Mast cell and macrophage counts and microvessel density in invasive breast carcinoma-comparison analysis with clinicopathological parameters.
The purpose of this study was to evaluate the clinicopathological significance of the microvessel density and macrophage and mast cell counts in invasive breast carcinomas. 45 invasive breast carcinomas were immunohistochemically stained with the endothelial antigen, CD34, and macrophage marker, CD68. 0.1% toluidine blue was used to highlight mast cells. The microvessel and mast cell counts were performed at x200 magnification and the macrophages at x400 magnification. With the 45 invasive breast carcinomas, there were no statistically significant associations between the mast cell, macrophage and microvessel counts and the tumor size and lymph node status. ER and PR negative mast cells infiltrated more than in cases of positive stati, with statistical significance (p-value=0.010 and 0.005, respectively). The macrophage counts were negatively correlated with the PR status (p-value=0.030). With respect to the c-erbB-2 status, there was no significance correlation with the mast cell, macrophage and microvessel counts. The mast cell counts showed significantly positive correlation with the microvessel counts in the invasive breast carcinomas (p-value=0.015). In a comparison of the macrophage counts with the microvessel counts, a positive tendency for both parameters, but without statistical significance (p-value=0.310). Increasing numbers of mast cells and macrophages were recruited in invasive breast carcinomas, which contribute to angiogenesis. The microvessel density in invasive breast carcinomas had no statistically significant association with the tumor size, lymph node status, and histological grade, presence of DCIS component, estrogen/progesterone receptor status and cerbB-2 status. The evaluation of angiogenesis using these methods is not thought to provide an independent clinicopathological factor in invasive breast carcinomas.


A histochemical study on the adrenal components of the teleost Cirrhinus mrigala (Ham.).
The adrenal components of C. mrigala are embedded in the pronephric cephalic kidney around the post cardinal vein. The cortical cells responded positively to the lipids, ascorbic acid, delta 5-3 beta-HSD, G-6-PD, MAO, acid and alkaline phosphatase tests. The presence of intense MAO activity may suggest the possible involvement of monoamines in the adrenocortical function. Localization of lipids and delta 5-3 beta-HSD show the sites of corticosteroid synthesis. In the chromaffin cells, MAO, acid and alkaline phosphatase activity was moderate whereas they gave a strong reaction to ascorbic acid test in comparison to the cortical cells. Noradrenaline (NA) and adrenaline (A) storing cells were differentiated adopting glutaraldehyde silver, dichromate and iodate techniques. NA and A storing cells are almost totally depleted of their contents after reserpine treatment. The histochemical response of the adrenal gland of this species is largely comparable to that of higher vertebrates.


Fire regimes, fire ecology, and fire management in Mexico.
I propose several broad fire regimes and provide an analysis of fire ecology for the principal vegetation types in Mexico. Forty percent of Mexican ecosystems are fire-dependent (pine forests, several oak forests, grasslands, several shrublands, savannas, palm lands, wet prairies, "popal" and "tular" swamps), 50% are fire-sensitive (tropical rain forests and tropical seasonal forests, tropical cloud forests, mangrove, fir forests, several oak forests, and several shrublands), and the remaining 10% fall into fire-influenced (such as several gallery forests) and fire-independent categories (shrublands in most xeric environments, very high-altitude prairies). I also present an analysis of current fire-management trends, highlighting the trend toward integral fire management, which merges prevention and control, community-based fire management, and ecological fire management.


Amyloid-β-Induced Dysregulation of AMPA Receptor Trafficking.
Evidence from neuropathological, genetic, animal model, and biochemical studies has indicated that the accumulation of amyloid-beta (Aβ) is associated with, and probably induces, profound neuronal changes in brain regions critical for memory and cognition in the development of Alzheimer's disease (AD). There is considerable evidence that synapses are particularly vulnerable to AD, establishing synaptic dysfunction as one of the earliest events in pathogenesis, prior to neuronal loss. It is clear that excessive Aβ levels can disrupt excitatory synaptic transmission and plasticity, mainly due to dysregulation of the AMPA and NMDA glutamate receptors in the brain. Importantly, AMPA receptors are the principal glutamate receptors that mediate fast excitatory neurotransmission. This is essential for synaptic plasticity, a cellular correlate of learning and memory, which are the cognitive functions that are most disrupted in AD. Here we review recent advances in the field and provide insights into the molecular mechanisms that underlie Aβ-induced dysfunction of AMPA receptor trafficking. This review focuses primarily on NMDA receptor- and metabotropic glutamate receptor-mediated signaling. In particular, we highlight several mechanisms that underlie synaptic long-term depression as common signaling pathways that are hijacked by the neurotoxic effects of Aβ.


Comorbidity and functional trajectories from midlife to old age: the Health and Retirement Study.
The number of diseases and physical functioning difficulties tend to increase with age. The aim of this study was to examine the trajectories of physical functioning across age groups and whether the trajectories differ according to disease status in different population subgroups. Repeat data from a nationally representative population sample, the Health and Retirement Study, was used. Participants were 10,709 men and 13,477 women aged 60-107 years at baseline with biennial surveys from 1992 to 2010. Average length of follow-up was 10.3 years ranging from 0 to 18 years. Disease status and physical functioning was asked about at all study phases and 10 items were summed to obtain a physical functioning score (0-10). Age modified the relationship between number of chronic diseases and physical functioning with older participants having more physical functioning difficulties with increasing number of diseases. An average 70-year-old participant with no diseases had 0.89 (95% CI: 0.85-0.93) physical functioning difficulties, with one disease 1.72 (95% CI: 1.69-1.76) difficulties, with two diseases 2.57 (95% CI: 2.52-2.62) difficulties, and with three or more diseases 3.82 (95% CI: 3.76-3.88) difficulties. Of the individual diseases memory-related diseases, stroke, pulmonary diseases, and arthritis were associated with significantly higher physical functioning difficulties compared with other diseases. Comorbidity is associated with greater burden of physical functioning difficulties. Of the studied diseases, memory-related diseases, stroke, pulmonary diseases, and arthritis alone or in combination limit most physical functioning.


Integrating Hyperthermia into Modern Radiation Oncology: What Evidence Is Necessary?
Hyperthermia (HT) is one of the hot topics that have been discussed over decades. However, it never made its way into primetime. The basic biological rationale of heat to enhance the effect of radiation, chemotherapeutic agents, and immunotherapy is evident. Preclinical work has confirmed this effect. HT may trigger changes in perfusion and oxygenation as well as inhibition of DNA repair mechanisms. Moreover, there is evidence for immune stimulation and the induction of systemic immune responses. Despite the increasing number of solid clinical studies, only few centers have included this adjuvant treatment into their repertoire. Over the years, abundant prospective and randomized clinical data have emerged demonstrating a clear benefit of combined HT and radiotherapy for multiple entities such as superficial breast cancer recurrences, cervix carcinoma, or cancers of the head and neck. Regarding less investigated indications, the existing data are promising and more clinical trials are currently recruiting patients. How do we proceed from here? Preclinical evidence is present. Multiple indications benefit from additional HT in the clinical setting. This article summarizes the present evidence and develops ideas for future research.


A clinical study of radiographic selection criteria for edentulous patients.
This study was designed to determine if radiographic selection criteria could be developed and applied in the examination and treatment planning of edentulous patients. Fifty-one patients were examined and radiographs were prescribed for seven patients, where indicated by the selection criteria chosen. Previously-obtained screening panoramic films were interpreted first, for findings in the areas covered by the prescribed films, and then for occult findings in the remaining areas. Thirty-three patients showed occult positive findings, none of which had clinical significance. For this population, the prescription of radiographs provided the appropriate radiographic information for making treatment decisions. For the vast majority of patients (49), screening panoramic films were unproductive and therefore unnecessary.


Tarlov cyst: Case report and review of literature.
We describe a case of sacral perineural cyst presenting with complaints of low back pain with neurological claudication. The patient was treated by laminectomy and excision of the cyst. Tarlov cysts (sacral perineural cysts) are nerve root cysts found most commonly in the sacral roots, arising between the covering layer of the perineurium and the endoneurium near the dorsal root ganglion. The incidence of Tarlov cysts is 5% and most of them are asymptomatic, usually detected as incidental findings on MRI. Symptomatic Tarlov cysts are extremely rare, commonly presenting as sacral or lumbar pain syndromes, sciatica or rarely as cauda equina syndrome. Tarlov cysts should be considered in the differential diagnosis of patients presenting with these complaints.


Bayesian regression analysis of skewed tensor responses.
Tensor regression analysis is finding vast emerging applications in a variety of clinical settings, including neuroimaging, genomics, and dental medicine. The motivation for this paper is a study of periodontal disease (PD) with an order-3 tensor response: multiple biomarkers measured at prespecified tooth-sites within each tooth, for each participant. A careful investigation would reveal considerable skewness in the responses, in addition to response missingness. To mitigate the shortcomings of existing analysis tools, we propose a new Bayesian tensor response regression method that facilitates interpretation of covariate effects on both marginal and joint distributions of highly skewed tensor responses, and accommodates missing-at-random responses under a closure property of our tensor model. Furthermore, we present a prudent evaluation of the overall covariate effects while identifying their possible variations on only a sparse subset of the tensor components. Our method promises Markov chain Monte Carlo (MCMC) tools that are readily implementable. We illustrate substantial advantages of our proposal over existing methods via simulation studies and application to a real data set derived from a clinical study of PD. The R package BSTN available in GitHub implements our model.


Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment.
Subjects with mild cognitive impairment (MCI) have been shown to have reduced hippocampal volumes relative to normal elderly control subjects. The presence of the apolipoprotein E epsilon4 (APOE*E4) allele has been associated with greater hippocampal atrophy in women than in men with Alzheimer disease. This relationship has not been demonstrated in MCI. To examine the relationship between APOE genotype and hippocampal volume in men and women with MCI. This study evaluated MCI in 193 subjects (86 women and 107 men) participating in a multicenter clinical trial, all of whom underwent magnetic resonance imaging at their baseline visit. We evaluated the association among the number of APOE*E4 alleles, memory performance, and hippocampal volume in men and women with tests of means and multiple linear regressions. Compared with MCI subjects with no APOE*E4 alleles, women with 1 or 2 APOE*E4 alleles were found to have significantly reduced hippocampal volume, whereas men only showed a significant reduction in hippocampal volume when carrying 2 APOE*E4 alleles. Worsening of performance on a delayed word recall task (Alzheimer's Disease Assessment Scale cognitive subscale) showed an identical pattern in association with APOE*E4 allele dose and sex. Furthermore, when controlling for memory performance on delayed word recall, the APOE*E4 effect on hippocampal volumes was attenuated in men, but remained significant in women. The APOE*E4 genotype status appears to have a greater deleterious effect on gross hippocampal pathology and memory performance in women than in men.


Crystallin proteins and amyloid fibrils.
Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, alpha-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of alphaB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.


UV-C irradiation disrupts platelet surface disulfide bonds and activates the platelet integrin alphaIIbbeta3.
UV-C irradiation has been shown to be effective for pathogen reduction in platelet concentrates, but preliminary work indicated that UV-C irradiation of platelets can induce platelet aggregation. In this study, the mechanism underlying this phenomenon was investigated. Irradiation of platelets with UV-C light (1500 J/m(2)) caused platelet aggregation, which was dependent on integrin alphaIIbbeta3 activation (GPIIb/IIIa). This activation occurred despite treatment with several signal transduction inhibitors known to block platelet activation. UV-C also induced activation of recombinant alphaIIbbeta3 in Chinese hamster ovary (CHO) cells, an environment in which physiologic agonists fail to activate. Activation of alphaIIbbeta3 requires talin binding to the beta3 tail, yet alphaIIbbeta3-Delta724 (lacking the talin binding site) was activated by UV-C irradiation, excluding a requirement for talin binding. The UV-C effect appears to be general in that beta(1) and beta(2) integrins are also activated by UV-C. To explain these findings, we investigated the possibility of UV-C-induced photolysis of disulfide bonds, in analogy with the activating effect of reducing agents on integrins. Indeed, UV-C induced a marked increase in free thiol groups in platelet surface proteins including alphaIIbbeta3. Thus, UV-C appears to activate alphaIIbbeta3 not by affecting intracellular signal transduction, but by reduction of disulfide bonds regulating integrin conformation.


Oral immunotherapy and tolerance induction in childhood.
Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food-allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long-term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy.


A blended learning approach to teaching basic pharmacokinetics and the significance of face-to-face interaction.
To assess pharmacy students' attitudes towards a blended-learning pharmacokinetics course. Narrated visual presentations and animations that illustrated kinetic processes and guided students through the use of software programs used for calculations were created. Other learning techniques used included online self-assessment quizzes, practice problem sets, and weekly face-to-face problem-solving tutorials. A precourse questionnaire to assess students' level of enthusiasm towards the blended-learning course and to solicit any concerns they had was administered at the beginning of the course. A postcourse questionnaire that included the same 4 Likert-scale items from the precourse questionnaire and follow-up open-ended questions was administered. Individual changes in level of enthusiasm were compared for individuals who completed both the precourse and postcourse questionnaire. Students' concerns about the blended method of learning had decreased postcourse while their enthusiasm for the benefits of blended learning had increased. Students' initial concerns about the blended learning experience were focused on their ability to communicate with the instructor about the online components, but shifted to their own time management skills at the end of the course. Face-to-face interactions with each other and with the instructor were more highly rated than online interactions in this course.


Mode of action of VegT in mesoderm and endoderm formation.
mRNA encoding the T-box transcription factor VegT is located throughout the vegetal pole of the Xenopus egg and is believed to play an important part in endoderm and mesoderm formation. We find that VegT generates endoderm both by cell-autonomous action and by generating TGF-beta family signals, the latter being entirely responsible for its mesoderm-inducing activity. Signalling molecules induced cell-autonomously by VegT include derrière, Xnr4 and activin B. Xnr1 and Xnr2 are also induced, but primarily in a non-autonomous manner. All of these signalling molecules are found in the blastula and gastrula vegetal pole and induce both endoderm and mesoderm in the animal cap assay, and hence are good candidates both for the endogenous zygotic mesoderm-inducing signal and for reinforcing the vegetal expression of endoderm markers.


Predicting Nocturnal Hypoglycemia from Continuous Glucose Monitoring Data with Extended Prediction Horizon.
Nocturnal hypoglycemia is a serious complication of insulin-treated diabetes, which commonly goes undetected. Continuous glucose monitoring (CGM) devices have enabled prediction of impending nocturnal hypoglycemia, however, prior efforts have been limited to a short prediction horizon (~ 30 minutes). To this end, a nocturnal hypoglycemia prediction model with a 6-hour horizon (midnight-6 am) was developed using a random forest machine- learning model based on data from 10,000 users with more than 1 million nights of CGM data. The model demonstrated an overall nighttime hypoglycemia prediction performance of ROC AUC = 0.84, with AUC = 0.90 for early night (midnight-3 am) and AUC = 0.75 for late night (prediction at midnight, looking at 3-6 am window). While instabilities and the absence of late-night blood glucose patterns introduce predictability challenges, this 6-hour horizon model demonstrates good performance in predicting nocturnal hypoglycemia. Additional study and specific patient-specific features will provide refinements that further ensure safe overnight management of glycemia.


Effect of surface roughness on retention and removal of Escherichia coli O157:H7 on surfaces of selected fruits.
This study was undertaken to evaluate the effect of surface roughness on the attachment and removal of Escherichia coli O157:H7 on selected fruit and metal surfaces. A new method to determine surface roughness was developed using confocal laser scanning microscopy (CLSM). A series of 2-D layered images were taken by CLSM optical slicing of the surfaces of Golden Delicious apples, navel oranges, avocadoes, and cantaloupes. The average roughness (R(a)) of the fruit surfaces was assessed by reconstructing a series of 2-D images into 3-D images. A cocktail of 5 E. coli O157:H7 strains were spot inoculated onto fruit skin surfaces with different R(a). The fruits were then treated with acidic electrolyzed water (AEW), peroxyacetic acid (POAA), and sterilized deionized water. Aluminum stubs with different R(a) values as a model system were also spot inoculated with E. coli O157:H7 and subjected to a sonication treatment. Test results indicated that there was a positive linear correlation between R(a) and adhesion rate of E. coli O157:H7, and a negative correlation between R(a) and the efficacy of inactivation by AEW and POAA, respectively, on fruit surfaces. A linear increase of residual bacteria population with increased surface roughness of aluminum stubs was also observed. The relationship between surface roughness and surface hydrophobicity was negative linear for the aluminum stubs, but was quadratic for the 4 fruits. The environmental scanning electron microscopy images showed that bacteria tended to attach to or be entrapped in the grooves or cavities of fruits, which provided protection to the cells against washing treatments.


Supporting Surgical Teams: Identifying Needs and Barriers for Exoskeleton Implementation in the Operating Room.
The objective of this study was to identify potential needs and barriers related to using exoskeletons to decrease musculoskeletal (MS) symptoms for workers in the operating room (OR). MS symptoms and injuries adversely impact worker health and performance in surgical environments. Half of the surgical team members (e.g., surgeons, nurses, trainees) report MS symptoms during and after surgery. Although the ergonomic risks in surgery are well recognized, little has been done to develop and sustain effective interventions. Surgical team members (n = 14) participated in focus groups, performed a 10-min simulated surgical task with a commercial upper-body exoskeleton, and then completed a usability questionnaire. Content analysis was conducted to determine relevant themes. Four themes were identified: (1) characteristics of individuals, (2) perceived benefits, (3) environmental/societal factors, and (4) intervention characteristics. Participants noted that exoskeletons would benefit workers who stand in prolonged, static postures (e.g., holding instruments for visualization) and indicated that they could foresee a long-term decrease in MS symptoms with the intervention. Specifically, raising awareness of exoskeletons for early-career workers and obtaining buy-in from team members may increase future adoption of this technology. Mean participant responses from the System Usability Scale was 81.3 out of 100 (SD = 8.1), which was in the acceptable range of usability. Adoption factors were identified to implement exoskeletons in the OR, such as the indicated need for exoskeletons and usability. Exoskeletons may be beneficial in the OR, but barriers such as maintenance and safety to adoption will need to be addressed. Findings from this work identify facilitators and barriers for sustained implementation of exoskeletons by surgical teams.


