Impairments in analgesic, hypothermic, and glucoprivic stress responses following neonatal monosodium glutamate.
Neonatal administration of monosodium glutamate (MSG) produces in rats neurotoxic degeneration of the circumventricular system, including the medial-basal hypothalamus, depleting several neuropeptides and neurotransmitters in this area. In addition, a number of behavioral and neuroendocrine responses are impaired, including a significant decrease in the analgesic response to cold-water swims (CWS). The present study examined whether the alterations in the analgesic responses following CWS and 2-deoxy-D-glucose (2-DG) induced by neonatal MSG treatment were due either to direct alterations in a pain-inhibitory system, or alternatively, to alterations in a system that processes the stressful consequences or properties of a stimulus. To accomplish this, the analgesic, hypothermic, and locomotor responses following CWS and the analgesic, hyperphagic, and locomotor responses following 2-DG were assessed in rats treated neonatally (days 2, 4, 6, 8, and 10) with either MSG or a vehicle solution. MSG-treated rats displayed significant reductions in both their analgesic and hypothermic responses following CWS, suggesting that MSG treatment impairs an animal's ability to process sufficiently the stimulus properties of the swim as stressful. While MSG treatment potentiated 2-DG analgesia, it reduced 2-DG hyperphagia, suggesting that MSG treatment also impairs coping responses to glucoprivation. These data indicate the importance of the circumventricular system in the coding of stimuli as potential stressors and in the subsequent activation of requisite systems necessary to provide a sustained, coordinated, and synchronous coping response.


Front interaction induces excitable behavior.
Spatially extended systems can support local transient excitations in which just a part of the system is excited. The mechanisms reported so far are local excitability and excitation of a localized structure. Here we introduce an alternative mechanism based on the coexistence of two homogeneous stable states and spatial coupling. We show the existence of a threshold for perturbations of the homogeneous state. Subthreshold perturbations decay exponentially. Superthreshold perturbations induce the emergence of a long-lived structure formed by two back to back fronts that join the two homogeneous states. While in typical excitability the trajectory follows the remnants of a limit cycle, here reinjection is provided by front interaction, such that fronts slowly approach each other until eventually annihilating. This front-mediated mechanism shows that extended systems with no oscillatory regimes can display excitability.


Analyzing the mechanisms that facilitate the subtype-specific assembly of γ-aminobutyric acid type A receptors.
Impaired inhibitory signaling underlies the pathophysiology of many neuropsychiatric and neurodevelopmental disorders including autism spectrum disorders and epilepsy. Neuronal inhibition is regulated by synaptic and extrasynaptic γ-aminobutyric acid type A receptors (GABA A Rs), which mediate phasic and tonic inhibition, respectively. These two GABA A R subtypes differ in their function, ligand sensitivity, and physiological properties. Importantly, they contain different α subunit isoforms: synaptic GABA A Rs contain the α1-3 subunits whereas extrasynaptic GABA A Rs contain the α4-6 subunits. While the subunit composition is critical for the distinct roles of synaptic and extrasynaptic GABA A R subtypes in inhibition, the molecular mechanism of the subtype-specific assembly has not been elucidated. To address this issue, we purified endogenous α1- and α4-containing GABA A Rs from adult murine forebrains and examined their subunit composition and interacting proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quantitative analysis. We found that the α1 and α4 subunits form separate populations of GABA A Rs and interact with distinct sets of binding proteins. We also discovered that the β3 subunit, which co-purifies with both the α1 and α4 subunits, has different levels of phosphorylation on serines 408 and 409 (S408/9) between the two receptor subtypes. To understand the role S408/9 plays in the assembly of α1- and α4-containing GABA A Rs, we examined the effects of S408/9A (alanine) knock-in mutation on the subunit composition of the two receptor subtypes using LC-MS/MS and quantitative analysis. We discovered that the S408/9A mutation results in the formation of novel α1α4-containing GABA A Rs. Moreover, in S408/9A mutants, the plasma membrane expression of the α4 subunit is increased whereas its retention in the endoplasmic reticulum is reduced. These findings suggest that S408/9 play a critical role in determining the subtype-specific assembly of GABA A Rs, and thus the efficacy of neuronal inhibition.


Cyclophosphamide-loaded nanospheres: analysis of the matrix structure by thermal and spectroscopic methods.
This study reports on the preparation and evaluation of cyclophosphamide loaded-polyalkylcyanoacrylate nanospheres obtained by emulsion polymerization. Characterization by differential scanning calorimetry, infrared spectroscopy and X-ray diffraction can reveal state dispersion of the drug inside the nanospheres. Such information predicts the stability of the particles and the drug release behaviour. The study has indicated the prescence of a molecular dispersed system. The drug release behaviour was also studied.


Glucose-Responsive Microgel Comprising Conventional Insulin and Curcumin-Laden Nanoparticles: a Potential Combination for Diabetes Management.
Successful management of type 2 diabetes mellitus (T2DM), a complex and chronic disease, requires a combination of anti-hyperglycemic and anti-inflammatory agents. Here, we have conceptualized and tested an integrated "closed-loop mimic" in the form of a glucose-responsive microgel (GRM) based on chitosan, comprising conventional insulin (INS) and curcumin-laden nanoparticles (nCUR) as a potential strategy for effective management of the disease. In addition to mimicking the normal, on-demand INS secretion, such delivery systems display an uninterrupted release of nCUR to combat the inflammation, oxidative stress, lipid metabolic abnormality, and endothelial dysfunction components of T2DM. Additives such as gum arabic (GA) led to a fivefold increased INS loading capacity compared to GRM without GA. The GRMs showed excellent in vitro on-demand INS release, while a constant nCUR release is observed irrespective of glucose concentrations. Thus, this study demonstrates a promising drug delivery technology that can simultaneously, and at physiological/pathophysiological relevance, deliver two drugs of distinct physicochemical attributes in the same formulation.


Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery.
Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years. This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach. As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery.


Experimental and DFT studies: novel structural modifications greatly enhance the solvent sensitivity of live cell imaging dyes.
Structural modifications of previously reported merocyanine dyes (Toutchkine, A.; Kraynov, V.; Hahn, K. J. Am. Chem. Soc. 2003, 125, 4132-4145) were found to greatly enhance the solvent dependence of their absorbance and fluorescence emission maxima. Density functional theory (DFT) calculations have been performed to understand the differences in optical properties between the new and previously synthesized dyes. Absorption and emission energies were calculated for several new dyes using DFT vertical self-consistent reaction field (VSCRF) methods. Geometries of ground and excited states were optimized with a conductor-like screening model (COSMO) and self-consistent field (SCF) methods. The new dyes have enhanced zwitterionic character in the ground state and much lower polarity in the excited state, as shown by the DFT-VSCRF calculations. Consistently, the position of the absorption bands are strongly blue-shifted in more polar solvent (methanol compared to benzene), as predicted by the DFT spectral calculations. Inclusion of explicit H-bonding solvent molecules within the quantum model further enhances the predicted shifts and is consistent with the observed spectral broadening. Smaller but significant spectral shifts in polar versus nonpolar solvent are predicted and observed for emission bands. The new dyes show large fluorescence quantum yields in polar hydrogen-bonding solvents; qualitatively, the longest bonds along the conjugated chain at the excited S1 state minimum are shorter in the more polar solvent, inhibiting photoisomerization. The loss of photostability of the dyes is a consequence of the reaction with and electron transfer to singlet oxygen, starting oxidative dye cleavage. The calculated vertical ionization potentials of three dyes I-SO, AI-SO(4), and AI-BA(4) in benzene and methanol are consistent with their relative photobleaching rates; the charge distributions along the conjugated chains for the three dyes are similarly predictive of higher reaction rates for AI-SO(4) and AI-BA(4) than for I-SO. Time-dependent DFT calculations were also performed on AI-BA(4); these were less accurate than the VSCRF method in predicting the absorption energy shift from benzene to methanol.


Single-Cell Analysis of CX3CR1+ Cells Reveals a Pathogenic Role for BIRC5+ Myeloid Proliferating Cells Driven by Staphylococcus aureus Leukotoxins.
Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage-tracing cells derived from CX3CR1+ precursors in mice during infection and profiling by single-cell RNA sequencing, in this study, we identify a cluster of BIRC5+ myeloid cells that expanded in the liver during chronic infection with either the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus. In the absence of tissue-damaging toxins, S. aureus infection does not elicit these BIRC5+ cells. Moreover, deletion of BIRC5 from CX3CR1-expressing cells results in improved survival during S. aureus infection. Hence the combination of single-cell RNA sequencing and genetic fate-mapping CX3CR1+ cells revealed a toxin-dependent pathogenic role for BIRC5 in myeloid cells during S. aureus infection.


Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN.
Tumor macrophages are generally considered to be alternatively/M2 activated to induce secretion of pro-angiogenic factors such as VEGF and MMPs. EMMPRIN (CD147, basigin) is overexpressed in many tumor types, and has been shown to induce fibroblasts and endothelial cell expression of MMPs and VEGF. We first show that tumor cell interactions with macrophages resulted in increased expression of EMMPRIN and induction of MMP-9 and VEGF. Human A498 renal carcinoma or MCF-7 breast carcinoma cell lines were co-cultured with the U937 monocytic-like cell line in the presence of TNFα (1 ng/ml). Membranal EMMPRIN expression was increased in the co-cultures (by 3-4-folds, p < 0.01), as was the secretion of MMP-9 and VEGF (by 2-5-folds for both MMP-9 and VEGF, p < 0.01), relative to the single cultures with TNFα. Investigating the regulatory mechanisms, we show that EMMPRIN was post-translationally regulated by miR-146a, as no change was observed in the tumoral expression of EMMPRIN mRNA during co-culture, expression of miR-146a was increased and its neutralization by its antagomir inhibited EMMPRIN expression. The secretion of EMMPRIN was also enhanced (by 2-3-folds, p < 0.05, only in the A498 co-culture) via shedding off of the membranal protein by a serine protease that is yet to be identified, as demonstrated by the use of wide range protease inhibitors. Finally, soluble EMMPRIN enhanced monocytic secretion of MMP-9 and VEGF, as inhibition of its expression levels by neutralizing anti-EMMPRIN or siRNA in the tumor cells lead to subsequent decreased induction of these two pro-angiogenic proteins. These results reveal a mechanism whereby tumor cell-macrophage interactions promote angiogenesis via an EMMPRIN-mediated pathway.


