Altered transition metal homeostasis in the cuprizone model of demyelination.
In the cuprizone model of demyelination, the neurotoxin cuprizone is fed to mice to induce a reproducible pattern of demyelination in the brain. Cuprizone is a copper chelator and it has been hypothesized that it induces a copper deficiency in the brain, which leads to demyelination. To test this hypothesis and investigate the possible role of other transition metals in the model, we fed C57Bl/6 mice a standard dose of cuprizone (0.2% dry chemical to dry food weight) for 6 weeks then measured levels of copper, manganese, iron, and zinc in regions of the brain and visceral organs. As expected, this treatment induced demyelination in the mice. We found, however, that while the treatment significantly reduced copper concentrations in the blood and liver in treated animals, there was no significant difference in concentrations in brain regions relative to control. Interestingly, cuprizone disrupted concentrations of the other transition metals in the visceral organs, with the most notable changes being decreased manganese and increased iron in the liver. In the brain, manganese concentrations were also significantly reduced in the cerebellum and striatum. These data suggest a possible role of manganese deficiency in the brain in the cuprizone model.


Amino acid patterns within short consensus repeats define conserved duplicons shared by genes of the RCA complex.
Complement control proteins (CCPs) contain repeated protein domains, short consensus repeats (SCRs), which must be relevant to diverse functions such as complement activation, coagulation, viral binding, fetal implantation, and self-nonself recognition. Although SCRs share some discontinuous and imperfect motifs, there are many variable positions and indels making classification in subfamilies extremely difficult. Using domain-by-domain phylogenetic analysis, we have found that most domains can be classified into only 11 subfamilies, designated a, b, c, d, e, f, g, h, i, j, or k and identified by critical residues. Each particular CCP is characterized by the order of representatives of the subfamilies. Human complement receptor 1 (CR1) has ajefbkd repeated four times and followed by ch. The classification crosses CCPs and indicates that a particular CCP is a function of the mix of SCRs. The aje set is a feature of several CCPs including human CR1 and DAF and murine Crry and appears to be associated with the success or failure of implantation inter alia. This approach facilitates genomic analysis of available sequences and suggests a framework for the evolution of CCPs. Units of duplication range from single SCRs, to septamers such as efbkdaj, to extensive segments such as MCP-CR1L. Imperfections of duplication with subsequent deletion have contributed to diversification.


Estimation of maximal oxygen uptake via submaximal exercise testing in sports, clinical, and home settings.
Assessment of the functional capacity of the cardiovascular system is essential in sports medicine. For athletes, the maximal oxygen uptake [Formula: see text] provides valuable information about their aerobic power. In the clinical setting, the (VO(2max)) provides important diagnostic and prognostic information in several clinical populations, such as patients with coronary artery disease or heart failure. Likewise, VO(2max) assessment can be very important to evaluate fitness in asymptomatic adults. Although direct determination of [VO(2max) is the most accurate method, it requires a maximal level of exertion, which brings a higher risk of adverse events in individuals with an intermediate to high risk of cardiovascular problems. Estimation of VO(2max) during submaximal exercise testing can offer a precious alternative. Over the past decades, many protocols have been developed for this purpose. The present review gives an overview of these submaximal protocols and aims to facilitate appropriate test selection in sports, clinical, and home settings. Several factors must be considered when selecting a protocol: (i) The population being tested and its specific needs in terms of safety, supervision, and accuracy and repeatability of the VO(2max) estimation. (ii) The parameters upon which the prediction is based (e.g. heart rate, power output, rating of perceived exertion [RPE]), as well as the need for additional clinically relevant parameters (e.g. blood pressure, ECG). (iii) The appropriate test modality that should meet the above-mentioned requirements should also be in line with the functional mobility of the target population, and depends on the available equipment. In the sports setting, high repeatability is crucial to track training-induced seasonal changes. In the clinical setting, special attention must be paid to the test modality, because multiple physiological parameters often need to be measured during test execution. When estimating VO(2max), one has to be aware of the effects of medication on heart rate-based submaximal protocols. In the home setting, the submaximal protocols need to be accessible to users with a broad range of characteristics in terms of age, equipment, time available, and an absence of supervision. In this setting, the smart use of sensors such as accelerometers and heart rate monitors will result in protocol-free VO(2max) assessments. In conclusion, the need for a low-risk, low-cost, low-supervision, and objective evaluation of VO(2max) has brought about the development and the validation of a large number of submaximal exercise tests. It is of paramount importance to use these tests in the right context (sports, clinical, home), to consider the population in which they were developed, and to be aware of their limitations.


Mechanisms of vasopressin-induced increase in intracellular Na+ in vascular smooth muscle cells.
The present study was undertaken to examine the interrelationship between the arginine vasopressin (AVP)-induced dynamic changes in intracellular Ca2+ and Na+ concentrations in cultured rat aortic vascular smooth muscle cells (VSMC) by the direct measurements of intracellular Na+ concentration [( Na+]i), cytosolic free calcium [( Ca2+]i), and intracellular pH (pHi) using fluorescence dyes. AVP increased [Ca2+]i and [Na+]i in a dose-dependent manner; the rise in [Ca2+]i preceded the rise in [Na+]i. Pretreatment with the V1 antagonist [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid) 2-(O-methyl)-tyrosine] AVP [( d(CH2)5Tyr(Me)]AVP) completely blocked the effects of AVP on [Ca2+]i and [Na+]i. The V2 agonist 1-desamino-8-D-AVP, DDAVP, did not affect basal [Na+]i or the AVP-induced increase in [Na+]i. Also, Ca(2+)-free solution completely blocked the AVP-induced increase in [Na+]i. Moreover, Ca(2+)-free solution decreased the AVP-induced intracellular acidification and blunted the later AVP-induced intracellular alkalinization. These results therefore indicate that after binding to the V1 receptor AVP increases [Na+]i mediated by the activation of Na(+)-Ca2+ and Na(+)-H+ exchanges in VSMC. All of these cellular events are completely dependent on an increase in cellular Ca2+ uptake produced by AVP.


Histone acetylation dynamics modulates chromatin conformation and allele-specific interactions at oncogenic loci.
In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or increased deposition of acetylated histone H3 lysine 27 (H3K27ac) can support oncogene expression. However, how the chromatin conformation of enhancer-promoter interactions is affected by these events is unclear. In the present study, by comparing chromatin structure and H3K27ac levels in normal and lymphoma B cells, we show that enhancer-promoter-interacting regions assume different conformations according to the local abundance of H3K27ac. Genetic or pharmacological depletion of H3K27ac decreases the frequency and the spreading of these interactions, altering oncogene expression. Moreover, enhancer hijacking mediated by chromosomal translocations influences the epigenetic status of the regions flanking the breakpoint, prompting the formation of distinct intrachromosomal interactions in the two homologous chromosomes. These interactions are accompanied by allele-specific gene expression changes. Overall, our work indicates that H3K27ac dynamics modulates interaction frequency between regulatory regions and can lead to allele-specific chromatin configurations to sustain oncogene expression.


Histocompatibility and in vivo signal throughput for PEDOT, PEDOP, P3MT, and polycarbazole electrodes.
Stimulation and recording of the in vivo electrical activity of neurons are critical functions in contemporary biomedical research and in treatment of patients with neurological disorders. The electrodes presently in use tend to exhibit short effective lifespans due to degradation of signal transmission resulting from the tissue response at the electrode-brain interface, with signal throughput suffering most at the low frequencies relevant for biosignals. To overcome these limitations, new electrode designs to minimize tissue responses, including conducting polymers (CPs) have been explored. Here, we report the short-term histocompatibility and signal throughput results comparing platinum and CP-modified platinum electrodes in a Sprague-Dawley rat model. Two of the polymers tested elicited significantly decreased astrocyte responses relative to platinum. These polymers also showed improved signal throughput at low frequencies and comparable signal-to-noise ratios during targeted intracranial electroencephalograms. These results suggest that CP electrodes may present viable alternatives to the metal electrodes that are currently in use.


Muscle pump and central command during recovery from exercise in humans.
We sought to determine the relative contributions of cessation of skeletal muscle pumping and withdrawal of central command to the rapid decrease in arterial pressure during recovery from exercise. Twelve healthy volunteers underwent three exercise sessions, each consisting of a warm-up, 3 min of cycling at 60% of maximal heart rate, and 5 min of one of the following recovery modes: seated (inactive), loadless pedaling (active), and passive cycling. Mean arterial pressure (MAP), cardiac output, thoracic impedance, and heart rate were measured. When measured 15 s after exercise, MAP decreased less (P < 0.05) during the active (-3 +/- 1 mmHg) and passive (-6 +/- 1 mmHg) recovery modes than during inactive (-18 +/- 2 mmHg) recovery. These differences in MAP persisted for the first 4 min of recovery from exercise. Significant maintenance of central blood volume (thoracic impedance), stroke volume, and cardiac output paralleled the maintenance of MAP during active and passive conditions during 5 min of recovery. These data indicate that engaging the skeletal muscle pump by loadless or passive pedaling helps maintain MAP during recovery from submaximal exercise. The lack of differences between loadless and passive pedaling suggests that cessation of central command is not as important.


