Protein networks, pleiotropy and the evolution of senescence.
The number of interactions, or connectivity, among proteins in the yeast protein interaction network follows a power law. I compare patterns of connectivity for subsets of yeast proteins associated with senescence and with five other traits. I find that proteins associated with ageing have significantly higher connectivity than expected by chance, a pattern not seen for most other datasets. The pattern holds even when controlling for other factors also associated with connectivity, such as localization of protein expression within the cell. I suggest that these observations are consistent with the antagonistic pleiotropy theory for the evolution of senescence. In further support of this argument, I find that a protein's connectivity is positively correlated with the number of traits it influences or its degree of pleiotropy, and further show that the average degree of pleiotropy is greatest for proteins associated with senescence. I explain these results with a simple mathematical model combining assumptions of the antagonistic pleiotropy theory for the evolution of senescence with data on network topology. These findings integrate molecular and evolutionary models of senescence, and should aid in the search for new ageing genes.


Laparoscopic repair of enterocele.
The repair of an enterocele has classically been via a transvaginal or open abdominal route. With the availability of minimally invasive procedures, we applied established laparoscopic techniques to enterocele repair. Three women with a history of hysterectomy had a symptomatic enterocele as well as a cystocele or rectocele. Each underwent a transperitoneal laparoscopic enterocele repair prior to a transvaginal rectocele or cystocele repair or laparoscopic colposuspension. Using three trocars and transvaginal digital manipulation, the enterocele was reduced and repaired utilizing a modified Moschocowitz technique. The cul-de-sac was obliterated by approximating the posterior vaginal fascia to the anterior wall of the rectum with a running suture. There was no operative morbidity. The average length of stay was 3.3 days. All patients were asymptomatic with no enterocele recurrence identified during a mean follow-up of 10.5 (range 7-15) months. Laparoscopic enterocele repair is a feasible surgical procedure with minimal morbidity. A larger series with longer follow-up is necessary before the efficacy and proper indications for this minimally invasive procedure are determined.


Novel coronavirus disease 2019: predicting prognosis with a computed tomography-based disease severity score and clinical laboratory data.
Currently, there are known contributing factors but no comprehensive methods for predicting the mortality risk or intensive care unit (ICU) admission in patients with novel coronavirus disease 2019 (COVID‑19). The aim of this study was to explore risk factors for mortality and ICU admission in patients with COVID‑19, using computed tomography (CT) combined with clinical laboratory data. Patients with polymerase chain reaction-confirmed COVID‑19 (n = 63) from university hospitals in Tehran, Iran, were included. All patients underwent CT examination. Subsequently, a total CT score and the number of involved lung lobes were calculated and compared against collected laboratory and clinical characteristics. Univariable and multivariable proportional hazard analyses were used to determine the association among CT, laboratory and clinical data, ICU admission, and in‑hospital death. By univariable analysis, in‑hospital mortality was higher in patients with lower oxygen saturation on admission (below 88%), higher CT scores, and a higher number of lung lobes (more than 4) involved with a diffuse parenchymal pattern. By multivariable analysis, in‑hospital mortality was higher in those with oxygen saturation below 88% on admission and a higher number of lung lobes involved with a diffuse parenchymal pattern. The risk of ICU admission was higher in patients with comorbidities (hypertension and ischemic heart disease), arterial oxygen saturation below 88%, and pericardial effusion. We can identify factors affecting in‑hospital death and ICU admission in COVID-19. This can help clinicians to determine which patients are likely to require ICU admission and to inform strategic healthcare planning in critical conditions such as the COVID‑19 pandemic.


IRF7: activation, regulation, modification and function.
Interferon regulatory factor 7 (IRF7) was originally identified in the context of Epstein-Barr virus (EBV) infection, and has since emerged as the crucial regulator of type I interferons (IFNs) against pathogenic infections, which activate IRF7 by triggering signaling cascades from pathogen recognition receptors (PRRs) that recognize pathogenic nucleic acids. Moreover, IRF7 is a multifunctional transcription factor, underscored by the fact that it is associated with EBV latency, in which IRF7 is induced as well as activated by the EBV principal oncoprotein latent membrane protein-1 (LMP1). Aberrant production of type I IFNs is associated with many types of diseases such as cancers and autoimmune disorders. Thus, tight regulation of IRF7 expression and activity is imperative in dictating appropriate type I IFN production for normal IFN-mediated physiological functions. Posttranslational modifications have important roles in regulation of IRF7 activity, exemplified by phosphorylation, which is indicative of its activation. Furthermore, mounting evidence has shed light on the importance of regulatory ubiquitination in activation of IRF7. Albeit these exciting findings have been made in the past decade since its discovery, many questions related to IRF7 remain to be addressed.


Interpretation and Potential Biases of Mendelian Randomization Estimates With Time-Varying Exposures.
Mendelian randomization (MR) is used to answer a variety of epidemiologic questions. One stated advantage of MR is that it estimates a "lifetime effect" of exposure, though this term remains vaguely defined. Instrumental variable analysis, on which MR is based, has focused on estimating the effects of point or time-fixed exposures rather than "lifetime effects." Here we use an empirical example with data from the Rotterdam Study (Rotterdam, the Netherlands, 2009-2013) to demonstrate how confusion can arise when estimating "lifetime effects." We provide one possible definition of a lifetime effect: the average change in outcome measured at time t when the entire exposure trajectory from conception to time t is shifted by 1 unit. We show that MR only estimates this type of lifetime effect under specific conditions-for example, when the effect of the genetic variants used on exposure does not change over time. Lastly, we simulate the magnitude of bias that would result in realistic scenarios that use genetic variants with effects that change over time. We recommend that investigators in future MR studies carefully consider the effect of interest and how genetic variants whose effects change with time may impact the interpretability and validity of their results.


Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway.
Mutations in the non-lysosomal cysteine protease calpain 3 cause limb-girdle muscular dystrophy type 2A (LGMD2A). Our previous studies of the calpain 3 knockout mouse (C3KO) suggested a role for calpain 3 in sarcomere formation and remodeling. Calpain 3 may mediate remodeling by cleavage and release of myofibrillar proteins, targeting them for ubiquitination and proteasomal degradation. Loss of proper protein turnover may be the basis for this muscle disease. To test this hypothesis in vivo, we used an experimental model of hindlimb unloading and reloading that has been shown to induce sarcomere remodeling. We showed that the rate of atrophy and especially the rate of growth are decreased in C3KO muscles under conditions promoting sarcomere remodeling. In wild-type mice, an elevated level of ubiquitinated proteins was observed during muscle reloading, which is presumably necessary to remove atrophy-specific and damaged proteins. This increase in ubiquitination correlated with an increase in calpain 3 expression. C3KO muscles did not show any increase in ubiquitination at the reloading stage, suggesting that calpain 3 is necessary for ubiquitination and that it acts upstream of the ubiquitination machinery. We found upregulation of heat shock proteins in C3KO muscles following challenge with a physiological condition that requires highly increased protein degradation. Furthermore, old C3KO mice show evidence of insoluble protein aggregate formation in skeletal muscles. These studies suggest that accumulation of aged and damaged proteins can lead to cellular toxicity and a cell stress response in C3KO muscles, and that these characteristics are pathological features of LGMD2A.


Sleep, depression and the effects of antidepressant drugs.
We have investigated the modifications of paradoxical sleep (PS) induced by antidepressant drugs acting on two different neurotransmitters, noradrenaline (NA) and serotonin (5-HT). Desipramine (DMI) decreased PS in the rat and this effect was reduced by pretreatment with alpha-methyl-paratyrosine (aMPT), but unmodified by parachlorophenylalanine (pCPA). Indalpine (IND), which inhibits specifically the reuptake of 5-HT, also decreased PS; this effect was enhanced by pretreatment with aMPT and decreased by pretreatment with pCPA. Taken together, these results suggest that DMI and IND decrease PS by enhancing the extracellular concentration of NA and 5-HT respectively. In addition, they evoke the possibility of interaction between 5-HT and NA systems, with an inhibitory effect of 5-HT on NA systems.


Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus.
We compared two strategies for treating patients infected with multidrug-resistant human immunodeficiency virus (HIV). Patients with multidrug-resistant HIV and HIV RNA levels of more than 5000 copies per milliliter were randomly assigned to a four-month structured interruption of treatment followed by a change in antiretroviral regimen (treatment-interruption group) or to an immediate change in regimen (control group). Genotypic and phenotypic resistance testing was performed. Disease progression, death, and changes in genotypic resistance, CD4 cell counts, HIV RNA levels, and quality of life were assessed. After a median follow-up of 11.6 months, disease progression or death occurred in 22 of the 138 patients in the treatment-interruption group and in 12 of the 132 patients in the control group (P=0.01), with a hazard ratio of 2.57 (95 percent confidence interval, 1.2 to 5.5) for the treatment-interruption group. There were eight deaths in each group. In the treatment-interruption group, the mutant HIV populations completely or partially reverted to wild type by four months in 64.0 percent of patients. As compared with the control group, the treatment-interruption group had a mean CD4 cell count that was 85 cells per cubic millimeter lower from months 0 through 4 (P<0.001), 47 cells per cubic millimeter lower from months 5 through 8 (P<0.001), and 31 cells per cubic millimeter lower after eight months (P=0.11). The mean HIV RNA levels were 1.2 log copies per milliliter higher (on a base-10 scale) in the treatment-interruption group during months 0 through 4 (P<0.001), but they were not significantly different from those in the control group after month 4. The overall quality of life was similar in the two groups. In patients infected with multidrug-resistant HIV, structured interruption of treatment was associated with greater progression of disease and did not confer immunologic or virologic benefits or improve the overall quality of life.