Polarity effects on wound healing using electric stimulation in rabbits.
The aims of this study were to examine effects of high-voltage stimulation (HVS) on wound closure, tensile properties, and mitotic activity. Thirty-six rabbits were assigned to experimental (n = 18) or control groups. Each animal was anesthetized and a full-thickness incision, 3.5 cm long, was made on its back. After 24 hours, experimental rabbits received HVS for two hours, twice daily, for seven days. Polarity was negative the first three days and positive thereafter. Wound closure for HVS treated rabbits was 100%, which was significantly better than that of control rabbits (87%). Tensile strength values and mitotic activity for experimental and control rabbits were comparable. Histologic examination of the wounds suggested a more rapid rate of epithelialization in treated rabbits. Results suggest that electric stimulation, as given, augments wound closure.


In Vitro Skin Models for the Evaluation of Sunscreen-Based Skin Photoprotection: Molecular Methodologies and Opportunities.
Identifying and understanding the biological events that occur following ultraviolet (UV) exposure are mandatory to elucidate the biological and clinical consequences of sun exposure, and to provide efficient and adequate photoprotection strategies. The main UVinduced biological features (markers related to sunburn, cancer, photoaging immunosuppression, pigmentation), characterized in human skin in vivo, could be reproduced in adapted models of reconstructed skin in vitro, attesting their high relevance in the field of photobiology. In turn, 3D skin models were useful to discover precise biological pathways involved in UV response and were predictive of in vivo situation. Although they did not follow a strict validation process for the determination of protection factors, they enabled to evidence important concepts in photoprotection. Indeed, the use of reconstructed skin model highlighted the importance of broad spectrum sunscreen use to protect essential cellular functions, and biologically proved that SPF value was not predictive of the level of protection in the UVA wavelength domain. New biological approaches, such as transcriptomic or proteomic studies as well as quantitative and qualitative determination of DNA damage, will indisputably increase the added value of such systems for sunscreen efficiency evaluation.


Permeability studies with exogenous macromolecules: problems arising from the use of iodinated PVP and dextrans.
The permeability of the glomerular filtration barrier with respect to molecular size could best be studied by substances which are neither secreted nor reabsorbed and have a mean molecular weight of about 40,000--80,000 daltons. Uncharged molecules are preferred because the charge definitely influences the glomerular filtration. Several such substances are available; however, in most permeability studies labelled PVP, mainly 125I- or 131I-PVP, and dextrans have been applied. Gel filtration and binding studies with 125I-PVP have demonstrated that this substance should not be used because of unspecific binding of radioactive material. The application of dextran gives more reliable results. Disadvantages, however, include the large amounts which must be administered and some cases of intolerance, particularly in rats. Therefore, experiments with dextran seem feasible in some species but not in others. Ficoll, a synthetic polysucrose, is better tolerated than dextran but still causes allergic reactions in susceptible animals.


Preparation of highly exfoliated epoxy/clay nanocomposites by "slurry compounding": process and mechanisms.
Epoxy/clay nanocomposites with a high degree of exfoliation were achieved using a so-called "slurry-compounding" process with which the dispersed state of clay in water can be successfully transferred to an epoxy matrix. In this process sodium montmorillonite was first exfoliated and suspended in water. This suspension was further treated with acetone to form a clay-acetone slurry followed by chemical modification using silane. The modified slurry was then mixed extensively with epoxy to form epoxy/nanoclay composites. It has been shown that the morphologies of clay before and after curing are quite similar and the exfoliation process is termed "slurry compounding". Furthermore, the amount of organic modifier used is only 5 wt % of clay, in contrast to conventional organoclays which normally contain at least 25-45 wt % of organic surfactant. The resulting epoxy/nanoclay composites exhibit a high degree of clay exfoliation and a better thermal mechanical property.


[Analysis of clinical features of 3 201 cases of adult intertrochanteric fractures: a single center experience].
To analyze the gender, age, fracture classification and variation trend of adult intertrochanteric fractures treated in a single-center hospital in ten years. The data of adult (age ≥ 16 years) intertrochanteric fractures admitted to the Third Hospital of Hebei Medical University from January 2003 to December 2012 were collected retrospectively. All the fractures were acute and the pathological or periprosthetic fractures were excluded. The radiography of fracture were classified by same experienced orthopedic resident and verified by two orthopedic deans and one radiologist. The gender, age and fracture classification were analyzed and compared between January 2003 to December 2007 and January 2008 to December 2012. A total of 3 201 cases were collected. The adult intertrochanteric fractures accounted for 2.97% of all adult fractures and 43.76% of adult proximal femoral fractures. Of all fractures 64.98% were elderly ( ≥ 60 years) and 35.02% were middle-aged (16-59 years). In elderly, female were common (57.78%) while in middle-aged were male commonly (79.13%). According to Evans classification, instable fractures were more common (68.92%). According to AO classification, the most common type was A2 (49.67%) and the least was A3 (15.93%). Comparing between January 2003 to December 2012 and January 2008 to December 2012, the proportion of intertrochanteric fracture of adult fracture was decreased by 0.31% (χ² = 9.29, P = 0.002)and the proportion of intertrochanteric fracture of adult proximal femoral fractures was decreased by 3.15% (χ² = 7.35, P = 0.007). The proportion of elderly patients, female and stable fractures was increased by 14.35% (χ² = 71.98, P < 0.01), 4.04% (χ² = 8.16, P = 0.004) and 5.62% (χ² = 11.7, P = 0.001), respectively. The proportion of AO classification was not significantly verified (χ² = 3.24, P = 0.198). The intertrochanteric fractures are most common in elderly patients, A2-type of AO Classification and stable (Evans III, IV, V) in Evans classification. Compared with the previous five years, the proportions of female, elderly and stable (Evans I, II) fracture increase in last 5 years.


Valproic Acid Induced Thrombocytopenia and Dysmegakaryopoiesis in a Pediatric Patient.
Valproic acid (VPA) is an effective first-line anticonvulsant that is associated with several side effects including bone marrow suppression and subsequent cytopenia. However, VPA associated myelodysplasia is not a well described entity that can be seen in patients on VPA treatment. Herein, we describe a 9-year-old female patient with a past medical history of seizure disorder who presented with 3-week history of intermittent fevers, fatigue, weakness, and multiple unexplained bruises. Complete blood count (CBC) was remarkable for marked thrombocytopenia. Trephine biopsy showed a normocellular marrow with maturing trilineage hematopoiesis and scattered atypical megakaryocytes including numerous small hypolobated forms with frequent forms showing separated nuclei. Her CBC showed normalization 7 months after VPA was stopped. The presence of bone marrow suppression and myelodysplasia in patients on VPA treatment should be taken into consideration as it can cause a diagnostic pitfall especially in pediatric and elderly populations. A careful review of past medical history and medications can help make the correct diagnosis.


Membrane lipid composition affects plant heat sensing and modulates Ca(2+)-dependent heat shock response.
Understanding how plants sense and respond to heat stress is central to improve crop tolerance and productivity. Recent findings in Physcomitrella patens demonstrated that the controlled passage of calcium ions across the plasma membrane regulates the heat shock response (HSR). To investigate the effect of membrane lipid composition on the plant HSR, we acclimated P. patens to a slightly elevated yet physiological growth temperature and analysed the signature of calcium influx under a mild heat shock. Compared to tissues grown at 22°C, tissues grown at 32°C had significantly higher overall membrane lipid saturation level and, when submitted to a short heat shock at 35°C, displayed a noticeably reduced calcium influx and a consequent reduced heat shock gene expression. These results show that temperature differences, rather than the absolute temperature, determine the extent of the plant HSR and indicate that membrane lipid composition regulates the calcium-dependent heat-signaling pathway.


A computational pipeline for protein structure prediction and analysis at genome scale.
Experimental techniques alone cannot keep up with the production rate of protein sequences, while computational techniques for protein structure predictions have matured to such a level to provide reliable structural characterization of proteins at large scale. Integration of multiple computational tools for protein structure prediction can complement experimental techniques. We present an automated pipeline for protein structure prediction. The centerpiece of the pipeline is our threading-based protein structure prediction system PROSPECT. The pipeline consists of a dozen tools for identification of protein domains and signal peptide, protein triage to determine the protein type (membrane or globular), protein fold recognition, generation of atomic structural models, prediction result validation, etc. Different processing and prediction branches are determined automatically by a prediction pipeline manager based on identified characteristics of the protein. The pipeline has been implemented to run in a heterogeneous computational environment as a client/server system with a web interface. Genome-scale applications on Caenorhabditis elegans, Pyrococcus furiosus and three cyanobacterial genomes are presented. The pipeline is available at http://compbio.ornl.gov/proteinpipeline/


Creating a Culture for Interdisciplinary Collaborative Professional Practice.
The future of the health system is dependent on health professionals re-tooling the way we practice together. No longer can a multi-disciplinary model support the complex health needs of many clients nor can any one-health profession have all the knowledge needed to provide total patient-centred care. However, our current education and health systems are structured around a multidisciplinary model of practice with physicians or nurse practitioners as decision-makers and rarely are clients included in care planning. True interdisciplinary practice is defined as a partnership between a team of health professionals and a client in a participatory, collaborative and coordinated approach to shared decision-making around health issues, requires a revamping of how future health professionals are educated and how the system can accommodate shared decision-making. A client-centered collaborative professional practice model is proposed in this paper as a means for fostering and facilitating the culture for this change.


