A High-Performance Computing Implementation of Iterative Random Forest for the Creation of Predictive Expression Networks.
As time progresses and technology improves, biological data sets are continuously increasing in size. New methods and new implementations of existing methods are needed to keep pace with this increase. In this paper, we present a high-performance computing (HPC)-capable implementation of Iterative Random Forest (iRF). This new implementation enables the explainable-AI eQTL analysis of SNP sets with over a million SNPs. Using this implementation, we also present a new method, iRF Leave One Out Prediction (iRF-LOOP), for the creation of Predictive Expression Networks on the order of 40,000 genes or more. We compare the new implementation of iRF with the previous R version and analyze its time to completion on two of the world's fastest supercomputers, Summit and Titan. We also show iRF-LOOP's ability to capture biologically significant results when creating Predictive Expression Networks. This new implementation of iRF will enable the analysis of biological data sets at scales that were previously not possible.


Feasibility of evaluating the CHIPRA care quality measures in electronic health record data.
The Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA) includes provisions for identifying standardized pediatric care quality measures. These 24 "CHIPRA measures" were designed to be evaluated by using claims data from health insurance plan populations. Such data have limited ability to evaluate population health, especially among uninsured people. The rapid expansion of data from electronic health records (EHRs) may help address this limitation by augmenting claims data in care quality assessments. We outline how to operationalize many of the CHIPRA measures for application in EHR data through a case study of a network of >40 outpatient community health centers in 2009-2010 with a single EHR. We assess the differences seen when applying the original claims-based versus adapted EHR-based specifications, using 2 CHIPRA measures (Chlamydia screening among sexually active female patients; BMI percentile documentation) as examples. Sixteen of the original CHIPRA measures could feasibly be evaluated in this dataset. Three main adaptations were necessary (specifying a visit-based population denominator, calculating some pregnancy-related factors by using EHR data, substituting for medication dispense data). Although it is feasible to adapt many of the CHIPRA measures for use in outpatient EHR data, information is gained and lost depending on how numerators and denominators are specified. We suggest first steps toward application of the CHIPRA measures in uninsured populations, and in EHR data. The results highlight the importance of considering the limitations of the original CHIPRA measures in care quality evaluations.


Reconstruction of the molecular evolution of Usutu virus in Germany: Insights into virus emersion and circulation.
Usutu virus (USUV) is a mosquito-borne flavivirus that is widely distributed in southern and central Europe. The zoonotic virus circulates primarily between birds and mosquitoes, can, however, in rare cases infect other mammals including humans. In the past, USUV has been repeatedly associated with mass mortalities in birds, primarily blackbirds and owls. Birds commonly succumb either due to the peracute nature of the infection or due to severe encephalitis. In Germany, USUV has spread rapidly since its first detection in 2010 in mosquitoes under the presence of susceptible host and vector species. Nonetheless, there is to date limited access to whole genome sequences resulting in the absence of in-depth phylogenetic and phylodynamic analyses. In this study, 118 wild and captive birds were sequenced using a nanopore sequencing platform with prior target enrichment via amplicons. Due to the high abundancy of Europe 3 and Africa 3 in Germany an ample quantity of associated whole genome sequences was generated and the most recent common ancestor could be determined for each lineage. The corresponding clock phylogeny revealed an introduction of USUV Europe 3 and Africa 3 into Germany three years prior to their first isolation in the avifauna in 2011 and 2014, respectively. Based on the clustering and temporal history of the lineages, evidence exists for the genetic evolution of USUV within Germany as well as new introductions thereof into the country.


Caregivers of People With Disabilities: A Program to Enhance Wellness Self-Care.
Caregivers are a source of support for family members with disabilities. However, caregivers are at risk for caregiver burden, which can erode self-care skills and lead to poor physical and mental health outcomes. Caregiver Wellness Self-Care, developed to address that risk, is a 5-week group program in which participants learn about strategies that cultivate their inner resources, while connecting with others for support. Wellness, self-care, mindfulness, and yoga-based information and practices are taught in the sessions and included in participant handouts. Self-reflection and planning activities with facilitated discussions further support awareness and personal transformation. Designed by and for people providing care to an adult family member with a mental health disorder and a developmental/intellectual disability, the program was piloted three times. The current article describes the development of the program through caregiver involvement, participant and facilitator feedback, and implications for future efforts to build caregiver wellness self-care skills. Implications for nurses are highlighted. [Journal of Psychosocial Nursing and Mental Health Services, 59(5), 25-32.].


VERITAS?: A time for VERIQAS™ and a new approach to training, education, and the quality assessment of CD4+ T lymphocyte counting (I).
The aim of clinical laboratories is to produce accurate and reproducible results to enable effective and reliable clinical practice and patient management. The standard approach is to use both internal quality control (IQC) and external quality assessment (EQA). IQC serves, in many instances, as a "go, no go" tool to provide real time assurance that instruments and reagent or test systems are performing within defined specifications. EQA however, takes a snapshot at a specific point in time of the full testing process, results are compared to other laboratories performing similar testing but inevitably has some built in delay from sample issue to performance data review. In addition, if IQC or EQA identify areas of concern it can be difficult to determine the exact nature of the problem. In an attempt to address this problem, we have developed an instant QA panel that we have termed VERIQAS™, specifically for CD4(+) T lymphocyte counting, and have undertaken a "proof of principle" pilot study to examine how the use of VERIQAS™ could result in improvement of laboratory performance. In addition, we have examined how this approach could be used as a training and education tool (in a domestic/international setting) and potentially be of value in instrument validation/switch studies (a switch study being defined as a laboratory changing from one method/instrument to a new method/instrument with the VERIQAS™ panel being used as an adjunct to their standard switch study protocol). The basic panel consists of 20 stabilized samples, with predefined CD4(+) T lymphocyte counts, that span low clinically relevant to normal counts, including some blinded replicates (singlet up to quadruplicate combinations). The CD4(+) T lymphocyte target values for each specimen is defined as the trimmed mean ± 2 trimmed standard deviations, where the trimmed values are derived from the CD4(+) T lymphocyte counts reported by the participating centers (~780 laboratories) that receive each UK NEQAS for Leucocyte Immunophenotyping send out. Results for the VERIQAS™ panel were returned online, via a specially designed website, and the participant was provided with an immediate assessment (pass or fail). To date, the panel has been preliminary trialed by eight laboratories to (i) assess pre-EQA qualification (two laboratories); (ii) address performance issues (two laboratories); or (iii) validate new instruments or techniques (four laboratories). Interestingly, even in this pilot study, the panel has been instrumental in identifying specific technical problems in laboratories with EQA performance issues as well as confirming that implementation of new techniques or instruments have been successful. We report here a new and novel "proof of principle" pilot study to quality assessment, that we have termed VERIQAS™, designed to provide instant feedback on performance. Participating laboratories receive 20 "blinded" samples that are in singlet up to quadruplicate combinations. Once a centre reports its results via a website, immediate feedback is provided to both the participant and the EQA organizers, enabling, if required, the initiation of targeted remedial action. We have also shown that this approach has the potential to be used as a tool for prequalification, troubleshooting, training and instrument verification. Pilot phase field trials with VERIQAS™ have shown that the panel can highlight laboratory performance problems, such as suboptimal instrument set up, pipetting and gating strategies, in a rapid and efficient manner. VERIQAS™ will now be introduced, where appropriate, as a second phase study within UK NEQAS for Leucocyte Immunophenotyping to assist those laboratories that have performance issues and also made available to laboratories for training and education of staff and instrument validation studies.


Microlunatus elymi sp. nov., a novel actinobacterium isolated from rhizospheric soil of the wild plant Elymus tsukushiensis.
An actinobacterial strain, designated KUDC0627T, was isolated from rhizospheric soil that contained Elymus tsukushiensis on the Dokdo Islands, Republic of Korea. Cells were Gram-stain-positive, facultative anaerobic, non-motile and non-endospore-forming cocci. Results of phylogenetic analysis based on 16S rRNA gene sequences indicated that strain KUDC0627T belongs to the genus Microlunatus and is most closely related to Microlunatus soli DSM 21800T (98.5 %), Microlunatus endophyticus DSM 100019T (97.7 %) and Microlunatus ginsengisoli Gsoil 633T (96.5 %). The average nucleotide identity scores and average amino acid identity values were all below the 95.0 % cut-off point. In silico DNA-DNA hybridization, using the Genome-to-Genome Distance Calculator, estimated that there is 22.3 % DNA relatedness between KUDC0627T and M. soli DSM 21800T. The genomic DNA G+C content was 66.9 mol%. The major menaquinone was MK-9(H4) and the major diagnostic diamino acid in the cell-wall peptidoglycan was ll-diaminopimelic acid. The polar lipid profile included diphosphatidylglycerol, phosphatidylglycerol, unidentified phospholipids, unidentified glycolipids and unidentified lipids. The major cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0 and iso-C16 : 0. Based on phenotypic, chemotaxonomic, and phylogenetic data, strain KUDC0627T (=KCTC 39853T=JCM 32702T) represents a novel species, for which the name Microlunatus elymi sp. nov. is proposed.


Gene variants of adhesion molecules act as modifiers of disease severity in MS.
To assess the potential effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the clinical phenotype of multiple sclerosis (MS). A total of 389 Greek MS cases and 336 controls were recruited in 3 MS centers from Cyprus and Greece. We genotyped 147 tagging single nucleotide polymorphisms (SNPs) in 9 genes encoding for P-selectin (SELP), integrins (ITGA4, ITGB1, and ITGB7), adhesion molecules (ICAM1, VCAM1, and MADCAM1), fibronectin 1 (FN1), and osteopontin (SPP1) involved in lymphocyte adhesion and trafficking into the CNS. Clinical end points of the study were age at MS onset and MS severity as measured by the Multiple Sclerosis Severity Score. Permutation testing was applied to all analyses. SNPs rs6721763 of the ITGA4 and rs6532040 of the SPP1 were found to significantly influence disease severity (permutation p values: 3.00e-06 and 0.009884, respectively). SNP rs1250249 of the FN1 had a dose-dependent effect on age at disease onset (permutation p value: 0.0002). This study provides evidence implicating variants encoding adhesion molecules, responsible for lymphocyte adhesion and trafficking within the CNS, as modifiers of MS disease severity. These genetic biomarkers, which can be available at the time of diagnosis, may be used to assess the biological aggressiveness of the disease and thus guide decisions on treatment.


