Phenotype forecasting with SNPs data through gene-based Bayesian networks.
Bayesian networks are powerful instruments to learn genetic models from association studies data. They are able to derive the existing correlation between genetic markers and phenotypic traits and, at the same time, to find the relationships between the markers themselves. However, learning Bayesian networks is often non-trivial due to the high number of variables to be taken into account in the model with respect to the instances of the dataset. Therefore, it becomes very interesting to use an abstraction of the variable space that suitably reduces its dimensionality without losing information. In this paper we present a new strategy to achieve this goal by mapping the SNPs related to the same gene to one meta-variable. In order to assign states to the meta-variables we employ an approach based on classification trees. We applied our approach to data coming from a genome-wide scan on 288 individuals affected by arterial hypertension and 271 nonagenarians without history of hypertension. After pre-processing, we focused on a subset of 24 SNPs. We compared the performance of the proposed approach with the Bayesian network learned with SNPs as variables and with the network learned with haplotypes as meta-variables. The results were obtained by running a hold-out experiment five times. The mean accuracy of the new method was 64.28%, while the mean accuracy of the SNPs network was 58.99% and the mean accuracy of the haplotype network was 54.57%. The new approach presented in this paper is able to derive a gene-based predictive model based on SNPs data. Such model is more parsimonious than the one based on single SNPs, while preserving the capability of highlighting predictive SNPs configurations. The prediction performance of this approach was consistently superior to the SNP-based and the haplotype-based one in all the test sets of the evaluation procedure. The method can be then considered as an alternative way to analyze the data coming from association studies.


Detection of chromosome 13 deletions by fluorescent in situ hybridization.
Multiple myeloma (MM), like other hematological malignancies, has both normal and clonal neoplastic cells coresiding in the bone marrow. To perform interphase fluorescent in situ hybridization (FISH) analysis accurately, for the detection of clonal chromosome abnormalities, it is crucial to restrict the analysis to the tumoral cells. The correct detection of these abnormalities may have diagnostic, prognostic, and therapeutic implications. Our laboratory has developed a clone-specific cytoplasmic immunoglobulin (cIg) staining method coupled with FISH (cIg-FISH) for the study of plasma cell (PC) neoplasms. An unlimited combination of DNA probes can be used with this technique to examine the genetic changes that frequently occur in patients with these diseases, one of which is abnormalities of chromosome 13. Using the two techniques simultaneously (i.e., cIg-FISH), we have demonstrated that approx 50% of patients with MM have abnormalities of chromosome 13, mostly monosomy, and when present involving the majority of the cells. In this chapter, we present the technical methodology for detecting chromosome abnormalities and how to restrict the analysis to the clonal PCs.


Visualization of Electron Density Changes Along Chemical Reaction Pathways.
We propose a simple procedure for visualizing the electron density changes (EDC) during a chemical reaction, which is based on a mapping of rectangular grid points for a stationary structure into (distorted) positions around atoms of another stationary structure. Specifically, during a small step along the minimum energy pathway (MEP), the displacement of each grid point is obtained as a linear combination of the motion of all atoms, with the contribution from each atom scaled by the corresponding Hirshfeld weight. For several reactions (identity SN2, Claisen rearrangement, Diels-Alder reaction, [3+2] cycloaddition, and phenylethyl mercaptan attack on pericosine A), our EDC plots showed an expected reduction of electron densities around severed bonds (or those with the bond-order lowered), with the opposite observed for newly-formed or enhanced chemical bonds. The EDC plots were also shown for copper triflate catalyzed N2O fragmentation, where the N-O bond weakening initially occurred on a singlet surface, but continued on a triplet surface after reaching the minimum-energy crossing point (MECP) between the two potential energy surfaces.


Display of the Viral Epitopes on Lactococcus lactis: A Model for Food Grade Vaccine against EV71.
In this study, we have developed a system for display of antigens of Enterovirus type 71 (EV71) on the cell surface of L. lactis. The viral capsid protein (VP1) gene from a local viral isolate was utilized as the candidate vaccine for the development of oral live vaccines against EV71 using L. lactis as a carrier. We expressed fusion proteins in E. coli and purified fusion proteins were incubated with L. lactis. We confirmed that mice orally fed with L. lactis displaying these fusion proteins on its surface were able to mount an immune response against the epitopes of EV71. This is the first example of an EV71 antigen displayed on the surface of a food grade organism and opens a new perspective for alternative vaccine strategies against the EV71. We believe that the method of protein docking utilized in this study will allow for more flexible presentations of short peptides and proteins on the surface of L. lactis to be useful as a delivery vehicle.


Neural mass model-based tracking of anesthetic brain states.
Neural mass model-based tracking of brain states from electroencephalographic signals holds the promise of simultaneously tracking brain states while inferring underlying physiological changes in various neuroscientific and clinical applications. Here, neural mass model-based tracking of brain states using the unscented Kalman filter applied to estimate parameters of the Jansen-Rit cortical population model is evaluated through the application of propofol-based anesthetic state monitoring. In particular, 15 subjects underwent propofol anesthesia induction from awake to anesthetised while behavioral responsiveness was monitored and frontal electroencephalographic signals were recorded. The unscented Kalman filter Jansen-Rit model approach applied to frontal electroencephalography achieved reasonable testing performance for classification of the anesthetic brain state (sensitivity: 0.51; chance sensitivity: 0.17; nearest neighbor sensitivity 0.75) when compared to approaches based on linear (autoregressive moving average) modeling (sensitivity 0.58; nearest neighbor sensitivity: 0.91) and a high performing standard depth of anesthesia monitoring measure, Higuchi Fractal Dimension (sensitivity: 0.50; nearest neighbor sensitivity: 0.88). Moreover, it was found that the unscented Kalman filter based parameter estimates of the inhibitory postsynaptic potential amplitude varied in the physiologically expected direction with increases in propofol concentration, while the estimates of the inhibitory postsynaptic potential rate constant did not. These results combined with analysis of monotonicity of parameter estimates, error analysis of parameter estimates, and observability analysis of the Jansen-Rit model, along with considerations of extensions of the Jansen-Rit model, suggests that the Jansen-Rit model combined with unscented Kalman filtering provides a valuable reference point for future real-time brain state tracking studies. This is especially true for studies of more complex, but still computationally efficient, neural models of anesthesia that can more accurately track the anesthetic brain state, while simultaneously inferring underlying physiological changes that can potentially provide useful clinical information.


Considering health equity when moving from evidence-based guideline recommendations to implementation: a case study from an upper-middle income country on the GRADE approach.
The availability of evidence-based guidelines does not ensure their implementation and use in clinical practice or policy making. Inequities in health have been defined as those inequalities within or between populations that are avoidable, unnecessary and also unjust and unfair. Evidence-based clinical practice and public health guidelines ('guidelines') can be used to target health inequities experienced by disadvantaged populations, although guidelines may unintentionally increase health inequities. For this reason, there is a need for evidence-based clinical practice and public health guidelines to intentionally target health inequities experienced by disadvantaged populations. Current guideline development processes do not include steps for planned implementation of equity-focused guidelines. This article describes nine steps that provide guidance for consideration of equity during guideline implementation. A critical appraisal of the literature followed by a process to build expert consensus was undertaken to define how to include consideration of equity issues during the specific GRADE guideline development process. Using a case study from Colombia we describe nine steps that were used to implement equity-focused GRADE recommendations: (1) identification of disadvantaged groups, (2) quantification of current health inequities, (3) development of equity-sensitive recommendations, (4) identification of key actors for implementation of equity-focused recommendations, (5) identification of barriers and facilitators to the implementation of equity-focused recommendations, (6) development of an equity strategy to be included in the implementation plan, (7) assessment of resources and incentives, (8) development of a communication strategy to support an equity focus and (9) development of monitoring and evaluation strategies. This case study can be used as model for implementing clinical practice guidelines, taking into account equity issues during guideline development and implementation.


Ruptured aneurysm of the internal iliac artery.
Our case and others reported in the literature illustrate that isolated aneurysms of the internal iliac artery are uncommon lesions with a highly lethal potential. The classic signs of ruptured abdominal aneurysm--pain, palpable mass, and shock--are usually altered with rupture of these aneurysms because of their deep location in the pelvis. Rectal examination will aid diagnosis. Surgical management of IIA aneurysms 4 cm or larger is indicated at the time of diagnosis, since rupture is usually fatal.


Feeding currents facilitate a mixotrophic way of life.
Mixotrophy is common, if not dominant, among eukaryotic flagellates, and these organisms have to both acquire inorganic nutrients and capture particulate food. Diffusion limitation favors small cell size for nutrient acquisition, whereas large cell size facilitates prey interception because of viscosity, and hence intermediately sized mixotrophic dinoflagellates are simultaneously constrained by diffusion and viscosity. Advection may help relax both constraints. We use high-speed video microscopy to describe prey interception and capture, and micro particle image velocimetry (micro-PIV) to quantify the flow fields produced by free-swimming dinoflagellates. We provide the first complete flow fields of free-swimming interception feeders, and demonstrate the use of feeding currents. These are directed toward the prey capture area, the position varying between the seven dinoflagellate species studied, and we argue that this efficiently allows the grazer to approach small-sized prey despite viscosity. Measured flow fields predict the magnitude of observed clearance rates. The fluid deformation created by swimming dinoflagellates may be detected by evasive prey, but the magnitude of flow deformation in the feeding current varies widely between species and depends on the position of the transverse flagellum. We also use the near-cell flow fields to calculate nutrient transport to swimming cells and find that feeding currents may enhance nutrient uptake by ≈75% compared with that by diffusion alone. We argue that all phagotrophic microorganisms must have developed adaptations to counter viscosity in order to allow prey interception, and conclude that the flow fields created by the beating flagella in dinoflagellates are key to the success of these mixotrophic organisms.