Multimetallic core/interlayer/shell nanostructures as advanced electrocatalysts.
The fine balance between activity and durability is crucial for the development of high performance electrocatalysts. The importance of atomic structure and compositional gradients is a guiding principle in exploiting the knowledge from well-defined materials in the design of novel class of core-shell electrocatalysts comprising Ni core, Au interlayer, and PtNi shell (Ni@Au@PtNi). This multimetallic system is found to have the optimal balance of activity and durability due to the synergy between the stabilizing effect of subsurface Au and modified electronic structure of surface Pt through interaction with subsurface Ni atoms. The electrocatalysts with Ni@Au@PtNi core-interlayer-shell structure exhibit high intrinsic and mass activities as well as superior durability for the oxygen reduction reaction with less than 10% activity loss after 10,000 potential cycles between 0.6 and 1.1 V vs the reversible hydrogen electrode.


[Local intravenous treatment of algodystrophy of the hand: buflomedil versus guanethidine, long term follow-up].
This report compares the results obtained after treatment of reflex sympathetic dystrophies (algodystrophies) of the hand by pharmacological segmental blocks with buflomedil (51 cases) versus guanethidine (30 cases). The results were similar for all the different stages of algodystrophies treated: 65% satisfactory to excellent results with buflomedil, versus 63% with guanethidine. The sooner the algodystrophy is treated after its onset, the better the results. On TPBS, when the technique is effective, both hemovelocity and blood pool return to normal, along with the improvement in the patient's condition. Early and delayed bone fixations evolve independently of the treatment. These techniques should always be associated with active, mild physiotherapy, and in some cases with dynamic splints in order to prevent the development of functional sequelae in the form or capsulo-aponeurotic retraction.


[Research on Wang Mengying's theory of nourishing - Yin and protecting - fluid].
As a famous physician of Zhejiang and Jiangsu in the late Qing dynasty, Wang Mengying was especially conversant with Wen Bing (Warm Disease). By reading Wang's works and his 16 - volume clinical case records now extant, it can be held that the clinical career of Wang was penetrated with the idea of nourishing - yin and protecting - fluid, which can be summarized into as. plain nourishing, reducing yang to nourish yin, activating Qi and distributing fluid, and protection prior to having been injured.


Abdominal aortic aneurysm presenting as meralgia paraesthetica.
A case of abdominal aortic aneurysm is reported in a patient with long standing low back pain, presenting as meralgia paraesthetica and an increase in the severity of back pain. The case highlights the need for objective assessment of new symptoms arising in a chronic condition, and for a systematic approach to the assessment of radiographs performed in the accident and emergency department.


Epithelioid Leiomyosarcoma of the Uterus: Modern Outcome-based Appraisal of Diagnostic Criteria in a Large Institutional Series.
Epithelioid leiomyosarcoma of the uterus is rare and poorly understood. Herein, we characterize a large institutional series of epithelioid leiomyosarcomas aiming to define outcome-determinant diagnostic pathologic features. We also retrieved epithelioid smooth muscle tumors of unknown malignant potential and evaluated a consecutive cohort of leiomyomas for epithelioid subtypes. Of a total of 1177 uterine leiomyosarcomas, 81 (7%) were categorized as epithelioid after review. Epithelioid leiomyosarcoma was strictly defined as having round to polygonal cells with visible pink cytoplasm and round to ovoid nuclei in ≥50% of the tumor volume. Average age was 55 years (range: 26 to 81 y). Median tumor size was 11 cm; tumor was >5 cm in 93% of subjects; 47% were stage 1 at presentation. An infiltrative tumor border was observed, grossly and/or microscopically, in 89% of cases; necrosis was noted in 80%, and vascular invasion in 47%. Mitotic count in 2.4 mm2 (totalling 10 high-power fields, each field 0.55 mm in diameter) ranged from 3 to 100 (median: 26). All cases had moderate, severe or highly pleomorphic atypia. All cases had 2 or 3 of the following: necrosis, at least moderate atypia and ≥4 mitoses in 2.4 mm2. Immunohistochemistry revealed frequent expression of smooth muscle markers including SMA (96%), desmin (95%), and caldesmon (81%). HMB45 and Melan-A were negative in 92% and 100% of cases, respectively. Estrogen and progesterone receptors were expressed by 65% and 54% of tumors, respectively. Follow-up information was available in 68 subjects (median: 23 mo, range: 1 to 254); cancer-related death occurred in 63%, and an additional 15% had recurrent or metastatic disease at last follow-up. Disease-specific survival was shorter in epithelioid leiomyosarcoma patients (median: 44 mo; 35% at 5-y) than in a matched cohort of nonepithelioid leiomyosarcoma (median: 55 mo; 46% at 5-y) (P=0.03). Three epithelioid smooth muscle tumors of unknown malignant potential were evaluated, all <5 cm in size and with atypia and/or irregular borders but mitotic count below the threshold for malignancy. Two of these had follow-up available, which was uneventful. Of 142 consecutive leiomyomas assessed, none had epithelioid morphology as defined. Epithelioid leiomyosarcoma is an aggressive neoplasm, sometimes with a remarkably low mitotic count. In the setting of an epithelioid smooth muscle tumor of the uterus, we postulate that the diagnosis of malignancy is made in the presence of ≥2 of the following: moderate or severe atypia, ≥4 mitoses/2.4 mm2 and tumor cell necrosis. In their absence, the finding of tumor size ≥5 cm, vascular invasion, infiltrative edges or atypical mitoses should be treated with caution, and designation as of at least uncertain malignant potential is warranted.


Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy.
The immunobiology of breast cancer (BC) subtypes, including luminal cancer, remains unclear. Cluster of differentiation (CD)8+ tumor-infiltrating lymphocytes (TIL) are essential components of tumor-specific cellular adaptive immunity. However, only few studies have addressed the significance of cluster of differentiation 8+(CD8+) TIL in patients with luminal BC. The present study aimed to evaluate the predictive and prognostic significance of CD8+ TIL in patients with luminal B/human epidermal growth factor receptor 2 (HER 2)-negative BC treated with anthracycline-based neoadjuvant chemotherapy (NC). A total of 31 patients who underwent breast-conserving surgery or mastectomy post-NC were enrolled. Immunostaining for CD8+ TIL was performed using rabbit monoclonal antibodies against human CD8+. Intra- and peritumoral CD8+ TIL expression levels were classified into high and low, based on the median value of each. CD8+ TIL expression data were demonstrated to be correlated with disease-free survival (DFS) and overall survival (OS), using Kaplan-Meier and Cox's proportional hazards regression tests. The results revealed that, among all clinicopathological characteristics, only pathological complete response (pCR) was significantly correlated with intratumoral CD8+ TIL expression (P=0.016). A total of 9/16 patients (56%) with high intratumoral CD8+ TIL expression achieved pCR, in contrast with 2 out of 15 patients (13.3%) with low expression (P=0.016). High expression of intratumoral CD8+ TIL was significantly associated with OS (log-rank test, P=0.023). Multivariate Cox regression analysis revealed that intratumoral expression of CD8+ TIL was an independent prognostic factor for OS [hazard ratio (HR)=2.82; 95% confidence interval (CI)=0.911-4.833, P=0.007], but not for DFS (HR=1.11; 95% CI=0.282-2.078; P=0.508). In conclusion, the results of the present study suggested that high intratumoral CD8+ TIL expression was significantly predictive of pCR post-NC, and represented an independent prognostic factor for improved OS. In contrast, low intratumoral CD8+ TIL expression was a strong predictor of lack of pCR to NC, as well as an independent prognostic factor for poor OS. Assessment of the immune response in conjunction with the usual parameters may aid in the further stratification of patients with luminal B/HER 2-negative BC regarding the prediction of pCR post-NC and overall prognosis.


A Study on the Diagnostic Elements of Cold-Heat Pattern Identification by Korean Medicine Doctors: Association with Objective and Subjective Body Temperature.
Although the Cold-Heat Pattern is the most important diagnostic factor in Traditional Korean Medicine (TKM), its relationship to body temperature and subjective temperature has not been clearly revealed. In this study, based on clinical data from 551 patients, we classified patients treated with herbal medicines into a Cold-prescription group (CG) and a Heat-prescription group (HG), and we compared the ordinary symptoms between the two groups. Subjective body temperature was higher in the HG than in the CG (OR = 1.68, p < 0.01) and digestive ability was better in the HG than in the CG (expert's questionnaire, OR = 1.91, p < 0.001). However, objectively measured body temperature did not show any significant difference between the HG and CG in both gender groups (p = 0.383 and 0.181 for males and females, resp.). Our study suggests that the subjective body temperature and digestive ability may be the principal diagnostic elements of Cold-Heat Pattern identification by Korean Medicine Doctors. These findings may contribute to the investigation of an objective method to measure the Cold-Heat Pattern.


Separation of allelic variants by two-dimensional electrophoresis.
The resolving power of two-dimensional (2-D) gel electrophoresis has been tested using 17 allele products at five loci. Standard O'Farrell gels could separate 13 of these isozymes. The addition of a second pH gradient made it possible to separate all but one of the variant proteins. These results indicate that 2-D gel electrophoresis can resolve more than 90% of variants originally detected by one-dimensional (1-D) electrophoresis. The implications of these results for the low estimates of average heterozygosity obtained in surveys using 2-D gel electrophoresis are discussed.


