Breakdown of the round window membrane permeability barrier evoked by streptolysin O: possible etiologic role in development of sensorineural hearing loss in acute otitis media.
Sensorineural hearing loss is a common sequela of acute and chronic otitis media, and the round window membrane (RWM) is currently being considered as a major route for noxious agents to pass from the middle ear cavity to the cochlea. Streptococcus pneumoniae, a major causative agent of otitis media, and Streptococcus pyogenes A produce molecularly related toxins, pneumolysin and streptolysin O (SLO), that form large pores in target membranes. In this study, we analyzed the effects of SLO on the permeability of the RWM. Resected RWMs from a total of 104 guinea pigs were embedded between two chambers of an in vitro system. One chamber was designated as the tympanal (cis) compartment, and the other was designated as the inner ear (trans) compartment. The permeability of normal and SLO-damaged RWMs towards Na+, [14C]mannitol, and proteins was investigated. SLO evoked permeability defects dose dependently in the RWM with fluxes of both Na+ and [14C]mannitol being demonstrable over a time span of up to 8 h. Serum proteins and radioiodinated SLO were also shown to pass through the damage RWM. Scanning electron microscopy revealed the morphological correlates to these results. We propose that damage to the RWM by potent pore-forming cytolysins leads to leakage of ions from the perilymph. Ionic disequilibrium and passage of noxious macromolecules to the cochlea could contribute to disturbances of the inner ear function.


Evaluation of early post-transplant leukocyte recovery using the undiluted erythrocyte lysing technique.
The undiluted erythrocyte lysing technique was evaluated to see if it provides more accurate total leukocyte counts and differential leukocyte counts of severely leukopenic blood samples, in order to detect the onset of hematopoietic recovery after stem cell transplantation. Leukocyte counts using the conventional automated cell counting technique were found to be inaccurate, especially in blood samples with total leukocyte counts < 500/microl. In cases where the difference between results by the two methods was >100/microl, a positive correlation was found between the difference value and the blood reticulocyte count (r = 0.39, p = 0.002). Hematopoietic recovery after stem cell transplantation in a group of patients with chronic myelogenous leukemia (CML) was different from that of non-CML groups. In the CML group, the initial leukocyte counts were higher and the number of days until neutrophil recovery was higher than in the non-CML groups. Also, the day on which the absolute neutrophil count (ANC) exceeds 100/microl could serve as an indicator of neutrophil recovery. This study shows that the undiluted erythrocyte lysing technique can be used to count leukocytes accurately, especially in severely leukopenic samples. This new method can detect neutrophil recovery at ANC > 100/microl, as well as at an earlier date than the conventional method.


Regulation of Myogenic Differentiation by Topologically Microgrooved Surfaces for Skeletal Muscle Tissue Engineering.
Inspired by the natural topological structure of skeletal muscle tissue, the topological surface construction of bionic scaffolds for skeletal muscle repair has attracted great interest. Many previous studies have focused on the effects of the topological structure on myoblasts. However, these studies used only specific repeating sizes and shapes to achieve the myoblast alignment and myotube formation; moreover, the regulatory effects of the size of a topological structure on myogenic differentiation are often neglected, leading to a lack of guidance for the design of scaffolds for skeletal muscle tissue engineering. In this study, we fabricated a series of microgroove topographies with various widths and depths via a combination of soft lithography and melt-casting and studied their effects on the behaviors of skeletal muscle cells, especially myogenic differentiation, in detail. Microgrooved poly(lactic-co-glycolic acid) substrates were found to effectively regulate the proliferation, myogenic differentiation, and myotube formation of C2C12 cells, and the degree of myogenic differentiation was significantly dependent on signals in response to the size of the microgroove structure. Compared with their depth, the width of the microgroove structures can more strongly affect the myogenic differentiation of C2C12 cells, and the degree of myoblast differentiation was enhanced with increasing groove width. Microgroove structures with relatively large groove widths and small groove depths promoted the myogenic differentiation of C2C12 cells. In addition, the integrin-mediated focal adhesion kinase signaling pathway and MAPK signaling pathway were activated in cells in response to the external topological structure, and the size of the topological structure of the material surface effectively regulated the degree of the cellular response to the external topological structure. These results can guide the design of scaffolds for skeletal muscle tissue engineering and the construction of effective bionic scaffold surfaces for skeletal muscle regeneration.