Telomere 1 (POT1) gene expression and its association with telomerase activity in colorectal tumor samples with different pathological features.
The ends of chromosoms, telomeres are bound with a number of proteins which protect and stabilize telomeres against degredation, end to end fusion and aberrant recombinations. Telomeric DNA is bound of two groups of proteins, which are double-stranded telomeric DNA bindings proteins, and single stranded telomeric binding proteins. Among telomere binding proteins, protections of telomere 1 protein is a single stranded telomere binding proteins and suggested to be a significant player for telomere elongation and has an association with an enzyme called as telomerase which is an intrinsic reverse transcriptase. Telomerase synthesizes hexameric telomeric repeats onto the chromosomes thereby compansating telomere loss in immortal cells, such as tumor cells, whereas telomeres are shorthened with each division in normal cells. PCR-based TRAP (telomeric repeat amplification protocol) assay is a very sensitive assay for the detection of enzymatic activity of telomerase even if a few numbers of cancerous cells are available. The association between telomerase activity and hPOT1 expression in colorectal cancer is still unclear. Protein extraction was performed from specimens of matched normal and colorectal cancer specimens. Protein concentrations were determined by Bradford assay. Optimized protein concentrations were used for TRAP Assay. TRAP products were seperated by vertical gel electrophoresis on 12.5% polyacrylamide gels and visualized by silver staining. Gene expression of hPOT1 was determined by qPCR analysis. The results demonstrated that all tumor tissues were telomerase positive whereas all corresponding normal tissue was telomerase negative. Among clinicopathological findings, telomerase activity was found to be associated with stage, histology, localization, distant metastasis and lymph node metastasis of tumor in the current study. Although all of the clinicopathological findings differed in the expression of hPOT1 compared to normal tissues, they did not differ from each other significantly, except side of tumor and lymph node metastasis. Telomerase activity and hPOT1 gene expression may serve as a promising tumor marker for colorectal cancer and there is a close association between the enzymatic activty of telomerase and the expression of human protection of telomere 1 gene.


Using HIV transmission networks to investigate community effects in HIV prevention trials.
Effective population screening of HIV and prevention of HIV transmission are only part of the global fight against AIDS. Community-level effects, for example those aimed at thwarting future transmission, are potential outcomes of treatment and may be important in stemming the epidemic. However, current clinical trial designs are incapable of detecting a reduction in future transmission due to treatment. We took advantage of the fact that HIV is an evolving pathogen whose transmission network can be reconstructed using genetic sequence information to address this shortcoming. Here, we use an HIV transmission network inferred from recently infected men who have sex with men (MSM) in San Diego, California. We developed and tested a network-based statistic for measuring treatment effects using simulated clinical trials on our inferred transmission network. We explored the statistical power of this network-based statistic against conventional efficacy measures and find that when future transmission is reduced, the potential for increased statistical power can be realized. Furthermore, our simulations demonstrate that the network statistic is able to detect community-level effects (e.g., reduction in onward transmission) of HIV treatment in a clinical trial setting. This study demonstrates the potential utility of a network-based statistical metric when investigating HIV treatment options as a method to reduce onward transmission in a clinical trial setting.


Solubilized receptor for intrinsic factor-Vitamin B12 complex from guinea pig intestinal mucosa.
the absorption of vitamin B(12) in many animals requires its prior association with intrinsic factor (IF) and attachment to a specific receptor in the intestine. Employing Triton X-100, we have solubilized from guinea pig ileum a factor that binds intrinsic factor-vitamin B(12) complex (IF-B(12)). This binding factor was soluble to the extent that it was not sedimented by centrifugation at 100,000 g for 1 h and was small enough to enter the included volume of a Sepharose 4-B column. Furthermore, the ileal extract contained no microfine particles of membrane upon electron microscopic search. When a portion of the extract was incubated with a mixture of gastric juice and (57)Co-labeled vitamin B(12), a portion of the radioactivity was excluded from a Sephadex G-200 column. When gastric juice from a patient with a congenital abnormality of IF that prevented its binding to intestine was substituted for normal human gastric juice, radioactivity was not excluded from the gel, indicating failure of this abnormal IF-B(12) to bind to the intestinal extract. These data suggested the presence of a specific binder of IF-B(12) in the ileal mucosal extract. The reactions of normal IF-B(12) with the solubilized binding factor and with the membrane-bound "receptor" had several characteristics in common, including calcium dependence, temperature independence, and pH optimum near neutral. Extracts from the distal intestine showed more activity than did those from the proximal. The solubilized binding facter seemed specific for IF-B(12) in that it was not blocked by prior incubation with excesses of either free vitamin B(12) or IF. Binding activity of the extract was decreased by incubation at pH 2.0, by heating to 56 degrees C, and by incubation with chymotrypsin and dithiothretiol. Incubation with trypsin, neuraminidase, and sulphydryl blockers did not affect it. The Triton X-100 extract of guinea pig ileal mucosa contains a specific binding factor that probably is the receptor for IF-B(12). This appears to be a protein with function dependent on peptide and disulphide linkages.


Plasma concentration of pyridostigmine and effects in myastenia gravis.
The relation between the plasma concentration of pyridostigmine and its effects was studied in 5 patients with myasthenia gravis. In 4 patients with typical electromyographic decrement in the adductor pollicis, there was a positive correlation between the concentration of pyridostigmine in plasma and the effect on neuromuscular transmission. The plasma concentration of pyridostigmine required to restore transmission to normal (as calculated from the regression line relating plasma concentration to neuromuscular function) varied over a 5-fold range, reflecting the variable severity of the disease. In another myasthenic patient with purely ocular symptoms, there was a significant correlation between the plasma concentration of the drug and the diameter of the palpebral fissure. It is suggested that the routine measurement of the plasma concentration of pyridostigmine may be of value in the management of myasthenia gravis. A method to calculate the optimal daily dose of pyridostigmine in individual myasthenic patients is described.


A Deese-Roediger-McDermott study of trauma memory among employees of New York City companies affected by the September 11, 2001, attacks.
Posttraumatic stress disorder (PTSD) has been found to be associated with abnormalities in memory function. This relationship has not previously been studied using the Deese-Roediger-McDermott (DRM) false memory paradigm in disaster-exposed populations. Three years after the September 11, 2001 (9/11) attacks, 281 participants from a volunteer sample of 379, recruited from 8 companies directly affected by the attacks, completed an interview about their disaster experience, a structured diagnostic interview, and the DRM paradigm. It was hypothesized that participants with PTSD would demonstrate more associative errors, termed false alarms to critical lures, compared to those without PTSD. This hypothesis was not supported; the only predictor of false alarms to critical lures was direct 9/11 trauma exposure. The finding that 9/11 trauma-exposure was associated with false alarms to critical lures suggests that neural processing of trauma-exposure memory may involve associative elements of overgeneralization coupled with insufficient inhibition of responses to related but harmless stimuli. Future research will be needed to differentiate psychopathology, such as PTSD, from physiological fight-or-flight responses to trauma.


N-Acetylglucosamine and its dimer ameliorate inflammation in murine colitis by strengthening the gut barrier function.
Ulcerative colitis (UC) is a chronic gastrointestinal disease whose incidence is increasing rapidly worldwide. Anti-inflammatory medications, including 5-aminosalicylic acid (5-ASA), corticosteroids, and immunosuppressants, are used for its treatment; however, new alternatives would be required due to the serious side effects of some of these medications. N-Acetylglucosamine (NAG) is an amino sugar composed of mucin that is secreted by intestinal epithelial cells. It is also used to promote the growth of intestinal bacteria. The current study aimed to determine the efficacy of NAG against dextran sulfate sodium (DSS)-induced chronic colitis and elucidate its mechanism of action. Mice were randomly divided into control, DSS, 0.1% sulfasalazine, 0.1% NAG, 0.3% NAG, and 0.3% NAG-dimer (NAG-D) groups, and results showed that colitis-induced body weight loss, disease activity, colonic tissue damage, colon length shortening, and the loss of mucin-secreting area were significantly improved in the NAG-D group. The intestinal permeability indicator, serum CD 14 level, and expression of the tight junction protein, occludin, were both improved in the 0.3% NAG group. Inflammatory biomarkers, including GATA3, IFN-γ, p-IκBα, COX2, TGF-β1, and Smad7, were significantly lower in the 0.3% NAG and NAG-D groups than in the DSS group. The intestinal microbial composition was most significantly altered in the 0.3% NAG group, showing decreased ratios of pathogenic bacteria, such as Betaproteobacteria, especially Burkholderiales. The results overall suggested that NAG or NAG-D supplementation can alleviate inflammation by strengthening the intestinal barrier function and maintaining gut microbiota homeostasis in a DSS-induced colitis mouse model.


One-Step 18F-Labeling of Estradiol Derivative for PET Imaging of Breast Cancer.
Positron emission tomography (PET) imaging is a useful method to evaluate in situ estrogen receptor (ER) status for the early diagnosis of breast cancer and optimization of the appropriate treatment strategy. The 18F-labeled estradiol derivative has been successfully used to clinically assess the ER level of breast cancer. In order to simplify the radiosynthesis process, one-step 18F-19F isotope exchange reaction was employed for the 18F-fluorination of the tracer of [18F]AmBF3-TEG-ES. The radiotracer was obtained with the radiochemical yield (RCY) of ~61% and the radiochemical purity (RCP) of >98% within 40 min. Cell uptake and blocking assays indicated that the tracer could selectively accumulate in the ER-positive human breast cancer cell lines MCF-7 and T47D. In vivo PET imaging on the MCF-7 tumor-bearing mice showed relatively high tumor uptake (1.4~2.3 %D/g) and tumor/muscle uptake ratio (4~6). These results indicated that the tracer is a promising PET imaging agent for ER-positive breast cancers.


