lobe pneumonia requiring hospitalization and treatment. This is the first demonstration that high-dose daclizumab can reduce inflammation in active uveitis. Daclizumab was well tolerated but there may be a potential increased risk of infection associated with immunosuppression. All five patients demonstrated a decrease in vitreous haze and measures of intraocular inflammation at final follow-up. The results of this small, non-randomized pilot study support the consideration of high-dose daclizumab therapy in cases of active posterior uveitis.


EzMap: a simple pipeline for reproducible analysis of the human virome.
In solid-organ transplant recipients, a delicate balance between immunosuppression and immunocompetence must be achieved, which can be difficult to monitor in real-time. Shotgun sequencing of cell-free DNA (cfDNA) has been recently proposed as a new way to indirectly assess immune function in transplant recipients through analysis of the status of the human virome. To facilitate exploration of the utility of the human virome as an indicator of immune status, and to enable rapid, straightforward analyses by clinicians, we developed a fully automated computational pipeline, EzMap, for performing metagenomic analysis of the human virome. EzMap combines a number of tools to clean, filter, and subtract WGS reads by mapping to a reference human assembly. The relative abundance of each virus present is estimated using a maximum likelihood approach that accounts for genome size, and results are presented with interactive visualizations and taxonomy-based summaries that enable rapid insights. The pipeline is automated to run on both workstations and computing clusters for all steps. EzMap automates an otherwise tedious and time-consuming protocol and aims to facilitate rapid and reproducible insights from cfDNA. EzMap is freely available at https://github.com/dekoning-lab/ezmap. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms.
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.


Similar patterns of cortical expansion during human development and evolution.
The cerebral cortex of the human infant at term is complexly folded in a similar fashion to adult cortex but has only one third the total surface area. By comparing 12 healthy infants born at term with 12 healthy young adults, we demonstrate that postnatal cortical expansion is strikingly nonuniform: regions of lateral temporal, parietal, and frontal cortex expand nearly twice as much as other regions in the insular and medial occipital cortex. This differential postnatal expansion may reflect regional differences in the maturity of dendritic and synaptic architecture at birth and/or in the complexity of dendritic and synaptic architecture in adults. This expression may also be associated with differential sensitivity of cortical circuits to childhood experience and insults. By comparing human and macaque monkey cerebral cortex, we infer that the pattern of human evolutionary expansion is remarkably similar to the pattern of human postnatal expansion. To account for this correspondence, we hypothesize that it is beneficial for regions of recent evolutionary expansion to remain less mature at birth, perhaps to increase the influence of postnatal experience on the development of these regions or to focus prenatal resources on regions most important for early survival.


Effects of chronic administration of ephedrine during very-low-calorie diets on energy expenditure, protein metabolism and hormone levels in obese subjects.
1. We investigated the effects of the chronic administration of a sympathomimetic agent on energy expenditure, protein metabolism and levels of thyroid hormones and catecholamines in 10 obese subjects after a 6-week very-low-calorie-diet programme (1965 kJ, 60 g of protein, 45 g of carbohydrates). L-(-)-Ephedrine hydrochloride (50 mg three times a day by mouth) or placebo were administered during 2-week periods (weeks 2-5 of the VLCD programme) in a randomized, double-blind, cross-over design. Five subjects began with ephedrine and five with placebo. 2. The results were analysed separately in the two groups. No difference was found between them as regards weight loss during the very-low-calorie diet and drug treatments. Conversely, ephedrine therapy induced a significantly lower daily urinary excretion of nitrogen (and, consequently, a better nitrogen balance) with respect to placebo, independently of the drug sequence. Daily urinary levels of 3-methylhistidine during ephedrine and placebo treatments were similar. The fasting resting metabolic rate (oxygen consumption, ml STP/min) fell significantly during the very-low-calorie diet in both groups, but this effect was partially and significantly prevented by administration of ephedrine. Diet therapy significantly reduced 24 h urine levels of vanillylmandelic acid and homovanillic acid, which, however, increased to pretreatment values during ephedrine treatment. No significant effects were shown on 24 h urinary concentrations of adrenaline, noradrenaline and dopamine during the very-low-calorie diet and/or ephedrine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Multimodal Neuroimaging of Frontolimbic Structure and Function Associated With Suicide Attempts in Adolescents and Young Adults With Bipolar Disorder.
Bipolar disorder is associated with high risk for suicidal behavior that often develops in adolescence and young adulthood. Elucidation of involved neural systems is critical for prevention. This study of adolescents and young adults with bipolar disorder with and without a history of suicide attempts combines structural, diffusion tensor, and functional MR imaging methods to investigate implicated abnormalities in the morphology and structural and functional connectivity within frontolimbic systems. The study had 26 participants with bipolar disorder who had a prior suicide attempt (the attempter group) and 42 participants with bipolar disorder without a suicide attempt (the nonattempter group). Regional gray matter volume, white matter integrity, and functional connectivity during processing of emotional stimuli were compared between groups, and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors. Compared with the nonattempter group, the attempter group showed significant reductions in gray matter volume in the orbitofrontal cortex, hippocampus, and cerebellum; white matter integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions; and amygdala functional connectivity to the left ventral and right rostral prefrontal cortex. In exploratory analyses, among attempters, there was a significant negative correlation between right rostral prefrontal connectivity and suicidal ideation and between left ventral prefrontal connectivity and attempt lethality. Adolescent and young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral frontolimbic neural system subserving emotion regulation. Among attempters, reductions in amygdala-prefrontal functional connectivity may be associated with severity of suicidal ideation and attempt lethality.


The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor.
SUL-compounds are protectants from cold-induced ischemia and mitochondrial dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in α1-adrenoceptor (α1-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (-11.9 ± 2.50 mmHg) and its (R)-enantiomer SUL-150 (-13.2 ± 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (-1.33 ± 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 ± 1.71 mL/min to 21.94 ± 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-3H]-prazosin in CHO cells. Docking simulation to the α1-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α1-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation.