Planning availability in stroke rehabilitation units.
The sequelae of cerebrovascular diseases constitute, and in the coming years will increasingly constitute, a major health problem. Stroke is already the leading cause of permanent invalidity, the second leading cause of dementia, and the third (on course to become the second) leading cause of death, after cardiovascular diseases and cancer. In view of the aging of the population and of the fact that stroke is strictly age-related, the incidence of stroke, in Italy, looks set to rise progressively over the coming years. In recent years, units have been set up for the specialist inpatient treatment of stroke victims, both in the acute phase (known as stroke units) and in the subsequent rehabilitative phase (stroke rehabilitation units), the aim being to improve both the management of these patients and, as a result, their functional outcome. Health policies and programming will have to take into account the need for more beds in both types of stroke unit.


Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin.
Age is the most common risk factor for Alzheimer's disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Upon systemic injection of 125I-Aβ40, 125I-Aβ42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. The brain influx of 125I-Aβ40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.


Estrogen-induced retinoic acid receptor alpha 1 gene expression: role of estrogen receptor-Sp1 complex.
Retinoic acid receptor alpha 1 (RAR alpha 1) gene expression is induced by 17 beta-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cells, and the -100 to -49 region of the RAR alpha 1 gene promoter was previously shown to be required for E2-responsiveness. This region of the RAR alpha 1 promoter was further analyzed using the following oligonucleotides: -100 to -49 (RAR4); -79 to -56 (RAR3); -79 to -49 (RAR2); -100 to -58 (RAR1); and their derived promoter reporter constructs (pRAR4, pRAR3, pRAR2, and pRAR1). In transient transfection studies in MCF-7 human breast cancer cells, pRAR2 and pRAR1 were E2-responsive; both of the RAR alpha 1 gene promoter inserts contained two GC-rich sites and bound Sp1 protein in gel mobility shift assays. Using wild-type [32P]RAR2 and oligonucleotides mutated in one or both GC-rich sites, it was shown that ER enhanced Sp1 binding to both sites, but a ternary ER-Sp1-DNA complex was not observed in gel mobility shift assays. In transient transfection assays, each of the GC-rich motifs were sufficient for E2-induced transactivation. In ER-negative MDA-MB-231 cells transiently transfected with pRAR2, E2 responsiveness was observed only in cells cotransfected with wild-type ER or 11C-ER containing a deletion of the DNA-binding domain but not with ER variants that express activation function-1 (AF-1) or AF-2. Using a similar approach, it was shown that the GC-rich sites in RAR1 were also sufficient for ER activation. These results demonstrate that interaction of a transcriptionally active ER/Sp1 complex with GC-rich motifs is required for hormone inducibility of the downstream region of the RAR alpha 1 gene promoter.


[Heart murmur--auscultation or echocardiography in the diagnostic assessment of congenital or valvular heart disease?].
The incidence of patients with degenerative valvular but also of patients with congenital heart disease surviving until adulthood or even old age will increase in the next decades. Auscultation with the stethoscope remains an important diagnostic means in the detection and treatment of heart disease. Heart murmurs (especially systolic heart murmurs) are extremely common. There are helpful clues to differentiate heart murmurs. It can occasionally be relatively simple to differentiate a systolic murmur due to valvular heart disease from an innocent, ejection murmur; however, there are important limitations of auscultation. Overall, auscultation and clinical examination alone do not suffice to correctly diagnose and treat patients with heart failure or a murmur Clinically significant aortic stenosis, aortic regurgitation and mitral regurgitation as well as hypertrophic cardiomyopathy are not uncommonly missed or misinterpreted. An echocardiographic exam is mandatory in all patients with more than a soft systolic murmur, any diastolic murmur, cardiac symptoms and/or ECG changes.


Characterizing Blunt Cerebrovascular Injuries and Stroke: A Single Center Retrospective Study.
To highlight the occurrence of ischemic stroke after blunt cerebrovascular injuries and discuss the neurologist's role in preventing and managing ischemic strokes in this trauma population. A retrospective chart review was performed and included data from 2016 to 2019 from a Level I trauma center. Demographics, injury mechanism, ischemic stroke occurrence, interventions, and neurology consultations were examined and descriptive statistics were utilized to characterize the nature of ischemic strokes and their management. A total of forty patients (81% male, average age 44) presented with blunt cerebrovascular injury, nine of whom later developed ischemic stroke. Eighteen patients had a carotid artery injury with six developing ischemic stroke. Twenty-seven patients had a vertebral artery injury with three developing ischemic stroke. Six of the nine ischemic strokes occurred on hospital day two, whereas neurology was generally consulted on hospital day four. A considerable portion of patients may go on to develop ischemic stroke following blunt cerebrovascular injuries. Polytrauma may interfere with prompt diagnosis which may contribute to delayed anti-thrombotic therapy for ischemic stroke prevention. Neurologists have the opportunity to reduce ischemic stroke burden in this trauma population and patients may benefit from earlier neurology consultation.


Ginkgo biloba extract reduces high-glucose-induced endothelial reactive oxygen species generation and cell adhesion molecule expression by enhancing HO-1 expression via Akt/eNOS and p38 MAP kinase pathways.
Hyperglycemia is one of the major risk factors leading to vascular complications in clinical diabetes mellitus. Ginkgo biloba extract (GBE), an antioxidant herbal medicine, possesses anti-inflammatory effects. We examined whether GBE can reduce high glucose-induced endothelial adhesiveness to monocytes, an in vitro sign mimicking in vivo early atherogenesis, through selective regulation of heme oxygenase (HO)-1 expression. Human aortic endothelial cells (HAECs) were cultured with normal glucose or high glucose (25 mM) for 4 days and subsequently combined with GBE (EGb761, Dr. Willmar Schwabe, Karlsruhe, Germany) treatment in the last 18 h of the 4-day period. The endothelial reactive oxygen species (ROS) generation, adhesion molecule expression and the adhesiveness to monocytes were examined. The specific signal pathways such as HO-1 were also examined. High glucose increased ROS generation, adhesion molecule expression and the adhesiveness to monocytes in HAECs. These high glucose-induced phenomena could be suppressed by GBE (100 μg/ml)-induced HO-1 expression in a dose-dependent and time-dependent manner. In addition, jun N-terminal kinases inhibitor or phosphoinositide 3 kinase inhibitor could reduce GBE-induced HO-1 expression. Furthermore, HO-1 inhibitor, HO-1 siRNA, endothelial nitric oxide synthase (eNOS) siRNA, or nuclear factor erythroid 2-related factor (Nrf) 2 siRNA blocked the cytoprotective effects of GBE. Meanwhile, p38/mitogen-activated protein kinase (MAPK) inhibitor could also reduce the effects of GBE on HO-1 induction. GBE could reduce high glucose-induced endothelial adhesion via enhancing HO-1 expression through the Akt/eNOS and p38/MAPK pathways. Our findings suggest a potential strategy targeting on HO-1 induction by GBE for endothelial protection in the presence of high glucose such as that in diabetes mellitus.


Genome-wide analysis of human hotspot intersected genes highlights the roles of meiotic recombination in evolution and disease.
Meiotic recombination events are not randomly located, but rather cluster at hotspot regions. Recently, the fine-scale mapping of genome-wide human recombination hotspots was performed. Here, we systematically analyzed the evolutionary and disease-associated features of hotspots that overlapped with protein-coding genes. In this study, we defined hotspot intersected genes as HI genes. We found that HI genes were prone to be located in the extracellular part and were functionally enriched in cell-to-cell communication. Tissue-specific genes and secreted protein encoding genes were overrepresented in HI genes, while housekeeping genes were underrepresented. Compared to slowly evolving housekeeping genes and random genes with lower recombination rates, HI genes evolved faster. The fact that brain and blood specific genes were overrepresented in HI genes indicates that they may be involved in the evolution of human intelligence and the immune system. We also found that genes related to disease were enriched in HI genes, especially genes with disease-associated chromosomal rearrangements. Hotspot sequence motifs were overrepresented in common sequences of HI genes and genes with disease-associated chromosomal rearrangements. We further listed repeat elements that were enriched both in hotspots and genes with disease-associated chromosomal rearrangements. HI genes are evolving and may be involved in the generation of key features of human during evolution. Disease-associated genes may be by-products of meiotic recombination. In addition, hotspot sequence motifs and repeat elements showed the connection between meiotic recombination and genes with disease-associated chromosomal rearrangements at the sequence level. Our study will enable us to better understand the evolutionary and biological significance of human meiotic recombination.


Effects of altering histone posttranslational modifications on mitotic chromosome structure and mechanics.
During cell division, chromatin is compacted into mitotic chromosomes to aid faithful segregation of the genome between two daughter cells. Posttranslational modifications (PTMs) of histones alter compaction of interphase chromatin, but it remains poorly understood how these modifications affect mitotic chromosome stiffness and structure. Using micropipette-based force measurements and epigenetic drugs, we probed the influence of canonical histone PTMs that dictate interphase euchromatin (acetylation) and heterochromatin (methylation) on mitotic chromosome stiffness. By measuring chromosome doubling force (the force required to double chromosome length), we find that histone methylation, but not acetylation, contributes to mitotic structure and stiffness. We discuss our findings in the context of chromatin gel modeling of the large-scale organization of mitotic chromosomes.