The coagulation system helps control infection caused by the ciliate parasite Philasterides dicentrarchi in the turbot Scophthalmus maximus (L.).
Many studies have shown that coagulation systems play an important role in the defence against pathogens in invertebrates and vertebrates. In vertebrates, particularly in mammals, it has been established that the coagulation system participates in the entrapment of pathogens and activation of the early immune response. However, functional studies investigating the importance of the fish coagulation system in host defence against pathogens are scarce. In the present study, injection of turbot (Scopthalamus maximus) with the pathogenic ciliate Philasterides dicentrarchi led to the formation of macroscopic intraperitoneal clots in the fish. The clots contained abundant, immobilized ciliates, many of which were lysed. We demonstrated that the plasma clots immobilize and kill the ciliates in vitro. To test the importance of plasma clotting in ciliate killing, we inhibited the process by adding a tetrapeptide known to inhibit fibrinogen/thrombin clotting in mammals. Plasma tended to kill P. dicentrarchi slightly faster when clotting was inhibited by the tetrapeptide, although the total mortality of ciliates was similar. We also found that kaolin, a particulate activator of the intrinsic pathway in mammals, accelerates plasma clotting in turbot. In addition, PMA-stimulated neutrophils, living ciliates and several ciliate components such as cilia, proteases and DNA also displayed procoagulant activity in vitro. Injection of fish with the ciliates generated the massive release of neutrophils to the peritoneal cavity, with formation of large aggregates in those fish with live ciliates in the peritoneum. We observed, by SEM, numerous fibrin-like fibres in the peritoneal exudate, many of which were associated with peritoneal leukocytes and ciliates. Expression of the CD18/CD11b gene, an integrin associated with cell adhesion and the induction of fibrin formation, was upregulated in the peritoneal leukocytes. In conclusion, the findings of the present study show that P. dicentrarchi induces the formation of plasma clots and that the fish coagulation system may play an important role in immobilizing and killing this parasite.


Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer.
There is growing evidence that uncontrolled activation of the PI3K/Akt/mTOR pathway contributes to the development and progression of breast cancer. Inhibition of this pathway has antitumour effects in preclinical studies and efficacy in combination with other agents in breast cancer patients. The aim of this study is to characterise the effects of pre-operative everolimus treatment in primary breast cancer patients and to identify potential molecular predictors of response. Twenty-seven patients with oestrogen receptor (ER)-positive breast cancer completed 11-14 days of neoadjuvant treatment with 5-mg everolimus. Core biopsies were taken before and after treatment and analysed using Illumina HumanRef-8 v2 Expression BeadChips. Changes in proliferation (Ki67) and phospho-AKT were measured on diagnostic core biopsies/resection samples embedded in paraffin by immunohistochemistry to determine response to treatment. Patients that responded to everolimus treatment with significant reductions in proliferation (fall in % Ki67 positive cells) also had significant decreases in the expression of genes involved in cell cycle (P = 8.70E-09) and p53 signalling (P = 0.01) pathways. Highly proliferating tumours that have a poor prognosis exhibited dramatic reductions in the expression of cell cycle genes following everolimus treatment. The genes that most clearly separated responding from non-responding pre-treatment tumours were those involved with protein modification and dephosphorylation, including DYNLRB2, ERBB4, PTPN13, ULK2 and DUSP16. The majority of ER-positive breast tumours treated with everolimus showed a significant reduction in genes involved with proliferation, these may serve as markers of response and predict which patients will derive most benefit from mTOR inhibition.


A randomized trial of stress management for the prevention of new brain lesions in MS.
This trial examined the efficacy of a stress management program in reducing neuroimaging markers of multiple sclerosis (MS) disease activity. A total of 121 patients with relapsing forms of MS were randomized to receive stress management therapy for MS (SMT-MS) or a wait-list control condition. SMT-MS provided 16 individual treatment sessions over 24 weeks, followed by a 24-week post-treatment follow-up. The primary outcome was the cumulative number of new gadolinium-enhancing (Gd+) brain lesions on MRI at weeks 8, 16, and 24. Secondary outcomes included new or enlarging T2 MRI lesions, brain volume change, clinical exacerbation, and stress. SMT-MS resulted in a reduction in cumulative Gd+ lesions (p = 0.04) and greater numbers of participants remained free of Gd+ lesions during the treatment (76.8% vs 54.7%, p = 0.02), compared to participants receiving the control treatment. SMT-MS also resulted in significantly reduced numbers of cumulative new T2 lesions (p = 0.005) and a greater number of participants remaining free of new T2 lesions (69.5% vs 42.7%, p = 0.006). These effects were no longer detectable during the 24-week post-treatment follow-up period. This trial indicates that SMT-MS may be useful in reducing the development of new MRI brain lesions while patients are in treatment. This study provides Class I evidence that SMT-MS, a manualized stress management therapy program, reduced the number of Gd+ lesions in patients with MS during a 24-week treatment period. This benefit was not sustained beyond 24 weeks, and there were no clinical benefits. ClinicalTrials.gov, number NCT00147446.


Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis.
Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.


Delimitation of Neonectria and Cylindrocarpon (Nectriaceae, Hypocreales, Ascomycota) and related genera with Cylindrocarpon-like anamorphs.
Neonectria is a cosmopolitan genus and it is, in part, defined by its link to the anamorph genus Cylindrocarpon. Neonectria has been divided into informal groups on the basis of combined morphology of anamorph and teleomorph. Previously, Cylindrocarpon was divided into four groups defined by presence or absence of microconidia and chlamydospores. Molecular phylogenetic analyses have indicated that Neonectriasensu stricto and Cylindrocarponsensu stricto are phylogenetically congeneric. In addition, morphological and molecular data accumulated over several years have indicated that Neonectria sensu lato and Cylindrocarponsensu lato do not form a monophyletic group and that the respective informal groups may represent distinct genera. In the present work, a multilocus analysis (act, ITS, LSU, rpb1, tef1, tub) was applied to representatives of the informal groups to determine their level of phylogenetic support as a first step towards taxonomic revision of Neonectriasensu lato. Results show five distinct highly supported clades that correspond to some extent with the informal Neonectria and Cylindrocarpon groups that are here recognised as genera: (1) N. coccinea-group and Cylindrocarpon groups 1 & 4 (Neonectria/Cylindrocarponsensu stricto); (2) N.rugulosa-group (Rugonectria gen. nov.); (3) N. mammoidea/N. veuillotiana-groups and Cylindrocarpon group 2 (Thelonectria gen. nov.); (4) N. radicicola-group and Cylindrocarpon group 3 (Ilyonectria gen. nov.); and (5) anamorph genus Campylocarpon. Characteristics of the anamorphs and teleomorphs correlate with the five genera, three of which are newly described. New combinations are made for species where their classification is confirmed by phylogenetic data.


Evaluation of the Value of the Y-Balance Test to Predict Lower Limb Injuries in Professional Male Footballers.
The aim of this prospective cohort study was to identify whether Y-Balance Test (YBT) performance and asymmetry are associated with lower limb injury in elite adult football athletes. A prospective cohort study. Preseason YBT measures were obtained from 121 male footballers participating in National League One across the 2021-2022 season. Lower limb injuries were tracked across the season to determine the relationship between YBT variables and injury incidence using logistic regression analysis. The statistical significance level was .05. The average YBT score was 111.0 (5.8) cm on the left limb and 112.0 (5.5) cm on the right limb, with an average asymmetry of 2.3 (1.4) cm. Athletes with lower YBT scores on both the left (odds ratio = 2.9; 95% confidence interval, 1.7 to 4.8: P ≤ .001) and right (odds ratio = 2.3; 95% confidence interval, 1.6 to 3.2: P ≤ .001) limbs were at a greater risk of injury. Similarly, athletes with greater amounts of asymmetry were also more likely to get injured (odds ratio = 2.1; 95% confidence interval, 1.3 to 3.3: P = .002). Results indicate that lower and asymmetrical YBT scores have a significant relationship with future lower limb injuries in professional male footballers. The YBT offers a simple, reliable, and effective screening tool that can be used by practitioners in football to help identify players at a greater risk of injury before the season commences.


Does Conventional Endodontic Treatment Impact Oral Health-related Quality of Life? A Systematic Review.
Could conventional endodontic treatment have an impact on oral health-related quality of life? There are still unresolved questions regarding this theme. In order to answer them, a systematic review on the available literature was undertaken to identify the methodological quality of and the risk of bias in all relevant studies. A broad search for articles was conducted, and only articles published before May 2016 were considered for review. The following portals were used: Pubmed, VHL (Medline, SciELO, Lilacs and BBO), Cochrane Library, and Web of Science. The keywords used for the search were 'quality of life' and 'root canal treatment.' Furthermore, we included MeSH synonyms, related terms and free terms. Articles written in any language were included according to the PICOS approach (population, intervention, comparison, outcome and study design). After application of these eligibility criteria, selected articles were qualified by assessing their methodological quality and potential risk of bias. The initial search identified 302 references. After excluding duplicated abstracts and analysing the titles and abstracts, 6 were selected. One study was added via manual search of the reference lists. From these, 2 were eligible for quality assessment and were classified as being of high methodological quality and as having low risk of bias. Based on these studies, it can be concluded that conventional endodontic treatment improves oral health-related quality of life. However, these results should be interpreted with caution, due to the lack of important methodological details in the included studies. Additional investigations are warranted to provide more evidence on this subject.


Location of sequences within rotavirus SA11 glycoprotein VP7 which direct it to the endoplasmic reticulum.
The Simian 11 rotavirus glycoprotein VP7 is directed to the endoplasmic reticulum (ER) of the cell and retained as an integral membrane protein. The gene coding for VP7 predicts two potential initiation codons, each of which precedes a hydrophobic region of amino acids (H1 and H2) with the characteristics of a signal peptide. Using the techniques of gene mutagenesis and expression, we have determined that either hydrophobic domain alone can direct VP7 to the ER. A protein lacking both hydrophobic regions was not transported to the ER. Some polypeptides were directed across the ER membrane and then into the secretory pathway of the cell. For a variant retaining only the H1 domain, secretion was cleavage dependent, since an amino acid change which prevented cleavage also stopped secretion. However, secretion of two other deletion mutants lacking H1 and expressing truncated H2 domains was unaffected by this mutation, suggesting that these proteins were secreted without cleavage of their NH2-terminal hydrophobic regions or secreted after cleavage at a site(s) not predicted by current knowledge.