Smelling the difference: Transcriptome, proteome and volatilome changes after mating.
Mushrooms, such as Schizophyllum commune, have a specific odor. Whether this is linked to mating, prerequisite for mushroom formation, or also found in monokaryotic, unmated strains, was investigated with a comprehensive study on the transcriptome and proteome of this model organism. Mating interactions were investigated using a complete, cytosolic proteome map for unmated, monokaryotic, as well as for mated, dikaryotic mycelia. The regulations of the proteome were compared to transcriptional changes upon mating and to changes in smell by volatilome studies. We could show a good overlap between proteome and transcriptome data, but extensive posttranslational regulation was identified for more than 80% of transcripts. This suggests down-stream regulation upon interaction of mating partners and formation of the dikaryon that is competent to form fruiting bodies. The volatilome was shown to respond to mating by a broader spectrum of volatiles and increased emission of the mushroom smell molecules 3-octanone and 1-octen-3-ol, as well as ethanol and β-bisabolol in the dikaryon. Putatively involved biosynthetic proteins like alcohol dehydrogenases, Ppo-like oxygenases, or sesquiterpene synthases showed correlating transcriptional regulation depending on either mono- or dikaryotic stages.


Importance of arginine 20 of the swine vesicular disease virus 2A protease for activity and virulence.
A major virulence determinant of swine vesicular disease virus (SVDV), an Enterovirus that causes an acute vesicular disease, has been mapped to residue 20 of the 2A protease. The SVDV 2A protease cleaves the 1D-2A junction in the viral polyprotein, induces cleavage of translation initiation factor eIF4GI, and stimulates the activity of enterovirus internal ribosome entry sites (IRESs). The 2A protease from an attenuated strain of SVDV (Ile at residue 20) is significantly defective at inducing cleavage of eIF4GI and the activation of IRES-dependent translation compared to the 2A protease from a pathogenic strain (J1/73, Arg at residue 20), but the two proteases have similar 1D-2A cleavage activities (Y. Sakoda, N. Ross-Smith, T. Inoue, and G. J. Belsham, J. Virol. 75:10643-10650, 2001). Residue 20 has now been modified to every possible amino acid, and the activities of each mutant 2A protease has been analyzed. Selected mutants were reconstructed into full-length SVDV cDNA, and viruses were rescued. The rate of virus growth in cultured swine kidney cells reflected the efficiency of 2A protease activity. In experimentally infected pigs, all four of the mutant viruses tested displayed much-reduced virulence compared to the J1/73 virus but a significant, albeit reduced, level of viral replication and excretion was detected. Direct sequencing of cDNA derived from samples taken early and late in infection indicated that a gradual selection-reversion to a more efficient protease occurred. The data indicated that extensive sequence change and selection may introduce a severe bottleneck in virus replication, leading to a decreased viral load and reduced or no clinical disease.


Does consuming isoflavones reduce or increase breast cancer risk?
Epidemiological studies suggest that consumption of phytoestrogens, in particular isoflavones, correlates with a lower incidence of breast cancer. However, data from human intervention studies have been less clear. Several meta-analyses have reported beneficial but relatively weak effects of isoflavone consumption on reduction of hot flushes and osteoporosis and improvement of cholesterol levels. However, the effects of isoflavones on early breast cancer markers differ between pre- and post-menopausal women. Conclusions on whether exposure of animals (mice and rats) to isoflavones protects against or promotes breast cancer development and growth vary between different studies. These results, taken together with the heterogeneous outcomes of human interventions, have led to a controversy surrounding the intake of isoflavone to reduce breast cancer risk. Here, we describe the results of recent human and animal intervention studies and discuss factors that might explain the variation in results. We also describe possible molecular mechanisms of action of isoflavones; distinguishing which mechanism(s) are involved is needed if we are to solve the controversy surrounding the actions of these compounds.


Pharmacokinetic model for predicting sulfamethazine disposition in pigs.
Concentration of sulfamethazine was measured in plasma and tissues (fat, liver, kidney, spleen, lungs, and skeletal muscle) of pigs given the drug IV and PO. The plasma concentration vs time curve was best described by a 2-compartment model, with a distribution half-life of 0.46 hour and an elimination half-life of 16.9 hours. Bioavailability after oral administration was 85.8 +/- 5.3%. The tissue and plasma sulfamethazine concentration vs time data were used to develop a multi-compartment pharmacokinetic model of sulfamethazine disposition in pigs. Plasma and tissue concentrations of sulfamethazine in pigs were measured at various intervals after multiple oral doses of sulfamethazine, and were compared to concentrations predicted by the model. Model predictions for tissue concentrations of sulfamethazine after addition of the drug to feed (110 micrograms/g of feed for 98 days; 550 micrograms/g for 30 days) were compared to results from other studies. The model accurately predicted the number of days for sulfamethazine concentration to fall below 0.1 micrograms of tissue/g (0.1 ppm, the tolerated concentration) in various tissues.


Model-based evaluation of the microhemodynamic effects of PEGylated HBOC molecules in the rat brain cortex: a laser speckle imaging study.
Hemoglobin-based oxygen carriers (HBOCs) were developed with the aim of substituting transfusions in emergency events. However, they exhibit adverse events, such as nitric oxide (NO) scavenging, vasoactivity, enhanced platelet aggregation, presently hampering their clinical application. The impact of two prototypical PEGylated HBOCs, Euro-PEG-Hb and PEG-HbO2, endowed by different oxygen affinities and hydrodynamic volumes, was assessed on the cerebrocortical parenchymal microhemodynamics, and extravasation through the blood-brain-barrier (BBB) by laser speckle contrast imaging (LSCI) method and near-infrared (NIR) imaging, respectively. By evaluating voxel-wise cerebrocortical red blood cell velocity, non-invasively for its mean kernel-wise value ( v ¯ RBC ), and model-derived kernel-wise predictions for microregional tissue hematocrit, THt, and fractional change in hematocrit-corrected vascular resistance, R', as measures of potential adverse effects (enhanced platelet aggregation and vasoactivity, respectively) we found i) no significant difference between tested HBOCs in the systemic and microregional parameters, and in the relative spatial dispersion of THt, and R' as additional measures of HBOC-related adverse effects, and ii) no extravasation through BBB by Euro-PEG-Hb. We conclude that Euro-PEG-Hb does not exhibit adverse effects in the brain microcirculation that could be directly attributed to NO scavenging.


Altered cytokinin metabolism affects cytokinin, auxin, and abscisic acid contents in leaves and chloroplasts, and chloroplast ultrastructure in transgenic tobacco.
Cytokinins (CKs) are involved in the regulation of plant development including plastid differentiation and function. Partial location of CK biosynthetic pathways in plastids suggests the importance of CKs for chloroplast development. The impact of genetically modified CK metabolism on endogenous CK, indole-3-acetic acid, and abscisic acid contents in leaves and isolated intact chloroplasts of Nicotiana tabacum was determined by liquid chromatography/mass spectrometry and two-dimensional high-performance liquid chromatography, and alterations in chloroplast ultrastructure by electron microscopy. Ectopic expression of Sho, a gene encoding a Petunia hybrida isopentenyltransferase, was employed to raise CK levels. The increase in CK levels was lower in chloroplasts than in leaves. CK levels were reduced in leaves of tobacco harbouring a CK oxidase/dehydrogenase gene, AtCKX3. The total CK content also decreased in chloroplasts, but CK phosphate levels were higher than in the wild type. In a transformant overexpressing a maize beta-glucosidase gene, Zm-p60.1, naturally targeted to plastids, a decrease of CK-O-glucosides in chloroplasts was found. In leaves, the changes were not significant. CK-O-glucosides accumulated to very high levels in leaves, but not in chloroplasts, of plants overexpressing a ZOG1 gene, encoding trans-zeatin-O-glucosyltransferase from Phaseolus lunatus. Manipulation of the CK content affected levels of indole-3-acetic and abscisic acid. Chloroplasts of plants constitutively overexpressing Sho displayed ultrastructural alterations including the occasional occurrence of crystalloids and an increased number of plastoglobuli. The other transformants did not exhibit any major differences in chloroplast ultrastructure. The results suggest that plant hormone compartmentation plays an important role in hormone homeostasis and that chloroplasts are rather independent organelles with respect to regulation of CK metabolism.


Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury.
Traumatic brain injury (TBI) is a recognised cause of hypopituitarism in adults but the prevalence after childhood TBI remains controversial. To investigate long-term endocrine outcomes and quality of life (PedsQL and QoL-AGHDA (Quality of Life in Adult Growth Hormone Deficiency Assessment)) following childhood TBI. Prospective study. Participants with moderate/severe TBI (n = 31) and controls (n = 17). Mean (range) age: 19.8 ± 4.2 (11-26), time post TBI: 9 (7-11) years. Detailed endocrine evaluation of stimulated (insulin tolerance test (ITT)) and spontaneous GH secretion (overnight profile) was undertaken in the TBI group; QoL and neuroimaging in both groups. No participant had seizures, short stature, precocious puberty or hypothyroidism. In 6/25 the ITT GH response was below age-defined cut-offs and cortisol <500 nmol/L in 2/25. Mean spontaneous GH secretion was <3.1 µg/L in 16/22 but peak GH was low only in 1/22 profiles. One patient had abnormal spontaneous and stimulated GH secretion and hypogonadism. Fatigue and depression scores were higher in TBI patients (P = .011 and P = .020). Fatigue correlated with measures of spontaneous but not stimulated GH secretion. Overall QoL (PedsQL) did not differ between groups but specific attributes of health state (cognition, memory) were impaired in TBI patients. Pituitary neuroimaging was normal in all participants. Fatigue and depression were common 8-10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.


Differential activation by xenoestrogens of ER alpha and ER beta when linked to different response elements.
The discovery of a second estrogen receptor (ER beta) has significant implications for our understanding of the molecular basis for the diverse actions of estrogen. Here we report the differential activation by natural and xenobiotic estrogens of ER alpha and ER beta when linked to different response elements. Receptor mediated activation of reporter constructs containing either the estrogen response element (ERE) from the vitellogenin (Vit) gene or from the luteinizing hormone beta (LH) gene were examined in transiently transfected Cos-1 cells. ER beta preferentially activated the consensus Vit ERE whereas ER alpha showed greater activation at the divergent LH ERE. This differential activation was observed for a number of ligands including estradiol, estrone, bisphenol A, octylphenol and diethystilbestrol. These findings show that the nature of the ERE, as well as the ratio of ER subtypes in a particular cell/tissue, will influence whether particular estrogen responsive genes are activated in the presence of natural or xenobiotic estrogens.