Text Messaging in Oncology: A Review of the Landscape.
Text messaging via short messaging service (SMS) is a common route of communication in the United States and offers many advantages to improve health care delivery compared with other forms of mHealth. Text messaging is easy to use, is convenient, is more likely to be viewed than e-mail, and can be tailored to an individual recipient's needs. Despite evidence that patients with cancer desire more mobile-based communication, there are few examples of successful text messaging interventions in the literature. This narrative review examines the current landscape of SMS-based interventions across the continuum of cancer care, including addressing behavioral change, attendance to screening and follow-up appointments, adherence to treatment, and assessment of symptoms and quality of life. Finally, we explore some of the barriers to implementation of a successful text messaging intervention.


The use of sound recording and oxygen saturation in screening snorers for obstructive sleep apnoea.
It is desirable to screen snoring patients for obstructive sleep apnoea (OSA) prior to surgical treatment. We postulated that the addition of a sound profile would increase the value of overnight oxygen saturation (SaO2) as a screening method. Thirty-nine polysomnographic studies including sound level measured by calibrated meter were performed on snorers being considered for uvulopalato-pharyngoplasty (UPPP). Polysomnography showed an apnoea/hypopnoea index (AHI) > or = 15 per hour of sleep in seven subjects. Two experienced observers independently, without knowledge of other data, classified paper records of SaO2 alone and SaO2 plus sound level obtained during polysomnography as OSA 'unlikely', 'equivocal' or 'definite'. The addition of sound to SaO2 reduced the number of equivocal results from 14 to six and increased the number classified as 'definite' or 'unlikely'. The sensitivity of oximetry +/- sound increased as the threshold AHI used in the definition of OSA increased; addition of sound improved recognition of mild OSA without impairing specificity.


Recent advances on liposomal nanoparticles: synthesis, characterization and biomedical applications.
Liposome is a new nanostructure for the encapsulation and delivery of bioactive agents. There are a lot of bioactive materials that could be incorporated into liposomes including cosmetics, food ingredients, and pharmaceuticals. Liposomes possess particular properties such as biocompatibility, biodegradability; accompanied by their nanosize they have potential applications in nanomedicine, cosmetics, and food industry. Nanoliposome technology offers thrilling chances for food technologists in fields including encapsulation and controlled release of food ingredients, also improved bioavailability and stability of sensitive materials. Amid numerous brilliant new drug and gene delivery systems, liposomes provide an advanced technology to carry active molecules to the specific site of action, and now days, various formulations are in clinical use. In this paper, we provide review of the main physicochemical properties of liposomes, current methods of the manufacturing and introduce some of their usage in food nanotechnology as carrier vehicles of nutrients, enzymes, and food antimicrobials and their applications as drug carriers and gene delivery agents in biomedicine.


[Coronary disease and hormonal treatment during the perimenopausal period].
Hormone replacement therapy (HRT) is widely recognized as probably most advisable treatment of perimenopausal women with cardiovascular disorders. Whenever HRT is administered for gynecological reasons, special attention should be paid to the presence of cardiological risk factors as these may be potentiated by high doses of gestogens. The authors undertake this problem inspired by a cases of a 53-years old patient (given oral lynestrol fair persisting uterine bleedings) who suffered from several complications, including venous thrombosis and myocardial infarction.


Molecular genetic, biochemical, and clinical implications of gonadotropin receptor mutations.
Human reproductive function is regulated mainly by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Mutations of the human LH/ chorionic gonadotropin receptor (LHR) and the FSH receptor (FSHR) leading to either constitutive activation or inactivation of the receptors have been identified. All activating mutations of the LHR and the FSHR are located within the exon encoding the transmembrane domain while the inactivating mutations are scattered throughout the coding sequence. A number of activating and inactivating mutations of the LHR have been found while only one activating and three inactivating mutations of the FSHR are known. Activating mutations of the LHR cause familial male-limited precocious puberty (FMPP) while that of the FSHR has been shown to restore the reproductive capability of a hypophysectomized male. Inactivating mutations of the LHR cause Leydig cell hypoplasia (LCH) in males while that of the FSHR causes hereditary hypergonadotropic ovarian dysgenesis (ODG) in females. Activating mutations of both receptors are dominant while inactivating mutations are recessive. Genotype-phenotype correlation is best established for the inactivating mutations of LHR. Severity of clinical phenotype in LCH correlates with the amount of residual activity of the mutated LHR. Comparison of the clinical impact of the activating and the inactivating mutations of the receptors indicates that male reproductive capacity depends primarily on LH while female reproductive capacity depends primarily on FSH.


PURIFICATION OF TYPE B STAPHYLOCOCCAL ENTEROTOXIN.
Frea, James I. (University of Wisconsin, Madison), Elizabeth McCoy, and F. M. Strong. Purification of type B staphylococcal enterotoxin. J. Bacteriol. 86:1308-1313. 1963.-A procedure for the production and isolation of type B staphylococcal enterotoxin in yields up to 4 mg per liter of toxic culture is presented. Staphylococcus aureus S6 was grown in shake flask cultures at 37 C for 24 hr in a medium consisting of 2% Hy-Case S.F., 0.3% yeast extract, calcium pantothenate, nicotinic acid, and thiamine. Cells were removed by centrifugation and the supernatant fluid was concentrated by dialysis against polyethylene glycol. Enterotoxin was isolated from the concentrate by ethanol precipitation, gel filtration on a G-100 Sephadex column, and Sephadex-column electrophoresis. The purified toxin was identical to type B reference enterotoxin on both disc electrophoresis and Ouchterlony gel diffusion. It contained no carbohydrates, lipids, or nucleic acids, gave positive tests for protein; and contained 11.6% N. The preparation showed no coagulase, alpha-hemolysin, or deoxyribonuclease activity. Emesis in monkeys resulted when the experimental toxin was injected at the rate of 0.26 mug of N per kg of body weight.


Restriction endonuclease patterns of some European and American isolates of avian infectious laryngotracheitis virus.
Eleven isolates of infectious laryngotracheitis virus (nine European and two American) were compared by restriction endonuclease analysis of their DNA after radiolabeling with 32P. Digestion with KpnI gave identical cleavage patterns for all the European isolates, but the two American viruses (one field and one vaccine) showed some differences from them and from each other. In the case of the American vaccine strain, however, these differences were only minor. After BamHI digestion, only the American field isolate appeared to be different, whereas with HindIII, all 11 isolates were identical.


[Intraarterial chemoembolization therapy for unresectable liver cancer using plachitin particles].
Plachitin formed of both poly-N-acetyl-D-glucosamine (chitin) and cis-diamminedichloroplatinum (CDDP), was used as an arterial chemoembolization therapy against unresectable liver cancer. One gram of Plachitin contained 300 mg of CDDP. The Plachitin particle was 50-100 microns in diameter. Plachitin particles (50-100 mg) were injected via hepatic artery once or twice every week, and the total amount of 300 mg was considered one course of this therapy. The size and number of tumors were measured by computer tomography (CT). Pharmacokinetics of this drug was also assessed by serum and urine platinum (Pt) concentration. Three patients underwent the chemoembolization therapy using plachitin particles. Case 1 had multiple hepatocellular carcinomas. The tumor regression rate was 39% after two courses of this therapy. Serum alpha-fetoprotein (AFP) level decreased from 1,182 ng/ml to 300 ng/ml. Case 2 suffered from bile duct cystadenocarcinoma. After three courses of the therapy, the tumor regression rate was 84.4%. Serum carbohydrate antigen 19-9 (CA19-9) decreased from 731 U/ml to 75 U/ml. Case 3 had synchronous multiple liver metastases from sigmoid colon cancer. The tumor regression rate was 77% after one course of the therapy. Carcinoembryonic antigen (CEA) and CA19-9 decreased from 406 ng/ml to 65 ng/ml and from 4,800 U/ml to 790 ng/ml, respectively. The response rate of the 3 cases was 66.7%. The peak levels of the serum Pt concentration of three patients were 0-0.4 microgram/g throughout the therapy, but peak urine Pt concentrations were observed during one course of the therapy of three patients ranging from 0.5 microgram/g to 3.2 micrograms/g, and decreased gradually for three weeks after the first course. Adverse effects of Plachitin particles for arterial chemoembolization were epigastralgia, nausea, fever, and elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. These adverse effects were observed in all patients, but were transient. Catheter obstruction occurred in one patient (case 2). Cholecystitis, pancreatic pseudocyst, and duodenal ulcer were noticed in case 3. No renal hypofunction was observed. Plachitin might be a useful agent for arterial chemoembolization therapy for primary and secondary liver cancer.


Cytomegalovirus polyradiculoneuropathy in acquired immune deficiency syndrome.
A 34-year-old homosexual man with acquired immune deficiency syndrome developed extraocular muscle deficits, chorioretinitis, and paraplegia without sensory symptoms. EMG showed severe diffuse denervation, but only mildly slowed nerve conduction velocities, in both legs. Meningitis persisted for 6 weeks and was exacerbated prior to the patient's death. Necropsy revealed subpial and subependymal cytomegalovirus (CMV) infection. Histology of ventral roots demonstrated proximal CMV infection and massive fiber loss. In this immunosuppressed patient, CMV caused a severe motor polyradiculopathy by selective destruction of the motor neurons of ventral spinal roots and motor cranial nerves.


Fault detection sensitivity enhancement based on high-order spatial mode trend filtering for few-mode fiber link.
In this paper, we propose and experimentally verify a method for optimizing the fault detection sensitivity of few mode fiber (FMF) link based on high-order spatial mode trend filtering. The employment of high-order mode trend filtering as a signal processing tool identifies meaningful level shifts from FMF optical time-domain reflectometer (FMF-OTDR) profile, which is associated with the problem of the minimization of the intrinsic random noise and modal crosstalk impact on the acquired data. A FMF link fault detection system is built, and the proposed method is utilized to detect the fault loss characteristics of 7.2 km 6-mode fiber with three fusion splice points with different fusion quality, and the detection results of each mode are compared with the results obtained by FMF-OTDR. The experimental results show that our proposed method can effectively improve the low fault detection sensitivity of high-order spatial mode caused by random noise and mode crosstalk.