Testing a model of suicide ideation in college students.
This study examined several risk factors-negative life events (NLE), hopelessness, and depressive symptoms-believed to commonly precipitate suicide ideation in college students. A total of 345 undergraduates participated in the study. Students completed four self-report questionnaires. Hierarchical regression analyses were used to construct a risk model of suicide ideation. This study confirmed depressive symptoms and hopelessness as predictors of suicide ideation in college students; however, NLE impacted suicidal thoughts through hopelessness and depressive symptoms. Interestingly, depressive symptoms exerted a stronger influence on suicide ideation than hopelessness. Hopelessness served as a partial mediator in the relationship between NLE and depressive symptoms; however, depressive symptoms fully mediated the relationship between NLE and hopelessness. Clinical implications for understanding suicide risk in college students are discussed.


Pattern of onychomycosis--a RIMS study.
Onychomycosis is a fungal infection of nails caused by dermatophytes, yeasts or non-dermatophytes moulds. In this study, 500 patients suspected of having onychomycosis reffered from the out patient department (OPD), Dermatology, Regional Institute of Medical Sciences (RIMS) Hospital Imphal Manipur during the period from January 2007 to December 2008 were processed in the Department of Microbiology RIMS. Nail clippings or scrapings depending on the variety of onychomycosis were collected with sterile blades under all aseptic measures. Specimens were put up for 10% KOH mount, fungal cultures on two sets of SDA (Sabouraud's dextrose agar) incorporated with antibiotics and lactophenol cotton blue preparation (LCB) from the cultures and examined microscopically. Slide cultures were also put up if necessary. Out of 500 samples processed, a total of 444 (88.8%) were positive for the various fungi. The positive fungi were dermatophytes 258 (58.1%), non-dermatophytes 139 (31.3%), yeasts and yeast-like 17 (3.8%) and mixed fungal isolates 30 (6.7%). Of the 230 males and 270 females studied,193 (83.9%) males and 251 (92.9%) females respectively were positive for various fungi causing onychomycosis. Maximum number of suspected cases were in the age group of 21-30 years. Among the dermatophytes, Trichophyton species (spp.) 250 (50%) was the commonest isolate followed by Epidermophyton spp. 8 (1.6%). Among the non-dermatophytes, Aspergillus spp. 70 (14%) was the commonest followed by Penicillium spp. 24 (4.8%), Acremonium spp. 9 (1.8%), Fusarium spp. 8 (1.6%), Curvularia spp. 7 (1.4%), Alternaria spp. 5 (1%), Scopulariopsis spp. 4 (0.8%), Cladosporium spp. 4 (0.8%), Nigrospora spp. 2 (0.4%), Mucor spp. 1 (0.2%), Paecilomyces spp. 1 (0.2%), Pseudallescheria spp. (0.2%), Rhizopus spp. 1 (0.2%), Verticillium spp. 1 (0.2%), Exophiala jeanselmei 1 (0.2%). Among the yeast and yeast-like i.e. Candida spp. 15, Geotrichum spp. 1, Rhodotorula spp. 1 were 17 (3.8%), mixed fungal isolates 30 (6.7%), respectively. Reports were given to the patient for follow up and treatment. Health awareness and suggestions were given for prevention and further spread of onychomycosis.


Phosphorylation of SUMO-1 occurs in vivo and is conserved through evolution.
Protein dynamics is regulated by an elaborate interplay between different post-translational modifications. Ubiquitin and ubiquitin-like proteins (Ubls) are small proteins that are covalently conjugated to target proteins with important functional consequences. One such modifier is SUMO, which mainly modifies nuclear proteins. SUMO contains a unique N-terminal arm not present in ubiquitin and other Ubls, which functions in the formation of SUMO polymers. Here, we unambiguously show that serine 2 of the endogenous SUMO-1 N-terminal protrusion is phosphorylated in vivo using very high mass accuracy mass spectrometry at both the MS and the MS/MS level and complementary fragmentation techniques. Strikingly, we detected the same phosphorylation in yeast, Drosophila and human cells, suggesting an evolutionary conserved function for this modification. The nearly identical human SUMO-2 and SUMO-3 isoforms differ in serine 2; thus, only SUMO-3 could be phosphorylated at this position. Our finding that SUMO can be modified may point to an additional level of complexity through modifying a protein-modifier.


Selective interactions of Co2+-Ca2+-concanavalin A with high mannose N-glycans.
Concanavalin A (ConA) has an intrinsic binding affinity to carbohydrates. Here, we obtained Co2+-Ca2+-ConA (2.83 Å, PDB: 8I7Q) via X-ray crystallography by substituting native ConA (Mn2+-Ca2+); it has binding selectivity for high-mannose N-glycan similar to native ConA. Our findings may thus inform antiviral reagent design.


Evolutionary morphology in shape and size of haptoral anchors in 14 Ligophorus spp. (Monogenea: Dactylogyridae).
The search for phylogenetic signal in morphological traits using geometric morphometrics represents a powerful approach to estimate the relative weights of convergence and shared evolutionary history in shaping organismal form. We assessed phylogenetic signal in the form of ventral and dorsal haptoral anchors of 14 species of Ligophorus occurring on grey mullets (Osteichthyes: Mugilidae) from the Mediterranean, the Black Sea and the Sea of Azov. The phylogenetic relationships among these species were mapped onto the morphospaces of shape and size of dorsal and ventral anchors and two different tests were applied to establish whether the spatial positions in the morphospace were dictated by chance. Overall significant phylogenetic signal was found in the data. Allometric effects on anchor shape were moderate or non-significant in the case of evolutionary allometry. Relatively phylogenetically distant species occurring on the same host differed markedly in anchor morphology indicating little influence of host species on anchor form. Our results suggest that common descent and shared evolutionary history play a major role in determining the shape and, to a lesser degree in the size of haptoral anchors in Ligophorus spp. The present approach allowed tracing paths of morphological evolution in anchor shape. Species with narrow anchors and long shafts were associated predominately with Liza saliens. This morphology was considered to be ancestral relative to anchors of species occurring on Liza haematocheila and M. cephalus possessing shorter shafts and longer roots. Evidence for phylogenetic signal was more compelling for the ventral anchors, than for the dorsal ones, which could reflect different functional roles in attachment to the gills. Although phylogeny and homoplasy may act differently in other monogeneans, the present study delivers a common framework to address effectively the relationships among morphology, phylogeny and other traits, such as host specificity or niche occupancy.