Corotating variations of cosmic rays near the South heliospheric pole.
Three-dimensional simulations of the heliospheric modulation of galactic cosmic ray protons show that corotating variations in the intensity can persist to quite high heliographic latitudes. Variations are seen at latitudes considerably higher than the maximum latitude extension of the heliographic current sheet, in regions where the solar wind velocity and magnetic field show no significant variation. Similar conclusions may apply also to lower energy particles, which may be accelerated at lower latitudes. Cosmic ray variations caused by corotating interaction regions present at low heliographic latitudes can propagate to significantly higher latitudes.


Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations.
Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8(+) T-cell epitope, nonstructural protein (NS)5B(2841-2849) (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B(2936-2944) (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a-infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27(+) subjects, rare escape mutations arose at the HLA-B27 anchor residue, R(2937) , which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from <5% to ≥ 70% of wild-type levels. The selection of rare CTL escape mutations in this HLA-B27-restricted epitope dramatically impairs viral replicative fitness, unless properly compensated. These data support a role for the targeting of highly constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens.


[Thyroid cancer in childhood and adolescence--report of 15 cases].
Thyroid tumors are rare in childhood and adolescence. A retrospective analysis was done of fifteen patients (8 female) with thyroid carcinoma attended in the Pediatric Endocrinology Unit of the HC-UFPR, from February 1988 to March 2003. The most frequent initial complaint was an anterior cervical nodule. Ten patients were papillary carcinoma (PTC) bearers, four had medullary carcinoma (MTC; three of them with MEN-2B) and one had follicular carcinoma. Two patients with MEN-2B have de novo proto-oncogene RET mutation (Met918Thr). Fine needle aspiration (FNA) was performed in ten patients and was malignancy positive in only five of them. All patients underwent total thyroidectomy. Adjuvant radioiodine (131I) therapy was made in ten patients. Two patients died from unrelated diseases. Nine patients presented no clinical or laboratorial evidence of disease; one (PTC) developed recurrence 5 years after initial treatment and three (1 PTC, 2 MTC) have disease evidence yet. Our prognosis and clinical manifestations data are according to the literature. However, MTC prevalence (27%), sex distribution and FNA results differ from the majority of published casuistics, that can be attributed to the number of cases reported here.


Identifying genetic loci controlling neonatal passive transfer of immunity using a hybrid genotyping strategy.
Colostrum intake is critical to a piglet's survival and can be measured by precipitating out the γ-immunoglobulins from serum with ammonium sulfate (immunocrit). Genetic analysis of immunocrits on 5312 piglets indicated that the heritabilities (se) for direct and maternal effects were 0.13 (0.06) and 0.53 (0.08) respectively. To identify QTL for direct genetic effects, piglets with the highest and lowest immunocrits from 470 litters were selected. Six sets of DNA pools were created based on sire of the litter. These 12 DNA pools were applied to Illumina Porcine SNP60 BeadChips. Normalized X and Y values were analyzed. Three different SNP selection methods were used: deviation of the mean from high vs. low pools, the deviation adjusted for variance based on binomial theory and ANOVA. The 25 highest ranking SNPs were selected from each evaluation for further study along with 12 regions selected based on a five-SNP window approach. Selected SNPs were individually genotyped in the 988 piglets included in pools as well as in 524 piglets that had intermediate immunocrits. Association analyses were conducted fitting an animal model using the estimated genetic parameters. Nineteen SNPs were nominally associated (P < 0.01) with immunocrit values, of which nine remained significant (P < 0.05) after Bonferroni correction, located in 16 genomic regions on 13 chromosomes. In conclusion, the pooling strategy reduced the cost to scan the genome by more than 80% and identified genomic regions associated with a piglet's ability to acquire γ-immunoglobulin from colostrum. Each method to rank SNPs from the pooled analyses contributed unique validated markers, suggesting that multiple analyses will reveal more QTL than a single analysis.


A mini scanning device for profiling charged beams.
In this article, we present the development of a mini scanner device to characterize the full transverse spatial density of a charged particle beam using computed tomography. The profiler consists of a wire mounted on a linear translator that can rotate around the beam. Tests were performed on a millimeter electron beam with 200 eV energy and 100 nA intensity, which allowed us to control and monitor both beam focusing and deflection.


Formulations of hormone therapy and risk of Parkinson's disease.
Hormone therapy (HT) is a class of medications widely prescribed to women in the Western world. Evidence from animal models and in vitro studies suggests that estrogen may protect against nigrostriatal system injury and increase dopamine synthesis, metabolism, and transport. Existing epidemiologic research indicates a possible reduced risk of Parkinson's disease (PD) associated with HT use. The objective of this study was to evaluate PD risk associated with specific HT formulations. Neurologist-confirmed cases and age-matched controls were identified from Group Health Cooperative (GHC) of Washington State. Final analysis included 137 female cases and 227 controls. Hormone therapy use was ascertained from the GHC pharmacy database, further classified as conjugated estrogens, esterified estrogens, and progestin. Ever use of HT formulation demonstrated a suggested elevated risk with esterified estrogen use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.0-9.8), and no risk associated with conjugated estrogen use (OR, 0.6; 95% CI, 0.6-1.3). Restricting this analysis to prescriptions that included progestin further elevated the risk associated with esterified estrogen use (OR, 6.9; 95% CI, 2.1-22.9); again, no risk was associated with conjugated estrogen use (OR, 1.7; 95% CI, 0.6-5.0). The findings from this study suggest an increase in PD risk associated with esterified estrogen use combined with progestin, and no risk associated with conjugated estrogen with progestin. These findings could have important implications for choice of HT in clinical practice.


Dynamical optimal training for interval type-2 fuzzy neural network (T2FNN).
Type-2 fuzzy logic system (FLS) cascaded with neural network, type-2 fuzzy neural network (T2FNN), is presented in this paper to handle uncertainty with dynamical optimal learning. A T2FNN consists of a type-2 fuzzy linguistic process as the antecedent part, and the two-layer interval neural network as the consequent part. A general T2FNN is computational-intensive due to the complexity of type 2 to type 1 reduction. Therefore, the interval T2FNN is adopted in this paper to simplify the computational process. The dynamical optimal training algorithm for the two-layer consequent part of interval T2FNN is first developed. The stable and optimal left and right learning rates for the interval neural network, in the sense of maximum error reduction, can be derived for each iteration in the training process (back propagation). It can also be shown both learning rates cannot be both negative. Further, due to variation of the initial MF parameters, i.e., the spread level of uncertain means or deviations of interval Gaussian MFs, the performance of back propagation training process may be affected. To achieve better total performance, a genetic algorithm (GA) is designed to search optimal spread rate for uncertain means and optimal learning for the antecedent part. Several examples are fully illustrated. Excellent results are obtained for the truck backing-up control and the identification of nonlinear system, which yield more improved performance than those using type-1 FNN.


Hybrid imaging is the future of molecular imaging.
Correlative imaging has long been used in clinical practice and particularly for the interpretation of nuclear medicine studies wherein detailed anatomical information is often lacking. Previously, side-by-side comparison or software co-registration techniques were applied but suffered from technical limitations related to the differing geometries of the imaging equipment, differences in the positioning of patients and displacement of mobile structures between studies. The development of the first hybrid PET and CT device struck a chord with the medical imaging community that is still ringing loudly throughout the world. So successful has been the concept of PET-CT that none of the major medical imaging manufacturers now offers stand-alone PET scanners. Following close behind this success, SPECT-CT devices have recently been adopted by the nuclear medicine community, already compelled by the benefits of hybrid imaging through their experience with PET-CT. Recent reports of adaptation of PET detectors to operate within the strong magnetic field of MRI scanners have generated further enthusiasm. Prototype PET-MRI devices are now in development. The complementary anatomical, functional and molecular information provided by these techniques can now be presented in an intuitive and aesthetically-pleasing format. This has made end-users more comfortable with the results of functional imaging techniques than when the same information is presented independently. Despite the primacy of anatomical imaging for locoregional disease definition, the molecular characterisation available from PET and SPECT offers unique complementary information for cancer evaluation. A new era of cancer imaging, when hybrid imaging will be the primary diagnostic tool, is approaching.


Avian influenza overview February - May 2021.
The 2020-2021 epidemic with a total of 3,555 reported HPAI detections and around 22,400,000 affected poultry birds in 28 European Countries appears to be one of the largest and most devastating HPAI epidemics ever occurred in Europe. Between 24 February and 14 May 2021, 1,672 highly pathogenic avian influenza (HPAI) virus detections were reported in 24 EU/EEA countries and the UK in poultry (n=580), and in wild (n=1,051) and captive birds (n=41). The majority of the detections in poultry were reported by Poland that accounted for 297 outbreaks occurring in a densely populated poultry area over a short period of time, followed by Germany with 168 outbreaks. Germany accounted for 603 detections in wild birds, followed by Denmark and Poland with 167 and 56 detections, respectively. A second peak of HPAI-associated wild bird mortality was observed from February to April 2021 in north-west Europe. The observed longer persistence of HPAI in wild birds compared to previous years may result in a continuation of the risk for juveniles of wild birds and mammals, as well as for virus entry into poultry farms. Therefore, enhanced awareness among farmers to continue applying stringent biosecurity measures and to monitor and report increases in daily mortality and drops in production parameters, are recommended. Sixteen different genotypes were identified to date in Europe and Russia, suggesting a high propensity of these viruses to reassort. The viruses characterized to date retain a preference for avian-type receptors; however, transmission events to mammals and the identification of sporadic mutations of mammal adaptation, indicate ongoing evolution processes and possible increased ability of viruses within this clade to further adapt and transmit to mammals including humans. Since the last report, two human infections due to A(H5N6) HPAI were reported from China and Laos and 10 human cases due to A(H9N2) low pathogenic avian influenza (LPAI) virus identified in China and Cambodia. The risk of infection for the general population in the EU/EEA is assessed as very low and for occupationally exposed people low. People exposed during avian influenza outbreaks should adhere to protection measures, strictly wear personal protective equipment and get tested immediately when developing respiratory symptoms or conjunctivitis within 10 days after exposure.