Treatment of massive cardiac thrombi in a patient with protein C and protein S deficiency.
Myocarditis and dilated cardiomyopathy is characterized by dilatation of all four cardiac chambers and decreased systolic function of the heart, especially in the left ventricle. In this report we presented a patient with myocarditis or dilated cardiomyopathy and deficiency of protein C and protein S with biventricular multiple intracardiac thrombi. Standard heparin infusion and acetyl salicylic acid was begun. On the 10th day of hospitalization the right ventricular thrombus disappeared, and on the 24th day all thrombi in the left ventricle disappeared. During the treatment we did not observe any complication such as hemorrhagia or embolism. We think that patients with dilated cardiomyopathy or myocarditis should be evaluated for hemostatic disorders, and should be anticoagulated if any of these disorders are presented.


BSA-Seq and Transcriptomic Analysis Provide Candidate Genes Associated with Inflorescence Architecture and Kernel Orientation by Phytohormone Homeostasis in Maize.
The developmental plasticity of the maize inflorescence depends on meristems, which directly affect reproductive potential and yield. However, the molecular roles of upper floral meristem (UFM) and lower floral meristem (LFM) in inflorescence and kernel development have not been fully elucidated. In this study, we characterized the reversed kernel1 (rk1) novel mutant, which contains kernels with giant embryos but shows normal vegetative growth like the wild type (WT). Total RNA was extracted from the inflorescence at three stages for transcriptomic analysis. A total of 250.16-Gb clean reads were generated, and 26,248 unigenes were assembled and annotated. Gene ontology analyses of differentially expressed genes (DEGs) detected in the sexual organ formation stage revealed that cell differentiation, organ development, phytohormonal responses and carbohydrate metabolism were enriched. The DEGs associated with the regulation of phytohormone levels and signaling were mainly expressed, including auxin (IAA), jasmonic acid (JA), gibberellins (GA), and abscisic acid (ABA). The transcriptome, hormone evaluation and immunohistochemistry observation revealed that phytohormone homeostasis were affected in rk1. BSA-Seq and transcriptomic analysis also provide candidate genes to regulate UFM and LFM development. These results provide novel insights for understanding the regulatory mechanism of UFM and LFM development in maize and other plants.


Relation between stabilization and rigidification of the three-dimensional structure of an enzyme.
Purified cellobiase was coupled to periodate-oxidized dextran by reductive alkylation using sodium cyanoborohydride, sodium borohydride, and dimethylaminoborane for various reaction times. The thermal stability of the different conjugates obtained was studied and correlated to the number of links introduced between the enzyme and the soluble support. We observe that resistance to heat inactivation increases as a function of the number of modified lysines. Sodium cyanoborohydride was the most effective reducing agent. After 24 h reaction, the modification of 92% of the lysines gave a cellobiase-dextran conjugate that is a most stable enzyme. We conclude that the thermal stability observed for the chemically modified enzyme results from the rigidification of the three-dimensional structure of the protein. This rigidification increases with the number of links introduced between the enzyme and the polysaccharide. We also observe that chemical modification leads to a heterogeneous population of stabilized enzymes. Because of this heterogeneous population, it is necessary to develop a mathematical model of the kinetics of enzyme inactivation.


Coercion and Access to Health Care.
In this issue of the Hastings Center Report, Paul Christopher and colleagues describe a study of why prisoners choose to enroll in clinical research. The article represents an important methodological and policy contribution to the literature on prisoner participation in research and medical experimentation. Given the methodological and ethical debates to which this research seeks to make an empirical contribution, the careful manner in which the study was conducted and the transparency with which the authors describe the research is especially noteworthy. In sum, I respect the research steps the authors took. However, I disagree with their conclusions about both the absence of coercion for prisoner clinical research participants and the merits of applying risk-benefit models to govern prisoner research participation.


Small bowel obstruction due to mesenteric abscess caused by Mycobacterium avium complex in an HIV patient: a case report and literature review.
Small bowel obstruction in HIV patients is reportedly caused by inflammatory pseudotumor, Kaposi's sarcoma, cryptococcal lymphadenopathy and intestinal tuberculosis. The incidence of Mycobacterium avium complex (MAC) infection in HIV patients is 3% for CD4 cell count of 100-199 /mm3. MAC causing small bowel obstruction is rarely reported in the literature. We report a rare case of MAC causing mesenteric abscess with small bowel obstruction in a HIV patient with a CD4 cell count of 144 /mm3. Patient was a 35-year-old HIV-positive male on highly active antiretroviral therapy who presented with partial small bowel obstruction secondary to mesenteric abscess. He underwent operative intervention for drainage with cultures growing MAC.


Prevalence of latent tuberculosis infection and its risk factors in schoolchildren and adolescents in Shanghai, China.
As tuberculosis (TB) infection in childhood contributes to the pool of individuals with latent tuberculosis infection (LTBI) from which future tuberculosis cases arise, this study aimed to determine the prevalence and risk factors associated with LTBI in schoolchildren and adolescents from Shanghai, China. In this cross-sectional study, we administered T-SPOT.TB and TB infection risk factor questionnaire to children and adolescents aged between 10 and 18 years in 2010 in Shanghai. LTBI cases were defined by positive T-SPOT.TB test results and X-ray confirmation. A total of 1106 schoolchildren and adolescents were enrolled, of which 46.1% were male, and 91.8% were vaccinated with Bacille Calmette Guerin (BCG). Overall, 52 (4.7%) children had a positive T-SPOT.TB result, with significant increase in age distribution. However, none of the participants demonstrated TB-related abnormality on X-ray examination. Multivariate analysis showed that LTBI was associated with no BCG vaccination (odds ratio: 2.40; 95% confidence interval: 1.182-5.335) and a history of TB exposure (odds ratio: 6.89; 95% confidence interval: 3.095-15.35). For 46 children and adolescents with history of TB exposure, contact hours per week of TB cases were significantly associated with risk of LTBI. Prevalence of LTBI in schoolchildren and adolescents in Shanghai is relatively low compared with other high epidemic areas of TB. A higher risk of LTBI was observed among children with no BCG vaccination and those with a history of TB exposure, which suggests that the prevalence of LTBI among schoolchildren could be further reduced by strengthening BCG vaccination under the national immunization programme and enhancing contact investigation of active TB patients.


Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2.
Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-γ signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-γ production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.


[Hematopoietic stem cell transplantation in the era of new molecular-targeted therapies].
Recent advances in the field of molecular-targeted therapy have revolutionized the treatment of hematological malignancies. Consequentially, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically changed. However, allo-HSCT remains vital in the treatment of hematological malignancies because cure is rarely achieved by targeted therapy only. In the new era of molecular-targeted treatment, its incorporation into allo-HSCT is key to achieving therapeutic success. In particular, the understanding of the immune impact of molecular-targeted therapy on graft-versus-host-disease and graft-versus-leukemia is essential to improve the outcome of allo-HSCT.


[Sinus histiocytosis with massive lymphadenopathy--a virus-associated disease?].
Clinical course and laboratory data of three patients with sinus histiocytosis and massive lymphadenopathy ( SHML ) are described. In 80% of the cases a massive and painless bilateral enlargement of the cervical lymphnodes is the presenting feature; 25% show extranodal involvement. The etiology of SHML is as yet unknown. In two patients with a high rubella antibody titer we were able to demonstrate rubella antigen in the involved lymphnodes thus supporting an infectious etiology of SHML . A virus isolation was not possible, so that the definite proof of a viral infection of SHML could not be demonstrated. As a rule therapy is not necessary. The exceptions are outlined. The prognosis is good.


Origin and mechanisms of non-disjunction in human autosomal trisomies.
Chromosomal aneuploidy is one of the major causes of pregnancy wastage. In this review we summarize the knowledge about the origin and mechanisms of non-disjunction in human autosomal trisomies 8, 13, 15, 16, 18, and 21, accumulated during the last decade by using DNA polymorphism analysis. Maternal meiosis I non-disjunction is the most important single class, but chromosome-specific patterns exist. For the acrocentric chromosomes 15 and 21, meiosis I errors predominate among the maternal errors, in contrast to trisomy 18 where meiosis II errors predominate. For trisomy 16, virtually all cases are due to maternal meiosis I non-disjunction. Postzygotic (mitotic) non-disjunction constitutes 5-15% of cases of trisomies 15, 18, and 21, whereas for trisomy 8 and trisomy 8 mosaicism the majority of cases are due to mitotic non-disjunction. For paternal non-disjunction of chromosomes 18 and 21, meiosis II or mitotic errors predominate. There is aberrant meiotic recombination associated with maternal meiotic non-disjunction in all trisomies studied in detail so far. Advanced maternal age remains the only well documented risk factor for maternal meiotic non-disjunction, but there is, however, still a surprising lack of understanding of the basic mechanism(s) behind the maternal age effect.