The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links.
DNA interstrand cross-links (ICLs) are perhaps the most formidable lesion encountered by the cellular DNA repair machinery, and the elucidation of the process by which they are removed in eukaryotic cells has proved a daunting task. In particular, the early stages of adduct recognition and uncoupling of the cross-link have remained elusive principally because genetic studies have not been highly revealing. We have developed a biochemical assay in which processing of a DNA substrate containing a site-specific psoralen ICL can be monitored in vitro. Using this assay we have shown previously that the mismatch repair factor MutSbeta, the nucleotide excision repair heterodimer Ercc1-Xpf, and the replication proteins RPA and PCNA are involved in an early stage of psoralen ICL processing. Here, we report the identification of two additional factors required in the ICL repair process, a previously characterized pre-mRNA splicing complex composed of Pso4/Prp19, Cdc5L, Plrg1, and Spf27 (Pso4 complex), and WRN the protein deficient in Werner syndrome. Analysis of the WRN protein indicates that its DNA helicase function, but not its exonuclease activity, is required for ICL processing in vitro. In addition, we show that WRN and the Pso4 complex interact through a direct physical association between WRN and Cdc5L. A putative model for uncoupling of ICLs in mammalian cells is presented.


Multiscale core-periphery structure in a global liner shipping network.
Maritime transport accounts for a majority of trades in volume, of which 70% in value is carried by container ships that transit regular routes on fixed schedules in the ocean. In the present paper, we analyse a data set of global liner shipping as a network of ports. In particular, we construct the network of the ports as the one-mode projection of a bipartite network composed of ports and ship routes. Like other transportation networks, global liner shipping networks may have core-periphery structure, where a core and a periphery are groups of densely and sparsely interconnected nodes, respectively. Core-periphery structure may have practical implications for understanding the robustness, efficiency and uneven development of international transportation systems. We develop an algorithm to detect core-periphery pairs in a network, which allows one to find core and peripheral nodes on different scales and uses a configuration model that accounts for the fact that the network is obtained by the one-mode projection of a bipartite network. We also found that most ports are core (as opposed to peripheral) ports and that ports in some countries in Europe, America and Asia belong to a global core-periphery pair across different scales, whereas ports in other countries do not.


Nonequilibrium thermodynamics. II. Application to inhomogeneous systems.
We provide an extension of a recent approach to study nonequilibrium thermodynamics [Gujrati, Phys. Rev. E 81, 051130 (2010), to be denoted by I in this work] to inhomogeneous systems by considering the latter to be composed of quasi-independent subsystems. The system Σ along with the (macroscopically extremely large) medium Σ[over ̃] form an isolated system Σ0. The fields (temperature, pressure, etc.) of Σ and Σ[over ̃] differ unless at equilibrium. We show that the additivity of entropy requires quasi-independence of the subsystems, which results from the interaction energies between different subsystems being negligible so the energy also becomes additive. The thermodynamic potentials such as the Gibbs free energy that continuously decrease during approach to equilibrium are determined by the fields of the medium and exist no matter how far the subsystems are out of equilibrium, so their fields may not even exist. This and the requirement of quasi-independence make our approach differ from the conventional approach used by de Groot and others, as discussed in the text. We find it useful to introduce the time-dependent Gibbs statistical entropy for Σ0, from which we derive the Gibbs entropy of Σ; in equilibrium this entropy reduces to the equilibrium thermodynamic entropy. As the energy depends on the frame of reference, the thermodynamic potentials and the Gibbs fundamental relation, but not the entropy, depend on the frame of reference. The possibility of relative motion between subsystems described by their net linear and angular momenta gives rise to viscous dissipation. The concept of internal equilibrium introduced in I is developed further here and its important consequences are discussed for inhomogeneous systems. The concept of internal variables (various examples are given in the text) as variables that cannot be controlled by the observer for nonequilibrium evolution is also discussed. They are important because the concept of internal equilibrium in the presence of internal variables no longer holds if internal variables are not used. The Gibbs fundamental relation, thermodynamic potentials, and irreversible entropy generation are expressed in terms of observables and internal variables. We use these relations to eventually formulate the nonequilibrium thermodynamics of inhomogeneous systems. We also briefly discuss the case when bodies form an isolated system without any medium to obtain their irreversible contributions and show that this case does not differ from when bodies are in an extremely large medium.