Treatment of noise caused by radiation damage during cryo-EM data collection.
Here, we discuss how noise that is caused by radiation damage during cryo-EM data collections accumulates during single-particle analysis (SPA), MicroED, and cryo-ET. For MicroED and SPA, bad data can be identified and excluded during data collection and processing, whereas cryo-ET will require systematic radiation damage assessments that can be derived from SPA.


Immunogenetic analysis of patients with post-schistosomal liver cirrhosis in man.
Immune responsiveness of 121 patients with post-schistosomal liver cirrhosis to schistosomal antigens was investigated. Out of 78 patients, only five (6.4%) showed low responsiveness to schistosomal adult worm antigen whereas 73 (93.6%) were high responders. Out of 57 healthy individuals with previous schistosomal infection, low responders were found in 17.5%. The frequency of low responders to schistosomal adult worm antigen was significantly decreased in the patients with post-schistosomal liver cirrhosis (P less than 0.05). Out of 121 patients, a significant increase in frequency of HLA-Bw44-DEn haplotype was observed (corrected P less than 0.02). On the other hand, HLA-Bw52-Dw12 haplotype which was reported to be in strong linkage disequilibrium with an immune suppression gene for schistosomal adult worm antigen was significantly decreased (corrected P less than 0.005). These observations suggested that an HLA-linked immune suppression gene controlled susceptibility or resistance to post-schistosomal liver cirrhosis through regulation of immune responsiveness of the hosts to schistosomal antigen in man.


Disparate chromatin landscapes and kinetics of inactivation impact differential regulation of p53 target genes.
The p53 transcription factor regulates the expression of genes involved in cellular responses to stress, including cell cycle arrest and apoptosis. The p53 transcriptional program is extremely malleable, with target gene expression varying in a stress- and cell type-specific fashion. The molecular mechanisms underlying differential p53 target gene expression remain elusive. Here we provide evidence for gene-specific mechanisms affecting expression of three important p53 target genes. First we show that transcription of the apoptotic gene PUMA is regulated through intragenic chromatin boundaries, as revealed by distinct histone modification territories that correlate with binding of the insulator factors CTCF, Cohesins and USF1/2. Interestingly, this mode of regulation produces an evolutionary conserved long non-coding RNA of unknown function. Second, we demonstrate that the kinetics of transcriptional competence of the cell cycle arrest gene p21 and the apoptotic gene FAS are markedly different in vivo, as predicted by recent biochemical dissection of their core promoter elements in vitro. After a pulse of p53 activity in cells, assembly of the transcriptional apparatus on p21 is rapidly reversed, while FAS transcriptional activation is more sustained. Collectively these data add to a growing list of p53-autonomous mechanisms that impact differential regulation of p53 target genes.


Longitudinal changes in within-salience network functional connectivity mediate the relationship between childhood abuse and neglect, and mental health during adolescence.
Understanding the neurobiological underpinnings of childhood maltreatment is vital given consistent links with poor mental health. Dimensional models of adversity purport that different types of adversity likely have distinct neurobiological consequences. Adolescence is a key developmental period, during which deviations from normative neurodevelopment may have particular relevance for mental health. However, longitudinal work examining links between different forms of maltreatment, neurodevelopment, and mental health is limited. In the present study, we explored associations between abuse, neglect, and longitudinal development of within-network functional connectivity of the salience (SN), default mode (DMN), and executive control network in 142 community residing adolescents. Resting-state fMRI data were acquired at age 16 (T1; M = 16.46 years, s.d. = 0.52, 66F) and 19 (T2; mean follow-up period: 2.35 years). Mental health data were also collected at T1 and T2. Childhood maltreatment history was assessed prior to T1. Abuse and neglect were both found to be associated with increases in within-SN functional connectivity from age 16 to 19. Further, there were sex differences in the association between neglect and changes in within-DMN connectivity. Finally, increases in within-SN connectivity were found to mediate the association between abuse/neglect and lower problematic substance use and higher depressive symptoms at age 19. Our findings suggest that childhood maltreatment is associated with altered neurodevelopmental trajectories, and that changes in salience processing may be linked with risk and resilience for the development of depression and substance use problems during adolescence, respectively. Further work is needed to understand the distinct neurodevelopmental and mental health outcomes of abuse and neglect.


Recognition of the centromere-specific histone Cse4 by the chaperone Scm3.
A specialized nucleosome is a component of all eukaryotic kinetochores. The core of this nucleosome contains a centromere-specific histone, CENP-A (the Cse4 gene product in budding yeast), instead of the usual H3. Assembly of a centromeric nucleosome depends on a specific chaperone, called Scm3 in yeast and HJURP in higher eukaryotes. We describe here the structure of a complex formed by an N-terminal fragment of Scm3 with the histone-fold domains of Cse4, and H4, all prepared as recombinant proteins derived from the budding yeast Kluyveromyces lactis. The contacts of Scm3 with Cse4 explain its selectivity for the centromere-specific histone; key residues at the interface are conserved in HJURP, indicating a common mechanism for centromeric-histone deposition. We also report the structure of a (Cse4 : H4)(2) heterotetramer; comparison with the structure of the Scm3:Cse4:H4 complex shows that tetramer formation and DNA-binding require displacement of Scm3 from the nucleosome core. The two structures together suggest that specific contacts between the chaperone and Cse4, rather than an altered overall structure of the nucleosome core, determine the selective presence of Cse4 at centromeres.


Effect of exercise intensity on abdominal fat loss during calorie restriction in overweight and obese postmenopausal women: a randomized, controlled trial.
Exercise intensity may affect the selective loss of abdominal adipose tissue. This study showed whether aerobic exercise intensity affects the loss of abdominal fat and improvement in cardiovascular disease risk factors under conditions of equal energy deficit in women with abdominal obesity. This was a randomized trial in 112 overweight and obese [body mass index (in kg/m(2)): 25-40; waist circumference >88 cm], postmenopausal women assigned to one of three 20-wk interventions of equal energy deficit: calorie restriction (CR only), CR plus moderate-intensity aerobic exercise (CR + moderate-intensity), or CR plus vigorous-intensity exercise (CR + vigorous-intensity). The diet was a controlled program of underfeeding during which meals were provided at individual calorie levels (approximately 400 kcal/d). Exercise (3 d/wk) involved treadmill walking at an intensity of 45-50% (moderate-intensity) or 70-75% (vigorous-intensity) of heart rate reserve. The primary outcome was abdominal visceral fat volume. Average weight loss for the 95 women who completed the study was 12.1 kg (+/-4.5 kg) and was not significantly different across groups. Maximal oxygen uptake ( O(2)max) increased more in the CR + vigorous-intensity group than in either of the other groups (P < 0.05). The CR-only group lost relatively more lean mass than did either exercise group (P < 0.05). All groups showed similar decreases in abdominal visceral fat (approximately 25%; P < 0.001 for all). However, changes in visceral fat were inversely related to increases in O(2)max (P < 0.01). Changes in lipids, fasting glucose or insulin, and 2-h glucose and insulin areas during the oral-glucose-tolerance test were similar across treatment groups. With a similar amount of total weight loss, lean mass is preserved, but there is not a preferential loss of abdominal fat when either moderate- or vigorous-intensity aerobic exercise is performed during caloric restriction. This trial was registered at (ClinicalTrials.gov) as: NCT00664729.


AT2 receptor activities and pathophysiological implications.
Although angiotensin II subtype-2 receptor (AT2R) was discovered over 2 decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1 receptor (AT1R). A major obstacle for AT2R investigations was the lack of specific agonists. Most of the earlier AT2R studies were performed using the peptidic agonist, CG42112A, or the nonpeptidic antagonist PD123319. CGP42112A is nonspecific for AT2R and in higher concentrations can bind to AT1R. Recently, the development of specific nonpeptidic AT2R agonists boosted the efforts in identifying the therapeutic potentials for AT2R stimulation. Unlike AT1R, AT2R is involved in vasodilation by the release of bradykinin and nitric oxide, anti-inflammation, and healing from injury. Interestingly, the vasodilatory effects of AT2R stimulation were not associated with significant reduction in blood pressure. In the kidney, AT2R stimulation produced natriuresis, increased renal blood flow, and reduced tissue inflammation. In animal studies, enhanced AT2R function led to reduction of cardiac inflammation and fibrosis, and reduced the size of the infarcted area. Similarly, AT2R stimulation demonstrated protective effects in vasculature and brain.


The submergence tolerance regulator Sub1A mediates stress-responsive expression of AP2/ERF transcription factors.
We previously characterized the rice (Oryza sativa) Submergence1 (Sub1) locus encoding three ethylene-responsive factor (ERF) transcriptional regulators. Genotypes carrying the Sub1A-1 allele are tolerant of prolonged submergence. To elucidate the mechanism of Sub1A-1-mediated tolerance, we performed transcriptome analyses comparing the temporal submergence response of Sub1A-1-containing tolerant M202(Sub1) with the intolerant isoline M202 lacking this gene. We identified 898 genes displaying Sub1A-1-dependent regulation. Integration of the expression data with publicly available metabolic pathway data identified submergence tolerance-associated pathways governing anaerobic respiration, hormone responses, and antioxidant systems. Of particular interest were a set of APETALA2 (AP2)/ERF family transcriptional regulators that are associated with the Sub1A-1-mediated response upon submergence. Visualization of expression patterns of the AP2/ERF superfamily members in a phylogenetic context resolved 12 submergence-regulated AP2/ERFs into three putative functional groups: (1) anaerobic respiration and cytokinin-mediated delay in senescence via ethylene accumulation during submergence (three ERFs); (2) negative regulation of ethylene-dependent gene expression (five ERFs); and (3) negative regulation of gibberellin-mediated shoot elongation (four ERFs). These results confirm that the presence of Sub1A-1 impacts multiple pathways of response to submergence.