Surgical, radiologic, and histologic findings of the antrochoanal polyp.
Of 15 patients with primary unilateral antrochoanal polyps (ACPs), we noticed that all ACPs except one extended through the accessory ostium of the maxillary sinus projected posterior along the nasal cavity. We observed no structural changes in ostiomeatal area on a coronal computed tomography scan. We classified 15 patients with ACP into three stages according to the coronal computed tomography findings of (i) status of the accessory ostium of the maxillary sinus and (ii) level of extension to the nasopharynx. The extent of inflammation in the computed tomography and histologic aspects were also evaluated according to such stages. In three patients, ACPs did not extend to the nasopharynx (stage I). Among the other ACPs reaching the nasopharynx, complete occlusion of the opening (stage II) was noted in seven patients, and partial occlusion of the opening (stage III) was noted in five patients. The extent of ipsilateral, as well as bilateral, inflammation in the maxillary sinus in stages I and II was greater than that in stage III. More severe inflammatory cell infiltration was observed in stage II in histologic examination. We hypothesize that stage I may correspond to an early stage, stage II to full-blown disorder, and stage III to a regression stage. When the exit site of an ACP is the accessory ostium, this opening should be connected to the natural ostium of the maxillary sinus to prevent a possible recirculation phenomenon.


Echocardiographic measurements of aortic root diameter (ARD) in collegiate football Athletes at pre-participation evaluation.
Some remodelling of the aortic root may be expected to occur with exercise but can already vary due to different body sizes, compositions and genetic predispositions. Attributing the cause of borderline aortic root diameter (ARD) values to either physiological or pathological conditions in American college football athletes is difficult as there is very limited normal reference values in this population. Body surface area (BSA) specific norms are thought to be useful in other cardiac measurements of football athletes. A retrospective cohort review of pre-participation examination (PPE) transthoracic echocardiogram data from collegiate football athletes was performed. ARD was analysed by field position (linemen, n=137; non-linemen, n=238), race (black, n=216; white, n=158) and BSA for predictive value and associations. Values were compared with non-athlete norms, and collegiate football athlete-specific normal tables were created. Only 2.7% of football athletes had ARD measurements above normal non-athlete reference values and the mean athlete ARD values were lower than non-athlete values. No athletes had an aortic root >40 mm or were disqualified due to underlying cardiac pathology. Univariate analyses indicated linemen position and increasing BSA was associated with larger values for ARD. BSA outperformed race in predicting ARD. Normal tables were created for ARD stratified by BSA group classification (low, average and high BSA). Proposed clinical cut-offs for normal and abnormal values are reported for raw echocardiograph metrics and their BSA indexed scores. Non-athlete reference values for ARD appear applicable for defining upper limits of normal for most collegiate football athletes. BSA-specific normal values may be helpful in interpreting results for athletes that exceed non-athlete norms.


A Taxonomy for Psycho-Oncological Intervention Techniques in an Acute Care Hospital in Germany.
Due to the establishment of a nationwide certification system for cancer centers in Germany, the availability of psycho-oncological services for cancer patients has increased substantially. However, little is known about the specific intervention techniques that are applied during sessions in an acute care hospital, since a standardized taxonomy is lacking. With this study, we aimed at the investigation of psycho-oncological intervention techniques and the development of a comprehensive and structured taxonomy thereof. In a stepwise procedure, a team of psycho-oncologists generated a data pool of interventions and definitions that were tested in clinical practice during a pilot phase. After an adaptation of intervention techniques, interrater reliability (IRR) was attained by rating 10 previously recorded psycho-oncological sessions. A classification of interventions into superordinate categories was performed, supported by cluster analysis. Between April and June 2017, 980 psycho-oncological sessions took place. The experts agreed on a total number of 22 intervention techniques. An IRR of 89% for 2 independent psycho-oncological raters was reached. The 22 techniques were classified into 5 superordinate categories. We developed a comprehensive and structured taxonomy of psycho-oncological intervention techniques in an acute care hospital that provides a standardized basis for systematic research and applied care. We expect our work to be continuously subjected to further development: future research should evaluate and expand our taxonomy to other contexts and care settings.


Relative importance of demographic, socioeconomic and health factors on life expectancy in low- and lower-middle-income countries.
We attempted to identify the pathways by which demographic changes, socioeconomic inequalities, and availability of health factors influence life expectancy in low- and lower-middle-income countries. Data for 91 countries were obtained from United Nations agencies. The response variable was life expectancy, and the determinant factors were demographic events (total fertility rate and adolescent fertility rate), socioeconomic status (mean years of schooling and gross national income per capita), and health factors (physician density and human immunodeficiency virus [HIV] prevalence rate). Path analysis was used to determine the direct, indirect, and total effects of these factors on life expectancy. All determinant factors were significantly correlated with life expectancy. Mean years of schooling, total fertility rate, and HIV prevalence rate had significant direct and indirect effects on life expectancy. The total effect of higher physician density was to increase life expectancy. We identified several direct and indirect pathways that predict life expectancy. The findings suggest that policies should concentrate on improving reproductive decisions, increasing education, and reducing HIV transmission. In addition, special attention should be paid to the emerging need to increase life expectancy by increasing physician density.


Effects of Clove Oil as a Euthanasia Agent on Blood Collection Efficiency and Serum Cortisol Levels in Danio rerio.
Zebrafish are an important laboratory animal model for biomedical research and are increasingly being used for behavioral neuroscience. Tricaine methanesulfonate (MS222) is the standard agent used for euthanasia of zebrafish. However, recent studies of zebrafish behavior suggest that MS222 may be aversive, and clove oil might be a possible alternative. In this study, we compared the effects of MS222 or clove oil as a euthanasia agent in zebrafish on the volume of blood collected and on serum levels of cortisol. Greater amounts of serum could be collected and lower serum levels of cortisol were present in fish euthanized with clove oil compared with equipotent dose of MS222. Euthanasia with clove oil did not blunt the expected elevation of serum cortisol levels elicited by an acute premortem stress. According to our findings, clove oil is a fast-acting agent that minimizes the cortisol response to euthanasia in zebrafish and allows the collection of large volumes of blood postmortem. These results represent a significant refinement in euthanasia methods for zebrafish.


Selecting ions by size in a calcium channel: the ryanodine receptor case study.
Many calcium channels can distinguish between ions of the same charge but different size. For example, when cations are in direct competition with each other, the ryanodine receptor (RyR) calcium channel preferentially conducts smaller cations such as Li(+) and Na(+) over larger ones such as K(+) and Cs(+). Here, we analyze the physical basis for this preference using a previously established model of RyR permeation and selectivity. Like other calcium channels, RyR has four aspartate residues in its GGGIGDE selectivity filter. These aspartates have their terminal carboxyl group in the pore lumen, which take up much of the available space for permeating ions. We find that small ions are preferred by RyR because they can fit into this crowded environment more easily.


W-band circular TM11 mode converter for gyrotrons.
This work proposes a methodology to convert a rectangular TE10 mode to a circular TM11 mode using an H-plane power divider at W-band. The divider evenly splits the input signal into two parts with the same amplitude and phase. One of the waves then goes through a wider rectangular waveguide with a lower cutoff frequency. After propagating through a specific length, the two waves differ by 180°. The two out-of-phase waves can jointly synthesize the circular TM11 mode with high mode purity. This power divider is structurally simple and capable of high-power operation. The full-wave simulation shows that the metal's conductivity affects the transmission of two-mode converters joined back-to-back. The measured back-to-back transmission agrees with the simulation result except for minor quantitative differences. The measured 3-dB bandwidth is 2.8 GHz with a center frequency of 93.6 GHz, which warrants the success of the TM11 mode gyrotrons.


Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer.
To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer. One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy. After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities. Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.


Isolation, identification, and synthesis of two oxidative degradation products of olanzapine (LY170053) in solid oral formulations.
Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two impurities are degradation products resulting from oxidation of the thiophene ring of olanzapine. The impurities were isolated by preparative HPLC from a thermally stressed formulation, and characterized by UV, IR, MS, and NMR. A synthetic preparation of compounds 1 and 2 by reaction of olanzapine with the singlet oxygen mimic 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is presented. The structure of 2 was also determined by single-crystal X-ray diffraction analysis. A degradation pathway for the formation of 1 and 2 is proposed.


Nucleotide and thioredoxin specificity of the manganese ribonucleotide reductase from Brevibacterium ammoniagenes.
The manganese-containing ribonucleotide reductase previously identified in gram-positive bacteria has been purified and its nucleotide specificity and other requirements were determined. The enzyme isolated from Brevibacterium ammoniagenes is a ribonucleoside-diphosphate reductase which, in the presence of allosteric effectors, reduces all four common substrates at comparable rates; very little activity is observed in the absence of effector nucleotides. Ribonucleoside triphosphates are reduced at 20% the rate of the diphosphates. Cytidine and uridine nucleotide reduction is specifically stimulated by ATP and dATP, adenylate reduction by dGTP, and guanosine nucleotide reduction by dTTP. Unlike the iron-containing ribonucleotide reductase systems, high concentrations of dATP do not inhibit substrate reduction. The new bacterial enzyme tolerates high salt concentrations (up to 250 mM ionic strength) and does not require divalent metal ions for activity in vitro. The presence of thioredoxin has been demonstrated in heat- and acid-treated protein extracts of B. ammoniagenes and the protein was purified to homogeneity. It is very similar to the thioredoxins isolated from other organisms in relative molecular mass (12,000), isoelectric point (4.3) and enzyme-activating properties. In the presence of 0.3 mM dithiothreitol, the bacterial thioredoxin can serve as hydrogen donor for B. ammoniagenes ribonucleotide reductase in vitro, indicating the presence of a functional ribonucleotide reductase-thioredoxin system in these bacteria. The properties described in this and in our preceding paper in this journal [Eur. J. Biochem. 170, 603-611 (1988)] suggest that the B. ammoniagenes ribonucleotide reductase is intermediate in structure and specificity between the deoxyadenosylcobalamin-dependent and the iron-containing enzyme classes and that it is adapted to the specific requirements of deoxyribonucleotide synthesis in this organism.