European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG).
Germ cell tumour is the most frequent malignant tumour type in young men with a 100% rise in the incidence every 20 years. Despite this, the high sensitivity of germ cell tumours to platinum-based chemotherapy, together with radiation and surgical measures, leads to the high cure rate of > or = 99% in early stages and 90%, 75-80% and 50% in advanced disease with 'good', 'intermediate' and 'poor' prognostic criteria (IGCCCG classification), respectively. The high cure rate in patients with limited metastatic disease allows the reduction of overall treatment load, and therefore less acute and long-term toxicity, e.g. organ sparing surgery for specific cases, reduced dose and treatment volume of irradiation or substitution of node dissection by surveillance or adjuvant chemotherapy according to the presence or absence of vascular invasion. Thus, different treatment options according to prognostic factors including histology, stage and patient factors and possibilities of the treating centre as well may be used to define the treatment strategy which is definitively chosen for an individual patient. However, this strategy of reduction of treatment load as well as the treatment itself require very high expertise of the treating physician with careful management and follow-up and thorough cooperation by the patient as well to maintain the high rate for cure. Treatment decisions must be based on the available evidence which has been the basis for this consensus guideline delivering a clear proposal for diagnostic and treatment measures in each stage of gonadal and extragonadal germ cell tumour and individual clinical situations. Since this guideline is based on the highest evidence level available today, a deviation from these proposals should be a rare and justified exception.


The Relationship Between Suicide-Related Exposure and Personal History of Suicidal Behavior in Transgender and Gender-Diverse Veterans.
Purpose: Transgender and gender-diverse (TGD) veterans experience a high prevalence of suicidal thoughts and behaviors (STBs). Within the general U.S. population, suicide-related exposure is an identified risk factor for STBs. This study explores the impact of suicide-related exposure in TGD veterans. Methods: Self-identified TGD veterans (n = 195) completed an online cross-sectional survey that included self-report measures of suicide-related exposures, experience of past-year suicidal ideation (SI), and history of suicide attempt (SA)(s). Results: A considerable number of respondents indicated that they were close to someone who attempted suicide (40.5%) or died by suicide (32.8%). When asked about the gender identity of decedents, 6.7% indicated that at least one individual was TGD and 18.5% indicated knowing at least one close TGD individual who attempted suicide. Exposure to SA and to suicide were both independently related to a history of at least one SA. Neither type of suicide exposure was related to past year SI. Participants exposed to the SA of a close TGD individual were more likely to report past-year SI than those not exposed. Conclusion: TGD veterans may be more vulnerable to suicidal behaviors if suicide-related exposures are experienced. Public health suicide prevention initiatives, both inside and outside of the TGD community, may help to reduce suicide in these veterans.


[Sensory binocular relationships in divergent strabismus and convergent strabismus].
The adaptive processes mentioned here (which include inhibitory phenomena and modifications in spatial localization) were observed, using a stereoprojector which polarized light. Comparing the adaptive processes in convergent and divergent strabismus has led to the following observations: (1) there are differences between the two types of strabismus; these differences appear not only at the level of the binocular sensory parameter but also at the level of motor and accommodative parameters; adaptive processes are less deep and less serious in divergent and strabismus; these differences are also manifest in therapy: divergent strabismus is curable whatever the age, treatment is much shorter. These observations were the starting point for using prismatic overcorrection to induce a state of 'sensory divergence' as treatment in cases of convergent strabismus with anomalous retinal correspondence. The excellent results obtained using this method of treatment are not only due to the action on sensory binocular relations, but also to the fact that prismatic overcorrection also modifies abnormal motor patterns. Treating strabismus must involve the entire disturbed optico-sensorimotor complex.


Acceptability and feasibility of smartphone-assisted 24 h recalls in the Chinese population.
To examine the acceptability and feasibility of using smartphone technology to assess beverage intake and evaluate whether the feasibility of smartphone use is greater among key sub-populations. An acceptability and feasibility study of recording the video dietary record, the acceptability of the ecological momentary assessment (EMA), wearing smartphones and whether the videos helped participants recall intake after a cross-over validation study. Rural and urban area in Shanghai, China. Healthy adults (n 110) aged 20-40 years old. Most participants reported that the phone was acceptable in most aspects, including that videos were easy to use (70%), helped with recalls (77%), EMA reminders helped them record intake (75%) and apps were easy to understand (85%). However, 49% of the participants reported that they had trouble remembering to take videos of the beverages before consumption or 46% felt embarrassed taking videos in front of others. Moreover, 72% reported that the EMA reminders affected their consumption. When assessing overall acceptability of using smartphones, 72% of the participants were favourable responders. There were no statistically significant differences in overall acceptability for overweight v. normal-weight participants or for rural v. urban residents. However, we did find that the overall acceptability was higher for males (81%) than females (61%, P=0·017). Our study did not find smartphone technology helped with dietary assessments in a Chinese population. However, simpler approaches, such as using photographs instead of videos, may be more feasible for enhancing 24 h dietary recalls.


[Mercury gauge plethysmography. Sensitivity and specificity compared with standard phlebography (author's transl)].
Mercury strain gauge plethysmography with programme and ECG synchronous venous occlusion was tested in 14 normal subjects (28 lower limbs). The results obtained in the case of recent deep venous thrombosis of the lower limbs were compared with those of phlebography ni 39 patients: 26 proximal thromboses and 15 calf thromboses. Interpretation of the results must take into account the strict conditions under which the plethysmography was carried out: position of the subject and especially of the lower limbs and the technical characteristics of the apparatus used. Specificity was 96.4% for the group of normal subjects. Sensitivity calculated for all the cases of venous thrombosis studied was 97.5% whilst it was 100% for proximal thromboses (femoral and iliac).


AC-DC Electropenetrography as a Tool to Quantify Probing and Injection Behaviors of Mosquitos (Aedes aegypti) in Mice under Briocontainment Housing.
A detailed understanding of mosquito probing and ingestion behaviors is crucial in developing novel interventions to interrupt the transmission of important human and veterinary pathogens, but these behaviors are difficult to observe as the mouthparts are inserted into the skin of the host. Electropenetrography (EPG) allows indirect observation, recording, and quantification of probing and ingestion behaviors of arthropods by visualizing the electrical waveform associated with these behaviors. The study of mosquito probing and ingestion behaviors has been limited to the use of human hands as host, which is not suitable for pathogen transmission studies. Mouse models of mosquito-borne diseases are a widely used and indispensable tool in this research, but previous attempts to use direct current EPG to study mosquito probing behaviors on mice have been unsuccessful. Accordingly, the present study used alternating or direct current (AC-DC) EPG to observe the ingestion behaviors of adult Aedes aegypti mosquitoes on a mouse host in real time under BSL-2 containment conditions with enhanced BSL-3 practices. Our results show that waveform families previously identified during Ae. aegypti probing and ingestion on human hands were observed using 100 mV of AC at an input resistance (Ri) of 107 Ohms (Ω) on CD1 mice. This work is a proof of concept for using mouse models for studying mosquito probing and ingestion behaviors with AC-DC EPG. In addition, these data show that the experimental setup used in these experiments is sufficient for conducting studies on mosquito probing and ingestion behaviors under BSL-2 containment conditions enhanced with BSL-3 practices. This work will serve as a foundation for using EPG to investigate the effects of pathogen infection on mosquito probing behaviors and to understand the real-time dynamics of pathogen transmission.


The association between long working hours and health: a systematic review of epidemiological evidence.
Many studies have investigated the association between long working hours and health. By focusing on differences in the definition of long working hours and the influence of shift work, we attempt to explain why the results of these studies remain inconclusive. We defined long working hours as working time greater than around 40 hours per week or 8 hours per day. Since previous studies have indicated that shift work is detrimental to health, we minimized the influence of shift work in the studies. We also placed importance on the existence of reference groups since this made the results clearer. Based on these points, we analyzed previous studies to clarify the epidemiological evidence regarding the association between long working hours and health. We established inclusion criteria and carried out a systematic search for articles published in the Medline and PsycINFO databases between 1995-2012. We identified a total of 17 articles and 19 studies (12 prospective cohort and 7 cross-sectional studies). The outcomes were all-cause mortality, circulatory disease, diabetes mellitus, metabolic syndrome, depressive state, anxiety, other psychological disorders, sleep condition, cognitive function, and health-related behavior. Long working hours had significant adverse effects on most health outcomes. We concluded that working long hours is associated with depressive state, anxiety, sleep condition, and coronary heart disease. However, further studies that appropriately deal with the definition of long working hours and shift work are needed.


Dynein Is Required for Rab7-Dependent Endosome Maturation, Retrograde Dendritic Transport, and Degradation.
In all cell types, endocytosed cargo is transported along a set of endosomal compartments, which are linked maturationally from early endosomes (EEs) via late endosomes (LEs) to lysosomes. Lysosomes are critical for degradation of proteins that enter through endocytic as well as autophagic pathways. Rab7 is the master regulator of early-to-late endosome maturation, motility, and fusion with lysosomes. We previously showed that most degradative lysosomes are localized in the soma and in the first 25 µm of the dendrite and that bulk degradation of dendritic membrane proteins occurs in/near the soma. Dendritic late endosomes therefore move retrogradely in a Rab7-dependent manner for fusion with somatic lysosomes. We now used cultured E18 rat hippocampal neurons of both sexes to determine which microtubule motor is responsible for degradative flux of late endosomes. Based on multiple approaches (inhibiting dynein/dynactin itself or inhibiting dynein recruitment to endosomes by expressing the C-terminus of the Rab7 effector, RILP), we now demonstrate that net retrograde flux of late endosomes in dendrites is supported by dynein. Inhibition of dynein also delays maturation of somatic endosomes, as evidenced by excessive accumulation of Rab7. In addition, degradation of dendritic cargos is inhibited. Our results also suggest that GDP-GTP cycling of Rab7 appears necessary not only for endosomal maturation but also for fusion with lysosomes subsequent to arrival in the soma. In conclusion, Rab7-dependent dynein/dynactin recruitment to dendritic endosomes plays multifaceted roles in dendritic endosome maturation as well as retrograde transport of late endosomes to sustain normal degradative flux.SIGNIFICANCE STATEMENT Lysosomes are critical for degradation of membrane and extracellular proteins that enter through endocytosis. Lysosomes are also the endpoint of autophagy and thus responsible for protein and organelle homeostasis. Endosomal-lysosomal dysfunction is linked to neurodegeneration and aging. We identify roles in dendrites for two proteins with links to human diseases, Rab7 and dynein. Our previous work identified a process that requires directional retrograde transport in dendrites, namely, efficient degradation of short-lived membrane proteins. Based on multiple approaches, we demonstrate that Rab7-dependent recruitment of dynein motors supports net retrograde transport to lysosomes and is needed for endosome maturation. Our data also suggest that GDP-GTP cycling of Rab7 is required for fusion with lysosomes and degradation, subsequent to arrival in the soma.