Long-lived charge carrier generation in ordered films of a covalent perylenediimide-diketopyrrolopyrrole-perylenediimide molecule.
The photophysics of a covalently linked perylenediimide-diketopyrrolopyrrole-perylenediimide acceptor-donor-acceptor molecule (PDI-DPP-PDI, 1) were investigated and found to be markedly different in solution versus in unannealed and solvent annealed films. Photoexcitation of 1 in toluene results in quantitative charge separation in τ = 3.1 ± 0.2 ps, with charge recombination in τ = 340 ± 10 ps, while in unannealed/disordered films of 1, charge separation occurs in τ < 250 fs, while charge recombination displays a multiexponential decay in ∼6 ns. The absence of long-lived, charge separation in the disordered film suggests that few free charge carriers are generated. In contrast, upon CH2Cl2 vapor annealing films of 1, grazing-incidence X-ray scattering shows that the molecules form a more ordered structure. Photoexcitation of the ordered films results in initial formation of a spin-correlated radical ion pair (electron-hole pair) as indicated by magnetic field effects on the formation of free charge carriers which live for ∼4 μs. This result has significant implications for the design of organic solar cells based on covalent donor-acceptor systems and shows that long-lived, charge-separated states can be achieved by controlling intramolecular charge separation dynamics in well-ordered systems.


[Capabilities of radiodiagnostic techniques for evaluating myocardial hemodynamics and contractility in ventricular arrhythmias].
As of now, the study of ventricular arrhythmias (VA) is of topical interest for modern arrhythmology and cardiology. These arrhythmias constitute about 30% of all the arrhythmias and have a diverse etiopathogenetic basis. Having no noticeable impact on a patient's quality of life, VA may cause ventricular fibrillation, severe circulatory disorders, and sudden cardiac death. Objective of this study--to compare the capabilities of radiation techniques for evaluating ventricular hemodynamics and contractility in patients with VA. A multitude of current radiodiagnostic methods, among which the most preferential technique cannot be set aside to reveal the causes of and to study hemodynamic disorders, is now used to evaluate ventricular hemodynamics and contractility in patients with VA. Each procedure has its usage features in a contingent of patients with arrhythmias.


Effect of zinc oxide nanocomposite and ginger extract on lipid profile, glucose, pancreatic tissue and expression of Gpx1 and Tnf-α genes in diabetic rat model.
Diabetes is a life-threatening health condition that requires expensive treatment and places a significant financial burden on society. Consequently, this study aimed to explore the potential of low and high concentrations of ginger extract, ZnO-NPs, and a combination of both to help manage diabetes and reduce high levels of lipids in diabetic rats. The research focused on agglomerated nanoparticles under 100 nm, specifically ZnO nanoparticles. The size of the nanoparticles was determined using X-ray diffraction analysis and scanning electron microscopy analysis, with a monodisperse particle size distribution of 20 to 48 nm and an average size of 38 nm, as shown by dynamic light scattering. Fourier transform infrared spectroscopy revealed the presence of typical peaks of ginger extract and ZnO-NPs in the nanocomposite structure. The pancreatic tissue histopathological study indicated that a concentration of 10 mg/kg of the composite had the most significant antidiabetic effect compared to other treatments. Lower concentrations could significantly reduce and balance fasting blood sugar and triglycerides levels while also increasing the high-density lipoproteins levels. However, all treatments induced a significant decrease in total cholesterol and low-density lipoproteins levels. Only metformin and ZnO-NPs in lower concentrations could decrease very low-density lipoproteins levels. The molecular technique showed that a low concentration of the composite led to the most significant decrease in Tnf-α gene expression compared to the diabetic group. The expression of the glutathione peroxidase 1 (Gpx1) gene in treated groups had no significant difference with the level of Gpx1 expression in the control rats. In general, this study demonstrated that lower concentrations of the treatments, especially composite, were more effective for treating diabetic rats due to reduced pancreatic tissue damage.


Long-Term Indomethacin Treatment in a Chinese Child with Gitelman Syndrome: Case Report and Literature Review on its Efficacy and Tolerance.
BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. CASE REPORT A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. CONCLUSIONS Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects.


Impact of redox-mediators in the degradation of olsalazine by marine-derived fungus, Aspergillus aculeatus strain bpo2: Response surface methodology, laccase stability and kinetics.
The indiscriminate disposal of olsalazine in the environment poses a threat to human health and natural ecosystems because of its cytotoxic and genotoxic nature. In the present study, degradation efficiency of olsalazine by the marine-derived fungus, Aspergillus aculeatus (MT492456) was investigated. Optimization of physicochemical parameters (pH. Temperature, Dry weight) and redox mediators {(2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), p-Coumaric acid and 1-hydroxybenzotriazole (HOBT)} was achieved with Response Surface Methodology (RSM)-Box-Behnken Design (BBD) resulting in 89.43% removal of olsalazine on 7th day. The second-order polynomial regression model was found to be statistically significant, adequate and fit with p < 0.0001, F value=41.87 and correlation coefficient (R2=0.9826). Biotransformation was enhanced in the redox mediator-laccase systems resulting in 99.5% degradation of olsalazine. The efficiency of ABTS in the removal of olsalazine was more pronounced than HOBT and p-Coumaric acid in the laccase-mediator system. This is attributed to the potent nature of the electron transfer mechanism deployed during oxidation of olsalazine. The pseudo-second-order kinetics revealed that the average half-life (t1/2) and removal rates (k1) increases with increasing concentrations of olsalazine. Michaelis-Menten kinetics affirmed the interaction between laccase and olsalazine under optimized conditions with maximum removal rate, Vmax=111.11 hr-1 and half-saturation constant, Km=1537 mg L-1. At the highest drug concentration (2 mM); 98%, 95% and 93% laccase was remarkably stabilized in the enzyme-drug degradation system by HOBT, ABTS and p-Coumaric acid respectively. This study further revealed that the deactivation of laccase by the redox mediators is adequately compensated with enhanced removal of olsalazine.


Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology.
KCC2 is a vital neuronal K+/Cl- cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007 We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+ ) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.


E (XSR) element contributes to the oncogenicity of Avian leukosis virus (subgroup J).
Among the six subgroups of Avian leukosis virus (ALV) that infect chickens, subgroup J (ALV-J) was isolated from meat-type chickens where it predominantly induces myeloid leukosis (ML) and erythroblastosis (EB). The sequence of HPRS-103, the ALV-J prototype virus, shows several distinct features, one of which is the presence of a distinct hairpin stem-loop structure called the E (also called XSR) element in the 3' untranslated region. In order to determine the role of the E element in ALV-induced pathogenicity, a comparison was made of the oncogenicity of viruses derived from the provirus clones of parental and E element-deleted HPRS-103 viruses in two genetically distinct lines of birds. In line 15I birds, deletion of the E element had profound effects on virus replication in vivo, as only 55 % of birds showed evidence of infection, compared with 100 % infection by the parental virus. Furthermore, none of the line 15I birds infected with this virus developed tumours, indicating that the E element does contribute to the oncogenicity of the virus. On the other hand, deletion of the E element had only a marginal effect on the incidence of tumours in line 0 birds. These results indicate that, although the E element per se is not absolutely essential for tumour induction by this subgroup of viruses, it does contribute to oncogenicity in certain genetic lines of chicken.


Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota.
A unique feature of hepatitis B virus (HBV) infection in humans is that viral clearance heavily depends on the age of exposure. However, the reason for this remains unclear. Here we show that gut microbiota contribute to the age dependence of HBV immunity in a hydrodynamic transfection mouse model. Although adult (12-wk-old) C3H/HeN mice cleared HBV within 6 wk postinjection (wpi), their young (6-wk-old) counterparts remained HBV-positive at 26 wpi. Sterilization of gut microbiota from 6 to 12 wk of age using antibiotics prevented adult mice from rapidly clearing HBV. Young mice with the Toll-like-receptor (TLR) 4 mutation (C3H/HeJ) exhibited rapid HBV clearance. The results suggest that an immuno-tolerating pathway to HBV prevailed in young mice, before the establishment of gut bacteria, through a TLR4-dependent pathway and that the maturation of gut microbiota in adult mice stimulated liver immunity, resulting in rapid HBV clearance.


Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood.
Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life. Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the quality of life (WHOQoL -BREF). Seventy three patients were included in the study, among them 59/73 (81%) were transferred to adult endocrinologist by their pediatricians for transition. WHOQoL -BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global quality of life than the group without regular follow-up after transition. Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and with better QoL in adults with CAH.