Fire drives functional thresholds on the savanna-forest transition.
In tropical landscapes, vegetation patches with contrasting tree densities are distributed as mosaics. However, the locations of patches and densities of trees within them cannot be predicted by climate models alone. It has been proposed that plant-fire feedbacks drive functional thresholds at a landscape scale, thereby maintaining open (savanna) and closed (forest) communities as two distinct stable states. However, there is little rigorous field evidence for this threshold model. Here we aim to provide support for such a model from a field perspective and to analyze the functional and phylogenetic consequences of fire in a Brazilian savanna landscape (Cerrado). We hypothesize that, in tropical landscapes, savanna and forest are two stable states maintained by plant-fire feedbacks. If so, their functional and diversity attributes should change abruptly along a community closure gradient. We set 98 plots along a gradient from open savanna to closed forest in the Brazilian Cerrado and tested for a threshold pattern in nine functional traits, five soil features, and seven diversity indicators. We then tested whether the threshold pattern was associated with different fire regimes. Most community attributes presented a threshold pattern on the savanna-forest transition with coinciding breakpoints. The thresholds separated two community states: (1) open environments with low-diversity communities growing in poor soils and dominated by plants that are highly resistant to high-intensity fires; and (2) closed environments with highly diverse plant communities growing in more fertile soils and dominated by shade-tolerant species that efficiently prevent light from reaching the understory. In addition, each state was associated with contrasting fire regimes. Our results are consistent with the hypothesis that forests and savannas are two coexisting stable states with contrasting patterns of function and diversity that are regulated by fire-plant feedbacks; our results also shed light on the mechanism driving each state. Overall, our results support the idea that fire plays an important role in regulating the distribution of savanna and forest biomes in tropical landscapes.


Trim36/Haprin plays a critical role in the arrangement of somites during Xenopus embryogenesis.
The TRIM family members contain a tripartite motif (TRIM), which includes RING, B-box, and coiled-coil domains, or collectively RBCC. They have been implicated in a variety of biological processes, such as the regulation of differentiation and development, and oncogenesis. In this study, we discovered a novel function of the TRIM family in early development. We report the expression of Trim36/Haprin during Xenopus laevis early embryogenesis and its involvement in somite formation. Temporal expression analysis indicated that Trim36/Haprin was present throughout embryogenesis. Spatial expression analysis showed that its expression was mainly confined to the nervous system and a portion of the posterior somite. Morpholino-mediated knockdown of Trim36/Haprin markedly and specifically inhibited the somite formation. We conclude that Trim36/Haprin plays an important role in the arrangement of somites during their formation.


Preparation and Performance of Regenerated Al2O3-Coated Cathode Material LiNi0.8Co0.15Al0.05O2 from Spent Power Lithium-Ion Batteries.
In this study, LiNi0.8Co0.15Al0.05O2@x%Al2O3-coated cathode materials were regeneratively compounded by the solid-phase sintering method, and their structural characterization and electrochemical performance were systematically analyzed. The regenerated ternary cathode material precursor synthesized by the co-precipitation method was roasted with lithium carbonate at a molar ratio of 1:1.1, and then completely mixed with different contents of aluminum hydroxide. The combined materials were then sintered at 800 °C for 15 h to obtain the regenerated coated cathode material, LiNi0.8Co0.15Al0.05O2@x%Al2O3. The thermogravimetry analysis, phase composition, morphological characteristics, and other tests show that when the added content of aluminum hydroxide is 3%, the regenerated cathode material, email@example.com%Al2O3, exhibits the highest-order layered structure with Al2O3 coating. This material can better inhibit the production of Ni2+, and improve material structure and electrochemical properties. The first charge-discharge efficiency of the battery assembled with this regenerated cathode material is 97.4%, a 50-cycle capacity retention is 93.4%, and a 100-cycle capacity retention is 87.6%. The first charge-discharge efficiency is far better than that of the uncoated regenerated battery.


Toward a global agenda for research in environmental epidemiology.
The global environment is in critical decline. Whether one's concern about environmental epidemiology stems from the perspectives of environmental health, climate change, ecological collapse, or growing inequity, clear problems exist. Natural capital resources are being depleted; disregard for the integrity of ecosystems is entrenched in current business practices. Indeed, despite increasing rhetoric to the contrary, the disregard displayed by those who hold power globally toward long-term sustainability and, thus, the health and well-being of future generations, could be described as wanton. Six years ago, the Millennium Development Goals were announced by the United Nations as a rallying point for action to achieve a sustainable future, particularly by reducing the gap between the "have mores" and "have nots." The attainment of these Goals is now endangered, as is, apparently, the spirit of optimism and idealism that inspired them at the Millennium Summit. We call for a reinvigoration of both concern about-and action on-sustainability. In particular, we appeal to those engaged in the field of environmental epidemiology (and other specialties with whom they engage) to consider how they might help by incorporating sustainability issues (including global ecological integrity and global environmental justice) into their own research programs. This incorporation would make a vital contribution to protect both present and future generations and to reduce resource and health gaps between North and South. Simply put, we propose that sustainability becomes integral to advancing the science of environmental epidemiology and related environmental disciplines.


Wolves-coyotes-foxes: a cascade among carnivores.
Due to the widespread eradication of large canids and felids, top predators in many terrestrial ecosystems are now medium-sized carnivores such as coyotes. Coyotes have been shown to increase songbird and rodent abundance and diversity by suppressing populations of small carnivores such as domestic cats and foxes. The restoration of gray wolves to many parts of North America, however, could alter this interaction chain. Here we use a 30-year time series of wolf, coyote, and fox relative abundance from the state of Minnesota, USA, to show that wolves suppress coyote populations, which in turn releases foxes from top-down control by coyotes. In contrast to mesopredator release theory, which has often considered the consequence of top predator removal in a three-species interaction chain (e.g., coyote-fox-prey), the presence of the top predator releases the smaller predator in a four-species interaction chain. Thus, heavy predation by abundant small predators might be more similar to the historical ecosystem before top-predator extirpation. The restructuring of predator communities due to the loss or restoration of top predators is likely to alter the size spectrum of heavily consumed prey with important implications for biodiversity and human health.


[Uveal melanoma: current insights into clinical relevance of genetic testing].
Uveal melanoma is the most common primary intraocular tumour in Caucasians. There are approximately 500 new cases of uveal melanoma in Germany per year and the incidence rate peaks at the age of 70 years. Half of all uveal melanoma patients develop metastatic disease, which can be observed even many years after successful treatment of the primary tumour. In most cases the liver is the location of first manifestation. Based on the chromosome 3 status uveal melanomas can be divided into two major classes that differ in their metastatic potential. Tumours with a high risk to metastasise usually show monosomy 3, whereas tumours showing disomy 3 rarely metastasise. If a patient wishes to know about his individual risk, prognostic testing of the primary tumour tissue can be performed after obtaining tumour material via transscleral or transretinal biopsy, or by enucleation. To date results of prognostic testing do not influence therapeutic strategies. Recently, major key genes involved in uveal melanoma development, GNAQ, GNA11, BAP1, SF3B1 and EIF1AX, have been identified. Mutation profiling, in addition to chromosomal 3 analysis, will further refine the classification or subclassification of uveal melanomas and will hopefully influence diagnostic or therapeutic concepts. Hereditary mutations in tumour suppressor gene BAP1 are associated with an increased risk for different tumour entities. Detection of germ line mutations in this tumour suppressor gene should implicate further general screening examinations of the patient to be able to detect these tumour entities. Moreover relatives of these patients should be offered a screening for BAP1 mutation.


The impact of community-acquired pneumonia on the health-related quality-of-life in elderly.
The sustained health-related quality-of-life of patients surviving community-acquired pneumonia has not been accurately quantified. The aim of the current study was to quantify differences in health-related quality-of-life of community-dwelling elderly with and without community-acquired pneumonia during a 12-month follow-up period. In a matched cohort study design, nested in a prospective randomized double-blind placebo-controlled trial on the efficacy of the 13-valent pneumococcal vaccine in community-dwelling persons of ≥65 years, health-related quality-of-life was assessed in 562 subjects hospitalized with suspected community-acquired pneumonia (i.e. diseased cohort) and 1145 unaffected persons (i.e. non-diseased cohort) matched to pneumonia cases on age, sex, and health status (EQ-5D-3L-index). Health-related quality-of-life was determined 1-2 weeks after hospital discharge/inclusion and 1, 6 and 12 months thereafter, using Euroqol EQ-5D-3L and Short Form-36 Health survey questionnaires. One-year quality-adjusted life years (QALY) were estimated for both diseased and non-diseased cohorts. Separate analyses were performed for pneumonia cases with and without radiologically confirmed community-acquired pneumonia. The one-year excess QALY loss attributed to community-acquired pneumonia was 0.13. Mortality in the post-discharge follow-up year was 8.4% in community-acquired pneumonia patients and 1.2% in non-diseased persons (p < 0.001). During follow-up health-related quality-of-life was persistently lower in community-acquired pneumonia patients, compared to non-diseased persons, but differences in health-related quality-of-life between radiologically confirmed and non-confirmed community-acquired pneumonia cases were not statistically significant. Community-acquired pneumonia was associated with a six-fold increased mortality and 16% lower quality-of-life in the post-discharge year among patients surviving hospitalization for community-acquired pneumonia, compared to non-diseased persons. ClinicalTrials.gov, NCT00812084 .