Functional neuroanatomy of the parvocellular vasopressinergic system: transcriptional responses to stress and glucocorticoid feedback.
This chapter summarizes the regulation of vasopressin (VP) transcription within the parvocellular neurosecretory cells of the hypothalamic paraventricular nucleus in vivo, with special reference to stress-response and glucocorticoid feedback. VP is commonly held as the first and the most potent among the co-secretagogues that act synergistically with corticotropin-releasing factor (CRF-41) to induce adrenocorticotropin (ACTH) from the anterior pituitary in response to various internal and external stimuli. Cellular levels of the primary transcripts of VP and CRF genes, revealed by in situ hybridization histochemistry using probes complementary to intronic sequences, are increased after acute challenges with different time courses. In contrast to the rapid stress-induced upregulation of CRF gene expression, VP transcription shows a delayed increase suggesting different regulatory mechanisms governing the two main ACTH releasing neuropeptides in the parvocellular neurosecretory neurons. With respect of transcription factors that may mediate these effects, besides rapid phosphorylation of the cAMP-response element-binding protein (CREB), VP activation in the parvocellular neurons requires additional newly synthesized factors such as those encoded by immediate-early genes, like c-fos. In addition, it has recently been revealed that glucocorticoid negative feedback during stress, selectively targets vasopressin transcription in the parvocellular neurons that is likely mediated by interaction of glucocorticoid receptors and immediate-early gene products. These data speak for the emerging consensus that VP is the principal factor that imparts situation-specific drive and represents the regulated variable governing hypothalamo-pituitary-adrenocortical axis during stress.


Infinite variance in fermion quantum Monte Carlo calculations.
For important classes of many-fermion problems, quantum Monte Carlo (QMC) methods allow exact calculations of ground-state and finite-temperature properties without the sign problem. The list spans condensed matter, nuclear physics, and high-energy physics, including the half-filled repulsive Hubbard model, the spin-balanced atomic Fermi gas, and lattice quantum chromodynamics calculations at zero density with Wilson Fermions, and is growing rapidly as a number of problems have been discovered recently to be free of the sign problem. In these situations, QMC calculations are relied on to provide definitive answers. Their results are instrumental to our ability to understand and compute properties in fundamental models important to multiple subareas in quantum physics. It is shown, however, that the most commonly employed algorithms in such situations have an infinite variance problem. A diverging variance causes the estimated Monte Carlo statistical error bar to be incorrect, which can render the results of the calculation unreliable or meaningless. We discuss how to identify the infinite variance problem. An approach is then proposed to solve the problem. The solution does not require major modifications to standard algorithms, adding a "bridge link" to the imaginary-time path integral. The general idea is applicable to a variety of situations where the infinite variance problem may be present. Illustrative results are presented for the ground state of the Hubbard model at half-filling.


Social dominance has limited effects on spatial cognition in a wild food-caching bird.
Social dominance has long been used as a model to investigate social stress. However, many studies using such comparisons have been performed in captive environments. These environments may produce unnaturally high antagonistic interactions, exaggerating the stress of social subordination and any associated adverse consequences. One such adverse effect concerns impaired cognitive ability, often thought to be associated with social subordination. Here, we tested whether social dominance rank is associated with differences in spatial learning and memory, and in reversal spatial learning (flexibility) abilities in wild food-caching mountain chickadees at different montane elevations. Higher dominance rank was associated with higher spatial cognitive flexibility in harsh environments at higher elevations, but not at lower, milder elevations. By contrast, there were no consistent differences in spatial learning and memory ability associated with dominance rank. Our results suggest that spatial learning and memory ability in specialized food-caching species is a stable trait resilient to social influences. Spatial cognitive flexibility, on the other hand, appears to be more sensitive to environmental influences, including social dominance. These findings contradict those from laboratory studies and suggest that it is critical to investigate the biological consequences of social dominance under natural conditions.


Accelerated prion disease pathogenesis in Toll-like receptor 4 signaling-mutant mice.
Prion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrP(Sc), in the brain. Toll-like receptors (TLRs) are a family of proteins that recognize microbial constituents and are central players in host innate immune responses. The TLR9 agonist unmethylated CpG DNA was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. Thus, it was predicted that ablation of TLR signaling would result in accelerated pathogenesis. C3H/HeJ (Tlr4(Lps-d)) mice, which possess a mutation in the TLR4 intracellular domain preventing TLR4 signaling, and strain-matched wild-type control (C3H/HeOuJ) mice were infected intracerebrally or intraperitoneally with various doses of scrapie inoculum. Incubation periods were significantly shortened in C3H/HeJ compared with C3H/HeOuJ mice, regardless of the route of infection or dose administered. At the clinical phase of disease, brain PrP(Sc) levels in the two strains of mice showed no significant differences by Western blotting. In addition, compared with macrophages from C3H/HeOuJ mice, those from C3H/HeJ mice were unresponsive to fibrillogenic PrP peptides (PrP residues 106 to 126 [PrP(106-126)] and PrP(118-135)) and the TLR4 agonist lipopolysaccharide but not to the TLR2 agonist zymosan, as measured by cytokine production. These data confirm that innate immune activation via TLR signaling interferes with scrapie infection. Furthermore, the results also suggest that the scrapie pathogen, or a component(s) thereof, is capable of stimulating an innate immune response that is active in the central nervous system, since C3H/HeJ mice, which lack the response, exhibit shortened incubation periods following both intraperitoneal and intracerebral infections.


Full vectorial imaging of electromagnetic light at subwavelength scale.
We propose a concept of near-field imaging for the complete experimental description of the structure of light in three dimensions around nanodevices. It is based on a near-field microscope able to simultaneously map the distributions of two orthogonal electric-field components at the sample surface. From a single 2D acquisition of these two components, the complementary electric and magnetic field lines and Poynting vector distributions are reconstructed in a volume beneath the sample using rigorous numerical methods. The experimental analysis of localized electric and magnetic optical effects as well as energy flows at the subwavelength scale becomes possible. This work paves the way toward the development of a complete electromagnetic diagnostic of nano-optical devices and metamaterials.


Suppressors of a genetic regulatory mutation affecting isoleucine-valine biosynthesis in Escherichia coli K-12.
Escherichia coli K-12 mutant PS187 carries a mutation, ilvA538, in the structural gene for the biosynthetic L-threonine deaminase that leads to a leucine-sensitive growth phenotype, an isoleucine- and leucine-hypersensitive L-threonine deaminase, and pleiotropic effects resulting in abnormally low and invariant expression of some of the isoleucine-valine biosynthetic enzymes. Fifty-eight derivatives of strain PS187 were isolated as resistant to growth inhibition by leucine, by valine, or by valine plus glycly-valine and were biochemically, genetically, and physiologically characterized. All of these derivatives produced the feedback-hypersensitive L-threonine deaminase, and thus presumably possess the ilvA538 allele of the parent strain. Elevated synthesis of L-threonine deaminase was observed in 41 of the 58 isolates. Among 18 strains analyzed genetically, only those with mutations linked to the ilv gene clusters at 83 min produced elevated levels of L-threonine deaminase. One of the strains, MSR91, isolated as resistant to valine plus glycyl-valine, was chosen for more detailed study. The locus in strain MSR91 conferring resistance was located in four factor crosses between ilvE and rbs, and is in or near the ilvO gene postulated to be a site controlling the expression of the ilvEDA genes. Synthesis of the ilvEDA gene products in strain MSR91 is constitutive and derepressed approximately 200-fold relative to the parent strain, indicating that the genetic regulatory effects of the ilvA538 allele have been suppressed. Strain MSR91 should be suitable for use in purification of the ilvA538 gene product, since enzyme synthesis is fully derepressed and the suppressor mutation is clearly not located within the ilvA gene.


Quantitative force and dissipation measurements in liquids using piezo-excited atomic force microscopy: a unifying theory.
The use of a piezoelectric element (acoustic excitation) to vibrate the base of microcantilevers is a popular method for dynamic atomic force microscopy. In air or vacuum, the base motion is so small (relative to tip motion) that it can be neglected. However, in liquid environments the base motion can be large and cannot be neglected. Yet it cannot be directly observed in most AFMs. Therefore, in liquids, quantitative force and energy dissipation spectroscopy with acoustic AFM relies on theoretical formulae and models to estimate the magnitude of the base motion. However, such formulae can be inaccurate due to several effects. For example, a significant component of the piezo excitation does not mechanically excite the cantilever but rather transmits acoustic waves through the surrounding liquid, which in turn indirectly excites the cantilever. Moreover, resonances of the piezo, chip and holder can obscure the true cantilever dynamics even in well-designed liquid cells. Although some groups have tried to overcome these limitations (either by theory modification or better design of piezos and liquid cells), it is generally accepted that acoustic excitation is unsuitable for quantitative force and dissipation spectroscopy in liquids. In this paper the authors present a careful study of the base motion and excitation forces and propose a method by which quantitative analysis is in fact possible, thus opening this popular method for quantitative force and dissipation spectroscopy using dynamic AFM in liquids. This method is validated by experiments in water on mica using a scanning laser Doppler vibrometer, which can measure the actual base motion. Finally, the method is demonstrated by using small-amplitude dynamic AFM to extract the force gradients and dissipation on solvation shells of octamethylcyclotetrasiloxane (OMCTS) molecules on mica.