Consequence of preterm birth in early adolescence: the role of language on auditory short-term memory.
This study tested the hypothesis that preterm early adolescents' short-term memory is compromised when presented with increasingly complex verbal information and that associated neuroanatomical volumes would differ between preterm and term groups. Forty-nine preterm and 20 term subjects were evaluated at age 12 years with neuropsychological measures and magnetic resonance imaging (MRI). There were no differences between groups in simple short-term and working memory. Preterm subjects performed lower on learning and short-term memory tests that included increased verbal complexity. They had reduced right parietal, left temporal, and right temporal white matter volumes and greater bilateral frontal gray and right frontal white matter volumes. There was a positive association between complex working memory and the left hippocampus and frontal white matter in term subjects. While not correlated, memory scores and volumes of cortical regions known to subserve language and memory were reduced in preterm subjects. This study provides evidence of possible mechanisms for learning problems in former preterm infants.


Cultural and economic determinants of geographical mortality patterns in The Netherlands.
The geographical pattern of mortality in The Netherlands is dominated by an area of relatively high mortality in the southern part of the country. The aim was to analyse the background of this geographical mortality pattern in the early 1980s, and its evolution over time since the early 1950s. Mortality data by district (n = 39), cause of death (13 large causes, "symptoms and ill defined conditions", all other causes), and time period (1950-54, 1960-64, 1970-74, 1980-84) were available from the Netherlands Central Bureau of Statistics. Standardised mortality ratios were calculated, and the logarithms of these were related to three sociodemographic characteristics using multiple, ordinary least squares regression analysis. This study used data for the whole Dutch population. Although the geographical mortality pattern has been rather stable over the last decades, a clear tendency towards convergence is also apparent. Approximately 90% of the current excess mortality in the southern part of the country is due to cardiovascular diseases. The results of regression analysis show that the excess mortality is primarily related to the high percentage of Roman Catholics in this part of the country, and additionally to a slightly lower average income. In The Netherlands, a higher percentage of Roman Catholics in the population is linked with higher all cause mortality rates, as well as with higher mortality rates for lung cancer, ischaemic heart disease, cerebrovascular disease, arterial disease, and chronic non-specific lung disease. Survey data show that these associations are partly due to a higher prevalence of smoking among Roman Catholics. As in many other countries, a lower average income is linked with high all cause mortality rates in The Netherlands. Cause specific data show negative associations for stomach cancer, ischaemic heart disease, cerebrovascular disease, chronic non-specific lung disease, and traffic accidents. Since the early 1950s the association between geographical mortality patterns and the percentage of Roman Catholics in the population has gradually become less strongly positive. This suggests that the convergence of the mortality rates in the South towards the national average may be related to a gradual lessening of differences in lifestyle between population groups. Both cultural and economic factors are important in the explanation of geographical mortality patterns in The Netherlands.


The adenoviral E1A oncoproteins interfere with the growth-inhibiting effect of the cdk-inhibitor p21(CIP1/WAF1).
The cdk-inhibitor p21(CIP1/WAF1) inhibits the activities of cyclin-dependent kinases and proliferating cell nuclear antigen, thereby repressing cell-cycle progression and DNA replication. Transforming oncogenes, such as E1A of human adenovirus 5 (Ad5), may interfere with such growth-inhibitory proteins. In this study, we show that in various Ad5E1-transformed cells, p21(CIP1/WAF1) is expressed and that, in general, expression is not downregulated. In addition, colony-formation assays show that in Ad5E1-transformed cells highly overexpressed p21(CIP1/WAF1) can still cause growth inhibition. FACS experiments indicate, however, that a G1 arrest induced by moderate overexpression of p21(CIP1/WAF1) can be overcome by E1A. The E1A proteins may interfere with the function of p21(CIP1/WAF1) by binding. Indeed, p21(CIP1/WAF1) binds with its cyclin/cdk-binding N terminus to the transforming N-terminal and CR1 region of the E1A proteins. Together, these results lend support to the model that E1A can interfere directly with p21(CIP1/WAF1) function and thereby stimulates cell growth.


Ultrafast relaxation investigated by photoelectron circular dichroism: an isomeric comparison of camphor and fenchone.
We study the isomeric effects using time resolved photoelectron circular dichroism (TR-PECD). Using a (1 + 1') pump-probe ionisation scheme with photoelectrons collected by the velocity map imaging technique, we compare the relaxation dynamics from the 3s-Rydberg state in 1R,4R-(+)-camphor with the one in its chiral isomer, 1R,4S-(-)-fenchone [Comby et al., 2016, JPCL, 7, 4514]. Our measurements revealed a similar lifetime for both isomers. However, the circular dichroism in the photoelectron angular distribution decays exponentially in ∼730 fs from a +9% forward amplitude during the first hundreds of femtoseconds to reach an asymptotic -2% backward amplitude. This time-scale is drastically shorter than in fenchone. Our analysis allows us to evaluate the impact of the anisotropy of excitation; the relaxation dynamics, following photoexcitation by the linearly polarized pump, is then compared to that induced by a circularly polarized pump pulse (CPL). With such a CPL pump, we then retrieve time constants of our chiral observables similar to the ones recorded in fenchone. Quantum and classical simulations are developed and used to decipher the dependence of the PECD on the anisotropy of excitation and the spatial distribution of the 3s-Rydberg electron wavefunction. Our experimental investigations, supported by our simulations, suggest that varying the pump ellipticity enables us to reveal the breakdown of the Franck-Condon approximation.