Triage of mechanical ventilation for pediatric patients during a pandemic.
The novel H1N1 influenza pandemic renewed the concern that during a severe pandemic illness, critical care and mechanical ventilation resources will be inadequate to meet the needs of patients. Several published protocols address the need to triage patients for access to ventilator resources. However, to our knowledge, none of these has addressed the pediatric populations. We used a systematic review of the pediatric critical care literature to evaluate pediatric critical care prognosis and multisystem organ failure scoring systems. We used multiple search engines, including MEDLINE and EMBASE, using a search for terms and key words including including multiple organ failure, multiple organ dysfunction, PELOD, PRISM III, pediatric risk of mortality score, pediatric logistic organ dysfunction, pediatric index of mortality pediatric multiple organ dysfunction score, "child+multiple organ failure + scoring system." Searches were conducted in the period January 2010-February 2010. Of the 69 papers reviewed, 22 were used. Five independently derived scoring systems were evaluated for use in a respiratory pandemic ventilator triage protocol. The Pediatric Logistic Organ Dysfunction (PELOD) scoring system was the most appropriate for use in such a triage protocol. We present a pediatric-specific ventilator triage protocol using the PELOD scoring system to complement the NY State adult triage protocol. Further evaluation of pediatric scoring systems is imperative to ensure appropriate triage of pediatric patients.


Markers of cognitive resilience and a framework for investigating clinical heterogeneity in ALS†.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Despite the unifying pathological hallmark of TDP-43 proteinopathy, ALS is clinically a highly heterogeneous disease, and little is known about the underlying mechanisms driving this phenotypic diversity. In a recent issue of The Journal of Pathology, Banerjee, Elliott et al use region-specific transcriptomic profiling in postmortem brains from a deeply phenotyped clinical cohort of ALS patients to detect molecular signatures differentiating cognitively affected and unaffected patients. They identified differential expression of specific genes, including upregulation of pro-inflammatory IL-6 in the cognitively affected group and anti-inflammatory IL-1 in the cognitively unaffected group. They then utilised BaseScope™ in situ hybridisation and immunohistochemistry to validate upregulation of NLRP3, an activator of the inflammasome, in the cognitively affected group, and upregulation of SIRT2, an inhibitor of NLRP3, in the cognitively unaffected group. In summary, Banerjee, Elliott et al demonstrate the usefulness of combining a well-curated clinical cohort with transcriptomic analysis of pathological samples to identify a perturbed pathway (e.g., the inflammasome), offering opportunities for novel therapeutic targets in ALS. © 2022 The Pathological Society of Great Britain and Ireland.


Influence of increased temperature on the inhibition of rat osteosarcoma cell multiplication "in vitro" by interferon.
Purified rat interferon preparations proved effective in inhibiting cell multiplication in a rat osteosarcoma cell line. A pronounced increase in the inhibitory activity was found with increasing temperature. At 39 degrees C 20 Interferon units/ml appeared to be cytotoxic whereas incubation of cells with 2,000 Interferon units/ml at 35 degrees C resulted in a cytostatic effect.


Control of bluetongue in Europe.
Since 1998, bluetongue virus (BTV) serotypes 1, 2, 4, 6, 8, 9, 11 and 16 have spread throughout Europe. In 2006, BTV serotype 8 (BTV-8) emerged unexpectedly in northern Europe throughout a region including Belgium, France, Germany, Luxembourg and the Netherlands. In the following year, it spread rapidly throughout the rest of Europe. In 2008, two more BTV serotypes were detected in northern Europe: BTV-6 in the Netherlands and Germany and BTV-11 in Belgium. The European incursion of BTV has caused considerable economic losses, comprising not only direct losses from mortality and reduced production but also indirect losses because of ensuing bans on trade of ruminants between BTV-infected and non-infected areas. Given the significance of the disease, all affected countries have established control and eradication measures, which have evolved with the availability of detection and prevention tools such as vaccines. Before 2005, BTV vaccination campaigns in affected countries used only modified live virus vaccines and only sheep were vaccinated, except in Italy, where all susceptible domestic ruminant species were included. After 2005, inactivated vaccines became available and cattle and goats were included in the vaccination campaigns. This review looks at how bluetongue disease has evolved in Europe and how effective vaccination strategies have been.


Correlations between pain in the back and neck/upper limb in the European Working Conditions Survey.
Recent research has suggested that wide international variation in the prevalence of disabling regional pain among working populations is driven largely by factors predisposing to musculoskeletal pain in general and not specific to individual anatomical sites. We sought to confirm this finding, using data from an independent source. Using data from the fifth (2010) and sixth (2015) European Working Conditions Surveys, we explored correlations between the one-year prevalence of pain in the back and neck/upper limb among people of working age across 33 European countries, and between changes in pain prevalence at the two anatomical sites from 2010 to 2015. Each survey recruited ≥1000 participants per country, response rates ranging from 11 to 78%. In 2010, the estimated one-year population prevalence of back pain ranged from 23% in Ireland to 66% in Portugal, and that of pain in the neck/upper limb from 25% in Ireland to 69% in Finland, the prevalence of pain at the two anatomical sites being correlated across the 33 countries (r = 0.42). A similar pattern was apparent in 2015. For back pain, the percentage change in prevalence from 2010 to 2015 varied from - 41.4% (Hungary) to + 29.6% (Ireland), with a mean across countries of - 3.0%. For neck/upper limb pain, the variation was from - 41.0% (Hungary) to + 44.1% (Romania), with an average of - 0.1%. There was a strong correlation across countries in the change in pain prevalence at the two anatomical sites (r = 0.85). Our findings accord with the hypothesis that international variation in common pain complaints is importantly driven by factors that predispose to musculoskeletal pain in general.


How subtle changes in 3D structure can create large changes in transcription.
Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD and preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than 2-fold, even though disruptions of TAD borders can change gene expression by 10-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between E-P contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of E-P biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression and suggest new experimental directions.


New nanocomposite materials reinforced with cellulose whiskers in atactic polypropylene: effect of surface and dispersion characteristics.
New nanocomposite films were prepared with atactic polypropylene as the matrix and either of three types of cellulose whiskers, with various surface and dispersion characteristics, as the reinforcing phase: aggregated without surface modification, aggregated and grafted with maleated polypropylene or individualized and finely dispersed with a surfactant. Films obtained by solvent casting from toluene were investigated by means of scanning electron microscopy, dynamic mechanical analysis, and tensile testing. In the linear region, the mechanical properties above the glass-rubber transition were found to be drastically enhanced for the nanocomposites as compared to the neat polypropylene matrix. These effects were ascribed to the formation of a rigid network with filler/filler interactions. In addition, interactions between the filler and the matrix as well as the dispersion quality were found to play a major role on the mechanical properties of the composites when investigation of the films was performed in the nonlinear region.


Systemic spironucleosis in 2 immunodeficient rhesus macaques (Macaca mulatta).
Spironucleus spp are parasites of fish and terrestrial vertebrates, including mice and turkeys, that rarely cause extraintestinal disease. Two rhesus macaques (Macaca mulatta) were experimentally inoculated with simian immunodeficiency virus mac251. Both progressed to simian acquired immune deficiency syndrome within 1 year of inoculation and developed systemic protozoal infections in addition to common opportunistic infections, including rhesus cytomegalovirus, rhesus lymphocryptovirus, and rhesus adenovirus. In the first case, the protozoa were associated with colitis, multifocal abdominal abscessation, and lymphadenitis. In the second case, they were one of a number of organisms associated with extensive pyogranulomatous pneumonia and colitis. Ultrastructural, molecular, and phylogenetic analysis revealed the causative organism to be a species of Spironucleus closely related to Spironucleus meleagridis of turkeys. This report is the first of extraintestinal infection with Spironucleus sp in higher mammals and expands the list of opportunistic infections found in immunocompromised rhesus macaques.


Genome Sequences of Three Phytopathogenic Species of the Magnaporthaceae Family of Fungi.
Magnaporthaceae is a family of ascomycetes that includes three fungi of great economic importance: Magnaporthe oryzae, Gaeumannomyces graminis var. tritici, and Magnaporthe poae. These three fungi cause widespread disease and loss in cereal and grass crops, including rice blast disease (M. oryzae), take-all disease in wheat and other grasses (G. graminis), and summer patch disease in turf grasses (M. poae). Here, we present the finished genome sequence for M. oryzae and draft sequences for M. poae and G. graminis var. tritici. We used multiple technologies to sequence and annotate the genomes of M. oryzae, M. poae, and G. graminis var. tritici. The M. oryzae genome is now finished to seven chromosomes whereas M. poae and G. graminis var. tritici are sequenced to 40.0× and 25.0× coverage respectively. Gene models were developed by the use of multiple computational techniques and further supported by RNAseq data. In addition, we performed preliminary analysis of genome architecture and repetitive element DNA.


Disease Activity in Inflammatory Bowel Disease Is Associated With Arterial Vascular Disease.
There is evidence that several inflammatory diseases are associated with increased cardiovascular risk. Whether this is true for inflammatory bowel diseases remains controversial. We aimed to assess this risk, corrected for the effects of conventional vascular risk factors and IBD disease activity. We conducted a cohort study in British general practice and hospital records from the Clinical Practice Research Datalink. We extracted the records of subjects with IBD and matched controls from 1997 to 2017. We conducted Cox proportional hazards and self-controlled case series analyses to examine the associations of IBD, disease activity, and hospitalization with the risk of myocardial infarction, stroke, and cardiovascular death in a manner attempting to remove the effect of likely confounders. We identified 31,175 IBD patients (16,779 UC, 10,721 Crohn's disease, and 3675 unclassifiable cases) and 154,412 matched controls. Five hundred thirty-two myocardial infarctions, 555 strokes, and 469 cardiovascular deaths were observed in IBD cases. Our Cox regression models, adjusted for potential confounders, showed no significant excess of vascular events for IBD patients overall. There was, however, an increased hazard of myocardial infarction in ambulatory patients for acute disease (hazard ratio, 1.83 [1.28-2.62]) and chronic activity (hazard ratio, 1.69 [1.24-2.30]). This effect of disease activity was confirmed in our case series analysis. Though we have found no evidence of an overall excess of vascular events in IBD patients, our findings of increased risk with more active disease suggest the potential for anti-inflammatory therapies to reduce cardiovascular risk in this patient group.