Cost-effective carbon fiber precursor selections of polyacrylonitrile-derived blend polymers: carbonization chemistry and structural characterizations.
Blending polyacrylonitrile (PAN) with plastic wastes and bio-based polymers provides a convenient and inexpensive method to realize cost-effective carbon fiber (CF) precursors. In this work, PAN-based blend precursors are investigated using ReaxFF reactive molecular dynamics simulations with respect to the formation of all-carbon rings, the evolutions of oxygen-containing and nitrogen-containing species, and the migration of carbon atoms to form turbostratic graphene. From these simulations, we identify that PAN/cellulose (CL) blend manifests the highest carbon yield and the most substantial all-carbon ring formation. This ReaxFF-based finding is confirmed by Raman and TEM experiments indicating high crystallinity for PAN/CL-derived blend CFs. We trace the pathway of gasification and carbonization of PAN/CL to elaborate the mechanism of the formation of all-carbon ring networks. We discover that the acetals of CL can catalyze the cyclization of the blend precursor, allowing for the search for CL derivatives or the other kinds of bio-based polymers with similar functionalities as alternative blends. In addition, we examine the structural characteristics using the carbon-carbon (C-C) radial distribution functions, C-C bond length distributions, and sp2 C atom ratios for the four representative precursors, i.e., PAN, oxidized PAN, PAN/nylon 6,6, and PAN/CL. Our simulation results show the most extensive all-carbon ring cluster and graphitic structure growths for PAN/CL. Therefore, we propose PAN/CL as a cost-effective alternative CF precursor, since (a) CL is naturally abundant and eco-friendly for production, (b) the blend precursor PAN/CL does not require oxidation treatment, (c) PAN/CL has a high carbon yield with substantial all-carbon ring formation, and (d) PAN/CL based CFs potentially provide a mechanical property enhancement.


Monitoring the species of arsenic, chromium and nickel in milled coal, bottom ash and fly ash from a pulverized coal-fired power plant in western Canada.
The concentration of As, Cr and Ni and their speciation (As3+;5+, Cr3+;6+ and Ni0;2+) in milled coal, bottom ash and ash collected by electrostatic precipitator (ESP) from a coal fired-power plant in western Canada were determined using HGAAS, ICP-AES and XANES. The chemical fractionation of these elements was also determined by a sequential leaching procedure, using deionized water, NH4OAC and HCI as extracting agents. The leachate was analyzed by ICP-AES. Arsenic in the milled coal is mostly associated with organic matter, and 67% of this arsenic is removed by ammonium acetate. This element is totally removed from milled coal after extraction with HCI. Arsenic occurs in both the As3+ and the As5+ oxidation states in the milled coal, while virtually all (>90%) of the arsenic in bottom ash and fly ash appears to be in the less toxic arsenate (As5+) form. Both Ni and Cr in the milled coal are extracted by HCI, indicating that water can mobilize Ni and Cr in an acidic environment. The chromium is leached by water from fly ash as a result of the high pH of the water, which is induced during the leaching. Ammonium acetate removes Ni from bottom ash through an ion exchange process. Chromium in milled coal is present entirely as Cr3+, which is an essential human trace nutrient. The Cr speciation in bottom ash is a more accentuated version of the milled coal and consists mostly of the Cr3+ species. Chromium in fly ash is mostly Cr3+, with significant contamination by stainless-steel from the installation itself.


Complications in the assignment of 14 and 28 Da mass shift detected by mass spectrometry as in vivo methylation from endogenous proteins.
Identification of protein methylation sites typically starts with database searching of MS/MS spectra of proteolytic digest of the target protein by allowing addition of 14 and 28 Da in the selected amino acid residues that can be methylated. Despite the progress in our understanding of lysine and arginine methylation, substrates and functions of protein methylation at other amino acid residues remain unknown. Here we report the analysis of protein methylation for p53, SMC3, iNOS, and MeCP2. We found that a large number of peptides can be modified on the lysine, arginine, histidine, and glutamic acid residues with a mass increase of 14 or 28 Da, consistent with methylation. Surprisingly, a majority of which did not demonstrate a corresponding mass shift when cells were cultured with isotope-labeled methionine, a precursor for the synthesis of S-adenosyl-l-methionine (SAM), which is the most commonly used methyl donor for protein methylation. These results suggest the possibility of either exogenous protein methylation during sample handling and processing for mass spectrometry or the existence of SAM-independent pathways for protein methylation. Our study found a high occurrence of protein methylation from SDS-PAGE isolated endogenous proteins and identified complications for assigning such modifications as in vivo methylation. This study provides a cautionary note for solely relying on mass shift for mass spectrometric identification of protein methylation and highlights the importance of in vivo isotope labeling as a necessary validation method.


Advances in bi-directional relationships for EZH2 and oxidative stress.
Over the past two decades, polycomb repressive complex 2(PRC2) has emerged as a vital repressive complex in overall cell fate determination. In mammals, enhancer of zeste homolog 2 (EHZ2), which is the core component of PRC2, has also been recognized as an important regulator of inflammatory, redox, tumorigenesis and damage repair signalling networks. To exert these effects, EZH2 must regulate target genes epigenetically or interact directly with other gene expression-regulating factors, such as LncRNAs and microRNAs. Our review provides a comprehensive summary of research advances, discoveries and trends regarding the regulatory mechanisms between EZH2 and reactive oxygen species (ROS). First, we outline novel findings about how EZH2 regulates the generation of ROS at the molecular level. Then, we summarize how oxidative stress controls EHZ2 alteration (upregulation, downregulation, or phosphorylation) via various molecules and signalling pathways. Finally, we address why EZH2 and oxidative stress have an undefined relationship and provide potential future research ideas.


Composition and similarity of bovine rumen microbiota across individual animals.
The bovine rumen houses a complex microbiota which is responsible for cattle's remarkable ability to convert indigestible plant mass into food products. Despite this ecosystem's enormous significance for humans, the composition and similarity of bacterial communities across different animals and the possible presence of some bacterial taxa in all animals' rumens have yet to be determined. We characterized the rumen bacterial populations of 16 individual lactating cows using tag amplicon pyrosequencing. Our data showed 51% similarity in bacterial taxa across samples when abundance and occurrence were analyzed using the Bray-Curtis metric. By adding taxon phylogeny to the analysis using a weighted UniFrac metric, the similarity increased to 82%. We also counted 32 genera that are shared by all samples, exhibiting high variability in abundance across samples. Taken together, our results suggest a core microbiome in the bovine rumen. Furthermore, although the bacterial taxa may vary considerably between cow rumens, they appear to be phylogenetically related. This suggests that the functional requirement imposed by the rumen ecological niche selects taxa that potentially share similar genetic features.


TCR-like human antibodies expressed on human CTLs mediate antibody affinity-dependent cytolytic activity.
The permanent genetic programming via gene transfer of autologous T cells with cell surface receptors directed toward tumor-related Ags holds great promise for the development of more-specific tumor therapies. In this study we have explored the use of Abs directed to MHC-peptide complexes (or TCR-like Abs) to engraft CTLs with exquisite specificity for cancer cells. First, we affinity matured in vitro a previously selected TCR-like Ab, Fab-G8, which is highly specific for the peptide melanoma-associated Ag-A1 presented by the HLA-A1 molecule. A combination of L chain shuffling, H chain-targeted mutagenesis, and in vitro selection of phage display libraries yielded a Fab-G8 Ab derivative, Fab-Hyb3, with an 18-fold improved affinity yet identical peptide fine specificity. Fab-G8 and Fab-Hyb3 were expressed on primary human T lymphocytes as cell surface-anchored Fab, demonstrating that T cells expressing the high-affinity Fab-Hyb3 molecule eradicate tumor cells much more effectively. Furthermore, the gain in ligand-binding affinity resulted in a 2-log improvement in the detection of peptide/MHC complexes on melanoma-associated Ag-A1 peptide-loaded cells. In summary, an affinity-matured Ab specifically recognizing a cancer-related peptide/MHC complex was generated and used to improve the tumor cell killing capacity of human T cells. This strategy, based on engraftment of T cells with in vitro engineered Abs, is an attractive alternative to the laborious, and in many cases unsuccessful, generation of highly potent tumor-specific T lymphocytes.


Entropy of isolated quantum systems after a quench.
A diagonal entropy, which depends only on the diagonal elements of the system's density matrix in the energy representation, has been recently introduced as the proper definition of thermodynamic entropy in out-of-equilibrium quantum systems. We study this quantity after an interaction quench in lattice hard-core bosons and spinless fermions, and after a local chemical potential quench in a system of hard-core bosons in a superlattice potential. The former systems have a chaotic regime, where the diagonal entropy becomes equivalent to the equilibrium microcanonical entropy, coinciding with the onset of thermalization. The latter system is integrable. We show that its diagonal entropy is additive and different from the entropy of a generalized Gibbs ensemble, which has been introduced to account for the effects of conserved quantities at integrability.