Daily production of human tumor necrosis factor in lipopolysaccharide (LPS)-stimulated ex vivo blood culture assays.
Tumor necrosis factor (TNF) is a pleiotropic cytokine with immunological and neuroendocrine activities. A useful tool for studying TNF is the measurement of its in vitro and/or ex vivo over-expression, induced by a variety of stimuli on isolated peripheral mononuclear cells or whole blood, respectively. The capacity to over-express TNF, in ex vivo LPS-stimulated whole blood from 18 normal individuals, showed inter-individual variations ranging from high (3 ng/ml) to low (0.7 ng/ml) producers. Although at a lower level, a similar situation was observed in the spontaneous production of the cytokine. In order to detect cyclic effects in these variations, blood samples were taken at 08:00, 12:00, 16:00 and 20:00 hours, from nine healthy volunteers, and cultured in the ex vivo system. TNF and cortisol were measured by immunometric assays. Both, LPS-stimulated whole blood and plasma showed important, individual variations in TNF levels. Although cortisol levels presented a normal circadian cycle, these individual patterns in TNF production were basically conserved during the day (p > 0.05), and no correlation was observed between the levels of the hormone and those of the cytokine. When total TNF levels were determined at 20:00 hours, a moderate, temporary variation pattern of the cytokine production was found. These results suggest that cortisol does not play a predominant role in determining the ex vivo capacity of blood to produce TNF. Presumably, the variable capacity to produce the cytokine may have a strong genetic component.


Corticobasal degeneration: a pathologically distinct 4R tauopathy.
Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.


Automatic quality control of brain T1-weighted magnetic resonance images for a clinical data warehouse.
Many studies on machine learning (ML) for computer-aided diagnosis have so far been mostly restricted to high-quality research data. Clinical data warehouses, gathering routine examinations from hospitals, offer great promises for training and validation of ML models in a realistic setting. However, the use of such clinical data warehouses requires quality control (QC) tools. Visual QC by experts is time-consuming and does not scale to large datasets. In this paper, we propose a convolutional neural network (CNN) for the automatic QC of 3D T1-weighted brain MRI for a large heterogeneous clinical data warehouse. To that purpose, we used the data warehouse of the hospitals of the Greater Paris area (Assistance Publique-Hôpitaux de Paris [AP-HP]). Specifically, the objectives were: 1) to identify images which are not proper T1-weighted brain MRIs; 2) to identify acquisitions for which gadolinium was injected; 3) to rate the overall image quality. We used 5000 images for training and validation and a separate set of 500 images for testing. In order to train/validate the CNN, the data were annotated by two trained raters according to a visual QC protocol that we specifically designed for application in the setting of a data warehouse. For objectives 1 and 2, our approach achieved excellent accuracy (balanced accuracy and F1-score >90%), similar to the human raters. For objective 3, the performance was good but substantially lower than that of human raters. Nevertheless, the automatic approach accurately identified (balanced accuracy and F1-score >80%) low quality images, which would typically need to be excluded. Overall, our approach shall be useful for exploiting hospital data warehouses in medical image computing.


The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II: Endorsed by the Society of Interventional Radiology and the Society for Vascular Medicine.
The Society for Vascular Surgery, the American Venous Forum, and the American Vein and Lymphatic Society recently published Part I of the 2022 clinical practice guidelines on varicose veins. Recommendations were based on the latest scientific evidence researched following an independent systematic review and meta-analysis of five critical issues affecting the management of patients with lower extremity varicose veins, using the patients, interventions, comparators, and outcome system to answer critical questions. Part I discussed the role of duplex ultrasound scanning in the evaluation of varicose veins and treatment of superficial truncal reflux. Part II focuses on evidence supporting the prevention and management of varicose vein patients with compression, on treatment with drugs and nutritional supplements, on evaluation and treatment of varicose tributaries, on superficial venous aneurysms, and on the management of complications of varicose veins and their treatment. All guidelines were based on systematic reviews, and they were graded according to the level of evidence and the strength of recommendations, using the GRADE method. All ungraded Consensus Statements were supported by an extensive literature review and the unanimous agreement of an expert, multidisciplinary panel. Ungraded Good Practice Statements are recommendations that are supported only by indirect evidence. The topic, however, is usually noncontroversial and agreed upon by most stakeholders. The Implementation Remarks contain technical information that supports the implementation of specific recommendations. This comprehensive document includes a list of all recommendations (Parts I-II), ungraded consensus statements, implementation remarks, and best practice statements to aid practitioners with appropriate, up-to-date management of patients with lower extremity varicose veins.


A Sensitive and Disposable Graphene Oxide Electrochemical Immunosensor for Label-free Detection of Human Immunoglobulin G.
In this work, a cost-effective and simple-to-prepare label-free electrochemical immunosensor was, for the first time, fabricated by modifying high-quality graphene oxide (GPO) onto a screen-printed carbon electrode (SPCE). The anti-IgG antibody was then covalently immobilized to the carboxylic group anchoring on the surface of GPO particles. Under the optimized condition, our newly developed immunosensor selectively bound to human immunoglobulin G (IgG), a model biomarker, with high sensitivity at a limit of detection of 1.99 ng mL(-1), potentially sensitive enough for IgG detection at the pathophysiological level, and had a linear range of 2.5 to 100 ng mL(-1). The proposed immunosensor also exhibited high reproducibility and regenerability, resulting in no significant change in electrochemical signals from different replicates of the electrode, and a robust electrochemical current after being subjected to alkaline base washing with several cycles. To this end, our immunosensor demonstrates ability as a promising diagnostic tool for clinical assessment.


Contribution of Arab countries to breast cancer research: comparison with non-Arab Middle Eastern countries.
Breast cancer is one of the most common types of cancers affecting women worldwide. The main objective of this study was to assess and compare research activity in breast cancer in Arab countries with non-Arab Middle Eastern countries. Publications about "breast cancer" as a research topic were retrieved using the ISI Web of Science database. Analysis was confined to original research and review articles. Research productivity was assessed by assessing number of publications and time trend of these publications, names of journals, citation analysis, top 10 active institutions as well as country contribution to breast cancer research. The quantity and quality of publications from Arab countries in addition to 3 other Middle East countries (Turkey, Iran and Israel) were assessed and compared using the h-index tool. A total of 1658 original research and review articles about "breast cancer" were published from Arab countries. Annual research productivity from Arab countries in the field of "breast cancer" was negligible but showed a significant increase in the last decade. Retrieved documents had relatively high citation parameters as measured by h-index of 61 and average citations of 17.46 per document. The highest research productivity was from Egypt with a total publication of 582 (35.10%). Cairo University with a total of 149 (8.99%) publications had the highest research productivity among institutions in Arab world. Forty four documents (2.65%) of breast cancer documents were published in Saudi Medical Journal. Arab researchers collaborated mostly with researchers from the United States of America (305; 18.40%) in breast cancer research. Compared with other non-Arab Middle Eastern countries, Arab countries had higher research productivity than some countries and lower than others, particularly Israel. The present data reveals a good contribution of some Arab countries to the field of "breast cancer" research. There is a gap between Arab countries and Israel in the quality of breast cancer research.


Archaeospora ecuadoriana sp. nov. from a mountainous biodiversity hotspot area in Ecuador, and transfer of Palaeospora spainiae to Archaeospora, as A. spainiae comb. nov.
A new glomeromycotan fungus, Archaeospora ecuadoriana sp. nov., was found in the south Ecuadorian mountain rainforest region, a global plant biodiversity hotspot. It was cultivated as single spore isolate originating from nursery-grown native tree seedlings inoculated with mixed soil from pristine forest and agricultural fields. The new species is known from the Loja area, southern Ecuador, at about 2100 m above mean sea level (mamsl) and has been detected in potato roots from an Andean region in Peru at 2658 mamsl by previous molecular data. The fungus forms small, colourless to frosted white, mainly globose spores, averaging 61 × 60 μm, formed singly or very rarely in clusters. There is no reaction to Melzer's reagent, other than a slight unspecific overall yellow iodine staining. The spores are very similar to those of Archaeospora trappei and A. schenckii. However, molecular phylogenetic analysis shows the species to be clearly separate from all other described Archaeospora species. The analysis of the available Archaeospora sequence data shows that sequences of Palaeospora spainiae, of the monospecific genus Palaeospora, cluster within the genus Archaeospora. Palaeospora therefore is synonymised with Archaeospora and P. spainiae is transferred to Archaeospora, as A. spainiae comb. nov.


Corrections for scattered photons in free-air ionisation chambers.
Although most recent interest and development in radiation dosimetry has been centered on higher energy radiations, calibrations of conventional x-ray machines for radiotherapy are still based on free-air ionisation chamber measurements. Such measurements require a correction for ionisation produced by secondary photons scattered out of the primary beam, and although the correction is relatively small (generally less than 1%) the data for deriving it are neither as complete or satisfactory as might be wished. This paper describes the derivation of theoretical expressions which allow the calculation of corrections, and compares calculated values with experimental results. It is apparent from the study that in determining the photon gain correction, account should be taken not only of the chamber geometry but also of photon scattering from the wall materials and, for higher energy beams in particular, of contributions from diaphragm scatter and possibly stray radiation penetration of the chamber.