Economic policy uncertainty and presidential approval: Evidence from Latin America.
This paper analyzes the extent to which economic policy uncertainty affects presidential approval in four Latin American countries (Brazil, Chile, Colombia, and Mexico). Using panel (time-series cross-sectional) estimation methods, we show that economic policy uncertainty has a negative impact on presidential approval in our sample. A one-standard-deviation increase in the level of economic uncertainty reduces presidential approval by approximately 12 percent. Our results are consistent with the political economy model of Alesina et al. (1993), which shows that voters are less likely to re-elect the incumbent when faced with uncertainty about economic policy. Incumbent competence signalling can exarcerbate this effect.


Is early anticoagulation with warfarin necessary after bioprosthetic aortic valve replacement?
Freedom from anticoagulation is the principal advantage of bioprosthesis; however, the American Heart Association/American College of Cardiology and the American College of Chest Physicians guidelines recommend early anticoagulation with heparin, followed by warfarin for 3 months after bioprosthetic aortic valve replacement. We examined neurologic events within 90 days of bioprosthetic aortic valve replacement at our institution. Between 1993 and 2000, 1151 patients underwent bioprosthetic aortic valve replacement with (641) or without (510) associated coronary artery bypass. By surgeon preference, 624 had early postoperative anticoagulation (AC+) and 527 did not (AC-). In the AC- group, 410 patients (78%) received antiplatelet therapy. Groups were similar with respect to gender (female, 36% AC+ vs 40% AC-, P = .21), hypertension (64% AC+ vs 61%, P = .27), and prior stroke (7.6% AC+ vs 8.5% AC-, P = .54). The AC+ group was slightly younger than the AC- group (median, 76 years vs 78 years, P = .006). Operative mortality was 4.1% with 43 (3.7%) cerebrovascular events within 90 days. Excluding 18 deficits apparent upon emergence from anesthesia, we found that postoperative cerebrovascular accident occurred in 2.4% of AC+ and 1.9% AC- patients. By multivariable analysis, the only predictor of operative mortality was hypertension ( P < .0001). Postoperative cerebrovascular accident was unrelated to warfarin use ( P = .32). The incidence of mediastinal bleeding requiring reexploration was similar (5.0% vs 7.4%), as were other bleeding complications in the first 90 days (1.1% vs 0.8%). No variables were predictive of bleeding by multivariate analysis. Although these data do not address the role of antiplatelet agents, early anticoagulation with warfarin after bioprosthetic aortic valve replacement did not appear to protect against neurologic events.


Enhanced intersystem crossing via a high energy charge transfer state in a perylenediimide-perylenemonoimide dyad.
The electronic relaxation processes of a photoexcited linear perylenediimide-perylenemonoimide (PDI-PMI) acceptor-donor dyad were studied. PDI-PMI serves as a model compound for donor-acceptor systems in photovoltaic devices and has been designed to have a high-energy PDI (-*)-PMI (+*) charge transfer (CT) state. Our study focuses on the minimal Gibbs free energy (Delta G ET) required to achieve quantitative CT and on establishing the role of charge recombination to a triplet state. We used time-resolved photoluminescence and picosecond photoinduced absorption (PIA) to investigate excited singlet (S 1) and CT states and complemented these experiments with singlet oxygen ( (1)Delta g) luminescence and PIA measurements on longer timescales to study the population of triplet excited states (T 1). In an apolar solvent like cyclohexene (CHX), photoinduced electron transfer does not occur, but in more polar solvents such as toluene (TOL) and chlorobenzene (CB), photoexcitation is followed by a fast electron transfer, populating the PDI (-*)-PMI (+*) CT state. We extract rate constants for electron transfer (ET; S 1-->CT), back electron transfer (BET; S 1<--CT), and charge recombination (CR) to lower-energy states (CT-->S 0 and CT-->T 1). Temperature-dependent measurements yield the barriers for the transfer reactions. For ET and BET, these correspond to predictions from Marcus-Jortner theory and show that efficient, near quantitative electron transfer ( k ET/ k BET >or= 100) can be obtained when Delta G ET approximately -120 meV. With respect to triplet state formation, we find a relatively low triplet quantum yield (Phi T < 25%) in CHX but much higher values (Phi T = 30-98%) in TOL and CB. We identify the PDI (-*)-PMI (+*) state as a precursor to the T 1 state. Recombination to T 1, rather than to the ground-state S 0, is required to rationalize the experimental barrier for CR. Finally, we discuss the relevance of these results for electron donor-acceptor films in photovoltaic devices.