Dynamic forces between bubbles and surfaces and hydrodynamic boundary conditions.
A bubble attached to the end of an atomic force microscope cantilever and driven toward or away from a flat mica surface across an aqueous film is used to characterize the dynamic force that arises from hydrodynamic drainage and electrical double layer interactions across the nanometer thick intervening aqueous film. The hydrodynamic response of the air/water interface can range from a classical fully immobile, no-slip surface in the presence of added surfactants to a partially mobile interface in an electrolyte solution without added surfactants. A model that includes the convection and diffusion of trace surface contaminants can account for the observed behavior presented. This model predicts quantitatively different interfacial dynamics to the Navier slip model that can also be used to fit dynamic force data with a post hoc choice of a slip length.


Atrial Fibrillation: Biomarkers Determining Prognosis.
Atrial fibrillation (AF) is a common cardiac arrhythmia known to incite increased thromboembolic and mortality risks, especially among patients not under anticoagulant therapy when indicated. Several routine scores exist to help stratify AF patients, such as the CHAD2DS2-VASc score and upon which physicians are based to decide whether to administer anticoagulant therapy. Being that anticoagulant regimen is a double- edged situation with both benefits and risks, decision-making process demands a definite and reliable, evidence-based set of data to rely on. Blood-based biological elements known as biomarkers are measurable indices that can provide crucial insights concerning not only underlying disease mechanisms but also prognostic and risk stratifying information. As AF is constituted by an overwhelming range of pathophysiological aspects such as inflammation, fibrosis, hypercoagulable states and myocardial damage, identifying and assessing relevant biomarkers will evidently support the clinician's prognostication efforts. The current reviewpresents studied biomarkers with proven prognostic potential in AF as well as possible enhancement of risk-scores when incorporated to them.


Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B.
Plasmid-mediated mobilized colistin resistance is currently known to be caused by phosphoethanolamine transferases termed MCR-1, MCR-2, MCR-3 and MCR-4. However, this study focuses on the dissection of a novel resistance mechanism in mcr-1-, mcr-2- and mcr-3-negative d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B (Salmonella Paratyphi B dTa+) isolates with colistin MIC values >2 mg/L. A selected isolate from the strain collection of the German National Reference Laboratory for Salmonella was investigated by WGS and bioinformatical analysis to identify novel phosphoethanolamine transferase genes involved in colistin resistance. Subsequently PCR screening, S1-PFGE and DNA-DNA hybridization were performed to analyse the prevalence and location of the identified mcr-5 gene. Cloning and transformation experiments in Escherichia coli DH5α and Salmonella Paratyphi B dTa+ control strains were carried out and the activity of MCR-5 was determined in vitro by MIC testing. In this study, we identified a novel phosphoethanolamine transferase in 14 mcr-1-, mcr-2- and mcr-3-negative Salmonella Paratyphi B dTa+ isolates with colistin MIC values >2 mg/L that were received during 2011-13. The respective gene, further termed as mcr-5 (1644 bp), is part of a 7337 bp transposon of the Tn3 family and usually located on related multi-copy ColE-type plasmids. Interestingly, in one isolate an additional subclone with a chromosomal location of the mcr-5 transposon was observed. Our findings suggest that the transfer of colistin-resistance-mediating phosphoethanolamine transferase genes from bacterial chromosomes to mobile genetic elements has occurred in multiple independent events raising concern regarding their variety, prevalence and impact on public health.


The genes encoding granule-bound starch synthases at the waxy loci of the A, B, and D progenitors of common wheat.
Three genes encoding granule-bound starch synthase (wx-TmA, wx-TsB, and wx-TtD) have been isolated from Triticum monococcum (AA), and Triticum speltoides (BB), by the polymerase chain reaction (PCR) approach, and from Triticum tauschii (DD), by screening a genomic DNA library. Multiple sequence alignment indicated that the wx-TmA, wx-TsB, and wx-TtD genes had the same extron and (or) intron structure as the previously reported waxy gene from barley. The lengths of the three wx-TmA, wx-TsB, and wx-TtD genes were 2834 bp, 2826 bp, and 2893 bp, respectively, each covering 31 bp in the untranslated leader and the entire coding region consisting of 11 exons and 10 introns. The three genes had identical lengths of exons, except exonl, and shared over 95% identity with each other within the exon regions. The majority of introns were significantly variable in length and sequence, differing mainly in length (1-57 bp) as a result of insertion and (or) deletion events. The deduced amino acid sequence from these three genes indicated that the mature WX-TMA, -TSB, and -TTD proteins contained the same number of amino acids, but differed in predicted molecular weight and isoelectric point (pI) due to amino acid substitutions (13-18). The predicted physical characteristics of the WX proteins matched the respective proteins in wheat very closely, but the match was not perfect. Furthermore the exon5 sequences of the wx-TmA, wx-TsB, and wx-TtD genes were different from a cDNA encoding a waxy gene of common wheat previously reported. The striking difference was that an insertion of 11 amino acids occurred in the cDNA sequence that could not be observed in the exons of the A, B, and D genes. It was noted, however, that the 3' end of intron4 of these genes could account for the additional 11 amino acids. The sequence information from the available waxy genes identified the intron4-exon5-intron5 region as being diagnostic for sequence variation in waxy. The sequence variation in the waxy genes provides the basis for primer design to distinguish the respective genes in common wheat, and its progenitors, using PCR.


Risk factors for potential drug interactions in general practice.
To identify patient- and practice-related factors associated with potential drug interactions. A register analysis study in general practices in the county of Funen, Denmark. Prescription data were retrieved from a population-based prescription database (Odense University Pharmacoepidemiologic Database, OPED) covering prescriptions to all inhabitants in the county of Funen, Denmark. All individuals exposed to concurrent use of two or more drugs (polypharmacy) were identified. Combinations of drugs with potential interactions were registered and classified as major, moderate, or minor, depending on the severity of outcome and the quality of documentation. A two-level random coefficient logistic regression model was used to investigate factors related to potential drug interactions. One-third of the population was exposed to polypharmacy, and 6% were exposed to potential drug interactions during 1 year. Patient factors associated with increased risk of potential drug interactions were high age, a high number of concurrently used drugs, and a high number of prescribers. Practice factors associated with potential drug interactions were a high percentage of elderly patients and a low percentage of female patients listed. Prescription data may be useful in quality-improvement programmes to identify groups of patients and practices at increased risk of drug interactions.


Phenolic profile within the fine-root branching orders of an evergreen species highlights a disconnect in root tissue quality predicted by elemental- and molecular-level carbon composition.
Fine roots constitute a significant source of plant productivity and litter turnover across terrestrial ecosystems, but less is known about the quantitative and qualitative profile of phenolic compounds within the fine-root architecture, which could regulate the potential contribution of plant roots to the soil organic matter pool. To understand the linkage between traditional macro-elemental and morphological traits of roots and their molecular-level carbon chemistry, we analyzed seasonal variations in monomeric yields of the free, bound, and lignin phenols in fine roots (distal five orders) and leaves of Ardisia quinquegona. Fine roots contained two-fold higher concentrations of bound phenols and three-fold higher concentrations of lignin phenols than leaves. Within fine roots, the concentrations of free and bound phenols decreased with increasing root order, and seasonal variation in the phenolic profile was more evident in lower order than in higher order roots. The morphological and macro-elemental root traits were decoupled from the quantity, composition and tissue association of phenolic compounds, revealing the potential inability of these traditional parameters to capture the molecular identity of phenolic carbon within the fine-root architecture and between fine roots and leaves. Our results highlight the molecular-level heterogeneity in phenolic carbon composition within the fine-root architecture, and imply that traits that capture the molecular identity of the root construct might better predict the decomposition dynamics within fine-root orders.


Comparison of Contrast Ratio, Translucency Parameter, and Flexural Strength of Traditional and "Augmented Translucency" Zirconia for CEREC CAD/CAM System.
Tetragonal zirconia polycrystals (TZP) can be used via CAD/CAM technique as metal replacement for fixed partial dentures. However, its intense white color and high opacity may represent an aesthetic limit. New TZPs with a claimed higher degree of translucency were recently marketed. The aim of the study was to investigate contrast ratio (CR), translucency parameter (TP), flexural strength (σ), Weibull characteristic strength (σ0 ), and Weibull modulus (m) of three "traditional" (IPS e.max Zir-CAD, inCoris ZI, VITA In-Ceram YZ) and two "increased translucency" (inCoris TZI, VITA In-Ceram YZ HT) Y-TZPs. For flexural strength, ISO 6872:2008 was followed. Bars (N = 40) were cut from pre-sintered blocks. Dense-sintering, finishing, and polishing were performed in order to obtain specimens of 15 × 4 × 1.2 mm. Samples were tested with three-point bending setup in a universal testing machine. For CR and TP, specimens (N = 10) were cut perpendicularly to the long axis from pre-sintered blocks. After the dense-sintering, specimens were finished and polished in order to obtain tiles of 12 × 15 × 1 mm. CR and TP were measured with a spectrophotometer equipped with an integrating sphere. No significant difference was found regarding flexural strength. A significant difference was found both for CR and TP among tested groups. VITA In-Ceram YZ HT and inCoris TZI showed the higher translucency. The difference was not statistically significant when compared with VITA In-Ceram YZ, and statistically significant when compared with IPS e.max Zir-CAD and inCoris ZI. The new "augmented translucency" TZPs showed higher translucency and similar flexural strength than "traditional" TZPs. Monolithic zirconia use is partially restricted due to the zirconia low translucency. The new "augmented translucency" zirconia showed a modest but perceptible increase in translucency and a similar flexural resistance, thus increasing the clinically suitable thickness range with optimized aesthetic and resistance. (J Esthet RestorDent 28:S32-S39, 2016).


Cadmium and nickel in smoke of cigarettes prepared from tobacco cultured on municipal sludge-amended soil.
Cigarettes prepared from tobacco grown on municipal sludge-amended soil were smoked, and the mainstream particulates and gaseous fractions were analyzed for total cadmium and nickel content. Sludge-grown and control (soil-grown) tobaccos contained, respectively, 67.4 and 3.18 ppm of cadmium and 19.4 and 1.29 ppm of nickel. The quantities of cadmium (microgram per cigarette) found in the mainstream particulate and gaseous fractions were, respectively, 6.67 and 0.04 for the sludge-grown and 0.21 and 0.03 for the control treatments. The quantities of nickel (microgram per cigarette) found in the mainstream particulates and gaseous fractions were, respectively, 0.11 and 0.07 for the sludge-grown and 0.01 and 0.01 for the control treatments. The potential public health implications of these results and modifying factors are discussed.