The Matrix Rib Plating System: improving aesthetic outcomes in microvascular breast reconstruction.
During microvascular breast reconstruction, exposure of internal mammary vessels (IMVs) is facilitated by the removal of a portion of the rib resulting in occasional chest contour deformity (CCD). The use of rib plating may reduce CCD and reduce postoperative pain. All patients underwent microvascular breast reconstruction using IMVs. In the retrospective arm, photographs were assessed by a blinded reviewer for CCDs. In the prospective cohort, patients were randomized to rib plating with the Synthes Matrix Rib Plating System or no rib plating. Postoperatively, patients were assessed for CCD and pain. In the retrospective arm, 11 of 98 (11.2%) patients representing 12 of 130 (9.2%) breast reconstructions had a noticeable contour deformity. The average body mass index (BMI) of patients with CCDs was 26.6 kg/m. In the prospective arm, there was 16% (3 of 19) rate of visible and palpable CCDs among controls, compared to 0% rate of palpable and visible contour deformity in the rib plating group. Pain was decreased in the rib plating group on all postoperative days. The pain reduction was statistically significant at rest by postoperative day 30. The majority of patients (9 of 11) with compromised aesthetic outcomes had a BMI less than 30 kg/m, suggesting a paucity of overlying soft tissue contributed to visibility of these bony defects. Rib plating prevented chest contour deformity, reduced postoperative pain, and added limited additional morbidity. We believe that rib plating is a safe, useful adjunct to microvascular breast reconstruction using IMVs, as it may improve aesthetic outcomes and reduce postoperative pain.


Serum Neudesin Levels in Obese Adolescents
Advances in knowledge of neurotrophic factors are now revealing the complex control of energy homeostasis and appetite, as well as the crucial role these factors play in nervous system function. The aim of this study was to assess serum levels of neudesin in adolescents with obesity and to examine the relationship between these levels and metabolic outcomes. Adolescents, aged 10-17 years were enrolled. Subjects were divided into normal weight, obese and morbidly obese subgroups. Serum neudesin concentrations were compared between the groups. In total, 88 adolescents were recruited, of whom 30 (34.1%) were normal weight, 15 (17.0%) were obese and 43 (48.9%) were morbidly obese. Neudesin levels were significantly lower in obese adolescents than in the control group (p=0.013). A correlation analysis applied to the whole study group revealed a negative correlation between serum neudesin concentration and body mass index (BMI) z scores (r=-0.40, p<0.001). Serum neudesin levels tended to increase in adolescents with metabolic syndrome, insulin resistance, dyslipidaemia, and hypertension but the differences were not significant (p=0.259, p=0.246, p=0.259, and p=0.523, respectively). Serum neudesin levels were significantly correlated with BMI z score in obese adolescents. Generally, serum neudesin levels were low in obese and morbidly obese adolescents and tended to increase with the appearance of metabolic disorders. Both obesity and associated metabolic disorders have multifactorial causes. Therefore, we suggest that the role of the neudesin molecule in the regulatory mechanisms of obesity and metabolic disorders should be further investigated with well-designed studies enrolling larger groups.


Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort.
The purpose of this study was to identify SQSTM1 gene mutations, estimate survival based on the progression rate of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (ΔFS), and characterize the relationships between SQSTM1 mutations and clinical phenotypes in Chinese ALS patients. We sequenced the SQSTM1 gene in 35 familial ALS patients, 436 sporadic ALS patients, and 384 healthy controls. SQSTM1 gene mutations were screened with PCR and direct sequencing; the correlations between genotype and phenotype and the progressive ALSFRS-R ratio were analyzed. Results revealed six heterozygous missense mutations in 471 ALS patients: c.241 G> A (p.E81K), c.717 C> A (p.N239K), c.889 G> A (p.G297S), c.1116 G> C (p.E372D), c.1162 C> T (p.P388S) and c.1175 C> T (p.P392 L). The gender ratio was 1:1, and the limb was the site of disease onset in mutation-positive patients. Notably, the ΔFS analysis revealed that the risk of death or tracheostomy was significantly increased in SQSTM1 mutation carriers (p < 0.05). In conclusion, E81K, N239K, G297S, E372D, P388S and P392 L were detected in the PB1, TRAF6, PEST and UBA domains, which are important to p62 function and prone to ALS. The incidence of ALS caused by the SQSTM1 mutation has increased from 30 to 35 worldwide.


Nutritional Status as a Risk Factor in COPD.
The third leading cause of death, chronic obstructive pulmonary disease COPD is gaining more and more attention in the literature and clinical practice. Precision medicine, already recognised as a right approach for COPD, requests a special attention to be allocated for nutritional status. Free fat mass index FFMI and visceral fat VFA area measurements should be added to body mass index (BMI) in order to have a complete perspective of the nutritional status and disease prognosis. Prospective medical nutrition therapy should consider caloric intake for achieving a BMI of 20-24 kg/m2, nutritionally dense, small and frequent meals, choosing the moment for the most important meal when the level of energy is the highest for the patient. A resting period before mealtime is adviced. Obesity paradox in COPD means a lower mortality associated with BMI between 25 and 32. This benefit is mainly related to higher muscular mass, as it has been described by some authors. The main objective in nutritional intervention will be to maintain muscular mass, adviced protein intake should be 1.2 g/kg body weight/day, higher vs general population. In the future, nutritional status evaluation should be included in pulmonary rehabilitation process, and a multidisciplinary team is expected to cooperate in order to achieve best pulmonary results.


Distinct short-term memory systems for sound content and sound localization.
Short-term memory for sound content and sound localization was investigated in normal subjects using the same/different comparison of two sound stimuli separated by an interval. Auditory or visual interference tasks requiring recognition or spatial judgements were introduced in the interval. Auditory interference tasks reduced memory for sound content and sound location in a specific way. Memory for sound content was significantly more reduced by auditory recognition than by auditory spatial interference task. Visual interference tasks reduced significantly memory for sound location but not for sound content. These results suggest that (i) short-term memory for sound content and that for sound location involve partially distinct processing; and (ii) auditory spatial functions are more closely linked to visual functions than auditory recognition.


Activation of pro-caspase-7 by serine proteases includes a non-canonical specificity.
As a model to investigate the mechanism of caspase activation we have analysed the processing of pro-caspase-7 by serine proteases with varied specificities. The caspase-7 zymogen was rapidly activated by granzyme B and more slowly by subtilisin and cathepsin G, generating active enzymes with similar kinetic properties. Significantly, cathepsin G activated the zymogen by cleaving at a Gln-Ala bond, indicating that the canonical cleavage specificity at aspartic acid is not required for activation.


Trends in Colorectal Cancer Mortality in the United States, 1999 - 2020.
The United States faces a significant public health issue with colorectal cancer (CRC), which remains the third leading cause of cancer-related fatalities despite early diagnosis and treatment progress. This investigation utilized death certificate data from the Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research (CDC WONDER) database to investigate trends in CRC mortality and location of death from 1999 to 2020. Additionally, the study utilized the annual percent change (APC) to estimate the average annual rate of change over the specific time period for the given health outcome. Incorporating the location of death in this study served the purpose of identifying patterns related to CRC and offering valuable insights into the specific locations where deaths occurred. Between 1999 and 2020, there were 1,166,158 CRC-related deaths. The age-adjusted mortality rates (AAMRs) for CRC consistently declined from 20.7 in 1999 to 12.5 in 2020. Men had higher AAMR (18.8) than women (13.4) throughout the study. Black or African American patients had the highest AAMR (21.1), followed by White (15.4), Hispanic/Latino (11.8), American Indian or Alaska native (11.4), and Asian or Pacific Islanders (10.2). The location of death varied, with 41.99% at home, 28.16% in medical facilities, 16.6% in nursing homes/long-term care facilities, 7.43% in hospices, and 5.80% at other/unknown places. There has been an overall improvement in AAMR among most ethnic groups, but an increase in AAMR has been observed among white individuals below the age of 55. Notably, over one-quarter of CRC-related deaths occur in medical facilities.


Progressive neurological disease associated with chronic cytomegalovirus infection.
Cytomegalovirus (CMV), the most common infectious cause of nervous system damage in the fetus and newborn infant, generally has been thought to exert its teratogenic effect during early pregnancy, and it has been assumed that clinical or postmortem abnormalities reflect static insults incurred earlier. Over the past two years we have identified two infants who presented with various clinical signs suggesting CMV infection. Serial CT head scans showed mild hydrocephalus progressing to extensive loss of brain substance and hydrocephalus in one and a normal scan going on to polycystic encephalomalacia in the other. Both infants had urine or leukocyte cultures that were repeatedly positive for CMV. These data suggest that CMV can cause progressive central nervous system damage after birth. The findings may account for some unexplained brain malformations and for a portion of the neurodegenerative disorders occurring in babies who appear normal at birth.


Numeral order and the operationalization of the numerical system.
Recent years have witnessed an increase in research on how numeral ordering skills relate to children's and adults' mathematics achievement both cross-sectionally and longitudinally. Nonetheless, it remains unknown which core competency numeral ordering tasks measure, which cognitive mechanisms underlie performance on these tasks, and why numeral ordering skills relate to arithmetic and math achievement. In the current study, we focused on the processes underlying decision-making in the numeral order judgement task with triplets to investigate these questions. A drift-diffusion model for two-choice decisions was fit to data from 97 undergraduates. Findings aligned with the hypothesis that numeral ordering skills reflected the operationalization of the numerical system, where small numbers provide more evidence of an ordered response than large numbers. Furthermore, the pattern of findings suggested that arithmetic achievement was associated with the accuracy of the ordinal representations of numbers.


Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas.
Recent studies have shown that there is a considerable heterogeneity in the response of melanoma cell lines to MEK and BRAF inhibitors. In the current study, we address whether dysregulation of cyclin-dependent kinase 4 (CDK4) and/or cyclin D1 contribute to the BRAF inhibitor resistance of melanoma cells. Mutational screening identified a panel of melanoma cell lines that harbored both a BRAF V600E mutation and a CDK4 mutation: K22Q (1205Lu), R24C (WM39, WM46, and SK-Mel-28), and R24L (WM902B). Pharmacologic studies showed that the presence of a CDK4 mutation did not alter the sensitivity of these cell lines to the BRAF inhibitor. The only cell line with significant BRAF inhibitor resistance was found to harbor both a CDK4 mutation and a CCND1 amplification. Array comparative genomic hybridization analysis showed that CCND1 was amplified in 17% of BRAF V600E-mutated human metastatic melanoma samples, indicating the clinical relevance of this finding. As the levels of CCND1 amplification in cell lines are lower than those seen in clinical specimens, we overexpressed cyclin D1 alone and in the presence of CDK4 in a drug-sensitive melanoma line. Cyclin D1 overexpression alone increased resistance and this was enhanced when cyclin D1 and CDK4 were concurrently overexpressed. In conclusion, increased levels of cyclin D1, resulting from genomic amplification, may contribute to the BRAF inhibitor resistance of BRAF V600E-mutated melanomas, particularly when found in the context of a CDK4 mutation/overexpression.


[Changes in morphofunctional condition of the cochlear vascular stripe in response to the ototoxic antibiotic].
The experiments were made on guinea pigs injected i.m. kanamycin for 7 and 14 days in a dose 400 mg/kg. The cochleas of the guinea pigs were studied electron microscopically after 7- and 14-day courses of the antibiotic and 30 days after the end of aminoglycoside administration. To assess the vascular stripe (VS) function, the number of secretory vacuoles in apical cytoplasm of the marginal cells on the ultrathin sections was calculated. The animals which had got kanamycin for 7 days exhibited insignificant VS ultrastructural alterations, the number of vacuoles in the marginal cells (38.9 +/- 2.4) was higher than normal (33.9 +/- 1.5) but the difference was insignificant. After 14-day administration of the antibiotic VS of the animals had noticeable ultrastructural disorders of the interstitial and marginal cells and statistically significant (p < 0.01) suppression of secretory activity of the marginal cells (18.6 +/- 1.1). Natural reparative processes normalized ultrastructure of all types of VS cells 30 days after kanamycin discontinuation though secretion in the marginal cells remained significantly subnormal (the number of the vacuoles reduced to 23.4 +/- 1.7). Thus, aminoglycoside antibiotic kanamycin induces morphofunctional disorders in VS cells which do not return to normal after 30 days of follow-up.


Correlation between baseline immature platelets fraction levels and peak troponin in patients with acute myocardial infarction.
Elevated peak cardiac troponin levels have been linked with increased morbidity and mortality in patients with acute myocardial infarction (AMI). Immature Platelets are young and relatively large platelets that are hyper-reactive and pro-thrombotic compared to regular platelets. Increased immature platelet fraction (IPF) has been associated with an elevated risk of thrombotic events. We hypothesize that patients with higher IPF levels during AMI, will experience a more severe infarct, leading to elevated peak troponin levels. Clinical data from patients admitted to the cardiology division between 2018 and 2022, who were diagnosed with AMI and underwent an IPF testing. Univariate and multivariate regression analyses were performed to identify predictors of elevated peak troponin. Among the 277 patients diagnosed with AMI who underwent IPF testing, 113 had (STEMI) and 164 had (NSTEMI). The median value of IPF of 4.2% was used as the threshold for defining elevated IPF. Notably, among STEMI patients, those with IPF ≥ 4.2% had significantly higher peak troponin levels ( P = 0.021). Conversely, no significant difference in peak troponin levels was observed among NSTEMI patients ( P = 0.348). Multivariate analysis identified patients with STEMI in the higher IPF group as one of the significant predictors for elevated peak troponin levels. This study revealed a correlation between higher baseline IPF levels and increased peak troponin levels specifically in STEMI patients, while no such association was found in NSTEMI patients. Incorporating IPF levels above the median into risk stratification scores for STEMI patients may provide valuable support for adopting a more proactive therapeutic approach.


[EEG and deep stereotaxic EEG in the diagnosis of bitemporal epilepsy].
Bitemporal epilepsy is characterized by complex hierarchical relationships between the contralateral temporal foci. On the basis of the clinical and electrophysiological examination of 61 patients with the clinical form of the disease which is discussed, the authors singled out definite characteristics the comprehensive evaluation of which allowed three possible types of subordination of the bitemporal foci that was studied to be identified. The authors believe that the singled out variants in the interrelationships of the foci of epileptic activity are not the only specific features in the organization of the epileptic system in bitemporal epilepsy.


Cortical networks subserving the perception of tinnitus--a PET study.
Subjective tinnitus is an auditory phantom perception that may arise from any aberrant signal within the auditory system. Further processing of this signal and the conscious perception of tinnitus takes place in the cerebral cortex. A few functional brain-imaging studies have been performed to elucidate the underlying cerebral mechanisms of this perception. These studies mostly concern rare types of tinnitus (e.g. tinnitus changeable by oral-facial movements), or compared tinnitus patients with healthy volunteers. These studies attributed variable activation of the primary auditory cortices, associative auditory cortices and the left hippocampus to the perception of tinnitus. Based on these heterogeneous results, no consensus on the underlying mechanisms has been reached. The aim of the present study was to obtain further details of the central perception and processing of the tinnitus signal. Positron emission tomography (PET) was used to map the tinnitus-specific central activity. By contrasting PET-images of suppressed tinnitus with PET-images of the habitual tinnitus sensation, we were able to identify a right prefrontal-temporal network associated with the perception of tinnitus. Besides the evidence of activation of associative auditory sensory regions, the results indicated that activation of cortical centres subserving attention and emotion may underlie the continuous irritability associated with severe tinnitus.


Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival.
Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi-omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi-omic computational gene regulatory inference framework and human in vitro and mouse in vivo genetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.


Quantitative method for determination of amphetamine in plasma using negative ion chemical ionisation GC-MS of o-(pentafluorobenzyloxycarbonyl)-benzoyl derivatives.
The use of a novel electrophoric derivatisation reagent, o-(pentafluorobenzyloxycarbonyl)-benzoyl chloride is described for the quantitative determination of amphetamine in plasma. Amphetamine can be quantitatively measured down to 49 pg/mL plasma using only 250 μL of sample due to the extraordinary sensitivity of the derivatives under negative ion chemical ionisation mass spectrometry. Plasma samples were made alkaline with carbonate buffer and treated with n-hexane and reagent solution for 20 min, which, after concentration was measured by negative ion chemical ionisation gas chromatography-mass spectrometry. The method is rapid as extraction and derivatisation occur in one single step. [(2)H(5)]-Amphetamine was used as an internal standard. Validation data are given to demonstrate the usefulness of the assay, including specificity, linearity, accuracy and precision, benchtop stability, freeze-thaw stability, autosampler stability, aliquot analysis and prospective analytical batch size accuracy.


Perceptual anisotropies in visual processing and their relation to natural image statistics.
The amplitude spectra of natural scenes are typically biased in terms of the amount of content at the cardinal orientations relative to the oblique orientations. This anisotropic distribution has been related to the 'oblique effect' (the greater visual sensitivity for simple line/grating stimuli at cardinal compared to oblique orientations). However, we have recently shown that with complex visual stimuli possessing broadband spatial content (i.e. random phase noise patterns), sensitivity for detecting oriented manipulations of amplitude is best for oblique orientations, and worst for horizontal orientations (the 'horizontal effect'). Here we investigated this effect with respect to the phase spectra of natural scenes. Oriented manipulations of both amplitude and phase were made on a set of natural scene images that were dominated by naturally occurring structure at one of four orientations in order to determine whether the presence of predominant scene content, carried by the Fourier phase spectra, altered the ability to detect an oriented increment of amplitude. The horizontal effect was observed regardless of any scene's content bias. In addition, a content-dependent effect was observed which could be related to the presence of spatial structure conveyed by the phase spectra of this set of natural scenes. Results are evaluated in the context of a divisive normalization model.


Sorafenib and omacetaxine mepesuccinate as a safe and effective treatment for acute myeloid leukemia carrying internal tandem duplication of Fms-like tyrosine kinase 3.
Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combination treatment of sorafenib and omacetaxine mepesuccinate (SOME). Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course onward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS). Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms-like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3-ITD variant allelic frequency [VAF] ≤ 0.1% or a nucleophosmin 1 [NPM1] mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS. SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML.


The 1999 Stockholm Consensus Conference on quality specifications in laboratory medicine.
The setting of analytical quality specifications in laboratory medicine has been a topic of discussion and debate for over 50 years: 15 years ago, as the subject matured and a profusion of recommendations appeared, many of them from expert groups, it was realised by a number of leading professionals that there was a need for a global consensus on the setting of such specifications. The Stockholm Conference held in 1999 on "Strategies to set global analytical quality specifications in laboratory medicine" achieved this and advocated the ubiquitous application of a hierarchical structure of approaches. The hierarchy has five levels, namely: 1) evaluation of the effect of analytical performance on clinical outcomes in specific clinical settings; 2) evaluation of the effect of analytical performance on clinical decisions in general using a) data based on components of biological variation, or b) analysis of clinicians' opinions; 3) published professional recommendations from a) national and international expert bodies, or b) expert local groups or individuals; 4) performance goals set by a) regulatory bodies, or b) organisers of external quality assessment (EQA) schemes; and 5) goals based on the current state of the art as a) demonstrated by data from EQA or proficiency testing scheme, or b) found in current publications on methodology. This approach has been much used since its wide promulgation, but there have been ongoing criticisms and new developments. The time seems right for an objective reappraisal of recommended strategies to set analytical performance goals.


Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children.
A recent increase in children admitted with hypotensive shock and fever in the context of the COVID-19 outbreak requires an urgent characterization and assessment of the involvement of SARS-CoV-2 infection. This is a case series performed at 4 academic tertiary care centers in Paris of all the children admitted to the pediatric intensive care unit (PICU) with shock, fever and suspected SARS-CoV-2 infection between April 15th and April 27th, 2020. 20 critically ill children admitted for shock had an acute myocarditis (left ventricular ejection fraction, 35% (25-55); troponin, 269 ng/mL (31-4607)), and arterial hypotension with mainly vasoplegic clinical presentation. The first symptoms before PICU admission were intense abdominal pain and fever for 6 days (1-10). All children had highly elevated C-reactive protein (> 94 mg/L) and procalcitonin (> 1.6 ng/mL) without microbial cause. At least one feature of Kawasaki disease was found in all children (fever, n = 20, skin rash, n = 10; conjunctivitis, n = 6; cheilitis, n = 5; adenitis, n = 2), but none had the typical form. SARS-CoV-2 PCR and serology were positive for 10 and 15 children, respectively. One child had both negative SARS-CoV-2 PCR and serology, but had a typical SARS-CoV-2 chest tomography scan. All children but one needed an inotropic/vasoactive drug support (epinephrine, n = 12; milrinone, n = 10; dobutamine, n = 6, norepinephrine, n = 4) and 8 were intubated. All children received intravenous immunoglobulin (2 g per kilogram) with adjuvant corticosteroids (n = 2), IL 1 receptor antagonist (n = 1) or a monoclonal antibody against IL-6 receptor (n = 1). All children survived and were afebrile with a full left ventricular function recovery at PICU discharge. Acute myocarditis with intense systemic inflammation and atypical Kawasaki disease is an emerging severe pediatric disease following SARS-CoV-2 infection. Early recognition of this disease is needed and referral to an expert center is recommended. A delayed and inappropriate host immunological response is suspected. While underlying mechanisms remain unclear, further investigations are required to target an optimal treatment.


Molecular characterization of Streptococcus mutans strains isolated from the heart valve of an infective endocarditis patient.
Streptococcus mutans, known to be an aetiological agent of dental caries, is occasionally isolated from patients with infective endocarditis (IE). S. mutans strains with a defect in all three types of glucosyltransferase (GTF) obtained from an infected heart valve extirpated from an IE patient have been reported previously. In this study, molecular analyses of strains detected in heart valve (strain V1) and dental plaque (strain P1) samples taken from the same patient were performed. Complete nucleotide alignments of the gtfB, gtfC and gtfD regions in strains V1 and P1, as well as in the reference strain MT8148, were determined, which revealed the existence of alignments with a high similarity to erythromycin- and spectinomycin-resistance genes in the middle of the gtfB-gtfC and gtfD genes, respectively, of V1. Strain V1 also showed a higher MIC for these two antibiotics compared with strain P1. Next, primers to detect the specific sequences of the antibiotic-resistance genes in strain V1 were constructed and PCR amplification was performed with template DNA from dental plaque and infected valve tissue samples taken from the patient. Attenuated expression of GTFs in V1 caused a significantly lower susceptibility to phagocytosis by human polymorphonuclear leukocytes compared with the reference strain. These results suggest that the blood isolate V1 found in the oral cavity invaded and survived in the bloodstream for a long duration and that this was related to its virulence in IE in our patient.


"Helping Somebody Else Has Helped Me Too": Resilience in Rural Women With Disabilities With Experiences of Interpersonal Violence.
The concept of resilience, the ability to "bounce back," from adversity, can inform interpersonal violence interventions and victim assistance services. Unfortunately, though women with disabilities (WWD) experience high rates of all forms of violence and multiple layers of adversity, existing resilience research overlooks this populations' experiences, perspectives, and resilience strategies. The impairment, socially misperceived as a personal tragedy, precludes individuals with disabilities from being considered resilient; rather, they are designated almost universally as "at risk" or "vulnerable." This study aims to remedy this gap in understanding and scholarship. This qualitative study engaged 33 rural women with diverse disabilities who experienced violence to learn about how they cultivated resilience to support recovery and growth after experiencing abuse. Women described key personal qualities and supportive networks and services, such as internal drive, connectedness, dedication, healthy and helpful outlets, and an evolution of thoughts and behaviors. Counter to prevailing perceptions of WWD as dependent and helpless, women described how living with a disability honed strengths fundamental to their resilience. Women also described an "altruism born of suffering" wherein their experiences of violence contributed to a desire to give back and help others in difficult circumstances.Women's insights help to build a more comprehensive understanding of effective strategies and supports to bolster WWD's resilience. These findings inform interventions and promote approaches to build on women's strengths and resourcefulness.


Treated follicular lymphoma, recurrent invasive pneumococcal disease, nonresponsiveness to vaccination, and a unique pneumococcus.
A nonneutropenic patient with treated low-grade non-Hodgkin's (Follicular) lymphoma and secondary hypogammaglobulinemia recovered from pneumococcal pneumonia and septicemia (serotype 7F; ST191) subsequent to influenza A H1N1 (2009). Both infections were potentially vaccine preventable. The patient then developed pneumococcal meningitis due to a serotype 35F pneumococcus with a unique Multilocus Sequence Type (ST7004) which was not vaccine preventable. Patient management was influenced by host predisposition to pneumococcal infection, antibiotic intolerance, and poor response to polysaccharide pneumococcal vaccine. Indirect immunofluorescence with anti-human immunoglobulin confirmed a poor or intermediate response to Pneumovax II. Prophylactic erythromycin was initiated, and immunoglobulin transfusions were also commenced as a preventive strategy. ST7004 is a single locus variant of ST1635 which has been associated with the serotype 35F capsule in England. The spi gene in ST7004, which differentiates it from ST1635, is the same as the spi gene present in ST191 which could have arisen from the first disease episode suggesting that horizontal gene transfer may have occurred between different populations of pneumococci present within the patient in an attempt to evade vaccination selection pressure.


Intraoperative Computed Tomography Versus 3D C-Arm Imaging for Navigated Spinal Instrumentation.
A prospective case-series study and a retrospective analysis of historical patients for comparison of data. To compare accuracy and limitations of intraoperative computed tomography (iCT)- versus 3D C-arm-based spinal navigation for posterior pedicle screw implantation. Despite the higher accuracy of navigated compared to non-navigated pedicle screw implantation, it remains a matter of debate whether the use of iCT imaging may further benefit navigated spinal instrumentation compared to more commonly used isocentric 3D C-arm imaging. Between 2013 and 2016, 1527 pedicle screws were implanted in 260 patients with iCT (1219 screws) or 3D C-arm (308 screws)-based spinal navigation. Screw positioning was intraoperatively assessed by a second iCT or 3D C-arm (intraoperative accuracy). If necessary, immediate intraoperative screw revision was performed. Thereafter, a third iCT or 3D C-arm scan was performed to confirm repositioning (final accuracy). Clinical and patient data, intraoperative screw assessability, and accuracy rates were retrospectively reviewed and analyzed by an independent observer. Intraoperative CT permitted immediate intraoperative assessment of each implanted screw. In contrast, 39 of the screws visualized with 3D C-arm imaging were intraoperatively not clearly assessable. Regarding the overall precision, iCT and 3D C-arm navigation yielded a comparable intraoperative accuracy (iCT 94.7% vs 3D C-arm 89.4%) and immediate correction of misplaced screws was feasible with both modalities (final accuracy: iCT 95.4% vs 3D C-arm 91.6%). Regarding the region specific performance, however, iCT-based navigation yielded significantly higher final accuracy rates in the cervical (iCT 99.5% vs 3D C-arm 88.9%, P < 0.01) and thoracic (iCT 97.7% vs 3D C-arm 88.8%, P < 0.001) regions. Both iCT and 3D C-arm-based spinal navigation provides high pedicle screw accuracy rates. Immediate screw assessability and placement accuracy in the cervical-thoracic spine, however, appear to be limited with intraoperative 3D C-arm imaging alone. 3.


Metastasis and angiogenesis.
The relationship of angiogenesis, the growth of new blood vessels, to the process of tumour metastasis is examined. While the occurrence of angiogenesis generally is a necessary prerequisite for the formation of secondary tumours its presence is not a guarantee that cancer dissemination will occur. Novel approaches to antimetastatic therapy, using the newly formed vascular bed of tumours as the target, have produced successful results in experimental animals though such approaches have yet to be undertaken in the clinic.