Prognostic factors in left-sided endocarditis: results from the Andalusian multicenter cohort.
Despite medical advances, mortality in infective endocarditis (IE) is still very high. Previous studies on prognosis in IE have observed conflicting results. The aim of this study was to identify predictors of in-hospital mortality in a large multicenter cohort of left-sided IE. An observational multicenter study was conducted from January 1984 to December 2006 in seven hospitals in Andalusia, Spain. Seven hundred and five left-side IE patients were included. The main outcome measure was in-hospital mortality. Several prognostic factors were analysed by univariate tests and then by multilogistic regression model. The overall mortality was 29.5% (25.5% from 1984 to 1995 and 31.9% from 1996 to 2006; Odds Ratio 1.25; 95% Confidence Interval: 0.97-1.60; p = 0.07). In univariate analysis, age, comorbidity, especially chronic liver disease, prosthetic valve, virulent microorganism such as Staphylococcus aureus, Streptococcus agalactiae and fungi, and complications (septic shock, severe heart failure, renal insufficiency, neurologic manifestations and perivalvular extension) were related with higher mortality. Independent factors for mortality in multivariate analysis were: Charlson comorbidity score (OR: 1.2; 95% CI: 1.1-1.3), prosthetic endocarditis (OR: 1.9; CI: 1.2-3.1), Staphylococcus aureus aetiology (OR: 2.1; CI: 1.3-3.5), severe heart failure (OR: 5.4; CI: 3.3-8.8), neurologic manifestations (OR: 1.9; CI: 1.2-2.9), septic shock (OR: 4.2; CI: 2.3-7.7), perivalvular extension (OR: 2.4; CI: 1.3-4.5) and acute renal failure (OR: 1.69; CI: 1.0-2.6). Conversely, Streptococcus viridans group etiology (OR: 0.4; CI: 0.2-0.7) and surgical treatment (OR: 0.5; CI: 0.3-0.8) were protective factors. Several characteristics of left-sided endocarditis enable selection of a patient group at higher risk of mortality. This group may benefit from more specialised attention in referral centers and should help to identify those patients who might benefit from more aggressive diagnostic and/or therapeutic procedures.


Evaluation of some biomonitoring markers in occupationally exposed populations to acrylonitrile.
In the present work we studied acrylonitrile (AN) occupationally exposed populations and respective control individuals working in a Portuguese plant producing acrylic textile fibers. Three subgroups of individuals were considered: controls (C), workers of the continuous polymerization (CP) area, and workers of equipment maintenance (MM). Besides aiming to contribute to a better understanding of the hazardous exposure of man to AN, the study aimed to help validate and optimize the use of a combination of methods applied to human populations exposed to genotoxic compounds. Three main compartments related to the dose or effect of the hazardous compound were evaluated using various assessment methods: 1) internal dose (genotoxicity in urine, indicators of oxidative stress, induction of cytochromes P450); 2) biological effective dose (hemoglobin adducts); and 3) early biological effects (chromosomal aberrations, sister chromatid exchanges). Although concern with exposure to AN has long been the subject of numerous studies, they have been carried out essentially in animals and using in vitro systems. The significant differences (P < 0.01) found in the chromosomal aberrations of MM are in agreement with the highly significant levels of hemoglobin adducts described in another study performed in the same population. Hemoglobin adducts were also sensitive in detecting a hazardous exposure in the case of CP. The results obtained for the lipid peroxidation indicator used seem to confirm the AN capability of inducing lipid peroxidation in vivo. From the results available it seems that chromosomal aberrations as well as hemoglobin adducts are accurate and sensitive biomonitoring markers for AN exposure.


A Rare Case of Hermansky-Pudlak Syndrome Type 3.
Hermansky-Pudlak syndrome (HPS) is a multi-system disorder characterized by oculocutaneous albinism and platelet storage deficiency, which can also lead to prolonged bleeding, pulmonary fibrosis, and granulomatous colitis. Lysosome-related organelle dysfunction is responsible for many of the systemic manifestations, including dense body and melanosome deficiency. This report aims to review a case of HPS type 3 in a male Puerto Rican patient who presented to our clinic.


Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study.
We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to some extent explain why this polymorphism is associated with low BMD or fracture in some study populations and not in others. It would also indicate that fractures associated with the TT genotype could be preventable by vitamin B supplementation. We have, therefore, reviewed baseline food record data from our original study to determine if BMD and fracture associations with the MTHFR genotype depended on the intake of folate, riboflavin, or other members of the vitamin B complex, associated with homocysteine metabolism. We analyzed genotype, BMD, and dietary records from 1700 healthy postmenopausal women who participated in the DOPS study. For the assessment of fracture risk, we used longitudinal observations from 854 women in the control group who remained compliant with their initial allocation of no treatment. Riboflavin intake was significantly correlated with femoral neck (FN) BMD in women with the TT genotype (r = 0.24, P < 0.01). FN and lumbar spine (LS) BMD were only associated with the MTHFR genotype in the lowest quartile of riboflavin intake. At the FN, similar threshold effects were shown for folate, vitamin B12, and vitamin B6. Among these vitamin B complex members, stepwise regression analysis identified riboflavin as the only significant predictor of FN BMD in the TT genotype. In conclusion, we confirm reports that BMD in the MTHFR TT genotype is only significantly reduced in the lowest quartile of riboflavin, B12, B6, and folate intake, at least at the time of menopause. Vitamin B supplementation would only be expected to benefit BMD in about 2% of the population, i.e., those with the TT genotype and low vitamin B intake.


Novel metrics of sleep-disordered breathing are associated with outcome after ischemic stroke.
Standard measures of sleep-disordered breathing (SDB) that rely on count data may not sufficiently capture SDB severity or reflect downstream consequences of SDB. We hypothesized that novel metrics derived from pulse rate, oxygen saturation, and nasal pressure would be associated with stroke outcomes. Shortly after ischemic stroke, participants in a population-based study were offered ApneaLink Plus testing. Signal analysis was used to generate 166 metrics from the nasal pressure cannula and finger probe, categorized as: autonomic (based on pulse rate variability), oximetry-derived, nasal pressure-derived, and mixed oxygen and nasal pressure-derived measures. Three-month outcome assessments included functional and cognitive outcomes and stroke recurrence. Tobit regression and Cox proportional hazards models were used to examine associations between each sleep apnea metric and the three outcomes, unadjusted and adjusted for multiple potential confounders. Models were adjusted for multiple comparisons. Of the 530 participants, the median age was 65 (IQR: 57, 73), 49 % were female, and 64 % were Mexican American. Without covariate adjustment, 23 of 166 variables were associated with functional outcome, 43 were associated with cognitive outcome, and 1 was associated with stroke recurrence. After adjustment, 7 mixed, oximetry, or nasal pressure-based metrics and 1 autonomic metric were associated with functional outcome, but none was associated with cognitive outcome or stroke recurrence. Many novel metrics of SDB were associated with important stroke outcomes, and 8 novel metrics were associated with functional outcome in adjusted models. This raises hypotheses about pathways by which SDB may negatively impact stroke outcomes.