Real-world effectiveness and safety of RC48-ADC alone or in combination with PD-1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study.
Previous RC48 (Disitamab Vedotin) studies established that the safety and efficacy of RC48-antibody-drug conjugate (ADC), either alone or combined with toripalimab, for metastatic urothelial carcinoma (mUC) patients exhibiting human epidermal growth factor receptor 2 (HER2)-positive or even HER2-negative status after standard chemotherapy failure. With locally advanced or metastatic urothelial carcinoma (la/mUC), patients who received RC48-ADC monotherapy or a combination with programmed cell death protein 1 (PD-1) inhibitors between August 2021 and October 2022 were enrolled in this retrospective observational study to evaluate the real-world antitumor effectiveness and safety. Among the 38 enrolled patients (29 males; median age 67.5 years [38-93]), 8 received RC48-ADC monotherapy, while 30 received combination therapy. Initially, 63.2% (24/38) of the patients had received ≥1 line of prior treatment, and 63.2% (24/38) had visceral metastasis. UC of the bladder represented the majority type in 68.4% (26/38) of cases. By the data cutoff in March 2023, the overall objective response rate (ORR) was 63.2% (95% CI, 47.1%-79.2%), with a disease control rate (DCR) of 89.5% (95% CI, 79.3%-99.7%). Median follow-up time was 10.6 months. The median progression-free survival (PFS) was 8.2 months (95% CI, 5.9-10.5), with a 6-month PFS rate of 63.2% and a 12-month PFS rate of 34.1%. Median overall survival (OS) was not reached, with a 12-month OS rate of 76.7%. The median duration of response was 7.3 months (95% CI, 4.6-10.0) among 24 patients evaluated as partial response (PR). The most common treatment-related adverse events (TRAEs) included anemia (71.1%), anorexia (57.9%), asthenia (52.6%), hypoesthesia (52.6%), bone marrow suppression (47.4%), alopecia (47.4%), nausea (44.7%), proteinuria (36.8%), vomiting (34.2%), and hypoalbuminemia (31.6%). No patient experienced TRAEs of Grade ≥3. One patient had an immune-related adverse event (irAE) of rash related to toripalimab. Both as monotherapy and in combination with PD-1 inhibitors, RC48-ADC exhibits promising effectiveness and manageable safety profile for mUC patients in real-world settings.


Comparison of Self-Reported and Behavioral Pain Assessment Tools in Critically Ill Patients.
Self-reported and behavioral pain assessment scales are often used interchangeably in critically ill patients due to fluctuations in mental status. The correlation between scales is not well elucidated. The purpose of this study was to describe the correlation between self-reported and behavioral pain scores in critically ill patients. Pain was assessed using behavioral and self-reported pain assessment tools. Behavioral pain tools included Critical Care Pain Observation Tool (CPOT) and Behavioral Pain Scale (BPS). Self-reported pain tools included Numeric Rating Scale (NRS) and Wong-Baker Faces Pain Scales. Delirium was assessed using the confusion assessment method for the intensive care unit. Patient preference regarding pain assessment method was queried. Correlation between scores was evaluated. A total of 115 patients were included: 67 patients were nondelirious and 48 patients were delirious. The overall correlation between self-reported (NRS) and behavioral (CPOT) pain scales was poor (0.30, P = .018). In patients without delirium, a strong correlation was found between the 2 behavioral pain scales (0.94, P < .0001) and 2 self-reported pain scales (0.77, P < .0001). Self-reported pain scale (NRS) and behavioral pain scale (CPOT) were poorly correlated with each other (0.28, P = .021). In patients with delirium, there was a strong correlation between behavioral pain scales (0.86, P < .0001) and a moderate correlation between self-reported pain scales (0.69, P < .0001). There was no apparent correlation between self-reported (NRS) and behavioral pain scales (CPOT) in patients with delirium (0.23, P = .12). Most participants preferred self-reported pain assessment. Self-reported pain scales and behavioral pain scales cannot be used interchangeably. Current validated behavioral pain scales may not accurately reflect self-reported pain in critically ill patients.


[Total replacement of both carotid arteries combined with ascending aorta and aortic arch replacement for acute DeBakey type I aortic dissection].
Involvement of supra-aortic vessels into acute DeBakey type I aortic dissection is a significant predictor of adverse postoperative neurological outcomes and mortality. The choice of surgical tactics remains open in such patients. We present total replacement of both common carotid arteries and proximal part of the right subclavian artery with reconstruction of ascending aorta and aortic arch for acute DeBakey type I dissection.


Calves as a potential reservoir of Cryptosporidium parvum and Giardia sp.
Studies on cryptosporidiosis and giardiosis were carried out between March and April 1997 on 75 calves from 9 selected farms of Wielkopolska macroregion. Faecal specimens from calves, 3-13 days old, were screened for oocysts of C. parvum using Ziehl-Neelsen staining and both for oocysts of C. parvum and cysts of Giardia sp. using direct immunofluorescent (MerIFluor Cryptosporidium/Giardia) assay. The oocysts of C. parvum assessed by Ziehl-Neelsen staining were revealed on 6 (67%) of 9 farms examined. The prevalence of infection ranged from 20-88%, and in some farms intensity of oocyst shedding was very high. However, in 35 calves assessed for mixed infections of C. parvum and Giardia sp., oocysts of Cryptosporidium were found in 18 (51%) calves and cysts of Giardia sp. were detected in 5 (14%) of 35 calves. Only in one calf was found coinfection with both parasites. The intensity of Giardia sp. infection was extremely low. Histological examination of the gut sections from immunosuppressed BALB/c mice experimentally infected with C. parvum isolates from calves revealed endogenous stages of C. parvum on the brush border of the ileum. The high prevalence and intensive shedding of cryptosporidial oocysts by calves in farms examined in this study suggests that naturally infected calves may be significant reservoirs for C. parvum infections in man and wild animals.


[The typology of chronic posttraumatic stress disorder].
Psychopathological chronic posttraumatic stress disorder (PTSD) was studied in relation to clinical peculiarities of depression included in PTSD structure. One hundred and sixty-five patients, 124 men and 41 women, aged 25-48 years, were examined in general outpatient clinics. PTSD duration was from 6 to 24 months. A stress was caused by situations related to combat events (60.6%), close person's death (25.4%), assault with physical and moral violence (8.2%) and rape (5.8%). With regard to depression structure and dominating affect, 4 PTSD types--anxious (36.6%), dysphoric (26.1%), apathic (20%) and somatoform (17.7%), were distinguished. Also, their significance for the formation of patient's personality features is emphasized. A role of depression in syndrome formation in chronic PTSD is suggested.


RSV N-nanorings fused to palivizumab-targeted neutralizing epitope as a nanoparticle RSV vaccine.
Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections in children, yet no vaccine is available. The sole licensed preventive treatment against RSV is composed of a monoclonal neutralizing antibody (palivizumab), which targets a conformational epitope located on the fusion protein (F). Palivizumab reduces the burden of bronchiolitis but does not prevent infection. Thus, the development of RSV vaccines remains a priority. We previously evaluated nanorings formed by RSV nucleoprotein (N) as an RSV vaccine, as well as an immunostimulatory carrier for heterologous antigens. Here, we linked the palivizumab-targeted epitope (called FsII) to N, to generate N-FsII-nanorings. Intranasal N-FsII immunization elicited anti-F antibodies in mice that were non-neutralizing in vitro. Nevertheless, RSV-challenged animals were better protected against virus replication than mice immunized with N-nanorings, especially in the upper airways. In conclusion, an N-FsII-focused vaccine is an attractive candidate combining N-specific cellular immunity and F-specific antibodies for protection.


The Dark Side of Humor: DSM-5 Pathological Personality Traits and Humor Styles.
Basic personality traits (e.g., extraversion) have been found to be associated with the humor styles that individuals employ. In the present study, we were interested in determining whether pathological personality traits were also associated with humor styles. We examined the associations between the pathological personality traits captured by the Personality Inventory for the DSM-5 (PID-5) and humor styles in a sample of college students (N = 594). Negative affectivity and detachment were negatively associated with the affiliative and self-enhancing humor styles. Antagonism was positively associated with the aggressive humor style but negatively associated with the affiliative humor style. Disinhibition was positively associated with the aggressive humor style, whereas disinhibition and psychoticism were both positively associated with the self-defeating humor style. Discussion focuses on the implications of these findings and how they can expand our understanding of the connections between the darker aspects of personality and humor.


Population attributable fraction of modifiable risk factors for Alzheimer disease: A systematic review of systematic reviews.
Alzheimer's disease (AD) is the most common type of dementia. Demonstrating the modifiable risk factors of AD can help to plan for prevention of this disease. The aim of the current review was to characterize modifiable cardiovascular risk factors of AD using existing data and determine their contribution in AD development in Iran and the world. The systematic search was done in Medline, Scopus, and Cochrane databases from inception to May 2014 to find systematic reviews or meta-analyses about association between AD and cardiovascular modifiable risk factors included diabetes, hypertension (HTN), physical inactivity, smoking, hypercholesterolemia, and overweight and obesity. The population attributable fraction (PAF) was calculated for these risk factors in Iran and the world. Of 2651 articles, 11 were eligible for data extraction after assessing relevancy and quality. Diabetes mellitus (DM) type 2, smoking, physical inactivity, overweight and obesity were significantly associated with increased risk of AD. Physical inactivity with 22.0% and smoking with 15.7% had the highest PAF for AD in Iran and the world, respectively. Our findings demonstrated that modifiable cardiovascular risk factors could increase the risk of AD. Moreover, about one-third of AD cases were attributed to five modifiable risk factors.