Stratum corneum basic protein: an interfilamentous matrix protein of epidermal keratin.
The stratum corneum basic protein (SCBP) aggregates specifically with keratin filaments, forming macrofibrils in which the filaments are highly aligned. The appearance of the macrofibrils formed in vitro is similar to the keratin pattern in the intact stratum corneum, suggesting that SCBP is an interfilamentous matrix substance of epidermal keratin (Dale et all., Nature, 276: 729, 1978, see Ref. 13). Electron microscope and biochemical analyses were performed to determine the optimum molar ratio of SCBP and keratin filaments (average subunit molecular weight, 62,000). The optimum mixtures, in which all of the proteins were aggregated into macrofibrils, contained 1-2 moles of SCBP per 3 moles filament subunits. At ratios below this value, free filaments were observed by electron microscopy; above this value, excess SCBP was observed in the supernate by immunologic assay. The precursor of SCBP has been purified after extraction from keratohyalin granules in 1 M potassium phosphate. The precursor is immunologically similar to SCBP. Their amino acid compositions are essentially identical. However, in contrast to SCBP, the precursor is an insoluble, neutral protein which contains approximately 10 moles of phosphate per mole protein. This phosphate is covalently bound to the precursor and is not due to the presence of nucleic acid. During the conversion of a granular cell to a cornified cell, the precursor, present in keratohyalin granules, must be converted by proteolysis and/or dephosphorylation to active SCBP which aggregates with keratin filaments and forms the complex of filaments embedded in a matrix.


Outcomes of home visits for pregnant mothers and their infants: a cluster randomized controlled trial.
To evaluate the effect of home visits by community health workers (CHWs) on maternal and infant well being from pregnancy through the first 6 months of life for women living with HIV (WLH) and all neighborhood mothers. In a cluster randomized controlled trial in Cape Town townships, neighborhoods were randomized within matched pairs to either standard care, comprehensive healthcare at clinics (n=12 neighborhoods; n=169 WLH; n=594 total mothers); or Philani Intervention Program, home visits by CHWs in addition to standard care (PIP; n=12 neighborhoods; n=185 WLH; n=644 total mothers). Participants were assessed during pregnancy (2% refusal) and reassessed at 1 week (92%) and 6 months (88%) postbirth. We analyzed PIP's effect on 28 measures of maternal and infant well being among WLH and among all mothers using random effects regression models. For each group, PIP's overall effectiveness was evaluated using a binomial test for correlated outcomes. Significant overall benefits were found in PIP compared to standard care among WLH and among all participants. Secondarily, compared to standard care, PIP WLH were more likely to complete tasks to prevent vertical transmission, use one feeding method for 6 months, avoid birth-related medical complications, and have infants with healthy height-for-age measurements. Among all mothers, compared to standard care, PIP mothers were more likely to use condoms consistently, breastfeed exclusively for 6 months, and have infants with healthy height-for-age measurements. PIP is a model for countries facing significant reductions in HIV funding whose families face multiple health risks.


Influence of ascorbic acid on selenium nutrition in the chick.
Experiments were conducted to determine the nature of the effect of dietary ascorbic acid on selenium nutrition in the chick. Results showed that ascorbic acid resulted in increased activities of the selenium-containing enzyme glutathione peroxidase in plasma, accompanied by an apparent reduction in the dietary selenium requirement of the vitamin E-deficient chick. The ascorbic acid contents of plasma, liver, kidney and adrenals were not affected by selenium or vitamin E deficiencies, indicating that selenium-vitamin E deficient chicks are not rendered scrobutic. Absorption experiments using ligated duodenal loops or oral doses indicated that dietary ascorbic acid promoted the enteric absorption of selenium but did not affect the absorption of vitamin E. These results support the hypothesis previously reported that factors which inhibit the oxidation of dietary selenium promote its absorption and, perhaps, its post-absorptive utilization in metabolically active components of the cell.