South Asian ethnicity, socioeconomic status, and psychological mediators of faecal occult blood colorectal screening participation: A prospective test of a process model.
Although ethnicity and socioeconomic status (SES) correlate with health inequality, efforts to explain variance in health behavior attributable to these factors are limited by difficulties in population sampling. We used ethnicity identification software to test effects of psychological beliefs about screening as mediators of ethnicity and SES on faecal occult blood colorectal screening behavior in a no-cost health care context. Adults aged 50-67 years (N = 1,678), of whom 28% were from minority South Asian religiolinguistic ethnic groups (Hindu-Gujarati/Hindi, Muslim-Urdu and Sikh-Punjabi), participated in a prospective survey study. Subsequent screening participation was determined from medical records. Screening nonparticipation in the most deprived SES quintile was 1.6 times that of the least deprived quintile. Nonparticipation was 1.6 times higher in South Asians compared with non-Asians. A process model in which psychological variables mediated effects of ethnicity and SES on uptake was tested using structural equation modeling. Self-efficacy and perceived psychological costs of screening were, respectively, positive and negative direct predictors of uptake. Paths from Hindu, Muslim, and Sikh ethnicity, and SES on uptake were fully mediated by lower self-efficacy and higher perceived psychological costs. Paths from South Asian ethnicity to participation via self-efficacy and psychological costs were direct, and indirect via SES. SES is implicated, but does not fully account for low colorectal screening uptake among South Asians. Targeting increased self-efficacy and reduced perceived psychological costs may minimize health inequality effects. Future research should test independent effects of SES and ethnicity on lower self-efficacy and higher psychological costs. (PsycINFO Database Record


Training in Ultrasound for Resident Physicians in Gastroenterology: a survey and training project by the Spanish Association of Digestive Ultrasound (Asociación Española de Ecografía Digestiva - AEED).
the training program of the gastroenterology specialty that is mandatory for resident physicians, obliges them to be proficient in diagnostic and therapeutic digestive ultrasound tools. the Asociación Española de Ecografía Digestiva (AEED) performed a survey of the 93 Departments of Gastroenterology with training programs for resident physicians in gastroenterology, in order to assess the exact situation of training in digestive ultrasound in Spain. only 31 of the 93 (33%) Departments of Gastroenterology were able to provide training in Digestive Ultrasound. Moreover, 33% (48 out of 148) of the residents in gastroenterology did not receive specific training in digestive ultrasound. Whereas, 31% (46 out of 148) had received some specific training, but with ample room for improvement. These deficiencies were spread throughout the Spanish regions (Autonomous Communities) in an uneven manner, with almost half totally lacking gastroenterology departments that were capable of providing digestive ultrasound training. there is a significant deficit of gastroenterology departments capable of providing training in digestive ultrasound to residents, causing a significant training inequality. Until this situation can be reversed, the AEED has designed a training project in digestive ultrasound aimed at providing adequate training to all residents in gastroenterology as required.


Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas.
B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.


Lesions in the skin, intestine, and central nervous system induced by an antimetabolite of niacin.
Pellagra in the human is characterized by the clinical "three D's," namely, dermatitis, diarrhea, and dementia. Newborn mice that received a single intraperitoneal injection of 6-aminonicotinamide (6-AN) (50 mg/kg body weight), an antagonist of niacin, consistently developed lesions in the skin, intestinal tract, and central nervous system. Anterior horn cells in the spinal cord as well as motor neurons in the brain showed the ultrastructural features of neuronal chromatolysis, while glial and ependymal cells showed postinjection (PI) edematous changes on Day 5. In the skin, correlating with clinical delay of hair growth, the first discernible microscopic abnormality was vacuolar change in the hair follicles on PI Day 3. By PI Day 5, hyperkeratosis and irregular acanthosis were noted. Edematous swelling of the enteric glial cells was observed in the myenteric plexus of the descending colon on PI Day 5. Although the pathologic features of these 6-AN-treated mice may not be exactly identical to those of human pellagra, possible contributory mechanisms in the development of pellagra lesions may be elucidated by this experimental model.


Spectrophotometric assay, solubilization and purification of brain 2':3'-cyclic nucleotide 3'-phosphodiesterase.
1. A spectrophotometric assay of 2':3'-cyclic nucleotide 3'-phosphodiesterase (EC 22.214.171.124) based on the use of an acid-base indicator and a buffer having identical pKa values is described. The assay is simple and rapid; it was particularly convenient for monitoring the enzyme activity at various stages of purification. 2. Several proteinases were examined for their ability to solubilize 2':3'-cyclic nucleotide 3'-phosphodiesterase from delipidated brain white matter. Trypsin (EC 188.8.131.52) and elastase (EC 126.96.36.199) appeared to be more effective than the other proteinases examined. Trypsin, however, caused inactivation; elastase was therefore chosen to solubilize 2':3'-cyclic nucleotide 3'-phosphodiesterase. When a partially purified preparation of 2':3'-cyclic nucleotide 3'-phosphodiesterase was treated with elastase, 2':3'-cyclic nucleotide 3'-phosphodiesterase was solubilized nearly quantitatively. Elastatinal, a specific inhibitor of elastase, specifically inhibited the solubilization with elastase. 3. 2':3'-cyclic nucleotide 3'-phosphodiesterase was purified from bovine brain white matter by: (i) delipidation; (ii) solubilization with hexadecyltrimethylammonium bromide; (iii) gel chromatography on Sepharose; (iv) ethanol precipitation and resolubilization by digestion with elastase; (v) chromatography on DEAE-Sephadex; (vi) affinity chromatography on 8-(6-aminohexyl)amino-2'-AMP-Sepharose. 4. The purified enzyme migrated as a single protein band on polyacrylamide-gel electrophoresis at pH 4.3 and on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis; the estimated mol.wt. in the latter electrophoresis was 27000-31000. Gel filtration of the purified enzyme through Sephadex G-150 indicated a mol.wt. of 31000. Therefore the purified enzyme is a monomer protein with a mol.wt. of approx. 30000.


Quantitative Human Paleogenetics: What can Ancient DNA Tell us About Complex Trait Evolution?
Genetic association data from national biobanks and large-scale association studies have provided new prospects for understanding the genetic evolution of complex traits and diseases in humans. In turn, genomes from ancient human archaeological remains are now easier than ever to obtain, and provide a direct window into changes in frequencies of trait-associated alleles in the past. This has generated a new wave of studies aiming to analyse the genetic component of traits in historic and prehistoric times using ancient DNA, and to determine whether any such traits were subject to natural selection. In humans, however, issues about the portability and robustness of complex trait inference across different populations are particularly concerning when predictions are extended to individuals that died thousands of years ago, and for which little, if any, phenotypic validation is possible. In this review, we discuss the advantages of incorporating ancient genomes into studies of trait-associated variants, the need for models that can better accommodate ancient genomes into quantitative genetic frameworks, and the existing limits to inferences about complex trait evolution, particularly with respect to past populations.


Phenotypic analysis of Arabidopsis mutants: trypan blue stain for fungi, oomycetes, and dead plant cells.
INTRODUCTIONTrypan blue stains vasculature, dead plant cells, and fungal and oomycete hyphae. It is useful for assessing the extent of colonization of tissue, and for detecting microlesions present in certain lesion-mimic mutants. Trypan blue staining requires chloral hydrate for destaining, which is inconvenient, because it is a controlled substance. The chloral hydrate can be replaced with 1:2 lactophenol:ethanol, but the background staining will be higher than it is when chloral hydrate is used.


Synthesis of earthworm trace metal uptake and bioaccumulation data: Role of soil concentration, earthworm ecophysiology, and experimental design.
Trace metals can be essential for organo-metallic structures and oxidation-reduction in metabolic processes or may cause acute or chronic toxicity at elevated concentrations. The uptake of trace metals by earthworms can cause transfer from immobilized pools in the soil to predators within terrestrial food chains. We report a synthesis and evaluation of uptake and bioaccumulation empirical data across different metals, earthworm genera, ecophysiological groups, soil properties, and experimental conditions (metal source, uptake duration, soil extraction method). Peer-reviewed datasets were extracted from manuscripts published before June 2019. The 56 studies contained 3513 soil-earthworm trace metal concentration paired data sets across 11 trace metals (As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Sb, U, Zn). Across all field and laboratory experiments studied, the median concentrations of Hg, Pb, and Cd in earthworm tissues that were above concentrations known to be hazardous for consumption by small mammals and avian predators but not for Cu, Zn, Cr, Ni, and As. Power regressions show only Hg and Cd earthworm tissue concentrations were well-correlated with soil concentrations with R2 > 0.25. However, generalized linear mixed-effect models reveal that earthworm concentrations were significantly correlated with soil concentrations for log-transformed Hg, Cd, Cu, Zn, As, Sb (p < 0.05). Factors that significantly contributed to these relationships included earthworm genera, ecophysiological group, soil pH, and organic matter content. Moreover, spiking soils with metal salts, shortening the duration of exposure, and measuring exchangeable soil concentrations resulted in significantly higher trace metal uptake or greater bioaccumulation factors. Our results highlight that earthworms are able to consistently bioaccumulate toxic metals (Hg and Cd only) across field and laboratory conditions. However, future experiments should incorporate greater suites of trace metals, broader genera of earthworms, and more diverse laboratory and field settings to generate data to devise universal quantitative relationships between soil and earthworm tissue concentrations.