Engineering toxins for 21st century therapies.
'Engineering Toxins for 21st Century Therapies' (9-10 September 2010) was part of the Royal Society International Seminar series held at the Kavli International Centre, UK. Participants were assembled from a range of disciplines (academic, industry, regulatory, public health) to discuss the future potential of toxin-based therapies. The meeting explored how the current structural and mechanistic knowledge of toxins could be used to engineer future toxin-based therapies. To date, significant progress has been made in the design of novel recombinant biologics based on domains of natural toxins, engineered to exhibit advantageous properties. The meeting concluded, firstly that future product development vitally required the appropriate combination of creativity and innovation that can come from the academic, biotechnology and pharma sectors. Second, that continued investigation into understanding the basic science of the toxins and their targets was essential in order to develop new opportunities for the existing products and to create new products with enhanced properties. Finally, it was concluded that the clinical potential for development of novel biologics based on toxin domains was evident.


Analysis of tobacco industry pricing strategies in 23 European Union countries using commercial pricing data.
The tobacco industry (TI) can act to undermine the impact of tobacco tax increases by adopting various pricing strategies. Little is known about strategies used across the European Union (EU), except for the UK. To examine pricing strategies adopted by the TI in the EU, and whether they differ by cigarette price segment, or between manufactured and roll-your-own (RYO) cigarettes. This is a longitudinal analysis of commercial pricing data for manufactured and RYO cigarettes from 23 EU countries in 2006-2017. Price and revenue trends were explored. Linear regression estimated the average annual change in revenue, and linear fixed-effects panel regression models were used to explore the association between changes in median revenue (net of tax and adjusted for inflation) and tax increases in different price segments of manufactured cigarettes. Over the 11-year period price gaps were observed in all countries. The average annual adjusted median net revenue per pack increased in 19 of 23 countries for manufactured and RYO cigarettes. A tax increase was associated with a significant decrease of -€0.09 in adjusted median net revenue per pack (95% CI -0.16 to -0.03) in the cheap cigarette price segment, while no change was detected in the expensive cigarette price segment (-€0.05, 95% CI -0.11 to 0.01). Across the EU, pricing strategies adopted by the TI maintained or increased price gaps and retained cheaper tobacco products in the market, diminishing the impact of tobacco tax increases. Further strengthening of tobacco taxation policy is needed to maximise public health impact.


Fractionated cyclophosphamide and etoposide for children with advanced or refractory solid tumors: a phase II window study.
Cyclophosphamide (CPA) has a broad spectrum of activity against solid tumors. Hepatic self-induction of the active metabolite 4-hydroxycyclophosphamide occurs after repeated administration. We evaluated the clinical efficacy of a window regimen that administers fractionated CPA in conjunction with etoposide (VP16) in children with advanced or refractory solid tumors. Seventeen children with advanced (n = 12) or refractory (n = 5) solid tumors were entered onto this phase II window study. The treatment regimen consisted of intravenous (IV) CPA 500 mg/m(2)/d and IV VP16 100 mg/m(2)/d. Both drugs were administered daily by short infusions for 5 consecutive days. A total of 34 courses were administered, with a median of two courses per patient. The median interval between chemotherapy courses was 21 days (range, 17 to 35 days). Thirty-three courses were assessable for toxicity, and all patients were assessable for response. No life-threatening toxicities were observed. The incidence of grade 3 or 4 neutropenia was 94% and of fever and neutropenia 38%. Fever and neutropenia occurred after 12 of 26 courses without recombinant human granulocyte colony-stimulating factor (rhG-CSF) and after one of eight courses with rhG-CSF (P =. 09). Grade 3 or 4 thrombocytopenia occurred after 10 courses (29%). There were no positive blood cultures. One heavily pretreated patient developed a localized perirectal abscess that required drainage. There were 10 patients (59%) with partial responses, four (23.5%) with stable disease, and three with progressive disease. Fractionated IV CPA and VP16 over 5 days can be safely administered in children with advanced or refractory solid tumors and has notable antineoplastic activity.


Exploration of NO2 and PM2.5 air pollution and mental health problems using high-resolution data in London-based children from a UK longitudinal cohort study.
Air pollution is a worldwide environmental health issue. Increasingly, reports suggest that poor air quality may be associated with mental health problems, but these studies often use global measures and rarely focus on early development when psychopathology commonly emerges. To address this, we combined high-resolution air pollution exposure estimates and prospectively-collected phenotypic data to explore concurrent and longitudinal associations between air pollutants of major concern in urban areas and mental health problems in childhood and adolescence. Exploratory analyses were conducted on 284 London-based children from the Environmental Risk (E-Risk) Longitudinal Twin Study. Exposure to annualized PM2.5 and NO2 concentrations was estimated at address-level when children were aged 12. Symptoms of anxiety, depression, conduct disorder, and attention-deficit hyperactivity disorder were assessed at ages 12 and 18. Psychiatric diagnoses were ascertained from interviews with the participants at age 18. We found no associations between age-12 pollution exposure and concurrent mental health problems. However, age-12 pollution estimates were significantly associated with increased odds of major depressive disorder at age 18, even after controlling for common risk factors. This study demonstrates the potential utility of incorporating high-resolution pollution estimates into large epidemiological cohorts to robustly investigate associations between air pollution and youth mental health.


Does protein kinase C control receptor-mediated phagocytosis in human neutrophils?
It was previously demonstrated that C3bi- but not IgG-mediated phagocytosis in human neutrophils is a Ca2+-independent process [(1985) Nature 315, 509-511]. The objective of this study was to elucidate the nature of an additional messenger signal(s) that may be involved in receptor-mediated phagocytosis in these cells. The C3bi- and IgG-mediated phagocytic ability of neutrophils was inhibited by forskolin, a potent activator of adenylate cyclase. It was found that forskolin induced a 3-fold increase in cAMP levels and simultaneously reduced the uptake of both C3bi- and IgG-opsonized particles by 65%. This inhibition was reversed by exposure to either phorbol myristate acetate (PMA) or diacylglycerol (OAG), which are both activators of protein kinase C, but not by the inactive analog 4 alpha-PMA. PMA could also restore the phagocytic ability of neutrophils with an experimentally impaired calcium response. These results suggest that activation of protein kinase C might be an important transducing signal controlling receptor-mediated phagocytosis in human neutrophils.


Substituting Cannabidiol for Opioids and Pain Medications Among Individuals With Fibromyalgia: A Large Online Survey.
People report substituting cannabis for pain medications, but whether cannabidiol (CBD) is used similarly remains unknown. CBD products can be CBD alone (isolate), hemp extract (containing <0.3% Δ-9-tetrahydrocannabinol [THC], other cannabinoids, and terpenes), or CBD-cannabis (containing >0.3% THC). In a secondary analysis from a cross-sectional survey, we examined substitution patterns among n = 878 individuals with fibromyalgia who currently used CBD. We sub-grouped participants by most commonly used CBD product (CBD isolate, hemp, CBD-cannabis, no preference) and whether they substituted CBD for medications. We investigated rationale for substituting, substitution-driven medication changes, CBD use patterns, and changes in pain-related symptoms (eg, sleep, anxiety). The study population was 93.6% female and 91.5% Caucasian, with an average age of 55.5 years. The majority (n = 632, 72.0%) reported substituting CBD products for medications, most commonly NSAIDs (59.0%), opioids (53.3%), gabapentanoids (35.0%), and benzodiazepines (23.1%). Most substituting participants reported decreasing or stopping use of these pain medications. The most common reasons for substitution were fewer side effects and better symptom management. Age, hemp products, past-year use of marijuana, and higher somatic burden were all associated with substituting (P's ≤ .05). Those who substituted reported larger improvements in health and pain than those who did not. Participants using CBD-cannabis reported significantly more substitutions than any other group (P's ≤ .001) and larger improvements in health, pain, memory, and sleep than other subgroups. This widespread naturalistic substitution for pain medications suggests the need for more rigorous study designs to examine this effect. PERSPECTIVE: This article shows that people with fibromyalgia are deliberately substituting CBD products for conventional pain medications despite the dearth of evidence suggesting CBD products may be helpful for fibromyalgia. CBD's medication-sparing and therapeutic potential should be examined in more rigorous study designs.


A ground-based model to study the effects of weightlessness on lymphocytes.
The mitogenic response of human lymphocytes was found to be markedly reduced in weightlessness conditions as compared to normal gravity. One possible explanation is that due to the non-existent sedimentation in space the lymphocytes could not adhere and spread on a substratum. Thus, we investigated the effect of substratum adhesiveness on lymphocyte responsiveness by reducing and blocking cell adhesion with poly-HEMA in a simple on-ground system. Lymphocyte adhesiveness was assessed by measuring the proportion of non-adhesive, slightly, and strongly adhesive 51Cr-radiolabelled cells on uncoated and poly-HEMA coated plastic. The amount of cell spreading on surfaces with varying adhesiveness was determined by measuring the area of cells. Cells grown on medium and thick poly-HEMA films were rounded in shape. By contrast, on tissue culture plastic, they showed clear signs of spreading. The mitogenic response of lymphocytes grown on thick poly-HEMA films was reduced by up to 68% of the control (tissue culture plastic). Interferon-gamma production was virtually nil when the cells were grown on the least adhesive substratum. These results show that activated lymphocytes need to anchor and spread prior to achieving an optimal proliferation response. We conclude that decreased lymphocyte adhesion could contribute to the depressed in vitro lymphocyte responsiveness found in the microgravity conditions of space flight.


Nanocrystalline Nd2Fe17 synthesized by high-energy ball milling: crystal structure, microstructure and magnetic properties.
Nanocrystalline Nd(2)Fe(17) powders have been obtained by means of high-energy ball milling from nearly single-phase bulk alloys produced by arc melting and high temperature homogenization annealing. The rhombohedral Th(2)Zn(17)-type crystal structure of the bulk alloy remains unaltered after the milling process, with almost unchanged values for the cell parameters. However, the severe mechanical processing induces drastic microstructural changes. A decrease of the mean crystalline size down to around 10 nm is observed, giving rise to a considerable augmentation of the disordered inter-grain boundaries. This modification of the microstructure affects the magnetic behaviour of the milled powders, although the magnetic structure remains collinear ferromagnetic. While a unique ferro-to-paramagnetic transition temperature, T(C) = 339 ± 2 K, is observed in the bulk alloy, the nanocrystalline samples exhibit a more likely distribution of T(C) values. The latter seems to be responsible for the significant broadening of the temperature range in which magneto-caloric effect is observed, and the lowering of the maximum value of the magnetic entropy change.