Crucial role of elusive isomeric eta-complexes in gas-phase electrophilic aromatic alkylations.
[isomers: see text] The kinetics and stereochemistry of the protonation-induced unimolecular isomerization of (R)-1-D1-3-(p-fluorophenyl)butane have been investigated in the gas phase at 40-100 degrees C and 70-760 Torr. This process leads to the formation of the relevant meta and ortho isomers with partial racemization of the migrating sec-butyl moiety. Complete racemization is observed, instead, when the isomerization reaction involves a 1,2-H shift in the moving alkyl group. These results, together with the relevant activation parameters, fully confirm the previous evidence of the occurrence in the alkyl cation/arene PES of noncovalent eta-type intermediates of defined structure and stability, lying well below the classical pi-complexes, as confirmed by ab initio calculations. Their crucial role in determining the positional selectivity of gas-phase electrophilic aromatic substitutions clearly emerges from the comparison of the present results with the site selectivity measured in the corresponding bimolecular arene alkylation carried out at the same temperatures and pressures.


Optometric findings in velocardiofacial syndrome.
Velocardiofacial syndrome (VCFS) is a congenital genetically determined condition with skeletal, heart, and facial anomalies. Almost all children have learning problems, despite an often normal or above average IQ. We have examined 10 children with a prior diagnosis of VCFS. All were mildly to moderately hyperopic. Most had poor accommodation, and convergence was clinically poor. About 30% had tortuous retinal vessels. VCFS may be detected in the optometry clinic, and optometric management may ameliorate the learning problems in some cases.


Transplanting Soil Microbiomes Leads to Lasting Effects on Willow Growth, but not on the Rhizosphere Microbiome.
Plants interact closely with microbes, which are partly responsible for plant growth, health, and adaptation to stressful environments. Engineering the plant-associated microbiome could improve plant survival and performance in stressful environments such as contaminated soils. Here, willow cuttings were planted into highly petroleum-contaminated soils that had been gamma-irradiated and subjected to one of four treatments: inoculation with rhizosphere soil from a willow that grew well (LA) or sub-optimally (SM) in highly contaminated soils or with bulk soil in which the planted willow had died (DE) or no inoculation (CO). Samples were taken from the starting inoculum, at the beginning of the experiment (T0) and after 100 days of growth (TF). Short hypervariable regions of archaeal/bacterial 16S rRNA genes and the fungal ITS region were amplified from soil DNA extracts and sequenced on the Illumina MiSeq. Willow growth was monitored throughout the experiment, and plant biomass was measured at TF. CO willows were significantly smaller throughout the experiment, while DE willows were the largest at TF. Microbiomes of different treatments were divergent at T0, but for most samples, had converged on highly similar communities by TF. Willow biomass was more strongly linked to overall microbial community structure at T0 than to microbial community structure at TF, and the relative abundance of many genera at T0 was significantly correlated to final willow root and shoot biomass. Although microbial communities had mostly converged at TF, lasting differences in willow growth were observed, probably linked to differences in T0 microbial communities.


Conventional versus stealth lipid nanoparticles: formulation and in vivo fate prediction through FRET monitoring.
The determination of the nanocarrier fate in preclinical models is required before any translation from laboratory to clinical trials. Modern fluorescent imaging techniques have gained considerable advances becoming a powerful technology for non-invasive visualization in living subjects. Among them, Forster (fluorescence) resonance energy transfer (FRET) is a particular fluorescence imaging which involves energy transfer between 2 fluorophores in a distance-dependent manner. Considering this feature, the encapsulation of an acceptor/donor pair in lipid nanoparticles (LNEs: lipid nanoemulsions, LNCs: lipid nanocapsules) allowed the carrier integrity to be tracked. Accordingly, we used this FRET technique to evaluate the behavior of LNEs, conventional LNCs and newly designed stealth LNCs. After the development through a one-step (OS) PEGylation process of these stealth LNCs (OS LNCs), in vitro guest exchange dynamics and release kinetics were evaluated for both LNC formulations. We thereafter assessed in vivo biodistribution of all types of lipid nanoparticles. Results showed enhanced stability of encapsulation in OS LNCs in comparison to conventional LNCs. Additionally, the presence of the long PEG chains on the lipid nanoparticle surface altered the biodistribution pattern. Despite different release kinetic profiles, OS LNCs and LNEs showed extended blood circulation time associated with a good structure stability over several hours after intravenous injection.


A preliminary spatial-temporal study of some soil characteristics in the calcareous massif of Sicó, Portugal.
The mountainous massif of Sicó, in the centre of Portugal, is an extensive area composed of calcareous Jurassic formations. Hillside calcareous soils, with high pH, present chemical restrictions to support plant growth and are subjected to important erosion processes leading to their degradation if not protected by vegetation. In a first year of study some soil physicochemical characteristics have been measured in some geo-referenced locations of a larger design experiment and an exploratory spatial analysis has been performed. The objective of this study was to present some suggestions in order to give sustainable phosphorus fertiliser recommendations aiming to establish pastures in these soils and thus support traditional livestock activity. Ten years apart, those soil characteristics have been measured again in the same locations and comparisions have been made. The objective was to understand the variability of the soil properties under study in order to better adequate the fertiliser soil management regarding the area restoration.


Clinicopathological correlates of lewy body disease: fundamental issues.
Lewy body pathology (LBP) is the pathological hallmark of Lewy body diseases, such as Parkinson's disease and Lewy body dementia. Recent studies have shed new light on the role of LBP, the interactions of LBP with concomitant pathologies, and the propagation of LBP from the olfactory bulb and enteric nervous system to the central nervous system. The intrinsic difficulty with identifying clinicopathological correlates could be overcome by improving our understanding of the pathological evolution of LBP.


Molecular dynamics simulations of rupture in lipid bilayers.
Magnetic fluid hyperthermia is a promising cancer therapy in which magnetic nanoparticles are acted upon by a high-frequency oscillating magnetic field. While the accepted mechanism is localized hyperthermia, it is plausible that shear stresses due to nanoparticles rotating near a cell membrane may induce rupture, enhancing the effectiveness of the treatment. With the goal of understanding this further, molecular dynamics simulations were carried out on a model cell membrane. A bilayer composed of dipalmitoylphosphatidylcholine lipids was subjected to an incremental tension as well as an incremental shear stress. In both cases, it was found that the bilayer could withstand a surface tension of approximately 90 mN/m prior to rupture. Under tension, the bilayer ruptured at double its initial area, whereas under shear, the bilayer ruptured at 1.8 times its initial area. The results show that both incremental tension and incremental shearing are able to produce bilayer rupture, with shear being more injurious, yielding a larger surface tension for a smaller deformation. This information allows for comparison between the estimated energy required to rupture a cell membrane and the energy that a magnetic nanoparticle would be able to generate while rotating in a cellular environment. Our estimates indicate that magnetically blocked nanoparticles with diameters larger than 50 nm may result in rupture due to shear.


Method for the microassay of endogenous creatinine in blood and urine of small murid rodents.
The estimation of endogenous creatinine clearance yields information useful to the renal physiologist without the need to introduce a marker compound. The method has been limited in its application to mammalian species of bodyweight 200 g and above due to the blood sample size required. A modification is described whereby this procedure may be applied to animals of bodyweight as low as 25 g. Use of this microassay is illustrated in an investigation of the effect of salt and urea loading on renal function in an Australian desert mouse, Notomys alexis.


Reversal of severe late left ventricular failure after pediatric heart transplantation and possible role of plasmapheresis.
Late acute cardiac graft failure carries a high mortality in adults. Vascular mediators and factors other than classic T-cell-mediated rejection may play a role in this process, and aggressive multimodality therapy may improve survival. We report experience with plasmapheresis in treating late severe acute left ventricular dysfunction in a group of pediatric heart transplant recipients. We retrospectively reviewed clinical records, echocardiograms, hemodynamics, coronary angiograms, biopsy specimens, and treatment regimens for 5 patients with 7 episodes of late-onset severe graft failure who recovered. Plasmapheresis was applied in all cases, in addition to methylprednisolone, cyclophosphamide, lympholytic agents, and aggressive supportive care including mechanical ventilation and hemofiltration. All patients presented with acute severe left ventricular dysfunction 1.4 to 7.9 years (mean 3.6) after orthotopic heart transplantation. Mean shortening fraction at presentation was 13 to 23% (mean 16), initial endomyocardial biopsy specimens were grade 0 to 3B, and immunofluorescence studies were negative. Treatment included plasmapheresis, cyclophosphamide, mechanical ventilation, hemofiltration, and inotropes. Clinical recovery was slow, with 4 to 8 weeks until left ventricular function normalized, and 2.2 to 9.4 (mean 4.6) weeks to hospital discharge. At follow-up (50 to 38 months, mean 24), all are alive. Two patients are well, whereas coronary vasculopathy developed in 3. Thus, survival may improve in patients with late graft failure with low biopsy score and plasmapheresis combined with multimodality therapy.


"Green" pyrotechnics: a chemists' challenge.
Fireworks are probably the application of chemistry which resonates best with the general public. However, fireworks and (civil and military) pyrotechnic applications cause environmental pollution and thus have given rise to the development of new, environmentally friendly pyrotechnic compounds and formulations. Nitrogen-rich energetic materials, such as the derivatives of tetrazoles and tetrazines, are about to revolutionize traditional pyrotechnic compositions. This Review summarizes the sources of pollution in current formulations and recent efforts toward "green" pyrotechnics.