Optimizing azole antifungal therapy in the prophylaxis and treatment of fungal infections.
Azole antifungals are widely used in the prophylaxis and treatment of fungal infections, but are associated with a range of pharmacokinetic challenges and safety issues that necessitate individualized therapy to achieve optimal clinical outcomes. Recent advances in our knowledge of azole exposure-response relationships, therapeutic drug monitoring and individualized dosing strategies are reviewed as follows. Recent studies have significantly improved the understanding of exposure-response relationships for efficacy and toxicity, increasing confidence in target exposure ranges for azole antifungal agents. Population pharmacokinetic modelling of voriconazole has led to studies demonstrating the feasibility of model-guided dose individualization strategies with the drug, which holds significant promise for optimizing therapy. The recent approval of a solid oral tablet formulation of posaconazole with improved bioavailability and once-daily dosing has significantly improved the clinical utility of this agent. Further clinical experience with the investigational azole isavuconazole is needed to determine the role of individualized therapy. The coordination of CYP2C19 pharmacogenomic testing with model-guided dose individualization holds significant promise for optimizing therapy with voriconazole. Pharmacokinetic challenges with itraconazole, voriconazole and posaconazole oral suspension continue to require therapeutic drug monitoring to individualize therapy and optimize treatment outcomes.


An atlas of the bone marrow bone proteome in patients with dysproteinemias.
Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.


Intestinal neoplasia in horses.
Intestinal neoplasia of horses is inadequately described. Intestinal neoplasia of horses has characteristic clinicopathologic features. Thirty-four horses with intestinal neoplasia. Retrospective study. Anamnesis, clinical signs, clinicopathologic and pathologic findings in 34 adult horses diagnosed histologically with intestinal neoplasia were reviewed. The horses ranged in age from 2 to 30 years (mean 16.6 years at presentation). The Arabian breed was most represented and there was no sex predisposition. The most common presenting complaints were weight loss, colic, anorexia, and fever. The most consistent clinical signs were poor body condition, tachycardia, tachypnea, fever, and diarrhea. Useful diagnostic tools included rectal examination, routine blood analyses, abdominocentesis, ultrasonographic examination, rectal biopsy, and exploratory laparotomy. Alimentary lymphoma was the most common intestinal neoplasia identified, followed by adenocarcinoma and smooth muscle tumors. The small intestine was the most common segment of intestine affected for all neoplasms. Intestinal neoplasia was diagnosed antemortem in 13 of 34 (38%) horses. The median time from onset of clinical signs to death or euthanasia was 1.9 months. The discharge rate was 15%. Although the longest survival was observed in horses with jejunal adenocarcinoma, all horses were eventually euthanized because of intestinal neoplasia. Arabian horses were 4.5 times more likely to have intestinal neoplasia diagnosed than were other breeds.


A comparison of shear bond strength of ceramic and resin denture teeth on different acrylic resin bases.
The purpose of this study is to compare the shear bond strength of different resin bases and artificial teeth made of ceramic or acrylic resin materials and whether tooth-base interface may be treated with aluminium oxide sandblasting. Experimental measurements were carried on 80 specimens consisting of a cylinder of acrylic resin into which a single tooth is inserted. An ad hoc metallic frame was realized to measure the shear bond strength at the tooth-base interface. A complete factorial plan was designed and a three-way ANalysis Of VAriance (ANOVA) was carried out to investigate if shear bond strength is affected by the following factors: (i) tooth material (ceramic or resin); (ii) base material (self-curing or thermal-curing resin); (iii) presence or absence of aluminium oxide sandblasting treatment at the tooth-base interface. Tukey post hoc test was also conducted to evaluate any statistically significant difference between shear strength values measured for the dif-ferently prepared samples. It was found from ANOVA that the above mentioned factors all affect shear strength. Furthermore, post hoc analysis indi-cated that there are statistically significant differences (p-value=0.000) between measured shear strength values for: (i) teeth made of ceramic material vs. teeth made of acrylic resin material; (ii) bases made of self-curing resin vs. thermal-curing resin; (iii) specimens treated with aluminium oxide sandblasting vs. untreated specimens. Shear strength values measured for acryl-ic resin teeth were on average 70% higher than those measured for ceramic teeth. The shear bond strength was maximized by preparing samples with thermal-curing resin bases and resin teeth submitted to aluminium oxide sandblasting.


Effect of acetylsalicylic acid on fatty acid omega-hydroxylation in rat liver.
The effect of acetylsalicylic acid on the cytochrome P-450-mediated fatty acid omega-hydroxylation system was assessed in male Sprague-Dawley rats after they were fed a diet containing 1% (w/w) acetylsalicylic acid. A 3-fold increase in the specific activity of laurate omega-hydroxylation was observed in the acetylsalicylic acid fed rats in comparison to control rats. This effect of acetylsalicylic acid was unique as the specific activities of other cytochrome P-450-mediated reactions were not increased. The induction of the laurate omega-hydroxylation system was also manifested in a rapid formation of its dicarboxylic acid derivative, dodecanedioic acid, as the omega-hydroxy derivative was further oxidized by alcohol and aldehyde dehydrogenases. These results suggest the acetylsalicylic acid is similar to other peroxisomal proliferating agents in that it also induces the microsomal fatty acid omega-hydroxylation system and may account for the appearance of unique dicarboxylic acids in Reye's syndrome patients.


Neuroprotective Potential of Gentongping in Rat Model of Cervical Spondylotic Radiculopathy Targeting PPAR-γ Pathway.
Cervical spondylotic radiculopathy (CSR) is the most general form of spinal degenerative disease and is characterized by pain and numbness of the neck and arm. Gentongping (GTP) granule, as a classical Chinese patent medicine, has been widely used in curing CSR, whereas the underlying mechanism remains unclear. Therefore, the aim of this study is to explore the pharmacological mechanisms of GTP on CSR. The rat model of CSR was induced by spinal cord injury (SCI). Our results showed that GTP could significantly alleviate spontaneous pain as well as ameliorate gait. The HE staining and Western blot results showed that GTP could increase the quantity of motoneuron and enhance the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the spinal cord tissues. Meanwhile, immunofluorescence staining analysis indicated that GTP could reduce the expression of TNF-α in the spinal cord tissues. Furthermore, the protein level of Bax was decreased whereas the protein levels of Bcl-2 and NF200 were increased after the GTP treatment. These findings demonstrated that GTP might modulate the PPAR-γ pathway by inhibiting the inflammatory response and apoptosis as well as by protecting the cytoskeletal integrity of the spinal cord, ultimately play a neuroprotective role in CSR.


The Effects of Interactive Virtual Reality in Patients with Chronic Musculoskeletal Disorders: A Systematic Review and Meta-Analysis.
Objective: Interactive virtual reality (iVR) has been widely used for treatment purposes in patients with chronic musculoskeletal disorders. However, no consensus has been reached on the effects of iVR on pain, psychological distress, and functional disability. Therefore, this study aims to investigate the effects of iVR on pain, psychological distress, and functional disability in patients with chronic musculoskeletal disorders compared with no rehabilitation and conventional rehabilitation. Methods: Five electronic databases (PubMed, Cochrane CENTRAL, Scopus, EMBASE, and Web of Science) were searched from January 2016 to December 2021. All randomized controlled trials using iVR for treating pain, psychological distress, and functional disability in patients with chronic musculoskeletal disorders were included. A subgroup analysis was conducted to compare the effects of nonimmersive and immersive types of iVR on the outcomes of interest. Results: Our study provides good quality evidence that iVR reduced overall pain by 9.28 points as compared with no rehabilitation and by 8.09 points as compared with conventional rehabilitation. In the subgroup analysis, nonimmersive iVR showed a reduction in psychological distress (standardized mean differences = -0.35) as compared with no rehabilitation. However, no statistically significant difference in the outcomes existed between nonimmersive and immersive iVR. Furthermore, there were no statistically significant differences in the outcomes of functional disability. Conclusions: iVR is recommended for reducing pain intensity more than no rehabilitation or conventional rehabilitation. Meanwhile, nonimmersive iVR has been proposed for psychological distress improvement, with effects similar to those of conventional rehabilitation. However, iVR may not be an effective intervention in the case of functional disability.


Vitamin C Intervention for Critical COVID-19: A Pragmatic Review of the Current Level of Evidence.
Severe respiratory infections are characterized by elevated inflammation and generation of reactive oxygen species (ROS) which may lead to a decrease in antioxidants such as vitamin C and a higher requirement for the vitamin. Administration of intravenous vitamin C to patients with pneumonia and sepsis appears to decrease the severity of the disease and potentially improve survival rate. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes pneumonia, sepsis and acute respiratory distress syndrome (ARDS) in severe cases, and is referred to as coronavirus disease 2019 (COVID-19). Patients with COVID-19 infection also appear to have depleted vitamin C status and require additional supplementation of vitamin C during the acute phase of the disease. To date there have been 12 vitamin C and COVID-19 trials published, including five randomised controlled trials (RCTs) and seven retrospective cohort studies. The current level of evidence from the RCTs suggests that intravenous vitamin C intervention may improve oxygenation parameters, reduce inflammatory markers, decrease days in hospital and reduce mortality, particularly in the more severely ill patients. High doses of oral vitamin C supplementation may also improve the rate of recovery in less severe cases. No adverse events have been reported in published vitamin C clinical trials in COVID-19 patients. Upcoming findings from larger RCTs will provide additional evidence on vitamin supplementation in COVID-19 patients.


Possible age-dependent adaptive response to a low dose of X-rays in human lymphocytes.
Human peripheral blood lymphocytes from 30 healthy donors aged from 5 to 65 years consisting of four groups, namely 5 (six males), 25 (six females), 45 (six males) and 65 years old (six males and six females), were exposed to a single adaptive dose of 0.01 Gy X-rays followed by a challenge dose of 2.0 Gy X-rays. All age groups responded with a significantly reduced incidence of chromatid and isochromatid breaks except Group 4 (65 years male and female groups), where adaptive and challenge doses did not significantly reduce chromatid and isochromatid breaks. Results indicate the possibility of an inducible chromosomal repair mechanism in human blood lymphocytes. It suggests that ageing could be a factor which abolishes the adaptive response.