The Management of Valgus Extension Overload Syndrome Experienced with Hitting in a High School Baseball Player: A Case Report.
Valgus extension overload syndrome (VEOS) of the elbow is a condition associated with overhead athletes. However, the non-surgical management of these individuals is not well documented. To discuss the unique presentation, management, and outcomes of an adolescent baseball player with a chronic history of VEOS experienced during hitting. A 15-year-old right-handed high school baseball catcher presented with a six-month history of right-sided ulnar elbow pain. Elbow MRI w/ contrast was consistent with VEOS. The initial examination demonstrated excessive resting right-sided humeral external rotation compared to his left. Valgus stress testing in the subject's hitting position reproduced symptoms, which were alleviated with retest while correcting excessive humeral external rotation. Weakness of the humeral internal rotators and stiffness/shortness of the posterior shoulder were found and thought to relate to the humeral contribution to his elbow movement dysfunction. Rehabilitation emphasized addressing impairments contributing to excessive humeral external rotation with reintegration into batting. After five weeks of physical therapy, the subject returned to soft toss hitting at approximately 75% velocity for the first time since symptom onset, without pain. At seven months after discharge, a phone conversation confirmed that the subject had returned to baseball without limitations. Despite the concept of 'regional interdependence', common proximal impairments are often assumed to contribute to elbow pain without a clear biomechanical rationale. Future research demonstrating the specific biomechanical effects of the shoulder on the elbow is needed, in addition to more accessible examination strategies to assess their relationship. 5.


Solid-tumor radionuclide therapy dosimetry: new paradigms in view of tumor microenvironment and angiogenesis.
The objective of this study is to evaluate requirements for radionuclide-based solid tumor therapy by assessing the radial dose distribution of beta-particle-emitting and alpha-particle-emitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells. Tumor blood vessels were modeled as a group of microcylindrical layers comprising endothelial cells (one-cell thick, 10 microm diameter), viable tumor cells (25-cell thick, 250 microm radius), and necrotic tumor region (> 250 microm from any blood vessel). Sources of radioactivity were assumed to distribute uniformly in either endothelial cells or in concentric cylindrical 10 microm shells within the viable tumor-cell region. The EGSnrc Monte Carlo simulation code system was used for beta particle dosimetry and a dose-point kernel method for alpha particle dosimetry. The radioactive decays required to deposit cytocidal doses (> or = 100 Gy) in the vascular endothelial cells (endothelial cell mean dose) or, alternatively, at the tumor edge [tumor-edge mean dose (TEMD)] of adjacent viable tumor cells were then determined for six beta (32P, 33P, 67Cu, 90Y 131I, and 1188Re) and two alpha (211At and 213Bi) particle emitters. Contrary to previous modeling in targeted radionuclide therapy dosimetry of solid tumors, the present work restricts the region of tumor viability to 250 microm around tumor blood vessels for consistency with biological observations. For delivering > or = 100 Gy at the viable tumor edge (TEMD) rather than throughout a solid tumor, energetic beta emitters 90Y, 32P, and 188Re can be effective even when the radionuclide is confined to the blood vessel (i.e., no diffusion into the tumor). Furthermore, the increase in tumor-edge dose consequent to beta emitter diffusion is dependent on the energy of the emitted beta particles, being much greater for lower-energy emitters 131I, 67Cu, and 33P relative to higher-energy emitters 90Y, 32P, and 188Re. Compared to alpha particle emitters, a approximately 150-400 times higher number of beta-particle-emitting radioactive atoms is required to deposit the same dose in tumor neovasculature. However, for the alpha particle emitters 211At and 213Bi to be effective in irradiating viable tumor-cell regions in addition to the vasculature the carrier molecules must diffuse substantially from the vasculature into the viable tumor. The presented data enable comparison of radionuclides used for antiangiogenic therapy on the basis of their radioactive decay properties, tumor neovasculature geometry, and tumor-cell viability. For alpha particle emitters or low-energy beta particle emitters, the targeting carrier molecule should be chosen to permit the radiopharmaceutical to diffuse from the endothelial wall of the blood vessel, while for long-range energetic beta particle emitters that target neovasculature, a radiopharmaceutical that binds to newly formed endothelial cells and does not diffuse is preferable. The work is a first approximation to modeling of tumor neovasculature that ignores factors such as pharmacokinetics and targeting capability of carrier molecules. The calculations quantify the interplay between irradiation of neovasculature, the surrounding viable tumor cells, and the physical properties of commonly used radionuclides and can be used to assist estimation of radioactivity to be administered for neovasculature-targeted tumor therapy.


Performance of SM8 on a test to predict small-molecule solvation free energies.
The SM8 quantum mechanical aqueous continuum solvation model is applied to a 17-molecule test set proposed by Nicholls et al. (J. Med. Chem. 2008, 51, 769) to predict free energies of solvation. With the M06-2X density functional, the 6-31G(d) basis set, and CM4M charge model, the root-mean-square error (RMSE) of SM8 is 1.08 kcal mol(-1) for aqueous geometries and 1.14 kcal mol(-1) for gas-phase geometries. These errors compare favorably with optimal explicit and continuum models reported by Nicholls et al., having RMSEs of 1.33 and 1.87 kcal mol(-1), respectively. Other models examined by these workers had RMSEs of 1.5-2.6 kcal mol(-1). We also explore the use of other density functionals and charge models with SM8 and the RMSE increases to 1.21 kcal mol(-1) for mPW1/CM4 with gas-phase geometries, to 1.50 kcal mol(-1) for M06-2X/CM4 with gas-phase geometries, and to 1.27-1.64 kcal mol(-1) with three different models at B3LYP gas-phase geometries.


Diagnostic value of soluble triggering receptor expressed on myeloid cells in paediatric sepsis: a systematic review.
Differential diagnosis between sepsis and non-infectious inflammatory disorders demands improved biomarkers. Soluble Triggering Receptor Expression on Myeloid cells (sTREM-1) is an activating receptor whose role has been studied throughout the last decade. We performed a systematic review to evaluate the accuracy of plasma sTREM-1 levels in the diagnosis of sepsis in children with Systemic Inflammatory Response Syndrome (SIRS). A literature search of PubMed, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and ISI Web of Knowledge databases was performed using specific search terms. Studies were included if they assessed the diagnostic accuracy of plasma sTREM-1 for sepsis in paediatric patients with SIRS. Data on sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic curve were extracted. The methodological quality of each study was assessed using a checklist based on the Quality Assessment Tool for Diagnostic Accuracy Studies. Nine studies comprising 961 patients were included, four of which were in newborns, three in children and two in children with febrile neutropenia. Some data from single studies support a role of sTREM-1 as a diagnostic tool in pediatric sepsis, but cannot be considered conclusive, because a quantitative synthesis was not possible, due to heterogeneity in studies design. This systematic review suggests that available data are insufficient to support a role for sTREM in the diagnosis and follow-up of paediatric sepsis.


Physician and coding errors in patient records.
The Veterans Administration's discharge abstract system was studied to identify error frequency, source, and effect in five Veterans Administration hospitals. We reviewed 1,829 medical records from 21 services for concordance with the abstract; sampling provided 95% confidence for each service. Of these records, 1,499 (82%) differed from the abstract in at least one item. Of 20,260 items, 4,360 (22%) were incorrect, with three error sources: physician (62%), coding (35%), and keypunch (3%). We projected 2.14 physician and 0.81 coding errors in the average abstract. Eighty-nine percent of projected physician errors were failures to report a procedure or diagnosis. Coding was subjective and errors were synergistic with physician errors. We projected that correction of errors would change 19% of the records for diagnosis-related group purposes and substantially increase future resource allocation. This effect varied considerably by service.


Primary adenoma of the middle ear.
Primary neoplasms of the ear are indeed unusual. Adenomatous middle ear tumors are even more unusual and have been, in previous presentations, uniformly labeled adenocarcinoma. Radical therapeutic approaches have therefore often been recommended. More recent literature has confidently established the existence of the entity of benign primary middle ear adenoma. In two reports only twenty-three cases have been recorded. The purpose of this article is to add two such cases to the literature. Current concepts in diagnosis and histopathogenesis are presented. Treatment guidelines are suggested.


Arthritis and drug therapy in the hypertension clinic.
Non-gouty arthritis is quite common in hypertensive populations and there have been suggestions that drugs used to treat hypertension may be the cause. This possibility has been investigated in a case-control study. We identified 127 hypertensive patients with arthritis other than gout and matched them for age and sex to 254 hypertensive controls who did not have arthritis. Use of antihypertensive drugs was similar in cases and controls for all patients, and for those with undiagnosed arthritis. There was no significant excess use of any type of antihypertensive drug by cases with arthritis. These findings do not support the hypothesis that drug treatment for hypertension commonly causes arthritis. It is more likely that hypertension and arthritis occur together frequently because non-steroidal anti-inflammatory drugs raise blood pressure, and because both problems are common in middle-age.


Na-H antiport in cultured rat aortic smooth muscle: its role in cytoplasmic pH regulation.
We have investigated the role of the Na-H antiport in the regulation of intracellular pH (pHi) in vascular smooth muscle. Experiments were conducted on contractile-state rat aortic smooth muscle cells grown in primary culture and loaded with the pH-sensitive, fluorescent indicator 2',7',-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). Cells equilibrated in a normal physiological salt solution (PSS) containing 135 mM Na, pH 7.4 at 37 degrees C, had a pHi of 7.16 +/- 0.04 (means +/- SE; n = 8). 5-(N-ethyl-N-isopropyl)amiloride (EIPA) caused a concentration-dependent fall in pHi. Removal of extracellular Na caused an intracellular acidification that was rapidly reversed on replacement of Na. The rate of recovery from NH4Cl-induced intracellular acidosis was dependent on extracellular Na concentration (Km 14.6 +/- 2.8 mM) and was accelerated by increasing the transmembrane Na gradient and slowed by decreasing it. Recovery from acidosis was completely abolished by either EIPA or the absence of extracellular Na. These results demonstrate that the Na-H antiport is an important mechanism for the maintenance and regulation of pHi in vascular smooth muscle cells. The BCECF fluorescence technique provides an ideal method for further studies on the mechanisms for pHi regulation in these cells.