Forming amorphous calcium carbonate within hydrogels by enzyme-induced mineralization in the presence of N-(phosphonomethyl)glycine.
Amorphous inorganic materials have a great potential in material science. Amorphous calcium carbonate (ACC) is a widely useable system, however, its stabilization often turns out to be difficult and the synthesis is mostly limited to precipitation in solution as nanoparticles. Stable ACC in bulk phases would create new composite materials. Previous work described the enzyme-induced mineralization of hydrogels with crystalline calcium carbonate by entrapping urease into a hydrogel and treating this with an aqueous mineralization solution containing urea und calcium chloride. Here, this method was modified using a variety of crystallization inhibitors attached to the hydrogel matrix or added to the surrounding mineralization solution. It was found that only N-(phosphonomethyl)glycine (PMGly) in solution completely inhibits the crystallization of ACC in the hydrogel matrix. The stability of the homogeneously precipitated ACC could be accounted to the combination of stabilizing effects of the additive and stabilization through confinement. The crystallization could be accelerated at higher temperatures up to 60 °C. Here, a combination of Mg ions and PMGly was required to stabilize ACC in the hydrogel. Variation of these two compounds can be used to control a number of different calcium carbonate morphologies within the hydrogel. While the ACC nanoparticles within the hydrogel are stable over weeks even in water, a calcite layer grows on the surface of the hydrogel, which might be used as self-hardening mechanism of a surface.


How Well Can Analytic Hierarchy Process be Used to Elicit Individual Preferences? Insights from a Survey in Patients Suffering from Age-Related Macular Degeneration.
In this study, we tested the feasibility of an interviewer-assisted analytic hierarchy process (AHP) in a special patient population with age-related macular degeneration (AMD). One aim was to generate preference weights regarding AMD treatment characteristics. A secondary aim was to explore the consistency of preference judgments and reasons for inconsistency. We generated quantitative importance weights for decision criteria using the matrix multiplication method. A qualitative study component in the form of asking patients to think aloud throughout their judgments was implemented to facilitate understanding of quantitative findings. Consistency ratios were calculated as a measure of logical judgment performance within AHP. If consistency ratios exceeded 0.2, we explored reasons for inconsistency. We interviewed 86 patients and generated preference weights for criteria. Patients rated the injection's effect on visual function the highest (0.44), followed by the frequency of monitoring visits (0.18), approval status (0.13), injection frequency (0.13), and side effects (0.12). Inconsistency in judgments was prevalent at the subcriteria level. Whereas much of the observed inconsistency was due to an excessive use of high/extreme value judgments, these judgments seemed to result from patients reasonably trying to highlight their strong preferences. Our study combines quantitative with qualitative data to explore patients' preference weights and decision processes using the AHP. It suggests that the type of inconsistency observed in judgments of AMD patients mostly results from rational decision making, not from error or lack of understanding. Further research should address which type and extent of inconsistency might be acceptable in different AHP settings.


[Analysis of anthocyanins in dietary supplements containing blueberry extract].
An extraction and analytical method was developed for determination of the content and profiles of anthocyanins in commercial dietary supplements containing blueberry extract. Dietary supplements were refluxed with hydrochloric acid-methanol solution, and spectrophotometric assay was performed to evaluate the total anthocyanidin content in extracted solutions as delphinidin, which is one of the anthocyanidins in blueberry extract. Twenty compounds (15 anthocyanins and 5 anthocyanidins) in extracted solutions were separated by HPLC analysis with gradient elution using formic acid and methanol-acetonitrile as the mobile phase, and each peak was confirmed by LC/MS analysis. The proposed method was applied to 25 kinds of commercial dietary supplements, and one supplement whose profile was different from that of the fresh bilberry extract was found.


The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast cancer.
Loss of the retinoblastoma protein tumor suppressor gene (RB) coding for a nuclear phosphoprotein that regulates the cell cycle is found in many human cancers and probably leads to disruption of the p16-cyclin D1-CDK4/6-RB pathway. Cyclin D1 is known to activate CDK4, which then phosphorylates the RB protein, leading to cell cycle progression. p16 inhibits CDK4, keeping RB hypophosphorylated and preventing cell cycle progression. The significance of these three markers, cyclin D1, CDK4 and p16, for breast cancer and carcinogenesis is nevertheless still controversial. The material consisted of 102 formalin-fixed human breast cancer samples, in which cyclin D1, CDK4 and p16 expression was evaluated immunohistochemically. The amounts of cyclin D1 mRNA present were analyzed by quantitative real time PCR. High cyclin D1 expression statistically significantly correlated with lower tumor grade, estrogen and progesterone receptor positivity and lower proliferation activity in breast tumors and increased breast cancer-specific survival and overall survival. Tumors with high cyclin D1 protein had 1.8 times higher expression of cyclin D1 mRNA. CDK4 expression did not correlate with cyclin D1 expression or the survival data. p16 expression was associated with Human Epidermal Growth Factor Receptor 2 (HER2) negativity and increased breast cancer-specific survival and disease-free survival. No statistical correlations between cyclin D1, CDK4 and p16 were found. Cyclin D1 was associated with a good breast cancer prognosis but functioned independently of CDK4. High cyclin D1 expression may be partially due to increased CCND1 transcription. p16 correlated with a better prognosis and may function without CDK4. In conclusion, it appears that cyclin D1, CDK4 and p16 function independently in human breast cancer.