Marital satisfaction in couples with rheumatoid arthritis.
To understand correlates of marital satisfaction in persons with rheumatoid arthritis (RA) and their spouses. In a cross-sectional survey, 79 persons with RA and 78 spouses completed the Kansas Marital Satisfaction Scale, the revised Ways of Coping Questionnaire scales, and the Health Assessment Questionnaire. A series of linear regression analyses were then performed to investigate correlates of marital satisfaction for patients and spouses. Seventy-six percent of patients were women. Mean patient age was 56.5 years (+/- 12.5 years), number of years married was 30.7 (+/- 13.5), and duration of RA was 14.2 years (+/- 9.0 years). Demographic features of spouses resembled those of patients. Patients and spouses were generally satisfied with their marriages. Linear regression analyses showed that lower marital satisfaction in patients was associated with higher education level (P < 0.01), patient's greater use of escape into fantasy (P < 0.01), patient's greater use of finding blame (P < 0.05), and spouse's higher use of escape into fantasy (P < 0.001). Spouses less satisfied with their marriages were more likely to use passive acceptance (P < 0.05) and less likely to find blame (P < 0.05). Female spouses were less likely to be satisfied in their marriages (P < 0.01) than male spouses. This study indicates that certain passive coping styles are associated with lower marital satisfaction in persons with RA and their spouses. More highly educated patients and female spouses are also less satisfied in their marriages. These cross-sectional correlations should not be regarded as causal and should be examined further in longitudinal studies.


Probabilistic modeling of systematic errors in two-hybrid experiments.
We describe a novel probabilistic approach to estimating errors in two-hybrid (2H) experiments. Such experiments are frequently used to elucidate protein-protein interaction networks in a high-throughput fashion; however, a significant challenge with these is their relatively high error rate, specifically, a high false-positive rate. We describe a comprehensive error model for 2H data, accounting for both random and systematic errors. The latter arise from limitations of the 2H experimental protocol: in theory, the reporting mechanism of a 2H experiment should be activated if and only if the two proteins being tested truly interact; in practice, even in the absence of a true interaction, it may be activated by some proteins - either by themselves or through promiscuous interaction with other proteins. We describe a probabilistic relational model that explicitly models the above phenomenon and use Markov Chain Monte Carlo (MCMC) algorithms to compute both the probability of an observed 2H interaction being true as well as the probability of individual proteins being self-activating/promiscuous. This is the first approach that explicitly models systematic errors in protein-protein interaction data; in contrast, previous work on this topic has modeled errors as being independent and random. By explicitly modeling the sources of noise in 2H systems, we find that we are better able to make use of the available experimental data. In comparison with Bader et al.'s method for estimating confidence in 2H predicted interactions, the proposed method performed 5-10% better overall, and in particular regimes improved prediction accuracy by as much as 76%. http://theory.csail.mit.edu/probmod2H


The Interventions to Minimize Pain During Photodynamic Therapy With 5-Aminolevulinic Acid for the Treatment of Cutaneous Diseases.
Photosensitization with 5-aminolevulinic acid (ALA) combined with photodynamic therapy (PDT) is approved in the United States for the treatment of actinic keratosis (AK) and is used off-label for other indications including acne treatment and photo rejuvenation. However, pain, particularly during the initial illumination period, limits the utility of this highly efficacious therapy. Although modifications to conventional ALA-PDT protocols that improve tolerability without diminishing efficacy have been identified, few have been evaluated in randomized, controlled trials, and the number of variables involved in ALA incubation (eg, duration, occlusion, ALA formulation, and strength) and PDT illumination (eg, light source, fluence rate, irradiance, and duration) confounds standardization.  Perhaps the most promising modifications to date involve continuous activation of low levels of protoporphyrin IX, the photoactive metabolite of ALA, as well as using shorter incubation times (with or without prolongation of illumination), lower irradiance, and daylight or combined (daylight and conventional) PDT. However, reimbursement of PDT with alternative light sources in the US is hampered by the US Food and Drug Administration (FDA) labeling, which specifies the blue or red light devices approved for use with corresponding marketed ALA 20% solution and 10% gel, respectively. This review summarizes the existing evidence with respect to pain control in patients undergoing ALA-PDT, recommendations from clinical experience, and goals for future research. J Drugs Dermatol. 2023;22(11):1082-1087   doi:10.36849/JDD.7637.


The effect of a low pH on the membrane skeleton of the erythrocyte ghost.
The effects of an acidic pH on the membrane skeleton of erythrocyte ghosts has been investigated by negative staining and thin-section methods. At neutral pH the membrane skeleton consisted of 6-7 nm wide filaments uniformly dispersed on the inner membrane surface. At pH 5.0 the filaments fused to form a coarse network with thick strands and large areas of membrane devoid of filaments. These changes were completely reversible in many cells. They can probably account for the clustering of surface anionic sites and membranous particles which occur at a low pH and may play a role in other related events such as the change in shape of the cell and increased membrane stiffness.


Synthetic extracellular matrices for tissue engineering and regeneration.
The need for replacement tissues or organs requires a tissue supply that cannot be satisfied by the donor supply. The tissue engineering and regeneration field is focused on the development of biological tissue and organ substitutes and may provide functional tissues to restore, maintain, or improve tissue formation. This field is already providing new therapeutic options to bypass the limitations of organ?tissue transplantation and will likely increase in medical importance in the future. This interdisciplinary field accommodates principles of life sciences and engineering and encompasses three major strategies. The first, guided tissue regeneration, relies on synthetic matrices that are conductive to host cells populating a tissue defect site and reforming the lost tissue. The second approach, inductive strategy, involves the delivery of growth factors, typically using drug delivery strategies, which are targeted to specific cell populations in the tissues surrounding the tissue defect. In the third approach, specific cell populations, typically multiplied in culture, are directly delivered to the site at which one desires to create a new tissue or organ. In all of these approaches, the knowledge acquired from developmental studies often serves as a template for the tissue engineering approach for a specific tissue or organ. This article overviews the development of synthetic extracellular matrices (ECMs) for use in tissue engineering that aim to mimic functions of the native ECM of developing and regenerating tissues. In addition to the potential therapeutic uses of these materials, they also provide model systems for basic studies that may shed light on developmental processes.


Lowering rumen-degradable protein maintained energy-corrected milk yield and improved nitrogen-use efficiency in multiparous lactating dairy cows exposed to heat stress.
The objective of this study was to examine the effect of reducing rumen-degradable protein (RDP) and rumen-undegradable protein (RUP) proportions on feed intake, milk production, and N-use efficiency in primiparous and multiparous cows exposed to warm climates. Eighteen primiparous and 30 multiparous mid-lactation Holstein cows were used in a completely randomized design with a 2 × 2 factorial arrangement of treatments. Cows were randomly assigned to 1 of 4 dietary treatments formulated to contain 2 proportions of RDP (10 and 8%) and 2 proportions RUP (8 and 6%) of dry matter (DM) indicated as follows: (1) 10% RDP, 8% RUP; (2) 8% RDP, 8% RUP; (3) 10% RDP, 6% RUP; and (4) 8% RDP, 6% RUP. Protein sources were manipulated to obtain desired RDP and RUP proportions. Diets were isoenergetic and contained 50% forage and 50% concentrate (DM basis). Cows were individually fed the 10% RDP, 8% RUP diet 3 wk before treatment allocation. Cows were exposed to the prevailing Tennessee July and August temperature and humidity in a freestall barn with no supplemental cooling. Main effects and their interaction were tested using the Mixed procedure of SAS (least squares means ± standard error of the mean; SAS Institute Inc., Cary, NC). Observed values of nutrient intake and milk production were used to obtain NRC (2001) model predictions. Cows showed signs of heat stress throughout the study. Reducing from 10 to 8% RDP decreased dry matter intake (DMI; 0.9 kg/d) at 8% RUP, but increased DMI (2.6 kg/d) at 6% RUP in primiparous cows. Reducing from 10 to 8% RDP decreased milk yield (10%) at 8% RUP, but increased yield (14%) at 6% RUP. Treatments did not affect yield of energy-corrected milk. For multiparous cows, treatments did not affect DMI. Reducing from 10 to 8% RDP decreased yield of energy-corrected milk (3.4%) at 8% RUP, but increased yield (8.8%) at 6% RUP. Reducing from 10 to 8% RDP and 8 to 6% RUP both increased N-use efficiency for primiparous and multiparous cows. The NRC model underestimated metabolizable protein and RUP supply, and overestimated RUP requirements, resulting in predictive losses of milk yield 1.4 to 5.8 times greater than observed values. In summary, the reduction of RDP and RUP proportions did not affect DMI, whereas the RUP reduction at 10% RDP had a small negative effect on energy-corrected milk yield. However, reduction of RDP and RUP consistently improved N-use efficiency of heat-stressed multiparous cows. The reduction of RDP and RUP proportions reduced DMI and milk yield but did not affect energy-corrected milk yield in primiparous cows, indicating a limited supply of nutrients.