Gene expression and immunohistochemistry in adipose tissue of HIV type 1-infected patients with nucleoside analogue reverse-transcriptase inhibitor-associated lipoatrophy.
Long-term use of both zidovudine (AZT) and stavudine (d4T) is associated with lipoatrophy, but it occurs possibly through different mechanisms. Surgical biopsy specimens of subcutaneous adipose tissue were obtained from 18 human immunodeficiency virus type 1 (HIV-1)-infected lipoatrophic patients (the LA+ group) who were treated with either zidovudine (the AZT+LA+ group; n = 10) or stavudine (the d4T+LA+ group; n = 8) and from 10 nonlipoatrophic HIV-1-infected patients (the LA- group) who received antiretroviral therapy. Mitochondrial DNA (mtDNA) copy numbers, gene expression, and immunohistochemistry data were analyzed. mtDNA copy numbers were significantly reduced in the LA+ group, compared with the LA- group, and in the d4T+LA+ group, compared with the AZT+LA+ group. The ratio of mtDNA-encoded cytochrome COX3 to nuclear DNA-encoded COX4 expression was significantly lower in the LA+ group than in the LA- group. Compared with the LA- group, the LA+ group had significantly lower expression of genes involved in adipogenesis (SREBP1c and CEBPB), lipid (fatty acid synthase), and glucose (GLUT4) metabolism. Expression of genes involved in mitochondrial biogenesis (PGC1B), apoptosis (FAS), inflammation (IL1B), oxidative stress (PCNA and SOD1), and lamin B was significantly higher in the LA+ group than in the LA- group. The d4T+LA+ group had significantly lower expression of genes involved in mitochondrial biogenesis (POLG1), energy metabolism (the COX3/COX4 ratio), adipogenesis (SREBP1c and CEBPA), perilipin, and hexokinase than did the AZT+LA+ group. There were 7-fold more macrophages in adipose tissue specimens obtained from patients in the LA+ group, compared with the LA- group. Lipoatrophy is characterized by mtDNA depletion, inflammation, and signs of apoptosis. Changes were more profound in the d4T+LA+ group than in the AZT+LA+ group.


The expression of limb gap genes in the mite Archegozetes longisetosus reveals differential patterning mechanisms in chelicerates.
The modular organization of arthropod limbs has lead to the evolution of a diversity of appendages within this phylum. A conserved trait within the arthropods is the utilization of a conserved set of regulatory genes that specify the appendage podomeres along the proximo-distal axis, termed the limb gap genes. These include extradenticle, homothorax, dachshund, and Distal-less. The deployment of these genes in the most basally branching arthropod group, the chelicerates, has only been studied in detail in two chelicerate groups, the harvestmen and spiders. Given the broad range of appendage diversity within the chelicerates, comparative studies of gap gene deployment in other chelicerates groups is needed. We therefore followed limb gap gene expression in a member of the largest chelicerate group, Acari, the oribatid mite Archegozetes longisetosus. We show that in contrast to many arthropod species, A. longisetosus expresses homothorax and extradenticle exclusively in the proximal portion of the appendages, which refutes the hypothesis of a sister-group relationship between chelicerates and myriapods. We also provide evidence that mites posses the ancestral chelicerate condition of possessing three-segmented chelicerae, which also express the gene dachshund. This adds support to the hypothesis that a cheliceral dachshund domain is ancestral to arachnids. Lastly, we provide evidence that the suppression of the fourth pair of walking legs, a putative synapomorphy for Acari, is accomplished by repressing the development of the medial and distal regions of the limb.


Thalidomide modulation of the immune response in female B6C3F1 mice: a host resistance study.
Previously, we have reported that thalidomide (Thd) treatment can modulate the immune responses in female B6C3F1 mice. The present study was designed to evaluate whether or not these immunomodulatory responses were of sufficient magnitude to alter host resistances in a number of pathogen and tumor models. B6C3F1 mice were treated intraperitoneally with Thd (30-150 mg/kg) for 14 or 28 days, then inoculated with either Plasmodium yeolii, PYB6 fibrosarcoma tumor cells, B16F10 melanoma tumor cells, Listeria monocytogenes, or Streptococcus pneumoniae. Significant dose-dependent protection against B16F10 and L. monocytogenes was observed in mice that were treated with Thd. Furthermore, time course study using bacterial colony-forming units per spleen and liver as the endpoints indicated that the protective effect of Thd on host resistance to L. monocytogenes was time-dependent. In contrast, Thd treatment did not affect host resistance to P. yeolii, S. pneumoniae and PYB6 tumor. Additionally, the effect of Thd on the phagocytic function of the mononuclear phagocyte system (MPS) was evaluated following intravenous injection of 51Cr-labeled sRBCs. The overall phagocytic activity of MPS was not significantly altered by Thd treatment. In conclusion, these results demonstrate that Thd immunomodulation altered host resistance to B16F10 and L. monocytogenes; and selective modulation of Thd on the immune system may be responsible for the pathogen or tumor-specific effect of this compound.


Relationship of a measure of selfqactualization to religious participation.
This study examined the hypothesis that self-actualization is negatively associated with reported frequency of active involvement in religious activities. A group of 63 male undergraduates enrolled in a Catholic coeducational institution indicated the extent of their involvement in religious activities and completed Shostrom's Personal Orientation Inventory (POI), a comprehensive measure of self-actualization. Results indicated substantial support for the hypothesis. Nine of the 12 Shostrom POI subscales were significantly correlated with the religious participation index in the predicted direction. It was suggested that self-actualizing students construe involvement in religious activities as being detrimental to thier psychosocial development.


Effect of different irrigation methods in the presence of a separated instrument: an in vitro study.
Objective: The aim of this study was to evaluate the effect of different irrigation methods on sodium hypochlorite (NaOCl)/debris extrusion and dentinal tubule penetration of 2.5% NaOCl in the presence of an apically separated instrument.Materials and methods: Sixty root canals of freshly extracted mandibular single-rooted premolars were chemomechanically prepared up to ProTaper F2. Manual needle irrigation (30-gauge/side-vented) with 2.5% NaOCl was performed between files and a smear layer was removed with 17% ethylenediaminetetraacetic acid. Three mm of notched ProTaper F3 files were separated in the apical third of the roots. Samples were then randomly divided according to the final irrigation systems as follows: EndoActivator, EndoVac, manual needle irrigation, passive ultrasonic activation, and RinsEndo. Samples were mounted to Eppendorf tubes and root canals were irrigated with 3-mL Rhodamine B-labelled 2.5% NaOCl, which was applied using one of the above-mentioned methods. The extruded NaOCl/debris weight was calculated by extracting pre-irrigation weights of tubes from post-irrigation ones. Samples embedded in acrylic resin were sectioned transversely in 1-mm thicknesses at apical 1- and 3-mm levels. NaOCl's penetration depth and percentage into the dentinal tubules were evaluated with the aid of a confocal laser scanning microscope. Data were analysed statistically with Kruskal-Wallis and post hoc Siegel-Castellan tests (p < .05).Results: EndoVac significantly decreased the extruded NaOCl/debris compared to RinsEndo, passive ultrasonic activation, and EndoActivator in the presence of a separated instrument (p < .05). The penetrability of NaOCl significantly increased with the use of RinsEndo and EndoVac compared to the remaining groups (p < .05).Conclusion: In the presence of an irretrievable separated instrument, it could be suggested that devices with apical negative pressure such as EndoVac may improve the penetrability of irrigation solutions to the apical part of the root while preserving periapical tissues from NaOCl/debris extrusion.


Central Nervous System Lymphoma.
Central nervous system lymphoma (CNSL) is a rare and aggressive malignancy that primarily affects the brain, spinal cord, and meninges. This article provides a comprehensive overview of the current understanding of CNSL encompassing its epidemiology, pathophysiology, clinical presentation, diagnosis, treatment modalities, and prognosis. Although the main focus is on primary CNS lymphoma (PCNSL), ocular lymphoma, primary leptomeningeal lymphoma, and secondary CNS lymphoma are also discussed. The pathobiology of CNSL involves the infiltration of malignant lymphocytes within the CNS parenchyma or leptomeninges. Various risk factors and immunological mechanisms contribute to its development, including immunodeficiency states, chronic inflammation, and genomic alterations. Accurate diagnosis is crucial for appropriate management, given the heterogeneous clinical presentation. The neuroimaging, systemic imaging, and other modalities for diagnosis and evaluation for extent of disease involvement will be discussed. Additionally, the importance of histopathological examination, cerebrospinal fluid (CSF) analysis, and molecular testing in confirming the diagnosis and guiding treatment decisions are highlighted. The treatment landscape for CNSL has evolved significantly. Therapeutic approaches encompass a multimodal strategy combining high-dose methotrexate-based chemotherapy, consolidation with whole-brain radiation therapy, and high-dose chemotherapy with stem cell rescue. Recent advancements in targeted therapies and immunomodulatory agents offer promising avenues for future treatment options. We review the clinical outcomes and prognostic factors influencing the survival of CNSL patients, including age, performance status, disease stage, and genetic abnormalities.


Bayesian clustering using hidden Markov random fields in spatial population genetics.
We introduce a new Bayesian clustering algorithm for studying population structure using individually geo-referenced multilocus data sets. The algorithm is based on the concept of hidden Markov random field, which models the spatial dependencies at the cluster membership level. We argue that (i) a Markov chain Monte Carlo procedure can implement the algorithm efficiently, (ii) it can detect significant geographical discontinuities in allele frequencies and regulate the number of clusters, (iii) it can check whether the clusters obtained without the use of spatial priors are robust to the hypothesis of discontinuous geographical variation in allele frequencies, and (iv) it can reduce the number of loci required to obtain accurate assignments. We illustrate and discuss the implementation issues with the Scandinavian brown bear and the human CEPH diversity panel data set.