Event based analysis of chlorothalonil concentrations following application to managed turf.
Chlorothalonil concentrations exceeding acute toxicity levels for certain organisms have been measured in surface water discharge events from managed turf watersheds. The duration of exceedence and the timing of these events related to precipitation/runoff and time since application, however, have not been explored. Chlorothalonil concentrations were measured from discharge waters draining a managed turf watershed in Duluth, Minnesota, USA, between 2003 and 2009. The median chlorothalonil concentration was 0.58 µg/L. Approximately 2% of all measured concentrations exceeded the 7.6 µg/L median lethal concentration (LC50) acute toxicity level for rainbow trout. One-twentieth the LC50 concentration, equivalent to the level of concern (0.38 µg/L) for endangered species, was exceeded 31% of the time during the present study. The concentrations that exceeded the LC50 threshold were associated with eight rainfall/runoff events. Low dose exposures are a more important biological concern than acute occurrences. Exceedence concentrations associated with acute effects were significantly (p < 0.05) correlated to time since application and were measured only in the fall following extensive application. A conflict exists between the transportability of chlorothalonil as suggested by its chemical properties and the data collected in the present study. With respect to course-wide golf course application, avoiding application until after the major autumn rainfall period but before the first snow coverage is recommended to reduce occurrence of chlorothalonil concentrations that exceed toxic levels associated with acute and chronic levels of concern.


Tunable High-Molecular-Weight Silk Fibroin Polypeptide Materials: Fabrication and Self-Assembly Mechanism.
Silk fibroin is a multisegment natural protein composed of a heavy (H) chain, a light (L) chain and a P25 glycoprotein chain. Herein, we developed a dialysis separation technique under reducing conditions to break the disulfide bond between the H-chain and L-chain and remove the low-molecular-weight portions of the protein. Thus, a high-molecular-weight silk fibroin polypeptide (HSF) material was obtained. SDS-PAGE electrophoresis showed that the molecular weight of HSF was over 80 kDa, similar to the size of the silk fibroin H-chain. Amino acid analysis result demonstrated that the amino acid composition of HSF was almost identical to that of H-chain composition. Importantly, the HSF material obtained has a high surface activity, which can reduce the surface tension of water to below 20 mN/m; at high temperature and high concentration, it can also form a unique nanofibrous network with a lamellar crystalline structure. HSF can further form a rod-shaped structure in a strong polar environment and become a star-shaped fibrous network in a weak polar environment. When the pH value of HSF solution was adjusted from 6 to 8, a structural transition from a folded crank sheet-like structure with micellar beads to a ring-like fibrous structure was observed. During the conversion of HSF from colloidal particles to nanofibers, its molecular conformation also transformed from random coils to β-sheets. These tunable properties indicate that HSF materials have a wide range of applications in biomedical and green chemistry fields.


Optimization of circulating biomarkers of obatoclax-induced cell death in patients with small cell lung cancer.
Small cell lung cancer (SCLC) is an aggressive disease in which, after initial sensitivity to platinum/etoposide chemotherapy, patients frequently relapse with drug-resistant disease. Deregulation of the Bcl-2 pathway is implicated in the pathogenesis of SCLC, and early phase studies of Bcl-2 inhibitors have been initiated in SCLC. Obatoclax is a small-molecule drug designed to target the antiapoptotic Bcl-2 family members to a proapoptotic effect. Preclinical studies were conducted to clarify the kinetics of obatoclax-induced apoptosis in a panel of SCLC cell lines to assist with the interpretation of biomarker data generated during early phase clinical trials. In vitro, obatoclax was synergistic with cisplatin and etoposide, and "priming" cells with obatoclax before the cytotoxics maximized tumor cell death. Peak levels of apoptosis, reflected by cleaved cytokeratin 18 (CK18) levels (M30 ELISA) and caspase activity (SR-DEVD-FMK), occurred 24 hours after obatoclax treatment. A phase 1b-2 trial of obatoclax administered using two infusion regimens in combination with carboplatin and etoposide has been completed in previously untreated patients with extensive-stage SCLC. Circulating pharmacodynamic biomarkers of cell death, full-length and/or cleaved CK18, and oligonucleosomal DNA were studied in the phase 1b trial. All SCLC patients classified as "responders" after two cycles of treatment showed significantly increased levels of full-length and cleaved CK18 (M65 ELISA) on day 3 of study. However, the preclinical data and the absence of a peak in circulating caspase-cleaved CK18 in trial patients suggest suboptimal timing of blood sampling, which will need refinement in future trials incorporating obatoclax.


[Appendectomy by minimally invasive surgery].
To analyze the results obtained with the laparoscopic appendectomy in a trial of 106 cases from 1997 to December of 2002 in a surgeons group. Comparing the results with the papers of the literature to qualified the safety and security of the method and to establish the advantages upon the open appendectomy. The laparoscopic appendectomy is a technique that in the past ten years has proof its safety and efficacy to resolve the problems of vermiform appendix. Prospective trial of 106 patients with probability or diagnosis of acute appendicitis approach to laparoscopic appendectomy. With statistical analysis of the data. 106 patients, 42 male and 62 female, average age 30.8, diagnosis of acute appendicitis before surgery of 70%, and with abdominal pain in 30%. Of the data obtained only the total count of leucocytes have the statistical value in the diagnosis of acute appendicitis. The average of surgical time was of 70.7 minutes, the average of length of hospital stay was of 74 hours. Diagnosis of acute appendicitis in 83% of the cases, normal appendix 10.3%, another pathology 6.7%. Conversion rate of 5.5% (6 patients). Abscess 3, peritonitis 1, hemorrhage 1, appendix rupture 1. Morbidity of 3.7% wound infection. Mortality 0%. The surgical indications for the laparoscopic appendectomy are the same that for open surgery. The technique is safe and effective that can be carried out in any patient, still in cases or perforated appendicitis or gangrenous. The success is depend of the experience of the surgical team. The wound infection, recovery time, postoperative pain are less in the laparoscopic appendectomy.