Inspiratory lung impedance in COPD: effects of PEEP and immediate impact of lung volume reduction surgery.
Frequency-dependent characteristics of lung resistance (RL) and elastance (EL) are sensitive to different patterns of airway obstruction. We used an enhanced ventilator waveform (EVW) to measure inspiratory RL and EL spectra in ventilated patients during thoracic surgery. The EVW delivers an inspiratory flow waveform with enhanced spectral excitation from 0.156 to 8.1 Hz. Estimates of the coefficients in a trigonometric approximation of the EVW flow and transpulmonary pressure inspirations yielded inspiratory RL and EL spectra. We applied the EVW in a group with mild obstruction undergoing various thoracoscopic procedures (n = 6), and another group with severe chronic obstructive pulmonary disease undergoing lung volume reduction surgery (n = 8). Measurements were made at positive end-expiratory pressure (PEEP) of 0, 3, and 6 cmH(2)O. Inspiratory RL was similar in both groups despite marked differences in spirometry. The chronic obstructive pulmonary disease patients demonstrated a pronounced frequency-dependent increase in inspiratory EL consistent with severe heterogeneous peripheral airway obstruction. PEEP appears to have beneficial effects by reducing peripheral airway resistance. Lung volume reduction surgery resulted in increased inspiratory RL and EL at all frequencies and PEEPs, possibly due to loss of diseased lung tissue, pulmonary edema, increased mechanical heterogeneity, and/or an improvement in airway tethering.


Hyaluronic acid and periodontitis.
Hyaluronic acid (HA; synonyms--Hyaluronan, Hyaluronate) is a glycosaminoglycan found in the connective tissue of vertebrates. It is the most abundant glycosaminoglycan of higher molecular weight in the extracellular matrix of soft periodontal tissues. The use of HA in the treatment of inflammatory process is established in medical areas such as orthopedics, dermatology and ophthalmology. In the field of dentistry, it has shown anti-inflammatory and anti-bacterial effects in gingivitis and periodontitis therapy. Due to its tissue healing properties, it could be used as an adjunct to mechanical therapy in the treatment of periodontitis.


[Measuring quality of life in every oncological patient].
There are indications that in cancer patients quality of life is a better predictor of survival than clinical measures such as tumour response and stage of disease. In addition, health care professionals' expectations about the effect of a particular treatment on quality of life often do not correspond with the experience of the patient. These are all reasons for every oncological patient to complete a short questionnaire on quality of life. Using this questionnaire can improve communication between care provider and patient, and also give the care provider insight into the problems that are important to the patient at that time. This insight could subsequently lead to counseling tailored to the patient, and, if necessary, modification of treatment or referral for supportive care. A second aim is to link information on quality of life to clinical pathways and treatment guidelines.


Autoerythrocyte sensitization (Gardner-Diamond syndrome) in men: a case report and review of the literature.
Autoerythrocyte sensitization (AES) is a rare syndrome particularly among males. A young male with typical AES is herewith described. We review all seven published cases of AES in men for which details are available and compare the age of onset, somatic manifestations, associated diseases and psychiatric disturbances between the sexes. We emphasize that the criteria essential for a diagnosis of AES should include typical clinical presentation, longstanding clinical history and a positive skin test with the patient's blood. Because of the rarity of AES there is a lack of awareness regarding it among many doctors.


Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated.
Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. The concept was introduced in Medical Genetics by Engel (1980); Am J Med Genet 6:137-143. Aside UPD 15, which is the most frequent one, up to now (February 2005) 197 cases with whole chromosome maternal UPD other than 15 (124 X heterodisomy, 59 X isodisomy, and 14 cases without information of the mode of UPD) and 68 cases with whole chromosome paternal UPD other than 15 (13 X heterdisomy, 53 X isodisomy, and 2 cases without information of the mode of UPD) have been reported. In this review we discuss briefly the problems associated with UPD and provide a comprehensive clinical summary with a bibliography for each UPD other than 15 as a guide for genetic counseling.


Congenital interruption of the portal vein and caudal vena cava in dogs: six case reports and a review of the literature.
To describe six dogs with congenital abnormalities involving the portal vein, caudal vena cava, or both. Six client-owned dogs with congenital interruption of the portal vein or the caudal vena cava, or both. Portal vein and caudal vena cava anatomy was evaluated by contrast radiography and visualization at surgery. Vascular casts or plastinated specimens were obtained in three animals. Portal blood shunted into the caudal vena cava in four dogs and the left hepatic vein in one. Two of these five dogs also had interruption of the caudal vena cava with continuation as azygous vein, as did an additional dog, in which the portal vein was normally formed. Portal vein interruption was present in 5 of 74 (6.8%) dogs with congenital portosystemic shunts evaluated at the Veterinary Teaching Hospital during the study period. Serious malformations of the abdominal veins were present in more than 1 in 20 dogs with single congenital portosystemic shunts. Veterinarians involved in diagnosis and surgery for portosystemic shunts should be aware of these potential malformations, and portal vein continuity should be evaluated in all dogs before attempting shunt attenuation.


Utility of F-18 fluorodeoxyglucose posıtron emıssıon tomography/computed ın carcınoma of unknown primary.
Carcinoma of unknown primary (CUP) is a heterogeneous group of tumors with various clinical features causing diagnostic and therapeutic challenges. The aim of this study was to evaluate the ability of F-18 FDG PET/CT for localizing the primary tumor, disclosing additional metastases, and changing the treatment in patients with CUP. One hundred and twelve metastatic patients (female = 40, male = 72, median age = 60.5 years) in whom conventional diagnostic work-up failed to disclose the primary tumor were included in the study. F-18 FDG PET/CT imaging was performed in a standard protocol (patient supine, arms on patient's side, vertex to thigh, 369.3 MBq (296-444 MBq) F-18 FDG, a 60-minute uptake period, 6-7 bed position). Histopathology was taken as the only reference standard. F-18 FDG PET/CT correctly detected primary tumor in 37 of 112 (33.03%) patients. The most common site of primary tumor detected by F-18 FDG PET/CT was lung (n = 18), which was followed by nasopharynx (n = 7), pancreas (n = 5), tonsil (n = 2), breast (n = 2), thyroid (n = 1), uterus (n = 1) and colon/rectum (n = 1). F-18 FDG PET/CT imaging disclosed additional previously undetected metastases in 32 (28.5%) and changed the treatment in 33 (29.4%) of 112 patients. There were false positive F-18 FDG PET/CT results in 21 (18.5%) patients. F-18 FDG PET/CT is able to disclose the primary tumor, disclose new metatases and change the treatment in about one third of patients with CUP.


Human subcutaneous dirofilariasis of forearm an unusual presentation.
Human subcutaneous dirofilariasis (HSD) is a rare zoonotic filarial infection caused by filarial worms of the genus Dirofilaria. In view, recent rise in human Dirofilaria repens infections in several regions of the world, is considered as emerging zoonotic infection transmitted to man by zooanthrophilic blood sucking insects. Most of the documented cases of human dirofilariasis recorded in India are ocular infections and very few cases of subcutaneous dirofilariasis have been reported. We hereby present a case of subcutaneous human dirofilariasis of forearm and also emphasize on increased awareness of this entity for clinicians and pathologists in the differential diagnosis of patients with subcutaneous nodules.


N-tert-butyl-N'-[5-cyano-2-(4-methylphenoxy)phenylsulfonyl]urea, a new TXA₂ receptor antagonist.
The title compound, C₁₉H₂₁N₃O₄S, crystallizes in the space group P2/c with two molecules in the asymmetric unit. The conformation of both molecules is very similar and is mainly determined by an intramolecular N-H∙∙∙O hydrogen bond between a urea N atom and a sulfonyl O atom. The O and second N atom of the urea groups are involved in dimer formation via N-H∙∙∙O hydrogen bonds. The intramolecular hydrogen-bonding motif and conformation of the C-SO₂-NH(C=O)-NH-C fragment are explored and compared using the Cambridge Structural Database and theoretical calculations. The crystal packing is characterized by π-π stacking between the 5-cyanobenzene rings.


[Oxygen diffusion through the walls of arterial vessels].
A newly developed mathematical model aided to study the regularities of the oxygen tension distribution in the wall of arterial vessels and in surrounding tissues at different physiological and morphological parameters determining the O2 transport in tissues. The model consists of a system of the second order differential equations. The maximal level of the oxygen tension in outer wall of the vessels was observed in arteriolar vessels of 80-160 mu diameter. The model computations suggest that the arteriolar vessels with the wall thickness over 120 mu, for normal functioning of their outer wall's cells, must obtain oxygen not only from their own blood but from an additional source, too.


A cluster of blood-based protein biomarkers reflecting coagulation relates to the burden of cerebral small vessel disease.
Biological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated with the burden of cSVD provides leads on underlying biological processes. In 494 participants (mean age 67.6 ± 8.7 years; 36% female; 75% cardiovascular diseases; 25% reference participants) we assessed the relation between 92 blood-based biomarkers from the OLINK cardiovascular III panel and cSVD, using cluster-based analyses. We focused particularly on white matter hyperintensities (WMH). Nineteen biomarkers individually correlated with WMH ratio (r range: 0.16-0.27, Bonferroni corrected p-values <0.05), of which sixteen biomarkers formed one biomarker cluster. Pathway analysis showed that this biomarker cluster predominantly reflected coagulation processes. This cluster related also significantly to other cSVD manifestations (lacunar infarcts, microbleeds, and enlarged perivascular spaces), which supports generalizability beyond WMHs. To study possible causal effects of biological processes reflected by the cluster we performed a mediation analysis that showed a mediation effect of the cluster on the relation between age and WMH ratio (proportion mediated 17%), and hypertension and WMH-volume (proportion mediated 21%). In conclusion, we identified a cluster of blood-based biomarkers reflecting coagulation, that is related to manifestations of cSVD, corroborating involvement of coagulation abnormalities in the etiology of cSVD.