Plaque characterization using shear wave elastography-evaluation of differentiability and accuracy using a combined ex vivo and in vitro setup.
Ultrasound elastography has shown potential for improved plaque risk stratification. However, no clear consensus exists on what output metric to use, or what imaging parameters would render optimal plaque differentiation. For this reason we developed a combined ex vivo and in vitro setup, in which the ability to differentiate phantom plaques of varying stiffness was evaluated as a function of plaque geometry, push location, imaging plane, and analysed wave speed metric. The results indicate that group velocity or phase velocity ⩾1 kHz showed the highest ability to significantly differentiate plaques of different stiffness, successfully classifying a majority of the 24 analysed plaque geometries, respectively. The ability to differentiate plaques was also better in the longitudinal views than in the transverse view. Group velocity as well as phase velocities <1 kHz showed a systematic underestimation of plaque stiffness, stemming from the confined plaque geometries, however, despite this group velocity analysis showed lowest deviation in estimated plaque stiffness (0.1 m s-1 compared to 0.2 m s-1 for phase velocity analysis). SWE results were also invariant to SWE push location, albeit apparent differences in signal-to-noise ratio (SNR) and generated plaque particle velocity. With that, the study has reinforced the potential of SWE for successful plaque differentiation; however the results also highlight the importance of choosing optimal imaging settings and using an appropriate wave speed metric when attempting to differentiate different plaque groups.


Age-related changes in the rhesus macaque eye.
To assess age-related changes in the rhesus macaque eye and evaluate them to corresponding human age-related eye disease. Data from eye exams and imaging tests including intraocular pressure (IOP), lens thickness, axial length, and retinal optical coherence tomography (OCT) images were evaluated from 142 individuals and statistically analyzed for age-related changes. Quantitative autofluorescence (qAF) was measured as was the presence of macular lesions as related to age. Ages of the 142 rhesus macaques ranged from 0.7 to 29 years (mean = 16.4 years, stdev = 7.5 years). Anterior segment measurements such as IOP, lens thickness, and axial length were acquired. Advanced retinal imaging in the form of optical coherence tomography and qAF were obtained. Quantitative assessments were made and variations by age groups were analyzed to compare with established age-related changes in human eyes. Quantitative analysis of data revealed age-related increase in intraocular pressure (0.165 mm Hg per increase in year of age), ocular biometry (lens thickness 7.2 μm per increase in year of age; and axial length 52.8 μm per increase in year of age), and presence of macular lesions. Age-related changes in thicknesses of retinal layers on OCT were observed and quantified, showing decreased thickness of the retinal ganglion cell layer and inner nuclear layer, and increased thickness of photoreceptor outer segment and choroidal layers. Age was correlated with increased qAF by 1.021 autofluorescence units per increase in year of age. The rhesus macaque has age-related ocular changes similar to humans. IOP increases with age while retinal ganglion cell layer thickness decreases. Macular lesions develop in some aged animals. Our findings support the concept that rhesus macaques may be useful for the study of important age-related diseases such as glaucoma, macular diseases, and cone disorders, and for development of therapies for these diseases.


Analysis of Funding Source and Spin in the Reporting of Studies of Intravitreal Corticosteroid Therapy for Diabetic Macular Edema: A Systematic Review.
This systematic review examined the relationship between industry funding and the presence of spin in high-impact studies evaluating intravitreal corticosteroid therapy for diabetic macular edema. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. MEDLINE and Embase were systematically searched from inception through July 16, 2018, for randomized controlled trials and meta-analyses investigating the treatment of patients with diabetic macular edema using intravitreal corticosteroid therapy. Only studies published in English journals with an impact factor greater than 2 as per the Clarivate Analytics 2017 Journal Citation Report were included. The authors independently assessed study quality, funding source and the presence of reporting bias using a standardized datasheet. Title and abstract screening were completed on 7158 unique hits and full-text review yielded 44 included studies. Overall, there was correspondence between the wording of abstract conclusions and study results in 41/44 (93%) articles. Correspondence between abstract conclusions and significance of main outcome was present in 14/14 (100%) industry-funded and 27/30 (90%) nonindustry-funded studies. The odds ratio of industry funding being associated with noncorrespondence was 0.27 (95% CI: 0.01-5.61, p=0.54). The most common reason for noncorrespondence was the failure to mention rates of steroid-related intraocular pressure elevation. The results of this systematic review indicate that biased abstract outcome reporting is rare in published randomized controlled trials and meta-analyses of intravitreal corticosteroid therapy for diabetic macular edema. Biased reporting was not associated with the presence of industry funding or a conflict of interest.


Green Tea Polyphenols Mitigate Gliadin-Mediated Inflammation and Permeability in Vitro.
Green tea, a polyphenol-rich beverage, has been reported to mitigate a number of inflammatory and hypersensitivity disorders in laboratory models, and has been shown to moderate pathways related to food allergies in vitro. The present study investigates the impact of decaffeinated green tea extract (GTE) on the digestion of gliadin protein in vitro and the effect of physical interactions with GTE on the ability of gliadin to stimulate celiac disease-related symptoms in vitro. Complexation of GTE and gliadin in vitro is confirmed by monitoring increases in turbidity upon titration of GTE into a gliadin solution. This phenomenon is also observed during in vitro digestion when gliadin is exposed to the digestive proteases pepsin and trypsin. SDS-PAGE and enzymatic assays reveal that GTE inhibits digestive protease activity and gliadin digestion. In differentiated Caco-2 cell monolayers as a model of the small intestinal epithelium, complexation of gliadin with GTE reduces gliadin-stimulated monolayer permeability and the release of interleukin (IL)-6 and IL-8. There are potential beneficial effects of GTE as an adjuvant therapy for celiac disease through direct interaction between gliadin proteins and green tea polyphenols.


Exposure Assessment of Multiple Mycotoxins in Black and White Sesame Seeds Consumed in Thailand.
This study was conducted to determine the occurrence of 16 well-recognized and emerging mycotoxins in black and white sesame seed samples sold in Thailand and to evaluate possible health risks to consumers. Samples were extracted and cleaned with a modified QuEChERS procedure. Multiple mycotoxins in sesame seed samples were analyzed with a validated liquid chromatography-tandem mass spectrometry method. The risk of mycotoxin exposure via dietary intake of sesame seeds was evaluated based on the hazard quotient, margin of exposure (MOE), and quantitative liver cancer risk established by European Food Safety Authority, the Food and Agriculture Organization of the United Nations, and the World Health Organization. Of the 200 samples, 21.5% were contaminated with mycotoxins, 19.5% were contaminated with a single mycotoxin, and 2% were contaminated with multiple mycotoxins. Although 9% of total samples were contaminated with aflatoxins (AFs), only one black sesame seed sample and one white sesame seed sample were above the regulatory limits for the European Union (2 μg/kg). The MOE values derived from consumption of black and white sesame seeds were generally <10,000, especially in the group consuming the most. The number of liver cancer cases over a lifetime associated with AFB1 exposure based on the upper bound values for the group consuming high level of black and white sesame seeds (97.5 percentile) was estimated at more than 1 case per one million persons. Therefore, a potential risk to consumer health exists through the consumption of black and white sesame seeds and subsequent exposure to AFB1. However, further evaluation with larger sample sizes is necessary for more accurate calculations. Continuous monitoring of mycotoxin contamination in sesame seeds with risk assessments is recommended.


Explore Interregional EEG Correlations Changed by Sport Training Using Feature Selection.
This paper investigated the interregional correlation changed by sport training through electroencephalography (EEG) signals using the techniques of classification and feature selection. The EEG data are obtained from students with long-time professional sport training and normal students without sport training as baseline. Every channel of the 19-channel EEG signals is considered as a node in the brain network and Pearson Correlation Coefficients are calculated between every two nodes as the new features of EEG signals. Then, the Partial Least Square (PLS) is used to select the top 10 most varied features and Pearson Correlation Coefficients of selected features are compared to show the difference of two groups. Result shows that the classification accuracy of two groups is improved from 88.13% by the method using measurement of EEG overall energy to 97.19% by the method using EEG correlation measurement. Furthermore, the features selected reveal that the most important interregional EEG correlation changed by training is the correlation between left inferior frontal and left middle temporal with a decreased value.


An extracellular pH-driven targeted multifunctional manganese arsenite delivery system for tumor imaging and therapy.
Expanding the use of arsenic trioxide (ATO, As2O3) in cancer chemotherapy has received extensive attention in recent years owing to its remarkable efficacy in treating acute promyelocytic leukemia (APL). To date, the use of ATO for clinical treatment of solid tumors is still limited by its poor biocompatibility and severe toxic side effects. To address these limitations, here we developed a pH-low insertion peptide (pHLIP) modified ATO-based multifunctional drug-delivery system (DDS), which is termed MnAs@SiO2-pHLIP. With the coating of pHLIP, MnAs@SiO2-pHLIP could efficiently target the acidic tumor microenvironment, resulting in high intracellular accumulation of the DDS. As a "smart" nanoparticle (NP) platform, the DDS could controllably discharge the loaded ATO in response to acidic environments, which promotes the apoptosis of cancer cells. The features of controlled release capacity and the outstanding targeting ability contribute to better anticancer efficacy and less toxicity towards normal tissues compared with free ATO. It is worth noting that the acidic tumor microenvironment would also trigger the release of manganese ions (Mn2+) that brighten the T1 signal, which is exploited for real-time monitoring via contrast-enhanced magnetic resonance imaging (MRI). These multifunctional features, as demonstrated by both in vitro and in vivo experiments, could potentially expand the use of ATO to the treatment of solid tumors. We believe that MnAs@SiO2-pHLIP could serve as an auspicious agent for cancer theranostics and find tremendous applications in cancer management.