Validation of telesimulation in the care of late preterm newborns with hypoglycemia for nursing students.
To develop and validate a telesimulation scenario for nursing students in the care of late preterm infants with hypoglycemia. A methodological study conducted between August 2021 and May 2022 in a virtual environment involved constructing and validating the scenario with 10 experts, and testing it with 10 students. The content validity index assessed validity, with a threshold of 80% or higher, and suggestions were analyzed using semantic approximation. Validation confirmed the appropriateness of all 14 scenario items, with an overall index of 97.8% and clarity and relevance indices of 98.5%. During testing, the overall index was 99.7%, with the "resources" item receiving the lowest score. Adjustments were made to objectives, technical terms, resources, and target audience based on feedback. Telesimulation is a widely accepted educational technology for training nursing students, with potential to enhance teaching quality and neonatal care.


A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase.
Mispairs in DNA of guanine with uracil and thymine can arise as a result of deamination of cytosine and 5-methylcytosine, respectively. In humans such mispairs are removed by thymine-DNA glycosylase (TDG). By deleting the carboxy and amino termini of this enzyme we have identified a core region capable of processing G/U but not G/T mispairs. We have further identified two bacterial proteins with strong sequence homology to this core and shown that the homologue from Escherichia coli (dsUDG) can remove uracil from G/U mispairs. This enzyme is likely to act as a back-up to the highly efficient and abundant enzyme uracil-DNA glycosylase (UDG) which is found in most organisms. Pupating insects have been reported to lack UDG activity, but we have identified an enzyme similar to dsUDG in cell lines from three different insect species. These data imply the existence of a family of double-strand-specific uracil-DNA glycosylases which, although they are subservient to UDG in most organisms, may constitute the first line of defence against the mutagenic effects of cytosine deamination in insects.


Converging Proton Minibeams with Magnetic Fields for Optimized Radiation Therapy: A Proof of Concept.
Proton MiniBeam Radiation Therapy (pMBRT) is a novel strategy that combines the benefits of minibeam radiation therapy with the more precise ballistics of protons to further optimize the dose distribution and reduce radiation side effects. The aim of this study is to investigate possible strategies to couple pMBRT with dipole magnetic fields to generate a converging minibeam pattern and increase the center-to-center distance between minibeams. Magnetic field optimization was performed so as to obtain the same transverse dose profile at the Bragg peak position as in a reference configuration with no magnetic field. Monte Carlo simulations reproducing realistic pencil beam scanning settings were used to compute the dose in a water phantom. We analyzed different minibeam generation techniques, such as the use of a static multislit collimator or a dynamic aperture, and different magnetic field positions, i.e., before or within the water phantom. The best results were obtained using a dynamic aperture coupled with a magnetic field within the water phantom. For a center-to-center distance increase from 4 mm to 6 mm, we obtained an increase of peak-to-valley dose ratio and decrease of valley dose above 50%. The results indicate that magnetic fields can be effectively used to improve the spatial modulation at shallow depth for enhanced healthy tissue sparing.


[Crystals in the epithelial nuclei of the midgut of fleas].
On studying the changes in the epithelium of the midgut of Ceratophyllus tesquorum, C. laeviceps and Leptopsylla segnis intranuclear crystals were found during the process of digestion. They were recorded both from young and adult insects. The crystals were absent from nuclei of cells of regeneration nests, epithelium of the fore-intestine, any other organs or from nuclei of epithelial cells of the stomach of young non-feeding individuals. They were found neither in young nor in adult individuals of Xenopsylla conformis and Neopsylla setosa.


Models for nutrition education to increase consumption of calcium and dairy products among African Americans.
Calcium and dairy consumption are documented to be low among African Americans and have demonstrated benefits to bone growth, overall nutritional status, and health throughout the life cycle. There is also an emerging relationship to the prevention of obesity. This low consumption has been attributed to both cultural and community/environmental barriers. Using a life course construct and an ecological model of health behavior, this paper will illustrate why nutrition education and food consumption behavior at one stage of the life cycle may influence health status at that stage as well as influence health and consumption of calcium and dairy products at subsequent stages. The life course construct recognizes that both past and present behavior and experiences (in this case food and nutrient intake) are shaped by the wider social, economic, and cultural context and therefore may provide clues to current patterns of health and disease. The ecological model, concerned with constructs of environmental change, behavior, and policies that may help people make choices in their daily life, complements the life course approach when examining the potential influence of nutrition education provided by federally funded food and nutrition programs on calcium and dairy consumption behavior across the life cycle. The "critical period model" within the life course construct is operative for calcium, a nutrient for which adequate intake is critically important during adolescence when peak bone density development, necessary for later protection against osteoporosis, is important.


Production and characterization of neutralizing and nonneutralizing monoclonal antibodies against listeriolysin O.
Listeriolysin O (LLO) is a thiol-activated toxin secreted by the facultative intracellular pathogen Listeria monocytogenes. LLO is essential for the survival of the bacterium in the infected cell because it promotes lysis of the phagosome membrane and escape of the bacterium into the cytosol. LLO was used as an antigen for the production of nine monoclonal antibodies (MAbs) in mice. Three of these could inhibit the hemolytic activity of LLO. One of them inhibited binding of LLO to erythrocyte membranes. The two other antibodies blocked the activity of LLO at a step subsequent to membrane binding. Only two of the nine MAbs recognized three other purified SH-activated toxins, streptolysin O, alveolysin, and pneumolysin. Western blot (immunoblot) analysis of culture supernatants of Listeria ivanovii and Listeria seeligeri, two hemolytic species of the genus Listeria, revealed that two MAbs recognized ivanolysin and seeligerolysin. The latter was also recognized by two other MAbs, including one of the neutralizing antibodies. MAbs raised against a peptide, ECTG LAWEWWR, present in all thiol-activated toxins sequenced to date, recognized all toxins and were not neutralizing. Taken together, these results demonstrate the existence of regions important for hemolytic activity that are unique to hemolysins of the genus Listeria and show that regions outside the conserved peptide are important for activity of LLO.


The diagnosis of esophageal eosinophilia is not increased in the summer months.
Smaller studies have suggested seasonal variation of the diagnosis of eosinophilic esophagitis with more patients being diagnosed in the aeroallergen season. We evaluated a large group of adult patients for a seasonal variation of the diagnosis of symptomatic eosinophilic esophageal infiltration. We performed a retrospective review of adult patients from a large Eosinophilic esophagitis database at the Mayo Clinic Rochester. We only included patients from three states in the upper Midwest, who had 15 or more eosinophils per high-power field on esophageal biopsy, symptomatic dysphagia, and were seen, in our Gastroenterology Clinic between 2000 and 2008. Clinical data were abstracted and the month of diagnosis was determined. The Rayleigh circular test and the Chi-square goodness-of-fit test were used to detect seasonality of symptomatic esophageal eosinophilia diagnosis and seasonality corrected for esophagogastroduodenoscopy monthly volume. The diagnosis of symptomatic eosinophilic esophageal infiltration was made in 372 patients. The mean number of eosinophils was 39.6 per high-power field. The December/January and May/June periods seem to have an increased presentation rate (p = 0.014). Of those tested, reactions to any aeroallergen was present in 69 % (48/70), reactions to >4 aeroallergens in 47 % (33/70) and reactions to any food allergen in 63 % (50/80) of patients. There was no evidence of monthly concentration of symptomatic esophageal eosinophilia diagnosis in the subgroups of patients with any positive aeroallergen, >4 positive aeroallergens, or history of atopy. The diagnosis of symptomatic esophageal eosinophilia is not made more frequently in the summer months.


Diabetes group medical visits and outcomes of care in low-income, rural, uninsured persons.
The purpose of this study was to test the effectiveness of Diabetes Group Medical Visits (DGMVs) verses usual care in a sample of low-income patients with diabetes receiving care at a rural free clinic. Data were collected through chart review, using direct data entry into Microsoft Access. Participants were included if they met the inclusion criteria: 1) age ≥ 18 years; 2) diagnosis of diabetes; 3) uninsured and received care between May 2007 and August 2009. Fifty-three participants attended DGMVs and were compared to 58 participants who received usual care. The personal characteristics and biophysical measures of this population differed from previously studied Group Visit populations. The majority of patients were female (73.9%), white (95.5%), younger than 50 (53.2%), driving long distances to receive care (mean miles = 21, SD 20.4) and had a high school education or less (95.4%). Participants were severely obese (mean BMI = 37.6, SD 28.48) and had 5 co-morbid conditions other than diabetes (mean = 5.5, SD 2.1). Those attending DGMVs had higher baseline A1C, depression scores, BMIs, and more pain than usual care. There was a statistically significant decrease in systolic pressure from time one to time two in patients who attended DGMVs t(52) = 2.18, (p = 0.03). There was no significant impact on outcomes of patients who received usual care. However, it is important to note that the majority of patients attended three or fewer DGMVs visits in one year. Group visits may not be enough to improve outcomes in this population. Previous studies suggest that improvements are seen in those who attend more frequently. Hence, the lack of improvement in biophysical outcomes may be due to low attendance. The limited impact of this traditional style intervention in relation to low attendance argues the need to test alternative interventions to reach this population.


Toxicogenetic, biochemical, and anatomical effects of the herbicide Clethodim on Allium cepa L.
Pesticides are compounds with several chemical or biological agents developed to potentiate the biocide action. Their use is associated with increased economic and agricultural productivity worldwide but can harm health and the environment, damaging existing biota. Clethodim is a systemic post-emergent herbicide for grasses, highly selective for cotton, coffee, onions, carrots, soybeans, etc. Therefore, this work aimed to evaluate the harmful effect of the herbicide Clethodim with the model plant Allium cepa. A series of tests were conducted to evaluate the effects of the herbicide under study. Germination tests, root growth, cell, and nucleolar cycle analysis, as well as oxidative stress assessment and histological analysis of the roots, were performed. The results indicated that the herbicide demonstrated phytotoxicity, inhibiting germination at C1 (1.92 g/L) and C3 (0.84 g/L), and root growth at all concentrations, presenting mutagenicity at C1 (1.92 g/L) and C4 (0.24 g/L), evidenced by the increased frequency of micronuclei. In addition, changes were observed in the enzymatic activity of the enzymes catalase at concentrations C1 (1.92 g/L) and C2 (0.96 g/L) and ascorbate peroxidase at concentrations C1 (1.92 g/L), C2 (0. 96 g/L), and C3 (0.48 g/L) and in cell elongation at concentrations C1 (1.92 g/L) and C3 (0.48 g/L), demonstrated in histological analyses of the root apex.