Selective activation of the calcium signaling pathway by altered peptide ligands.
We previously demonstrated that altered peptide ligands (APL) can partially activate T cells, resulting in multiple distinct functional phenotypes, including the induction of anergy. Such APL stimulate a unique pattern of T cell receptor (TCR) phospho-zeta species, and lack associated ZAP-70 kinase activity. While these data suggested that selective signaling pathways downstream of the TCR/CD3 molecules are activated upon APL stimulation, they did not directly demonstrate this. Thus, we pursued intracellular signaling events successfully stimulated by APL. Because our previous studies showed that cyclosporin A (CsA) completely inhibited anergy induction, we assessed whether TCR ligation by APL cause a rise in cytosolic calcium (Ca+2). Our results show that these ligands can induce Ca+2 transients, in contrast to data generated using analogue peptides in other antigen systems. These opposing results may reflect differences in the intracellular signaling pathways utilized by different APL, or may be due to the exquisite sensitivity of the assay used here. Importantly, the APL-stimulated Ca+2 induction is both initiated and sustained at lower levels than that stimulated by a strong agonist signal, but resembles that stimulated by a weaker agonist stimulus. Alone, the less than optimal Ca+2 induction does not cause anergy, because ionomycin treatment together with the APL does not result in a proliferative signal. Instead, we propose that a combination of this and other signaling pathways induces T cell anergy. Overall, these data support the concept of differential signaling in T cells, as a direct consequence of the phosphotyrosine status of the TCR/CD3 molecules.


Increased levels of interleukin-10 and IgG3 are hallmarks of Indian post-kala-azar dermal leishmaniasis.
Post-kala-azar dermal leishmaniasis (PKDL), an established sequela of visceral leishmaniasis (VL), is proposed to facilitate anthroponotic transmission of VL, especially during interepidemic periods. Immunopathological mechanisms responsible for Indian PKDL are still poorly defined. Our study attempted to characterize the immune profiles of patients with PKDL or VL relative to that of healthy control subjects by immunophenotyping, intracellular cytokine staining of peripheral blood mononuclear cells, and enzyme-linked immunosorbent assay for serum cytokines and immunoglobulin G (IgG) subclasses. Patients with PKDL had significantly raised percentages of peripheral CD3+CD8+ cells compared with control subjects, a difference that persisted after cure. Patients with PKDL showed an intact response to phytohemagglutinin, with the percentages of lymphocytes expressing interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 being comparable to those in control subjects. Patients with VL had decreased IFN-gamma and IL-2 expression, which was restored after cure, and increased IL-10 expression, which persisted after cure. In their response to Leishmania donovani antigen, patients with PKDL showed a 9.6-fold increase in the percentage of IL-10-expressing CD3+CD8+ lymphocytes compared with control subjects, and this percentage decreased with treatment. Patients with PKDL had raised levels of IgG3 and IgG1 (surrogate markers for IL-10), concomitant with increased serum levels of IL-10. IL-10-producing CD3+CD8+ lymphocytes are important protagonists in the immunopathogenesis of Indian PKDL.


The contribution of RNAs and retroposition to evolutionary novelties.
Retroposition is an ancient process dating back to the conversion of RNA to DNA genomes. Nevertheless, it continues to make tremendous structural and functional contributions to extant genomes. This process and the endurance, or even renaissance, of an RNA world in many lineages sheds a new light on the Central Dogma of Molecular Biology. The question of why reverse transcriptase has survived billions of years without an apparent cellular function is discussed. Retroposition constitutes one of the pervasive conflicts, in this case between host genome on one hand and mobile genetic elements on the other, that fuel the evolutionary process. It is obvious that retroposition has, thus far, contributed numerous useful novelties to genomes.


New fossils of Jurassic ophiurid brittle stars (Ophiuroidea; Ophiurida) provide evidence for early clade evolution in the deep sea.
Understanding of the evolutionary history of the ophiuroids, or brittle stars, is hampered by a patchy knowledge of the fossil record. Especially, the stem members of the living clades are poorly known, resulting in blurry concepts of the early clade evolution and imprecise estimates of divergence ages. Here, we describe new ophiuroid fossil from the Lower Jurassic of France, Luxembourg and Austria and introduce the new taxa Ophiogojira labadiei gen. et sp. nov. from lower Pliensbachian shallow sublittoral deposits, Ophiogojira andreui gen. et sp. nov. from lower Toarcian shallow sublittoral deposits and Ophioduplantiera noctiluca gen. et sp. nov. from late Sinemurian to lower Pliensbachian bathyal deposits. A Bayesian morphological phylogenetic analysis shows that Ophiogojira holds a basal position within the order Ophiurida, whereas Ophioduplantiera has a more crownward position within the ophiurid family Ophiuridae. The position of Ophioduplantiera in the evolutionary tree suggests that family-level divergences within the Ophiurida must have occurred before the late Sinemurian, and that ancient slope environments played an important role in fostering early clade evolution.


Characterization of E3Histone, a novel testis ubiquitin protein ligase which ubiquitinates histones.
During spermatogenesis, a large fraction of cellular proteins is degraded as the spermatids evolve to their elongated mature forms. In particular, histones must be degraded in early elongating spermatids to permit chromatin condensation. Our laboratory previously demonstrated the activation of ubiquitin conjugation during spermatogenesis. This activation is dependent on the ubiquitin-conjugating enzyme (E2) UBC4, and a testis-particular isoform, UBC4-testis, is induced when histones are degraded. Therefore, we tested whether there are UBC4-dependent ubiquitin protein ligases (E3s) that can ubiquitinate histones. Indeed, a novel enzyme, E3Histone, which could conjugate ubiquitin to histones H1, H2A, H2B, H3, and H4 in vitro, was found. Only the UBC4/UBC5 family of E2s supported E3Histone-dependent ubiquitination of histone H2A, and of this family, UBC4-1 and UBC4-testis are the preferred E2s. We purified this ligase activity 3,600-fold to near homogeneity. Mass spectrometry of the final material revealed the presence of a 482-kDa HECT domain-containing protein, which was previously named LASU1. Anti-LASU1 antibodies immunodepleted E3Histone activity. Mass spectrometry and size analysis by gel filtration and glycerol gradient centrifugation suggested that E3Histone is a monomer of LASU1. Our assays also show that this enzyme is the major UBC4-1-dependent histone-ubiquitinating E3. E3Histone is therefore a HECT domain E3 that likely plays an important role in the chromatin condensation that occurs during spermatid maturation.


Geometric optimisation of an accurate cosine correcting optic fibre coupler for solar spectral measurement.
Making accurate and reliable measurements of solar irradiance is important for understanding performance in the photovoltaic energy sector. In this paper, we present design details and performance of a number of fibre optic couplers for use in irradiance measurement systems employing remote light sensors applicable for either spectrally resolved or broadband measurement. The angular and spectral characteristics of different coupler designs are characterised and compared with existing state-of-the-art commercial technology. The new coupler designs are fabricated from polytetrafluorethylene (PTFE) rods and operate through forward scattering of incident sunlight on the front surfaces of the structure into an optic fibre located in a cavity to the rear of the structure. The PTFE couplers exhibit up to 4.8% variation in scattered transmission intensity between 425 nm and 700 nm and show minimal specular reflection, making the designs accurate and reliable over the visible region. Through careful geometric optimization near perfect cosine dependence on the angular response of the coupler can be achieved. The PTFE designs represent a significant improvement over the state of the art with less than 0.01% error compared with ideal cosine response for angles of incidence up to 50°.


Changes in survival and symptom relief in a longitudinal study of patients after bypass surgery.
The first 350 patients having coronary surgery at Stanford Medical Center (excluding patients with aneurysmectomy or valve replacement) have been followed sequentially utilizing a computer-based information system. Our experience spans 72 months (900 patient-years), with an average follow-up of 30 months. Hospital mortality was 4.9%. Actuarial analysis revealed survival of 91% at 1 year and 80% at 6 years. Forty patients (11.5%) had 43 late myocardial infarctions, of which 5 were fatal. Analyses of selected patient subgroups revealed significantly poorer survival in patients with prior myocardial infarction (P less than 0.05), significant congestive heart failure, or mitral regurgitation (P less than 0.01). Survival in multigrafted (and multivessel) patients was not significantly different from survival in single-grafted (predominantly single-vessel) patients. Actuarial studies suggest improved survival in patients with multivessel disease after coronary artery surgery. Between an initial evaluation at 9 months postoperatively (range: 2 to 40 months) and the most recent evaluation after 30 months (range: 6 to 72 months), 13% of patients showed further clinical improvement, 47% were unchanged, while 40% deteriorated with respect to chest pain. We conclude that initial symptomatic benefits may not be maintained in late follow-up studies owing to progression of underlying vascular disease.


Bilateral putaminal necrosis and bronopol toxicity.
Among alcohols, methanol intoxication is the most frequently associated with cerebral toxicity, causing retinal damage and putaminal necrosis. This consequence is believed to be due to the transformation of methanol into formic acid. We describe the case of a patient who presented with acute impairment of consciousness and tetraparesis after she had been drinking several bottles of a topical antiseptic solution (Lysoform Medical) containing 2-bromo-2-nitro-1,3-propandiol (bronopol) among excipients, in order to lose weight during previous months. Moreover, she had been on a strict slimming diet. Soon after admission, a severe respiratory and metabolic impairment became rapidly evident, requiring an intensive care unit admission. Cerebral MRI showed the presence of bilateral putaminal necrosis. She recovered in 10 days, surprisingly, without any evident clinical neurological signs. Methanol, also bronopol, when diluted in aqueous solution, at warm temperature and/or higher pH, may release formaldehyde, which is converted into formic acid, a basal ganglia toxic compound.