Influence of submonolayer sodium adsorption on the photoemission of the Cu(111)/water ice surface.
Photoemission from an ice film deposited on Cu(111) as a function of thickness has been observed in the presence and absence of sodium atoms at the surface-vacuum interface. For either adsorbate alone and photon energies below 4 eV, two-photon photoemission from the Cu(111) substrate dominates. The Cu(111) photoelectron spectrum is perturbed by low coverages of Na, and its intensity is strongly attenuated by a few monolayers of ice. For a low density amorphous ice film, strong charging effects are observed. For ice films annealed to yield either the dense amorphous or crystalline phase, this effect is absent. Deposition of only 0.02 monolayer of Na leads to a dramatic decrease in the threshold for photoemission to 2.3+/-0.2 eV. Thus, photoelectrons are generated by visible radiation in a one-photon process with a cross section that exceeds 10(-18) cm(2). The initial state for the photoemission is identified as a metastable surface trapped electron, which decays thermally with an activation energy of 10+/-2 kJ mol(-1). Quantum calculations are described which support this model and show that the Na atom is accommodated in the first layer of the ice surface.


A Quantitative Genomic Approach for Analysis of Fitness and Stress Related Traits in a Drosophila melanogaster Model Population.
The ability of natural populations to withstand environmental stresses relies partly on their adaptive ability. In this study, we used a subset of the Drosophila Genetic Reference Panel, a population of inbred, genome-sequenced lines derived from a natural population of Drosophila melanogaster, to investigate whether this population harbors genetic variation for a set of stress resistance and life history traits. Using a genomic approach, we found substantial genetic variation for metabolic rate, heat stress resistance, expression of a major heat shock protein, and egg-to-adult viability investigated at a benign and a higher stressful temperature. This suggests that these traits will be able to evolve. In addition, we outline an approach to conduct pathway associations based on genomic linear models, which has potential to identify adaptive genes and pathways, and therefore can be a valuable tool in conservation genomics.


Treatment of Pseudomonas aeruginosa infection in critically ill patients.
Critically ill patients are on the increase in the present clinical setting. Aging of our population and increasingly aggressive medical and therapeutic interventions, including implanted foreign bodies, organ transplantation and advances in the chemotherapy of malignant diseases, have created a cohort of particularly vulnerable patients. Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. This organism is frequently feared because it causes severe hospital-acquired infections, especially in immunocompromised hosts, and is often antibiotic resistant, complicating the choice of therapy. The epidemiology, microbiology, mechanisms of resistance and currently available and future treatment options for the most relevant infections caused by P. aeruginosa are reviewed.


Developmental programming of the ovine placenta.
The pattern of intrauterine growth and size at birth, in particular, programmes the structure and function of tissues later in life in many species, which has important implications for the incidence of adult-onset generative diseases in human populations. In mammals, the main determinant of intrauterine growth is the placental supply of nutrients which, in turn, depends on the size, morphology, transport characteristics and endocrine function of the placenta. However, compared to somatic tissues, little is known about the developmental programming of the placenta. This review examines the epigenetic regulation of placental phenotype with particular emphasis on the nutrient transfer capacity of the ovine placenta and environmental factors shown to cause developmental programming of other tissues. Overall, the placenta is responsive to environmental factors and uses a number of different strategies to adapt its phenotype to help support fetal growth during adverse intrauterine conditions. It is, therefore, not just a passive conduit for nutrient transfer to the fetus but alters its nutrient supply capacity dynamically to optimise fetal nutrient acquisition. Thus, the placental epigenome provides both a memory of environmental conditions experienced during development and an index of the future well being of the offspring.