Rapid real-time PCR for detection of Mycobacterium tuberculosis complex DNA in formalin-fixed paraffin embedded tissues: 16% of histological 'sarcoid' may contain such DNA.
To investigate the diagnostic accuracy of IS6110 real-time PCR for detection of Mycobacterium tuberculosis complex (MTBC) in DNA extracted from formalin-fixed paraffin embedded (FFPE) tissues using two different methods. In the absence of material submitted for tuberculosis (TB) culture, MTBC detection in FFPE tissue can be an important aid to diagnosis. We collected 144 FFPE tissue blocks (lung and lymph node) for IS6110 real-time PCR. Two DNA extraction methods (QIAamp FFPE tissue kit and NucliSENS easyMAG) were assessed within a general laboratory setting. PCR results were compared with histology and culture. In the histological MTBC and culture MTBC (TB-positive) groups, 72.4% were IS6110-positive and 27.6% negative. IS6110-negative results were obtained from 98%, 61.5% and 84% of the histologically MTBC-negative (TB-negative) group, histologically TB/no culture group and sarcoidosis group, respectively. Review of 19 IS6110-positive patients in the latter three groups showed that 15 had clinical TB. Thirteen of 15 (86.7%) IS6110-positive patients in the histological TB/no culture group and 2 of 4 (50%) IS6110-positive patients in the sarcoidosis group were clinically diagnosed with TB which highlights the difficulty of a pathological diagnosis. IS6110 real-time PCR using easyMAG extracted DNA is a moderately sensitive, specific and rapid method for MTBC detection in FFPE material, but must be interpreted in the overall clinical context. PCR results can be available in around 5 h from FFPE specimen receipt, with minimal hands-on time.


Implementing multimodal pain rehabilitation in primary care - a health care professional perspective.
To explore professional perspectives on how to start and work with multimodal pain rehabilitation within primary healthcare. Fourteen healthcare professionals (11 women, 3 men) were individually interviewed about their experiences of starting and working with multimodal pain. Interviews were transcribed and analyzed by qualitative content analysis. This study was part of a larger project, which aimed at evaluating multimodal pain rehabilitation in primary care. The analysis resulted in six categories. Two categories were about management engagement: putting the focus on rehabilitation and creating appropriate conditions. Three were about professional engagement: importance of driving spirits, creating a program - a process, and good teamwork - not a coincidence. The last category was about professional gain from multimodal rehabilitation (MMR): team work is enriching. To enable implementation of MMR in primary care, managers on all organizational levels must take responsibility for allowing rehabilitation to be a priority. A driving spirit among the professionals facilitates the start, but the entire team is important when processing a program. Creating good teamwork requires hard work, e.g., negotiations for consensus about rehabilitation, and assumption of responsibility by each team member. Collaboration between professionals was perceived to strengthen and enhance knowledge about the patients. Implications for rehabilitation Much can be gained from conducting multimodal pain rehabilitation in primary care. Front line managers and those at other organizational levels must prioritize and create appropriate conditions to facilitate multimodal pain rehabilitation in primary care. Creation of an effective multimodal rehabilitation team requires that each team member takes responsibility, drops the focus on individual rehabilitation, seek member consensus about the content of the rehabilitation, and confer equal worth to each team member. The process of creating a program can be facilitated, especially at the beginning, if the team is supported by speciality pain clinics or more experienced teams.


Genetic Enteropathies Linked to Epithelial Structural Abnormalities and Enteroendocrine Deficiency: A Systematic Review.
Congenital diarrhea and enteropathies linked to epithelial structural abnormalities constitute 3 different rare diseases: the tufting enteropathies (TE; EPCAM and SPINT2 mutations), microvillous inclusion disease (MVID; MYO5B and STX3 mutations), and tricho-hepato-enteric syndrome (THE; TTC37 and SKIV2L mutations). Moreover, enteroendocrine deficiencies (ED; PCSK1 and NEUROG3 mutations) share common clinical characteristics with TE, THE, and MVID in that the treatment requires, in most cases, long-term parenteral nutrition. Although numerous cases have been reported in the literature, aggregated data on morbidity and mortality are missing owing to the rarity of the diseases. We performed a systematic review of all published cases and retrieved 86 articles describing 323 patients (164 boys and 135 girls). The mortality rate was 20.28%, with a median age at death of 13.5 months (range 0-228 months); the mortality risk was 30.8/1000 person-year; in half of the cases, death was caused by infections. Parenteral nutrition was required in 95.4% of patients and weaning off from parenteral nutrition was achieved in 29.35% at a median age of 23 months (range 3.3-276 months). The patients with ED linked to PCSK1 were nearly all weaned at a median age of 14 months, but most of the patients became overweight. MVID patients with MYO5B mutations were most often born preterm. ED linked to NEUROG3 mutation and THE patients usually presented with intrauterine growth retardation. This review presents data from 323 patients with congenital diarrhea linked to EPCAM TE, SPINT2 TE, TTC37 THE, SKIV2L THE, MYO5B MVID, STX3 MVID, NEUROG3 ED, and PCSK1 ED mutations.


Context effects and observer bias--implications for forensic odontology.
Psychologists have long recognized the effects of contextual and extraneous information on decision making. Such information renders the subject susceptible to both motivational and cognitive bias; yet, it is difficult to assess the extent to which these influence forensic odontologists opinions as there have been no studies to date on this subject. This article explores the various types of contextual effects and biasing influences that potentially impact on the analysis of bitemarks in forensic odontology. It appears that the current practice of bitemark analysis is rich in sources of potentially biasing influences. In addition to the fundamental recognition that some form of bias is likely to exist, ways in which these should be minimized include: separation of the collection and analysis phases; limiting the amount of contextual information available to the odontologist responsible for the analysis; and ensuring that evidence that is ambiguous or of poor quality is identified as such prior to analysis.


An unconventional depiction of viewpoint in rock art.
Rock art in Africa sometimes takes advantage of three-dimensional features of the rock wall, such as fissures or protuberances, that can be incorporated into the artistic composition (Lewis-Williams, 2002). More commonly, rock artists choose uniform walls on which two-dimensional depictions may represent three-dimensional figures or objects. In this report we present such a two-dimensional depiction in rock art that we think reveals an intention by the artist to represent an unusual three-dimensional viewpoint, namely, with the two human figures facing into the rock wall, instead of the accustomed Western viewpoint facing out!


The role of the Staphylococcus aureus nasal carriage and type of vascular access in the outcome of high-risk patients on hemodialysis.
Populations of elderly and type-II diabetics are increasing worldwide. Therefore elderly diabetics on hemodialysis (HD), known to have higher nasal carriage rates, are also increasing. These patients are more often dialyzed through central venous catheters (CVCs). They represent the high-risk groups for Staphylococcus aureus linked vascular access-related septicemia (VRS) and ensuing mortality. The outcome of VRS in terms of mortality was studied in the three high-risk groups: elderly; type-II diabetics; elderly diabetics, following optimization of arteriovenous fistula (AVF) prevalence to at least 50%. Persistent nasal carriage was defined by two or more positive standardized nasal swab cultures performed on 187 ESRD patients undergoing HD from July 1997 to July 2000. Peripheral blood samples were collected for culture and sensitivity on clinical suspicion of septicemia. Overall, AVF prevalence of over 50% was achieved through joint efforts of nephrology and vascular surgery departments. A nasal carriage rate of 47.6% was observed in this HD cohort. This included nasal carriage rates of 16.4% in <65 years non-diabetic (reference) group, 55.8% in elderly and 70.7% among type-II diabetics along with that of 75.5% in elderly-diabetic group. We achieved an overall AVF prevalence of 72.7% inclusive of 66.17% in elderly, 65.5% in type-II diabetics and 86.8% in reference group along with 37.7% in elderly-diabetic group. We recorded a mortality due to S. aureus nasal carriage-related VRS of 6.86% in elderly (RR-1.50, p-NS), 10.91% in type-II diabetics (RR-1.52, p<0.02) and 13.20% in the elderly-diabetic group (RR-2.87, p<0.0004) as compared to that of 4.4% per year in the reference group (assigned RR of one) with overall mortality of 7.3% per year. AVF prevalence of over 50% is achievable in all the high-risk groups except among elderly-diabetics due to the predominance of peripheral vasculopathy. Optimizing AVF placement is a physiological and safer approach for achieving significant reductions in mortality associated with S. aureus nasal carriage-related VRS among high-risk groups.


Autophagy inhibition of hsa-miR-19a-3p/19b-3p by targeting TGF-β R II during TGF-β1-induced fibrogenesis in human cardiac fibroblasts.
Transforming growth factor-β1 (TGF-β1) plays an important role on fibrogenesis in heart disease. MicroRNAs have exhibited as crucial regulators of cardiac homeostasis and remodeling in various heart diseases. MiR-19a-3p/19b-3p expresses with low levels in the plasma of heart failure patients. The purpose of our study is to determine the role of MiR-19a-3p/19b-3p in regulating autophagy-mediated fibrosis of human cardiac fibroblasts. We elucidate our hypothesis in clinical samples and human cardiac fibroblasts (HCF) to provide valuable basic information. TGF-β1 promotes collagen I α2 and fibronectin synthesis in HCF and that is paralleled by autophagic activation in these cells. Pharmacological inhibition of autophagy by 3-methyladenine decreases the fibrotic response, while autophagy induction of rapamycin increases the response. BECN1 knockdown and Atg5 over-expression either inhibits or enhances the fibrotic effect of TGF-β1 in experimental HCF. Furthermore, miR-19a-3p/19b-3p mimics inhibit epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) prodution and invasion of HCF. Functional studies suggest that miR-19a-3p/19b-3p inhibits autophagy of HCF through targeting TGF-β R II mRNA. Moreover, enhancement of autophagy rescues inhibition effect of miR-19a-3p/19b-3p on Smad 2 and Akt phosphorylation through TGF-β R II signaling. Our study uncovers a novel mechanism that miR-19a-3p/19b-3p inhibits autophagy-mediated fibrogenesis by targeting TGF-β R II.