Face to face with the social brain.
Recent comparative evidence suggests that anthropoid primates are the only vertebrates to exhibit a quantitative relationship between relative brain size and social group size. In this paper, I attempt to explain this pattern with regard to facial expressivity and social bonding. I hypothesize that facial motor control increases as a secondary consequence of neocortical expansion owing to cortical innervation of the facial motor nucleus. This is supported by new analyses demonstrating correlated evolution between relative neocortex size and relative facial nucleus size. I also hypothesize that increased facial motor control correlates with enhanced emotional expressivity, which provides the opportunity for individuals to better gauge the trustworthiness of group members. This is supported by previous evidence from human psychology, as well as new analyses demonstrating a positive relationship between allogrooming and facial nucleus volume. I suggest new approaches to the study of primate facial expressivity in light of these hypotheses.


[Hyperthyroidism and cancer of the thyroid].
The relationship between hyperthyroidism due to Graves' disease or toxic nodular goiters and carcinoma of the thyroid remains uncertain. The incidence of thyroid carcinoma varies considerably from as low as 0.3% to as high as 16.6% with a higher rate in toxic nodular goiters than in diffuse goiters and in endemic goiter areas or after external radiation to head and neck. Occult thyroid carcinoma ( < 1.5 cm or microscopic foci) is the rule and only a few tumors are suspected preoperatively with ultrasonography or fine needle aspiration or 131I scan. Authors studied 11 patients found to have thyroid cancer concomitant with Graves' disease (2 patients) or toxic nodular goiter (9 patients) between 1979 and 1991 at University of Cagliari, Department of Surgical Oncology. Eight of the 11 cancers were papillary while three were follicular. A carcinoma was diagnosed intraoperatively on frozen section in only two patients, while on permanent section in nine patients. Two patients received subtotal thyroidectomy, because resection edges were safe and tumors were small. Nine patients received total thyroidectomy and three also lymphoadenectomy. All patients were alive and well with a mean follow-up of 91.8 months. The authors conclude that the incidence of coexisting thyroid malignancy and hyperthyroidism is rare, does not affect prognosis and is unimportant for therapeutic purposes because, currently, toxic nodular goiter, Graves' disease and carcinoma are treated by total thyroidectomy.


Role of protein kinase C zeta isoform in Fas resistance of immature myeloid KG1a leukemic cells.
Leukemic CD34(+) immature acute myeloid leukemia (AML) cells express Fas receptor but are frequently resistant to Fas agonistic reagents. Fas plays an important role in T-cell-mediated cytotoxicity, and recently it has been suggested that altered Fas signaling may contribute to drug resistance. Therefore, Fas resistance could be one of the mechanisms by which AML progenitors escape chemotherapy or T-cell-based immune intervention. However, the molecular mechanism of Fas resistance in AML cells has not been identified. Fas signaling can be interrupted at 3 mains levels: Fas clustering, alteration of death-inducing-signaling-complex (DISC) formation, and effector caspase inhibition of downstream caspase-8. This study shows that in the Fas-resistant CD34(+)CD38(-) KG1a cells, Fas agonists resulted in Fas aggregation but not in caspase-8 activation, related to a defect in DISC formation. However, pretreatment with chelerythrin, but not with calphostin C, resulted in the restoration of Fas-induced caspase-8 activation and cytotoxicity, suggesting that some atypical protein kinase C (PKC) isoforms contributed to the lack of DISC formation. Indeed, treatment with antisense oligonucleotides directed against PKC zeta and enforced expression of Par-4, a negative regulator of PKC zeta activity, restored Fas-induced caspase-8 activity and apoptosis. Moreover, it was found that PKC zeta interacts with FADD and that PKC zeta immunoextracts prepared from KG1a cells are able to phosphorylate FADD in vitro, whereas this phosphorylation is dramatically reduced in Par-4 transfectant cells. In conclusion, it is suggested that in AML cells, PKC zeta plays an important role in Fas resistance by inhibiting DISC formation, possibly by phosphorylating FADD.


Discovery of novel benzylquinazoline molecules as p97/VCP inhibitors.
Introduction: Protein p97 is an extensively investigated AAA ATPase with various cellular activities, including cell cycle control, ubiquitin-proteasome system, autophagy, and NF-κB activation. Method: In this study, we designed, synthesized and evaluated eight novel DBeQanalogs as potential p97 inhibitors in vivo and in vitro. Results: In the p97 ATPase inhibition assay, compounds 6 and 7 showed higher potency than the known p97 inhibitors, DBeQ and CB-5083. Compounds 4-6 dramatically induced G0/G1 phase arrest in the HCT116 cells, and compound 7 arrested the cells in both G0/G1 and S phases. Western blots showed elevated levels of SQSTM/p62, ATF-4, and NF-κB in HCT116 cells with the treatment of compounds 4-7, confirming their role in inhibiting the p97 signaling pathway in cells. In addition, the IC50 of compounds 4-6 against HCT116, RPMI-8226, and s180 proliferation were 0.24-6.9 µM with comparable potency as DBeQ. However, compounds 4-6 displayed low toxicity against the normal human colon cell line. Thus, compounds 6 and 7 were proved to be potential p97 inhibitors with less cytotoxicity. In vivo studies using the s180 xenograft model have demonstrated that compound 6 inhibited tumor growth, led to a significant reduction of p97 concentration in the serum and tumor, and indicated non-toxicity on the body weight and organ-to-brain weight ratios except for the spleen at the dose of 90 μmol/kg/day for 10 days. Furthermore, the present study indicated that compound 6 may not induce s180 mice myelosuppression often observed in the p97 inhibitors. Conclusion: Compound 6 displayed high binding affinity to p97, great p97 ATPase inhibition, selective cytotoxicity, remarkable anti-tumor effect, and upregulated safety, which improved the clinical potential of p97 inhibitors.


Carcinoma of the breast associated with pregnancy.
Sixty-three pregnant patients were treated for primary carcinoma of the breast at the Mayo Clinic between 1950 and 1980. These patients had a greater incidence of nodal metastasis and scirrhous histopathologic factors than did non-pregnant patients with a malignant condition of the breast. The five year survival rate of pregnant patients with localized malignant growths of the breast was 80 per cent. Improved survival time was not demonstrated for patients who terminated the pregnancy.


Autophagic degradation contributes to muscle wasting in cancer cachexia.
Muscle protein wasting in cancer cachexia is a critical problem. The underlying mechanisms are still unclear, although the ubiquitin-proteasome system has been involved in the degradation of bulk myofibrillar proteins. The present work has been aimed to investigate whether autophagic degradation also plays a role in the onset of muscle depletion in cancer-bearing animals and in glucocorticoid-induced atrophy and sarcopenia of aging. The results show that autophagy is induced in muscle in three different models of cancer cachexia and in glucocorticoid-treated mice. In contrast, autophagic degradation in the muscle of sarcopenic animals is impaired but can be reactivated by calorie restriction. These results further demonstrate that different mechanisms are involved in pathologic muscle wasting and that autophagy, either excessive or defective, contributes to the complicated network that leads to muscle atrophy. In this regard, particularly intriguing is the observation that in cancer hosts and tumor necrosis factor α-treated C2C12 myotubes, insulin can only partially blunt autophagy induction. This finding suggests that autophagy is triggered through mechanisms that cannot be circumvented by using classic upstream modulators, prompting us to identify more effective approaches to target this proteolytic system.


Defining the Role of Minimally Invasive Proctectomy for Locally Advanced Rectal Adenocarcinoma.
National examination of open proctectomy (OP), laparoscopic proctectomy (LP), and robotic proctectomy (RP) in pathological outcomes and overall survival (OS). Surgical management for rectal adenocarcinoma is evolving towards utilization of LP and RP. However, the oncological impacts of a minimally invasive approach to rectal cancer have yet to be defined. Retrospective review of the National Cancer Database identified patients with nonmetastatic locally advanced rectal adenocarcinoma from 2010 to 2014, who underwent neoadjuvant chemoradiation, surgical resection, and adjuvant therapy. Cases were stratified by surgical approach. Multivariate analysis was used to compare pathological outcomes. Cox proportional-hazard modeling and Kaplan-Meier analyses were used to estimate long-term OS. Of 6313 cases identified, 53.8% underwent OP, 31.8% underwent LP, and 14.3% underwent RP. Higher-volume academic/research and comprehensive community centers combined to perform 80% of laparoscopic cases and 83% of robotic cases. In an intent-to-treat model, multivariate analysis demonstrated superior circumferential margin negativity rates with LP compared with OP (odds ratio 1.34, 95% confidence interval 1.02-1.77, P = 0.036). Cox proportional-hazard modeling demonstrated a lower death hazard ratio for LP compared with OP (hazard ratio 0.81, 95% confidence interval 0.67-0.99, P = 0.037). Kaplan-Meier analysis demonstrated a 5-year OS of 81% in LP compared with 78% in RP and 76% in OP (P = 0.0198). In the hands of experienced colorectal specialists treating selected patients, LP may be a valuable operative technique that is associated with oncological benefits. Further exploration of pathological outcomes and long-term survival by means of prospective randomized trials may offer more definitive conclusions regarding comparisons of open and minimally invasive technique.


The capacity of visual short-term memory is set both by visual information load and by number of objects.
Previous research has suggested that visual short-term memory has a fixed capacity of about four objects. However, we found that capacity varied substantially across the five stimulus classes we examined, ranging from 1.6 for shaded cubes to 4.4 for colors (estimated using a change detection task). We also estimated the information load per item in each class, using visual search rate. The changes we measured in memory capacity across classes were almost exactly mirrored by changes in the opposite direction in visual search rate (r2=.992 between search rate and the reciprocal of memory capacity). The greater the information load of each item in a stimulus class (as indicated by a slower search rate), the fewer items from that class one can hold in memory. Extrapolating this linear relationship reveals that there is also an upper bound on capacity of approximately four or five objects. Thus, both the visual information load and number of objects impose capacity limits on visual short-term memory.