The early development of the hypoglossal nerve and occipital somites in staged human embryos.
Serial sections of 105 human embryos (including 20 silver preparations) from stage 11 (24 days) to stage 22 (54 days) were studied, and 23 graphic reconstructions were prepared. The hypoglossal nucleus is evident at stage 12 and becomes isolated from other efferent nuclei at stage 14. The first hypoglossal nerve fibers appear at stage 12. The roots unite at stage 14 and the main trunk arrives in the tongue at stage 15. Four occipital somites can be identified during stage 13, and the sclerotomic material forms two bilateral masses. The fourth sclerotome separates in stage 14 and develops like a vertebra. This and the remaining sclerotomic material form the basioccipital and exoccipital parts of the chondrocranium , which are the first to appear. Four occipital myotomes develop and grow towards the tongue as the "hypoglossal cord", which arrives prior to the hypoglossal nerve. The developmental similarity in the hypoglossal region between birds and mammals, combined with experimental studies in birds, renders it extremely likely that the hypoglossal musculature in mammals also is derived from occipital somites. The present study is the first in which this conclusion is adequately supported in the human. This investigation aids in the interpretation and timing of origin of variations (e.g., bipartite hypoglossal canal) and anomalies (e.g., persistent hypoglossal artery).


The Effect of Word Frequency on Phonemic Accuracy in Children With Cochlear Implants and Peers With Typical Levels of Hearing.
The frequency of occurrence of words and sounds has a pervasive influence on typically developing children's language acquisition. For instance, highly frequent words appear earliest in a child's lexicon, and highly frequent phonemes are produced more accurately. This study evaluates (a) whether word frequency influences word accuracy and (b) whether this is also the case for children with a history of auditory deprivation. More specifically, the influence of word frequency on phonemic accuracy is examined in deaf children with a cochlear implant (CI), and compared to age-matched children with typical hearing, between word onset and age 7. Results show that highly frequent words are produced more accurately, except for words in the highest frequency regions (i.e., predominantly closed-class words). This effect is more pronounced in children with typical hearing when compared with children with CI. Thus, children with CI are sensitive to word frequency, but to a lesser extent than peers with typical hearing.


Pain relief with epidural buprenorphine after spinal fusion: a comparison with intramuscular morphine.
In a prospective randomized trial, epidural buprenorphine was compared with intramuscular morphine for pain relief after spinal corrective surgery. Both forms of analgesia were given on demand and both produced excellent reduction of pain as assessed with visual linear analogue. The quality and duration of analgesia were similar for both groups of patients. Since the correct placement of epidural catheters could be done intraoperatively in difficult cases and since many patients for spinal corrective surgery have limited respiratory reserve, the authors feel that epidural buprenorphine provides an excellent alternative to conventional opiate analgesia after this type of surgery.


Demineralized dentin matrix scaffolds for alveolar bone engineering.
From the point of view of implant dentistry, this review discusses the development and clinical use of demineralized dentin matrix (DDM) scaffolds, produced from the patient's own extracted teeth, to repair alveolar bone defects. The structure and the organic and inorganic components of DDM are presented to emphasize the similarities with autogenous bone. Studies of DDM properties, such as osteoinductive and osteoconductive functions as well as efficacy and safety, which are mandatory for its use as a bone graft substitute, are also presented. The clinical applications of powder, block, and moldable DDM are discussed, along with future developments that can support growth factor and stem cell delivery.


Morphometric and DNA Image Analysis of Endometrial Hyperplasia and Carcinoma.
Endometrial hyperplasia is believed to increase the risk of endometrial carcinoma and represents a spectrum of morphologic and biological alterations of endometrial glands and stroma ranging from an exaggerated physiological state to carcinoma in situ. Considering the overlap between the various entities, it is not surprising that the morphologic assessment of endometrial lesions is particularly challenging. This work aimed to evaluate endometrial lesions according to their nuclear and glandular morphometric parameters, their D score, and their DNA ploidy, which help in making an accurate diagnosis. In this study, 50 endometrial biopsy specimens were stained with hematoxylin and eosin for their histopathologic and morphometric study and Feulgen stain for DNA analysis. The cases were classified into 20 cases of simple hyperplasia, 10 cases of atypical hyperplasia, and 20 cases of endometrial carcinoma. Morphometric analysis of nuclear, glandular, and stromal parameters was performed using the Leica Qwin 500 image analysis system. In the studied cases, a significant difference was found in the mean values of the morphometrical parameters of endometrial lesions, including the nuclear area and the nuclear roundness, and all glandular measurements including their complexity, area, volume percentage of stroma, and D score were significantly different. The DNA index and diploid and aneuploid values could differentiate significantly between endometrial lesions. We conclude that nuclear morphometric evaluation of the hyperplastic and carcinomatous endometrium may be used as an ancillary technique in the diagnosis of atypical changes occurring in precancerous endometrial lesions. In addition, DNA and D score assessment may be a reproducible and accurate predictor of the outcome of endometrial hyperplasia and may add some objective criteria for the correct diagnosis of difficult cases.