Effects of inactivity on glycolytic capacity of single skeletal muscle fibers in adult and aged rats.
The purpose of this study was to determine the effects of inactivity on lactate dehydrogenase (LDH) enzyme activity (expressed in nmol/g dry weight x hour) in single skeletal musclefibers from the soleus muscle in adult and aged rats. Fourteen 12-month-old andfifteen 30-month-old Fisher 344 Brown Norway F1 Hybrid rats were randomly assigned to control, 1 week of hindlimb unweighting (HU1), or 2 weeks of hindlimb unweighting (HU2). With age, a significant decrease in LDH enzyme activity occurred in type I skeletal muscle fibers (29.5%, P < 0.05). Following HU2, individual type I skeletal muscle fibers from the 12-month-old animals showed a 33.3% increase in LDH activity. In contrast, individual type I fibers from the aged animals showed a 50.0% increase after HU1. In conclusion, the baseline levels of LDH activity were significantly less in aged versus adult rats. The timing of the skeletal muscle adaptation to inactivity was different between young and old animals, such that the older animals responded to inactivity before the younger animals. These biochemical changes may have an impact on the fatigability of the muscle following inactivity. Thefindings indicate that treatment during bed rest for the older adult may be different than that for the younger adult.


Fast Image-Guided Stratification Using Anti-Programmed Death Ligand 1 Gold Nanoparticles for Cancer Immunotherapy.
Cancer immunotherapy has made enormous progress in offering safer and more effective treatments for the disease. Specifically, programmed death ligand 1 antibody (αPDL1), designed to perform immune checkpoint blockade (ICB), is now considered a pillar in cancer immunotherapy. However, due to the complexity and heterogeneity of tumors, as well as the diversity in patient response, ICB therapy only has a 30% success rate, at most; moreover, the efficacy of ICB can be evaluated only two months after start of treatment. Therefore, early identification of potential responders and nonresponders to therapy, using noninvasive means, is crucial for improving treatment decisions. Here, we report a straightforward approach for fast, image-guided prediction of therapeutic response to ICB. In a colon cancer mouse model, we demonstrate that the combination of computed tomography imaging and gold nanoparticles conjugated to αPDL1 allowed prediction of therapeutic response, as early as 48 h after treatment. This was achieved by noninvasive measurement of nanoparticle accumulation levels within the tumors. Moreover, we show that the nanoparticles efficiently prevented tumor growth with only a fifth of the standard dosage of clinical care. This technology may be developed into a powerful tool for early and noninvasive patient stratification as responders or nonresponders.


Four-millimeter implants supporting fixed partial dental prostheses in the severely resorbed posterior mandible: two-year results.
Reduced alveolar bone volume complicates implant dentistry. In this prospective multicenter study, a new, 4-mm long Straumann SLActive implant (Ø 4.1 mm) supporting a fixed dental prosthesis (FDP) in the severely resorbed posterior mandible was evaluated for two years. Thirty-two patients (11 men, 21 women; mean age 64.1 years) participated. Ten to 12 weeks after single-stage surgery, a screw-retained FDP was attached to three or four 4-mm implants. One hundred implants were inserted. Three failed at surgery and four were lost before loading. Twenty-eight patients received FDPs (93 implants). Two patients were discontinued because of secondary exclusion criteria; therefore, 26 patients were followed up from baseline (BL). After 1 year, one patient insisted on removal of all implants and one patient died because of nonstudy-related complications. Twenty-four patients (87 implants) were eligible for examination 2 years post-loading. All implants were found to be stable [survival rate 95.7% (confidence interval, CI 88.8-98.3) after 1 year and 92.3% (CI 84.5-96.2) after 2 years]. The mean change from BL to 12 months was - 0.43 mm (CI 0.31-0.59; p < .001) and from 12 to 24 months - 0.11 mm (CI -0.01-0.23; p = .056). The survival rate is only slightly lower than in similar studies on 6 to 8.5 mm implants. This may be related to high initial stability and effective use of the residual bone volume with high primary bone-to-implant contact in dense bone structures. The surgical handling of the tested implant was found to be similar to that of implants of common length. However, the preparation procedure must be done with great care to avoid overdrilling. Careful planning and design of the prosthetic construction is mandatory to prevent unfavorable occlusion and avoid harmful shear forces. This study showed that 4 mm implants can support an FDP in severely resorbed posterior mandibles for at least 2 years and with healthy peri-implant conditions.


JOB INSECURITY AND WELL-BEING IN RICH DEMOCRACIES.
Precarious work (i.e., work that is insecure and uncertain, often low-paying, and in which the risks of work are shifted from employers and the government to workers) has emerged as a serious concern for individuals and families and underlies many of the insecurities that have fueled recent populist political movements. The impacts of precarious work differ among countries depending on their labor market and welfare system institutions, laws and policies, and cultural factors. This article examines how people in six advanced industrial countries representing different welfare and employment regimes-Denmark, Germany, Japan, Spain, the United Kingdom and the United States-differ both in their experience of precarious work and in outcomes of precarious work such as job and economic insecurity, entry into the labor force, and subjective well-being. It also suggests a new social and political contract needed to address precarious work and its consequences.


[Expression and Significance of Vitamin D Receptor Gene and NF-κB Pathway in Blood of Children with Acute Lymphoblastic Leukemia].
To investigate the expression, clinical significance and prognosis of vitamin D receptor (VDR) gene and NF-κB pathway in children with acute lymphoblastic leukemia (ALL). Thirty children with definitive diagnoses of ALL from December 2018 to December 2021 were selected as ALL group, and 30 healthy children under physical examination were selected as control group. Peripheral blood of all study subjects was collected. The VDR and NF-κB mRNA and protein expressions were detected by real-time quantitative PCR and Western blot, respectively. The relationship between mRNA expression of the above genes and clinical characteristics of children was retrospectively analyzed. The relative expression of VDR mRNA in peripheral blood of children with ALL was significantly lower than that in the control group (P < 0.05), while NF-κB mRNA was higher (P < 0.001). The expression of NF-κB mRNA in ALL children with peripheral blood white blood cell count (WBC) < 50×109/L at initial diagnosis was significantly higher than those with WBC≥50×109/L (P < 0.01). The expression of NF-κB mRNA in ALL children with infection was significantly higher than that those without infection (P < 0.05). There were no significant differences in NF-κB mRNA expression between children with different sex, age, hemoglobin at initial diagnosis, platelet, immunologic typing, risk and induced response (P >0.05). The expression of NF-κB is of value to diagnosis and prognosis of ALL in children.


[Surgical treatment of injured persons with the main blood vessels damage].
Retrospective analysis of the surgical treatment results of 45 injured persons with damage of main blood vessels was presented. Specific operative methods in injury of the different type main blood vessels, localized in thoracic and abdominal cavities, were depicted. In 35 (77.8%) injured persons good and fair results of restoration operations were noted. The lethality rate was 22.2%. The tactic of surgical treatment of the main blood vessels injury was presented.


Highlights of drug - and herb- induced liver injury in the literature from 2016: how best to translate new information into clinical practice?
Over 1500 papers on drug-induced liver injury (DILI) and herb-induced liver injury (HILI) were published in 2016, many of which have the potential to impact clinical practice. Areas covered: Clinical studies and case series that lent themselves to new concepts in diagnosing, and treating DILI were selected for inclusion. Epidemiology of DILI in large prospective registries was highlighted. Causality assessment of drug hepatotoxicity remains challenging, as seen with cases of OxyELITE Pro (OEP). In 2016 updates to the Roussel Uclaf Causality Assessment Method (RUCAM) were published to aid in the accuracy of diagnosing DILI/HILI. New reports of established hepatotoxins were again discussed in 2016, including genetic risk factors for DILI with respect to antituberculous agents. Expert opinion: 2016 marked a turning point in how much credence should be placed in the current causality assessment for DILI/HILI cases. Many recognized hepatotoxins are backed by a relatively few number of literature reports. Danan and Teschke make a strong case that an updated RUCAM should remain the gold standard for diagnosing DILI/HILI going forward, although the role of expert opinion is often still needed in cases where RUCAM falls short. The field of chemoinformatics continues to evolve while we await a truly predictive and diagnostic DILI biomarker.


Noninvasive tracking of mixed venous oxygen saturation via near-infrared spectroscopy cerebral oximetry: a retrospective observational study.
Although previous studies have shown correlation between regional cerebral oxygen saturation (rScO2) and mixed venous oxygen saturation (SvO2), there is a lack of pragmatic information on the clinical applicability of these findings, such as tracking ability. We retrospectively analyzed continuous intraoperative recordings of rScO2 and SvO2 obtained from a pulmonary artery catheter and either of two near-infrared spectroscopy (NIRS) devices (INVOS 5100C, Medtronic; O3, Masimo) during off-pump cardiopulmonary bypass (OPCAB) surgery in adult patients. The ability of rScO2 to track SvO2 was quantitatively evaluated with 5 min interval changes transformed into relative values. The analysis included 176 h of data acquired from 48 subjects (26 and 22 subjects for INVOS and O3 dataset, respectively). The area under ROC of the left-rScO2 for detecting change of SvO2 ≥ 10% in INVOS and O3 datasets were 0.919 (95% CI 0.903-0.936) and 0.852 (95% CI 0.818-0.885). The concordance rates between the interval changes of left-rScO2 and SvO2 in INVOS and O3 datasets were 90.6% and 91.9% with 10% exclusion zone. rScO2 can serve as a noninvasive tool for detecting changes in SvO2 levels, a critical hemodynamic measurement.


MET Genomic Alterations in Head and Neck Squamous Cell Carcinoma (HNSCC): Rapid Response to Crizotinib in a Patient with HNSCC with a Novel MET R1004G Mutation.
Identification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum-refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment.Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture-based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer-related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79%) with MET alterations (4 point mutation events and 9 focal amplification events). MET-mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC. KEY POINTS: This case report is believed to be the first reported pan-cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib.The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.