Public health implications of altered puberty timing.
Changes in puberty timing have implications for the treatment of individual children, for the risk of later adult disease, and for chemical testing and risk assessment for the population. Children with early puberty are at a risk for accelerated skeletal maturation and short adult height, early sexual debut, potential sexual abuse, and psychosocial difficulties. Altered puberty timing is also of concern for the development of reproductive tract cancers later in life. For example, an early age of menarche is a risk factor for breast cancer. A low age at male puberty is associated with an increased risk for testicular cancer according to several, but not all, epidemiologic studies. Girls and, possibly, boys who exhibit premature adrenarche are at a higher risk for developing features of metabolic syndrome, including obesity, type 2 diabetes, and cardiovascular disease later in adulthood. Altered timing of puberty also has implications for behavioral disorders. For example, an early maturation is associated with a greater incidence of conduct and behavior disorders during adolescence. Finally, altered puberty timing is considered an adverse effect in reproductive toxicity risk assessment for chemicals. Recent US legislation has mandated improved chemical testing approaches for protecting children's health and screening for endocrine-disrupting agents, which has led to changes in the US Environmental Protection Agency's risk assessment and toxicity testing guidelines to include puberty-related assessments and to the validation of pubertal male and female rat assays for endocrine screening.


New horizons in multimodality molecular imaging and novel radiotracers.
Positron emission tomography (PET)/computerised tomography is now established in clinical practice for oncologic and non-oncological applications. Improvement and development of scanner hardware has allowed faster acquisitions and wider application. PET/magnetic resonance imaging offers potential improvements in diagnostic accuracy and patient acceptability but clinical applications are still being developed. A range of new radiotracers and non-radioactive contrast agents is likely to lead to a growth in hybrid molecular imaging applications that will allow better characterisation of disease processes.


Norbornene-constrained cyclic peptides with hairpin architecture: design, synthesis, conformation, and membrane ion transport.
A novel family of hairpin cyclic peptides has been designed on the basis of the use of norbornene units as the bridging ligands. The design is flexible with respect to the choice of an amino acid, the ring size, and the nature of the second bridging ligand as illustrated here with the preparation of a large number of norborneno cyclic peptides containing a variety of amino acids in ring sizes varying from 12- to 29-membered, with the choice of the second bridging ligand being a rigid norbornene (11, 13a,b), an adamantane unit (7a,b and 8), or a flexible cystine residue (4a,b and 10). The presence of built-in handles (as protected COOH groups) permits the attachment of a variety of subunits as shown here with the ligation of Leu-Leu, Val-Val, or Aib-Aib pendants in 4b, 7b, and 13b, respectively. This novel class of constrained cyclic peptides are demonstrated to adopt beta-sheet- or hairpin-like conformation as shown by (1)H NMR and CD spectra. Membrane ion-transport studies have shown that the norborneno cyclic peptides 4b and 7b containing Leu-Leu or Val-Val pendants symmetrically placed on the exterior of the ring show high efficiency and selectivity in the transport of specifically monovalent cations. This property can be attributed to the hairpin-like architecture induced by the norbornene unit since the bis-adamantano peptide 15 containing two pairs of Leu-Leu pendants on the exterior is able to transport both monovalent (Na(+), K(+)) and divalent (Mg(2+)/Ca(2+)) cations.


Assessment of residual setup errors for anatomical sub-structures in image-guided head-and-neck cancer radiotherapy.
To quantify residual setup errors (RSE) and required planning target volumes (PTV) margins in head-and-neck cancer (HNC) radiotherapy when using daily image guidance (IG) and less-than-daily IG protocols. Daily on-line kV-image registrations of 80 HNC patients (2640 imaged treatment fractions) were retrospectively studied to analyze RSE. Less-than-daily imaging protocols, using different action levels, were simulated on the data. To quantify local RSE; single rigid bony structures were defined as landmarks. The RSEs and required PTV margins were computed for each sub-structure with and without daily IG. For less-than-daily IG protocols the setup accuracy was more dependent on frequent imaging throughout the treatment course than the number of initially imaged fractions. With daily IG the RSE of the sub-structures ranged from 0.6 mm to 2.3 mm (systematic) and from 1.0 mm to 1.7 mm (random). Required PTV margins for the sub-regions ranged from 4.5 mm to 9.3 mm with no IG and from 2.3 mm to 6.8 mm with daily IG. Anatomical changes over the treatment course require frequent IG to achieve accurate dose delivery using highly conformal radiotherapy techniques. The current study shows that considerable local RSE may remain even with daily IGRT. The comprehension of local RSEs in HNC radiotherapy is important when designating PTV margins as well as tolerance levels for couch correction and plan adaption.


Routines and Meaning in Life.
Previous research links the experience of meaning in life (MIL) with environmental structure and the coherence of external stimuli. The current studies directly test the association between one source of structure in everyday life-routines-and MIL. First, Study 1 ( N = 317) found a positive relationship between trait preference for routine and MIL. Study 2 expanded upon this cross-sectional finding with experience sampling data ( N = 85; 2,590 episodes) showing that the degree to which current, naturally occurring, behavior followed a typical routine positively related to participants' momentary feelings of MIL. These findings have implications for conceptualizations of MIL, suggesting a previously unnoted, mundane, and ubiquitous source of MIL. The potential roles of boredom and novelty and individual and situational differences for these effects are discussed.