IgG1 and IgG4 antibody responses to the Anopheles gambiae salivary protein gSG6 in the sympatric ethnic groups Mossi and Fulani in a malaria hyperhendemic area of Burkina Faso.
Human antibody response to the Anopheles gambiae salivary protein gSG6 has recently emerged as a potentially useful tool for malaria epidemiological studies and for the evaluation of vector control interventions. However, the current understanding of the host immune response to mosquito salivary proteins and of the possible crosstalk with early response to Plasmodium parasites is still very limited. We report here the analysis of IgG1 and IgG4 subclasses among anti-gSG6 IgG responders belonging to Mossi and Fulani from Burkina Faso, two ethnic groups which are known for their differential humoral response to parasite antigens and for their different susceptibility to malaria. The IgG1 antibody response against the gSG6 protein was comparable in the two groups. On the contrary, IgG4 titers were significantly higher in the Fulani where, in addition, anti-gSG6 IgG4 antibodies appeared in younger children and the ratio IgG4/IgG1 stayed relatively stable throughout adulthood. Both gSG6-specific IgG1 and IgG4 antibodies showed a tendency to decrease with age whereas, as expected, the IgG response to the Plasmodium circumsporozoite protein (CSP) exhibited an opposite trend in the same individuals. These observations are in line with the idea that the An. gambiae gSG6 salivary protein induces immune tolerance, especially after intense and prolonged exposure as is the case for the area under study, suggesting that gSG6 may trigger in exposed individuals a Th2-oriented immune response.


The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation.
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.


Long-term Risk of Colorectal Cancer and Related Deaths After a Colonoscopy With Normal Findings.
Guidelines recommend a 10-year rescreening interval after a colonoscopy with normal findings (negative colonoscopy results), but evidence supporting this recommendation is limited. To examine the long-term risks of colorectal cancer and colorectal cancer deaths after a negative colonoscopy result, in comparison with individuals unscreened, in a large, community-based setting. A retrospective cohort study was conducted in an integrated health care delivery organization serving more than 4 million members across Northern California. A total of 1 251 318 average-risk screening-eligible patients (age 50-75 years) between January 1, 1998, and December 31, 2015, were included. The study was concluded on December 31, 2016. Screening was examined as a time-varying exposure; all participants contributed person-time unscreened until they were either screened or censored. If the screening received was a negative colonoscopy result, the participants contributed person-time in the negative colonoscopy results group until they were censored. Using Cox proportional hazards regression models, the hazard ratios (HRs) for colorectal cancer and related deaths were calculated according to time since negative colonoscopy result (or since cohort entry for those unscreened). Hazard ratios were adjusted for age, sex, race/ethnicity, Charlson comorbidity score, and body mass index. Of the 1 251 318 patients, 613 692 were men (49.0%); mean age was 55.6 (7.0) years. Compared with the unscreened participants, those with a negative colonoscopy result had a reduced risk of colorectal cancer and related deaths throughout the more than 12-year follow-up period, and although reductions in risk were attenuated with increasing years of follow-up, there was a 46% lower risk of colorectal cancer (hazard ratio, 0.54; 95% CI, 0.31-0.94) and 88% lower risk of related deaths (hazard ratio, 0.12; 95% CI, 0.02-0.82) at the current guideline-recommended 10-year rescreening interval. A negative colonoscopy result in average-risk patients was associated with a lower risk of colorectal cancer and related deaths for more than 12 years after examination, compared with unscreened patients. Our study findings may be able to inform guidelines for rescreening after a negative colonoscopy result and future studies to evaluate the costs and benefits of earlier vs later rescreening intervals.


Inflamed by the flames? The impact of terrorism and war on immunity.
The physiological impact on citizens of prolonged exposure to violence and conflict is a crucial, yet underexplored, issue within the political science and biology literature. We examined the effect of high levels of exposure to rocket and terrorist attacks on biological markers of immunity and inflammation in a sample of 92 Israelis. A stratified random sample of individuals was drawn from a pool of subjects in Israel who had previously been interviewed regarding their stress exposure and psychological distress during a period of active rocket and terrorist attacks. These individuals were reinterviewed and blood samples were collected to assess antibodies to cytomegalovirus (CMV antibodies) and C-reactive protein (CRP). Posttraumatic stress disorder (PTSD) was significantly related to CRP, β = .33, p = .034, with body mass index, depression, and exposure to terrorism included in the model. Depression scores were not significantly associated with CRP or CMV antibody levels. In contrast to the established convention that psychological distress is the sole outcome of terrorism exposure, these findings reveal that individuals exposed to terrorism experience higher levels of both PTSD/depression, and inflammation. This study has important ramifications for how policy makers and medical health professionals should formulate public health policies and medically treat individuals living in conflict zones.


Generalized mode-coupling theory of the glass transition. I. Numerical results for Percus-Yevick hard spheres.
Mode-coupling theory (MCT) constitutes one of the few first-principles-based approaches to describe the physics of the glass transition, but the theory's inherent approximations compromise its accuracy in the activated glassy regime. Here, we show that microscopic generalized mode-coupling theory (GMCT), a recently proposed hierarchical framework to systematically improve upon MCT, provides a promising pathway toward a more accurate first-principles description of glassy dynamics. We present a comprehensive numerical analysis for Percus-Yevick hard spheres by performing explicitly wavenumber- and time-dependent GMCT calculations up to sixth order. Specifically, we calculate the location of the critical point, the associated non-ergodicity parameters, and the time-dependent dynamics of the density correlators at both absolute and reduced packing fractions, and we test several universal scaling relations in the α- and β-relaxation regimes. It is found that higher-order GMCT can successfully remedy some of MCT's pathologies, including an underestimation of the critical glass transition density and an overestimation of the hard-sphere fragility. Furthermore, we numerically demonstrate that the celebrated scaling laws of MCT are preserved in GMCT and that the predicted critical exponents manifestly improve as more levels are incorporated in the GMCT hierarchy. Although formally the GMCT equations should be solved up to infinite order to reach full convergence, our finite-order GMCT calculations unambiguously reveal a uniform convergence pattern for the dynamics. We thus argue that GMCT can provide a feasible and controlled means to bypass MCT's main uncontrolled approximation, offering hope for the future development of a quantitative first-principles theory of the glass transition.


Gene structure of human cytochrome P-450(SCC), cholesterol desmolase.
Four independent clones containing a part of the P-450(SCC), cholesterol desmolase, gene were isolated from human genomic libraries using bovine P-450(SCC) cDNA as a probe. These clones covered the entire P-450(SCC) gene except for a part of the 1st intron. The gene is at least 20 kb long and is split into 9 exons by 8 introns. The sequence analysis revealed that the nine separated exons code for a primary structure consisting of 521 amino acids which shows 72% homology with that of bovine P-450(SCC). A CATT sequence and a TATAAT sequence, which are possibly a "CAT" box, and a "TATA" box, respectively, are present 129 and 91 bp upstream from the initiation codon. An unusual exon/intron junctional sequence that begins with GC was found in the 6th intron of the gene. A putative extension peptide consisting of 39 amino acids was found in the sequence of human P-450(SCC) by comparison with that of the bovine counterpart. Two conserved regions were found in the extension peptide of these two forms of P-450(SCC), suggesting a functional role of the portions in the mitochondrial localization and processing of P-450(SCC) precursor. The mature form of human P-450(SCC) has only one cysteine residue, which was located in the center of the HR2 region (Gotoh et al. (1983) J. Biochem. 97, 807-817). This observation established beyond doubt that the sole cysteine residue in the HR2 region is the 5th ligand to the heme.


Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe.
On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized. Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive. To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled "Vitamin D Expert Meeting: Do we get enough?", was organized. Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population. To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 μg (800 IU), which is best achieved with a supplement.


Chagas cardiomyopathy and serologic testing in a small rural hospital in Chiapas, Mexico.
To conduct a study in a small rural hospital located in the state of Chiapas, Mexico, to: (1) examine the prevalence of chagasic cardiomyopathy among patients with the diagnosis of congestive heart failure and (2) assess the prevalence of positive serologic results in blood donors in the hospital, in an attempt to ascertain whether Chagas' disease remains an important cause of heart failure at least in some areas of Mexico. The study of patients with cardiomyopathy was conducted by retrospective chart review of patients with the diagnosis of congestive heart failure treated at the hospital during the years 2000-2002. With the blood donors, the results of their serologic screening were reviewed for a six-month period beginning in April 2002. Serologic testing was done in both groups with either indirect hemagglutination (IHA) or enzyme-linked immunosorbent assay (ELISA), or with both. Of 67 patients with heart failure and no risk factors for other causes of heart failure, 40 of them had serologic tests performed. Thirty-three of these 40 (82.5%) were positive by ELISA, IHA, or both. With 97 blood donors, one or both serologic tests were positive in 17 of them (17.5%). This research adds to the evidence that Chagas' disease continues to be a major cause of heart failure in some areas of Mexico and that there continues to be a risk of transmission by blood transfusion if donated blood is not consistently screened.


Comparative In Vitro Activities of Ceftaroline and Tedizolid against Clinical Strains of Staphylococcus aureus and Enterococcus: Results from the China Antimicrobial Surveillance Network (CHINET) in 2018.
The in vitro activities of ceftaroline and tedizolid were compared against Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium clinical isolates collected from the China Antimicrobial Surveillance Network. Ceftaroline demonstrated potent activity against S. aureus isolates (MIC50/90, ≤0.25/1 mg/liter). Tedizolid was also highly active against S. aureus (MIC50/90, 0.25/0.5 mg/liter) and Enterococcus (MIC50/90, 0.5/0.5 mg/liter) isolates. Our results support the clinical usefulness of ceftaroline and tedizolid in treating Gram-positive infections.