The medical audiological evaluation of tinnitus patients.
We outline our routine approach to tinnitus patients, highlighting the different aspects of our examination: the clinical history, objective ear, nose, and throat and general examination, and audiovestibular testing. We emphasize the interest in testing not only the cochlear but the vestibular function of the inner ear. In our view, this testing is of paramount importance, for the cochleovestibular system is a unit, acting as a whole. All these data are stored in a database bank. Then we present our preliminary results. Currently, we have 83 patients suffering from tinnitus, and their results are statistically presented. We characterize the population in terms of its gender distribution and mean age. The localization and characteristics of tinnitus and the associated symptoms also are noted. The results of the audiovestibulometric examinations-pure-tone audiometry, vocal audiometry, and brain evoked response audiometry craniocorpography and electronystagmography are discussed. We concluded that many tinnitus patients, even those who had no vestibular symptoms, showed some disturbances in the vestibular tests. This fact highlights the need for a complete cochleovestibular investigation in all patients complaining of tinnitus.


Insights into the reaction of protein-tyrosine phosphatase 1B: crystal structures for transition state analogs of both catalytic steps.
Catalysis by protein-tyrosine phosphatase 1B (PTP1B) occurs through a two-step mechanism involving a phosphocysteine intermediate. We have solved crystal structures for the transition state analogs for both steps. Together with previously reported crystal structures of apo-PTP1B, the Michaelis complex of an inactive mutant, the phosphoenzyme intermediate, and the product complex, a full picture of all catalytic steps can now be depicted. The transition state analog for the first catalytic step comprises a ternary complex between the catalytic cysteine of PTP1B, vanadate, and the peptide DADEYL, a fragment of a physiological substrate. The equatorial vanadate oxygen atoms bind to the P-loop, and the apical positions are occupied by the peptide tyrosine oxygen and by the PTP1B cysteine sulfur atom. The vanadate assumes a trigonal bipyramidal geometry in both transition state analog structures, with very similar apical O-O distances, denoting similar transition states for both phosphoryl transfer steps. Detailed interactions between the flanking peptide and the enzyme are discussed.


Diabetes Technology Meeting 2022.
Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 3 to November 5, 2022. Meeting topics included (1) the measurement of glucose, insulin, and ketones; (2) virtual diabetes care; (3) metrics for managing diabetes and predicting outcomes; (4) integration of continuous glucose monitor data into the electronic health record; (5) regulation of diabetes technology; (6) digital health to nudge behavior; (7) estimating carbohydrates; (8) fully automated insulin delivery systems; (9) hypoglycemia; (10) novel insulins; (11) insulin delivery; (12) on-body sensors; (13) continuous glucose monitoring; (14) diabetic foot ulcers; (15) the environmental impact of diabetes technology; and (16) spinal cord stimulation for painful diabetic neuropathy. A live demonstration of a device that can allow for the recycling of used insulin pens was also presented.


Reduction of Breakdown Pressure by Filter Cake Removal Using Thermochemical Fluids and Solvents: Experimental and Numerical Studies.
The process of well cleanup involves the removal of an impermeable layer of filter cake from the face of the formation. The inefficient removal of the filter cake imposes difficulty on fracturing operations. Filter cake's impermeable features increase the required pressure to fracture the formation. In this study, a novel method is introduced to reduce the required breakdown pressure to fracture the formation containing the water-based drilling fluid filter cake. The breakdown pressure was tested for five samples of similar properties using different solutions. A simulated borehole was drilled in the core samples. An impermeable filter cake using barite-weighted drilling fluid was built on the face of the drilled hole of each sample. The breakdown pressure for the virgin sample without damage (filter cake) was 6.9 MPa. The breakdown pressure increased to 26.7 MPa after the formation of an impermeable filter cake. Partial removal of filter cake by chelating agent reduced the breakdown pressure to 17.9 MPa. Complete dissolution of the filter cake with chelating agents resulted in the breakdown pressure approximately equivalent to the virgin rock breakdown pressure, i.e., 6.8 MPa. The combined thermochemical and chelating agent solution removed the filter cake and reduced the breakdown pressure to 3.8 MPa. Post-treatment analysis was carried out using nuclear magnetic resonance (NMR) and scratch test. NMR showed the pore size redistributions with good communication between different pores after the thermochemical removal of filter cake. At the same time, there was no communication between the different pores due to permeability impairment after filter cake formation. The diffusion coupling through NMR scans confirmed the higher interconnectivity between different pores systems after the combined thermochemical and chelating agent treatment. Compressive strength was measured from the scratch test, confirming that filter cake formation caused added strength to the rock that impacts the rock breakdown pressure. The average compressive strength of the original specimen was 44.5 MPa that increased to 73.5 MPa after the formation of filter cake. When the filter cake was partially removed, the strength was reduced to 61.7 MPa. Complete removal with chelating agents removed the extra strength that was added due to the filter cake presence. Thermochemical and chelating agents resulted in a significantly lower compressive strength of 25.3 MPa. A numerical model was created to observe the reduction in breakdown pressure due to the thermochemical treatment of the filter cake. The result presented in this study showed the engineering applications of thermochemical treatment for filter cake removal.


Hippocampal histamine receptors and conflictive exploration in the rat: studies using the elevated asymmetric plus-maze.
The possible role of histamine receptors in the hippocampal formation on the exploratory motivation and emotionality of the rat was studied. An elevated asymmetric plus-maze composed of 4 different arms (no walls, single high wall, high and low walls and two high walls) arranged at 90 degrees angles was used. The exploration score, considered to be an index of exploratory motivation, and the permanency score, considered to be an index of emotionality (anxiety), were determined. Histamine was administered locally into the ventral hippocampus at three different doses (9, 45 and 90 nmol). Another group of rats was also microinjected with 45 nmol of pyrilamine (a histamine H1 receptor antagonist) or ranitidine (a histamine H2 receptor antagonist) in addition to 9 nmol of histamine in order to identify the possible type of histamine receptor involved. Histamine administration significantly inhibited the exploration score and increased the permanency score at the doses of 9 and 45 nmol in two of four arms. These effects were completely blocked by the administration of either histamine receptor antagonist. The present results suggest that in the hippocampal formation histamine inhibits exploratory motivation and decreases emotionality by activating both types of histamine receptors. Also, the elevated asymmetric plus-maze appears to be a suitable technique to quantify exploration and possibly "anxiety".


High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates With Lower Survival.
Glioblastoma (GBM), the most aggressive brain tumor, is associated with a median survival at diagnosis of 16-20 months and limited treatment options. The key hallmark of GBM is altered tumor metabolism and marked increase in the rate of glycolysis. Aerobic glycolysis along with elevated glucose consumption and lactate production supports rapid cell proliferation and GBM growth. In this study, we examined the gene expression profile of metabolic targets in GBM samples from patients with lower grade glioma (LGG) and GBM. We found that gene expression of glycolytic enzymes is up-regulated in GBM samples and significantly associated with an elevated risk for developing GBM. Our findings of clinical outcomes showed that GBM patients with high expression of HK2 and PKM2 in the glycolysis related genes and low expression of genes involved in mitochondrial metabolism-SDHB and COX5A related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), respectively, was associated with poor patient overall survival. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in GBM compared to LGG but was lower compared to normal brain. The fact that in GBM the expression levels of TCA cycle and OXPHOS-related genes are higher than those in LGG patients suggests the metabolic shift in GBM cells when progressing from LGG to GBM. These results are an important step forward in our understanding of the role of metabolic reprogramming in glioma as drivers of the tumor and could be potential prognostic targets in GBM therapies.


[Primary retroperitoneal tumors. Our experience].
Primary retroperitoneal tumors are rare (0.05-0.2% of all tumors), often malignant and characterized by a poor and non-specific symptomatology and by a late diagnosis. Complete resection is possible in only a few patients, while recurrence is very common. The records of 29 adult patients who underwent operative treatment at Surgical Oncology Institute-University of Cagliari between November 1973 and June 1992 were reviewed; 9 were males, 20 females, median age 46.4 years (range 12-82). There were 4 benign tumors (13.8%) and 25 malignant (86.2%). Fibrosarcoma (9 cases, 31%) and liposarcoma (3 cases, 10.3%) were the most frequent histologic types. There were also two fibroleiomyomas, leiomyosarcomas, malignant fibrous histiocytomas and neuroblastomas, one case of fibroma, neurofibroma, rhabdomyosarcoma and schwannoma. Five sarcoma were not otherwise specified. Abdominal mass (25 cases, 86.2%), flank or abdominal pain (15 cases, 51.7%) and weight loss (8 cases, 27.6%) were most common symptoms; change in bowel habit and constipation (6 cases, 20.7%), fever (5 cases, 17.2%), urinary disorders (4 cases, 13.8%) nausea and vomiting (2 cases, 6.7%) were less common. Diagnosis was made by ultrasonography, computed tomography and traditional radiographic studies. median interval between first symptoms and diagnosis was 11 months. Complete surgical resection was possible in only 13 cases (46.4%): 10 of the 25 malignant tumors (40%) and 3 of the 4 benign tumors (75%).(ABSTRACT TRUNCATED AT 250 WORDS)


Rapidly progressive dementia due to neurosarcoidosis.
Rapidly progressive dementia (RPD) is typically defined as a cognitive decline progressing to severe impairment in less than 1-2 years, typically within weeks or months. Accurate and prompt diagnosis is important because many conditions causing RPD are treatable. Neurosarcoidosis is often cited as an unusual reversible cause of RPD. We report two cases of neurosarcoidosis presenting as RPD. Case 1: A 61-year-old woman developed a RPD associated with visual loss. In seven months she was dependent for self-care. Magnetic resonance imaging (MRI) revealed temporal and suprasellar brain lesions. Treatment with high-dose intravenous prednisolone was associated with partial improvement. Case 2: A 43-year-old woman who was being treated for diabetes insipidus developed a severe episodic amnesia one year after onset of cognitive symptoms. Previous MRI had shown a hypothalamic lesion and she had been treated with oral prednisone and cyclophosphamide. There was reduction of the MRI findings but no improvement in the cognitive deficits. Brain biopsy disclosed noncaseous granulomas and granulomatous angiitis; treatment was changed to high-dose intravenous methylprednisolone, with poor symptomatic response. The diagnosis of RPD due to neurosarcoidosis can be challenging when the disease is restricted to the nervous system. In these cases, clinical presentation of RPD associated with neuroendocrine and visual dysfunction, imaging findings showing hypothalamic lesions and, in some cases, brain biopsy, are the key to a correct diagnosis. It is possible that earlier diagnoses and treatment could have led to a better outcome in these patients.


Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human.
We have identified and characterized a novel human estrogen receptor (ER) beta isoform, ERbetacx, which is truncated at the C-terminal region but has an extra 26 amino acids due to alternative splicing. The ERbetacx transcript is expressed in testis, ovary, thymus and prostate as well as in human cultured cell lines such as HEC-1, HOS-TE85 and Saos-2 cells. ERbetacx protein is also immunodetectable in these human cells. Biochemical analysis reveals that the average dissociation constants ( K d) of ERalpha and ERbeta for 17beta-estradiol (E2) are 0.2 and 0.6 nM respectively, but ERbetacx has no ligand binding ability. ERalpha and ERbeta proteins bind to the estrogen response element, whereas ERbetacx does not form any shifted complex in gel shift assays. In a transient expression assay, ERbetacx shows no ligand-dependent transactivation ability of a basal promoter and also cannot interact with a cofactor, TIF1alpha, in the presence or absence of E2. ERbetacx preferentially forms a heterodimer with ERalpha rather than that with ERbeta, inhibiting DNA binding by ERalpha. Interestingly, however, it shows a significant dominant negative activity only against ERalpha transactivation. Thus, this study indicates that ERbetacx potentially inhibits ERalpha-mediated estrogen action and that alternative splicing of the C-terminal region and its inhibitory properties are characteristic of several members of nuclear receptor isoforms.


Cytokinins mediate resistance against Pseudomonas syringae in tobacco through increased antimicrobial phytoalexin synthesis independent of salicylic acid signaling.
Cytokinins are phytohormones that are involved in various regulatory processes throughout plant development, but they are also produced by pathogens and known to modulate plant immunity. A novel transgenic approach enabling autoregulated cytokinin synthesis in response to pathogen infection showed that cytokinins mediate enhanced resistance against the virulent hemibiotrophic pathogen Pseudomonas syringae pv tabaci. This was confirmed by two additional independent transgenic approaches to increase endogenous cytokinin production and by exogenous supply of adenine- and phenylurea-derived cytokinins. The cytokinin-mediated resistance strongly correlated with an increased level of bactericidal activities and up-regulated synthesis of the two major antimicrobial phytoalexins in tobacco (Nicotiana tabacum), scopoletin and capsidiol. The key role of these phytoalexins in the underlying mechanism was functionally proven by the finding that scopoletin and capsidiol substitute in planta for the cytokinin signal: phytoalexin pretreatment increased resistance against P. syringae. In contrast to a cytokinin defense mechanism in Arabidopsis (Arabidopsis thaliana) based on salicylic acid-dependent transcriptional control, the cytokinin-mediated resistance in tobacco is essentially independent from salicylic acid and differs in pathogen specificity. It is also independent of jasmonate levels, reactive oxygen species, and high sugar resistance. The novel function of cytokinins in the primary defense response of solanaceous plant species is rather mediated through a high phytoalexin-pathogen ratio in the early phase of infection, which efficiently restricts pathogen growth. The implications of this mechanism for the coevolution of host plants and cytokinin-producing pathogens and the practical application in agriculture are discussed.


Major ocular trauma in Taiwan: 2002-2004 versus 2012-2014.
We investigated the temporal changes in major eye injuries in Taiwan by reviewing the medical records of all patients with ocular trauma hospitalized at the National Cheng Kung University Hospital during 2002-2004 and 2012-2014. A total of 169 eyes (161 patients) during 2002-2004 and 121 eyes (120 patients) during 2012-2014 were enrolled (mean ± SD age: 41.9 ± 20.8 years in 2002-2004, and 51.8 ± 19.3 years in 2012-2014). Males accounted for ~75% of patients. The most frequent injury-causing object was metallic material (~24%), and blunt traumas were most frequently attributable to traffic accidents and falls. The most common locations of injuries for males and females were the workplace and home, respectively. Open-globe injuries occurred in ~70% of eyes, requiring primary repair, cataract extraction, and/or intraocular lens implantation. The frequencies of fall injury, lacrimal system laceration, lens injury, corneal/scleral foreign bodies, and use of intracameral antibiotics increased from 2002-2004 to 2012-2014, while those of closed-globe injury, vitreous haemorrhage, optic nerve injury, and medical treatment decreased. The final visual acuity remained poor (≤20/200) in >1/3 of injured eyes. Despite therapeutic advancements, major eye injuries still pose a high risk for poor visual outcome.


The birth pangs of monoclonal antibody therapeutics: the failure and legacy of Centoxin.
This paper examines the development and termination of nebacumab (Centoxin®), a human IgM monoclonal antibody (mAb) drug frequently cited as one of the notable failures of the early biopharmaceutical industry. The non-approval of Centoxin in the United States in 1992 generated major concerns at the time about the future viability of any mAb therapeutics. For Centocor, the biotechnology company that developed Centoxin, the drug posed formidable challenges in terms of safety, clinical efficacy, patient selection, the overall economic costs of health care, as well as financial backing. Indeed, Centocor's development of the drug brought it to the brink of bankruptcy. This article shows how many of the experiences learned with Centoxin paved the way for the current successes in therapeutic mAb development.


The poisoning of 'awa: the non-traditional use of an ancient remedy.
In the traditional practice of Native Hawaiians, 'awa (Piper methysticum) has long been revered as a medicine, a sacred plant central to religious ceremony, and a social drink. In the late 1990s, 'awa attracted global attention as an herbal alternative to existing pharmaceuticals for reducing stress, anxiety, pain and assorted ailments. Marketed since 1994 as a dietary supplement, within seven years 'awa had earned the title of a "superstar" and quickly became one of the top eight herbal remedies in an expanding $18 billion-plus herbal remedy industry. In one study, the plant was even argued to possess chemopreventive properties, when cancer incidence and kava consumption in Pacific island communities were correlated. In 2002, however, the remedy was banned in several European countries, after case reports of liver toxicity allegedly associated with its nontraditional use surfaced. In the United States (US), the Food and Drug Administration issued a consumer advisory leading several retailers to voluntarily withdraw products containing 'awa from their shelves. These actions have sent shock waves throughout Pacific Island communities seeking to derive economic benefit from a relatively new and little-regulated industry. Moreover, they threaten the vitality of centuries of Native Hawaiian cultural practice. Clinical studies advocating both sides of the safety debate have been published, as producers, marketers and users attempt to influence government action. At the same time, issues of cultural exploitation, religious freedom, traditional practice, and native intellectual property rights are absent from the debate, leaving the future of native practice hanging in the balance. Whether or not the herb's status is restored, the situation raises critical questions: Is 'awa toxic? Or, does the poison derive from its use outside of traditional practice?


Shear-stress function approach of hydration layer based on the Green-Kubo formula.
We present the analytic expression of the stress correlation (SC) function for the ubiquitous hydration water layer (HWL) using the Green-Kubo equation and the shear modulus of HWL. The SC function is then experimentally obtained by measuring the viscoelastic properties of HWL using shear-mode dynamic force spectroscopy. Interestingly, the SC changes sign from positive to negative as the HWL thickness increases, where the shear stresses acting on the HWLs bound to two nearby surfaces are out of phase. We also suggest that the repulsive hydration force originates from the SC of HWL. Our results provide the first demonstration of the microscopic understanding of the HWL viscoelasticity and may allow a deeper insight on the HWL dynamics as well as the complex liquids.


Inflammatory reaction in chronic periodontopathies in patients with diabetes mellitus. Histological and immunohistochemical study.
Chronic periodontopathies and diabetes mellitus are two clinical entities, which reciprocally condition one another. The periodontal disease is considered a major complication, which induces an unfavorable evolution of diabetes mellitus. Diabetes mellitus is an endocrine disease which favors the occurrence of periodontopathy through gum's microvascular disorders, the selection and development of an aggressive bacterial plaque and through an exaggerate inflammatory response to the microflora within the oral cavity. Both diabetes mellitus and periodontal disease have an increasing incidence in the whole world. Development of periodontopathy is related to the aggression of bacterial flora in dental plaque, flora that is influenced on its turn by the evolution of diabetes mellitus. In our study, we have evaluated the inflammatory reaction in periodontium in patients with slowly and progressive periodontitis in patients with diabetes mellitus who had diabetes longer than five years. It has been found that all patients presented a chronic inflammatory infiltrate, abundant, with round mononuclear cells of lymphocyte, plasma cells and macrophage type, with non-homogenous arrangement, more intensely where the covering epithelium presented erosions or necrotic areas. Out of the immunity system cells, the most numerous where of T-lymphocytes type.


Lung Function Decline in Relation to COVID-19 in the General Population: A Matched Cohort Study With Prepandemic Assessment of Lung Function.
To quantify the potential decline in dynamic lung volumes following coronavirus disease 2019 (COVID-19) in the general population. A prospective matched cohort study of adult Copenhagen General Population Study (CGPS) participants with a prepandemic spirometry available. CGPS individuals with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test performed repeat spirometry, a questionnaire regarding respiratory symptoms, and diffusing capacity test for carbon monoxide. A matched uninfected CGPS control sample was used, and simple regression and linear mixed effect models were computed to study lung function decline. A total of 606 individuals were included; 92/107 (85.9%) with positive SARS-CoV-2 PCR test experienced coronavirus disease 2019 (COVID-19) symptoms and 12 (11.2%) were hospitalized. Spirometry was performed at median 5.6 months (interquartile range, 3.9-12.8) after positive SARS-CoV-2 PCR test. COVID-19 was associated with adjusted 7.3 mL (95% confidence interval [CI], .3-14.3) and 22.6 mL (95% CI, 13.1-32.0) steeper decline in annual forced expiratory volume in first second (FEV1) and FVC or total 113.8 and 301.3 mL lower FEV1 and FVC from baseline to follow-up. Results were robust in analyses restricted to individuals not requiring hospitalization. COVID-19-related declines of dynamic lung volume in the general population not requiring hospitalization were small but measurable.


Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response.
Mitochondrial superoxide (O2-) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2- to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2-, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2- is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.