Utilization of age-adjusted shock index in a resource-strained setting.
Identification of injury severity and appropriate triage are critical to effective surgical care, especially where medical and surgical resources are strained. We hypothesized that pediatric age-adjusted shock index (SIPA) would outperform traditional shock index (SI) in a middle-income country (MIC) setting. Injured children hospitalized in two trauma centers (South Africa and the United States) from 2012 to 2017 were reviewed. Maximum heart rate and minimum systolic blood pressure defined SI. SI > 0.9 defined elevation. SIPA elevation was based on SI stratified by age: 1-6 years (SI > 1.22), 7-12 years (SI > 1.0), and 13-17 years (SI > 0.9). SI and SIPA were compared using univariate analyses and area under the receiver operating characteristic curves (AUROC). 1648 patients (741 MIC and 907 high-income country (HIC)) were evaluated with a median [IQR] age of 11 [6-15] years. SI was elevated in 377 (51%) MIC children, whereas SIPA was elevated in 248 (34%). In both the HIC and MIC, elevated SIPA was more associated with ISS ≥ 25, ICU admission, and mortality. In MIC patients specifically, elevated SIPA improved discrimination for in-hospital mortality (AUROC 0.66 vs AUROC 0.57, p < 0.01). In a multinational cohort including MIC patients, SIPA facilitated identification of injured children with altered physiology, reflecting greater injury severity and poorer outcomes. Use of SIPA has the potential for more effective resource utilization in MICs. Level III.


The redevelopment of heteropolar doublets and monster cells of Oxytricha fallax after cystment.
Heteropolar doublets of the hypotrichous ciliate Oxytricha fallax can encyst, as can monster cells containing multiple copies of at least part of the ciliature. The resulting cysts excyst as heteropolar doublets or monster cells, respectively. Transmission electron microscopy of resting cysts derived from monster cells and from singlets, however, indicates a complete loss of the ciliature - all kinetosomes, ciliary axonemes, and microtubules. Thus, the determination of each ciliature of a monster cell cannot be attributed to the persistence of any visible part of the ciliature. Transmission electron microscopy of monster and singlet cysts suggests that the information for a ciliature may be related to the system of cyst wall grooves and possibly to differentiations in the inner cell membrane which separates the cyst cytoplasm from the cyst wall. The redevelopment of heteropolar doublets upon excystment indicates that the anterior-posterior polarity is independently determined for each ciliature and is maintained through cystment. This polarity is not, however, reflected in a recognizable anterior-posterior polarity of any visible structure of the resting cyst. The number of adoral zones of membranelles (AZMs) may increase or decrease in some excysting monster cells compared with that observed in the encysting cells. Possible explanations for these changes are offered in the Discussion.


[Prevalence and factors associated with the consumption of fruit and vegetables by adolescents in public schools in Caruaru, Pernambuco state].
This is a cross-sectional school-based study that evaluated the prevalence and associated factors of the daily intake of fruit and vegetables by adolescents at public schools in Caruaru, Pernambuco. Poisson regression with a hierarchical model, including sociodemographic variables in the first hierarchical level, behavioral variables in the second and diet-related variables in the third was used to assess the factors associated with fruit and vegetable intake. The results showed that of the 600 adolescents interviewed, 10% reported never eating fruit and 30.7% mentioned not eating vegetables. Prevalence of fruit intake was 32.9% and vegetables 29.0%. Only 6.5% reported eating both kinds of food daily. Merely the daily vegetable intake showed a significant difference according to sex (higher among girls). Daily fruit intake was 63% higher among adolescents living in urban areas. Not consuming alcohol was associated with higher fruit intake, though not to vegetable intake. Daily intake of fruits and vegetables was 2.4 times higher among adolescents who consumed rice and beans daily. Daily fruit and vegetable intake among adolescents in Caruaru is below the recommendations, and was associated with gender, residence area, consumption of alcoholic beverages and consumption of rice and beans.


How plant architecture affects light absorption and photosynthesis in tomato: towards an ideotype for plant architecture using a functional-structural plant model.
Manipulation of plant structure can strongly affect light distribution in the canopy and photosynthesis. The aim of this paper is to find a plant ideotype for optimization of light absorption and canopy photosynthesis. Using a static functional structural plant model (FSPM), a range of different plant architectural characteristics was tested for two different seasons in order to find the optimal architecture with respect to light absorption and photosynthesis. Simulations were performed with an FSPM of a greenhouse-grown tomato crop. Sensitivity analyses were carried out for leaf elevation angle, leaf phyllotaxis, leaflet angle, leaf shape, leaflet arrangement and internode length. From the results of this analysis two possible ideotypes were proposed. Four different vertical light distributions were also tested, while light absorption cumulated over the whole canopy was kept the same. Photosynthesis was augmented by 6 % in winter and reduced by 7 % in summer, when light absorption in the top part of the canopy was increased by 25 %, while not changing light absorption of the canopy as a whole. The measured plant structure was already optimal with respect to leaf elevation angle, leaflet angle and leaflet arrangement for both light absorption and photosynthesis while phyllotaxis had no effect. Increasing the length : width ratio of leaves by 1·5 or increasing internode length from 7 cm to 12 cm led to an increase of 6-10 % for light absorption and photosynthesis. At high light intensities (summer) deeper penetration of light in the canopy improves crop photosynthesis, but not at low light intensities (winter). In particular, internode length and leaf shape affect the vertical distribution of light in the canopy. A new plant ideotype with more spacious canopy architecture due to long internodes and long and narrow leaves led to an increase in crop photosynthesis of up to 10 %.


Tissue response to chronically stimulated implanted epimysial and intramuscular electrodes.
Twenty-four epimysial and 16 intramuscular electrodes were implanted in five adult dogs for periods ranging from 11 to 50 months. Chronic stimulation was applied to half of the electrodes for eight weeks near the end of the implantation period. The tissue response was rated by the amount and appearance of the fibrous tissue and inflammatory cells seen in the capsule lining the region of the electrode. The encapsulation tissues were composed primarily of collagen and fibroblasts and some macrophages and few other inflammatory cells. The epimysial electrodes exhibited more variation between and within electrodes, but had more of the better scores than the intramuscular electrodes. No difference in the distribution of scores was measured between the control and stimulated groups for the epimysial electrodes. While the scores for the intra-muscular electrodes varied very little, variance was sufficient to indicate a trend for poorer ratings with the application of chronic stimulation. Fibrous capsules were generally thinner under the epimysial electrodes than around the intramuscular electrodes. For both electrode types, the thickness was not correlated with the application or level of chronic stimulation. Thickness was shown to be positively correlated to the degree of loss of the sutures used to anchor the epimysial electrodes.


STIMULATING EFFECT OF ANABAENA SP. (CYANOBACTERIA) EXUDATE ON PRYMNESIUM PARVUM (HAPTOPHYTA)(1).
Prymnesium parvum blooms have become more frequent in the south-central United States, leading to significant ecological and economic impacts. Allelopathic effects from cyanobacteria were suggested as a mechanism that might limit the development of P. parvum blooms. This research focused on the effects of cultured cyanobacteria, Anabaena sp., on P. parvum. Over a 6-d period, daily additions of filtrate from the senescent Anabaena culture were made to P. parvum cultures growing in log phase. All treatments, including several types of controls, showed reductions in P. parvum biomass over the course of the experiment, but the treatments receiving Anabaena filtrate were reduced to a lesser degree, suggesting that filtrate from the senescent cyanobacteria culture was beneficial to P. parvum in some way. This unexpected outcome may have resulted from stimulation of heterotrophic bacteria by the addition of Anabaena filtrate, which likely contained exudates rich in dissolved organic carbon compounds. P. parvum was then able to supplement its nutritional requirements for growth by feeding on the elevated bacteria population. These findings coupled to previous observations suggest that interactions between cyanobacteria and P. parvum in natural environments are complex, where both allelopathic and growth-stimulating interactions are possible.


Kinase/phosphatase regulation of CYP7A1.
Bile acid synthesis powerfully influences cholesterol homeostasis by providing an avenue for cholesterol disposal and by producing signaling molecules. Bile acids are multifaceted signals, regulating gene expression both by acting as a ligand for the nuclear hormone receptor, farnesoid X-receptor (FXR), and by activating cellular kinases. Though the exact identities and sequence of the signaling events are under investigation, there is mounting evidence for the involvement of c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) 1/2 pathway. The rate of bile acid synthesis is controlled by the activity of the enzyme, cholesterol 7alpha-hydroxylase, encoded on the CYP7A1 gene. Cholesterol 7alpha-hydroxylase activity and transcription of CYP7A1 gene promoter have been reported to be affected by protein kinases and phosphatases. Cellular protein kinases may provide the mechanisms for coordinate regulation of cholesterol transport, synthesis and breakdown to bile acids. Investigations into the interrelationships between various kinases/phosphatases and nuclear hormone receptors will clarify the roles that these pathways play in bile acid gene regulation and coordinate regulation of lipid metabolism, as well as in the connection of lipid metabolism with disease onset and progression of several human diseases.


Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811.
To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.


Principles and uses of HIV incidence estimation from recent infection testing--a review.
Since the 1990s, the development of laboratory-based methods has allowed to estimate incidence of human immunodeficiency virus (HIV) infections on single samples. The tests aim to differentiate recent from established HIV infection. Incidence estimates are obtained by using the relationship between prevalence, incidence and duration of recent infection. We describe the principle of the methods and typical uses of these tests to characterise recent infection and derive incidence. We discuss the challenges in interpreting estimates and we consider the implications for surveillance systems. Overall, these methods can add remarkable value to surveillance systems based on prevalence surveys as well as HIV case reporting.The assumptions that must be fulfilled to correctly interpret the estimates are mostly similar to those required in prevalence measurement. However, further research on the specific aspect of window period estimation is needed in order to generalise these methods in various population settings.