Physiologic basis for understanding quantitative dehydration assessment.
Dehydration (body water deficit) is a physiologic state that can have profound implications for human health and performance. Unfortunately, dehydration can be difficult to assess, and there is no single, universal gold standard for decision making. In this article, we review the physiologic basis for understanding quantitative dehydration assessment. We highlight how phenomenologic interpretations of dehydration depend critically on the type (dehydration compared with volume depletion) and magnitude (moderate compared with severe) of dehydration, which in turn influence the osmotic (plasma osmolality) and blood volume-dependent compensatory thresholds for antidiuretic and thirst responses. In particular, we review new findings regarding the biological variation in osmotic responses to dehydration and discuss how this variation can help provide a quantitative and clinically relevant link between the physiology and phenomenology of dehydration. Practical measures with empirical thresholds are provided as a starting point for improving the practice of dehydration assessment.


On topical application of fluorides and its inhibiting effect on caries.
The observations of interest made in this investigation may be summarized as follows: 1. Conventional fluoride application by mouthrinsing with neutral NaF solution (0.025% daily for three weeks or three months; or 0.05% solution daily; or 0.2% solution weekly for three weeks) is found to result in only moderate and insignificant uptake of F in facial enamel surfaces. The gain is in the order of a hundred ppm within 10 to 15 microns' depth (as determined by an acid etching technique) and a few hundred ppm at 0.02 to 0.05 microns (according to pilot ion probe analysis). 2. Painting, at one week's interval for three weeks with 2% NaF (pH=5) solution and application of an APF-gel (Flura-Kerr 1.23% F) results in the significant uptake of a few hundred ppm F within the first 10 microns of the enamel. Painting with 2% NaF (pH=7), with 8% SnF2, or with 5% Na2PO3F solutions does not yield a significant gain in F in the first 10 microns of the facial enamel, as determined by the etching technique under similar conditions. 3. A varnish (Duraphat) containing 5% NaF (applied three times at weekly intervals) is found to deposit considerable amounts of fluorine in outer facial enamel. Within the first 10 microns gains of more than 1000 ppm F are detected by the etching technique. Uptakes of the order about 500 ppm F are seen even at depths beyond 10 microns; penetration of F is detected down to about 100 microns' depth. Ion probe experiments show a F gain of more than 2000 ppm at a depth of about 0.3 microns. 4. In teeth extracted one day after a single application of NaF varnish, the retained fluorine is higher than in teeth retained in oral environment for one or five weeks after application. This suggests that loss of F occurs particularly during the first days after treatment. 5. The varnish, when applied every six months in permanent dentition of 15 year old children, is cariostatic on all tooth surfaces. 6. The secondary ion microanalyzer ("ion probe") is a useful instrument for the study of fluorine concentrations in dental hard tissue, and provides a special approach to the outermost regions of enamel. 7. The ion probe renders quantitative F determinations in dental hard tissue; a calibration method is available when the positive secondary ion ratios CaF+/Ca+ or F+/Ca++ are recorded versus Ca++/Ca+.


[Importance and outlook of research in the field of human molecular genetics].
We present a brief survey of the main results obtained in the studies of human molecular genetics. Principal attention is paid to the studies of normal genes and human genetic elements, to molecular genetics of inherited diseases, the use of DNA polymorphic regions for the analysis of genetic defects and to the development of genetic therapy methods. The survey presents both the main results obtained and most interesting data collected in this field by Soviet researchers.


Problematic internet use among high school students: Prevalence, associated factors and gender differences.
This study aimed to measure the prevalence of Problematic Internet Use (PIU) among high school students and to identify factors associated with PIU underlining gender differences. The students filled a self-administered, anonymous questionnaire collecting information on demographic characteristics and patterns of Internet use. Multiple logistic regression analysis was performed to identify factors associated with PIU in the overall sample and by gender. Twenty-five schools and 2022 students participated in the survey. Prevalence of PIU was 14.2% among males and 10.1% among females. Males 15-year-olds and females 14-year-olds had the highest PIU prevalence that progressively lowered with age among females. Only 13.5% of pupils declared parents controlled their Internet use. The sensation of feeling lonely, the frequency of use, the number of hours of connection, and visiting pornographic websites were associated with the risk of PIU in both genders. Attending vocational schools, the activities of chatting and file downloading, and the location of use at Internet point among males, and younger age among females were associated with PIU, whilst information searching was protective among females. PIU could become a public health problem in the next years. The physical and mental health consequences should be studied.


The unfolded protein response in familial amyotrophic lateral sclerosis.
Mutant superoxide dismutase type 1 (MTSOD1) is thought to cause ∼20% of cases of familial amyotrophic lateral sclerosis (FALS) because it misfolds and aggregates. Previous studies have shown that MTSOD1 accumulates inside the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR), suggesting that ER stress is involved in the pathogenesis of FALS. We used a genetic approach to investigate the role of the UPR in FALS. We crossed G85RSOD1 transgenic mice with pancreatic ER kinase haploinsufficient (PERK(+/-)) mice to obtain G85R/PERK(+/-) mice. PERK(+/-) mice carry a loss of function mutation of PERK, which is the most rapidly activated UPR pathway, but have no abnormal phenotype. Compared with G85R transgenic mice, G85R/PERK(+/-) mice had a dramatically accelerated disease onset as well as shortened disease duration and lifespan. There was also acceleration of the pathology and earlier MTSOD1 aggregation. A diminished PERK response accelerated disease and pathology in G85R transgenic mice presumably because the mice had a reduced capacity to turn down synthesis of misfolded SOD1, leading to an early overloading of the UPR. The results indicate that the UPR has a significant influence on FALS, and suggest that enhancing the UPR may be effective in treating ALS.