Treatment of hepatitis C virus infection with interferon and small molecule direct antivirals: viral kinetics and modeling.
Hepatitis C virus (HCV) infection remains a threat to global public health. Treatment with pegylated interferon (IFN) plus ribavirin leads to a sustained virologic response in about 50% of patients. New therapies using direct antiviral agents have the potential to cure patients unresponsive to IFN-based therapies. Mathematical modeling has played an important role in studying HCV kinetics. Using models, one can evaluate the effectiveness of new treatment agents, estimate important parameters that govern virus-host interactions, explore possible mechanisms of drug action against HCV, investigate the development of drug resistance, and study quasispecies dynamics during therapy. Here we review our current knowledge of HCV kinetics under IFN-based therapy and newly developed antiviral agents specifically targeted to attack HCV, and show how mathematical models have helped to improve our understanding of HCV infection and treatment.


Global Access to Radiotherapy Services: Have We Made Progress During the Past Decade?
The global incidence of cancer is rising, particularly in low- and middle-income countries. Radiotherapy is an important cancer treatment in the curative and palliative setting. We aimed to estimate the global demand for and supply of radiotherapy megavoltage machines (MVMs) and assess the changes in supply and demand during the past decade. Cancer incidences for 27 cancer types in 184 countries were extracted from the International Agency for Research on Cancer GLOBOCAN database. The Collaboration for Cancer Outcomes Research and Evaluation radiotherapy utilization rate (RTU) model was used to estimate the number of patients in each country with an indication for radiotherapy for each cancer type and estimate the demand for MVMs. The radiotherapy supply data were accessed from Directory of Radiotherapy Centres database maintained by the International Atomic Energy Agency. RTU varied by country, from 32% in Mongolia to 59% in Comoros. The average optimal world RTU was 50%, equating to 7 million people in 2012 who would benefit from radiotherapy. There remains a deficit of more than 7,000 machines worldwide. During the past decade, the gap between radiotherapy demand and supply has widened in low-income countries. RTU varies significantly between countries. Approximately half of all patients with cancer worldwide should receive radiotherapy; however, more than 2 million people are unable to access it because of a lack of MVMs. Low- and middle-income countries are particularly disadvantaged by this deficit.


Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease.
To study the efficacy of 15 Hz repetitive transcranial magnetic stimulation (rTMS) in treating depression in patients with Parkinson's disease. 42 patients were enrolled into two groups: group 1, active rTMS (15 Hz rTMS for 10 days) and placebo drug treatment; group 2, sham rTMS and fluoxetine 20 mg/day. A specially designed sham coil was used for sham stimulation. The unified Parkinson's disease rating scale (UPDRS), activities of daily living (ADL), Hamilton rating scale for depression (HRSD), Beck depression inventory (BDI), and mini-mental state examination (MMSE) were assessed by a rater blinded to treatment arm. HRSD and BDI were improved to the same extent in both groups after two weeks of treatment (38% and 32% for group 1, 41% and 33% for group 2, respectively). At week 8 there was a tendency for worse motor UPDRS scores in group 2 (NS). ADL showed improvement at week 8 only in group 1. MMSE improved in both groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2. rTMS has the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects.


Non-thermal plasma treatment of Radix aconiti wastewater generated by traditional Chinese medicine processing.
The wastewater effluent from Radix aconiti processing, an important step in the production processes of traditional Chinese medicine (TCM), is a type of toxic wastewater and difficult to treat. Plasma oxidation methods have emerged as feasible techniques for effective decomposition of toxic organic pollutants. This study examined the performance of a plasma reactor operated in a dielectric barrier discharge (DBD) to degrade the effluent from R. aconiti processing. The effects of treatment time, discharge voltage, initial pH value and the feeding gas for the reactor on the degradation of this TCM wastewater were investigated. A bacterium bioluminescence assay was adopted in this study to test the toxicity of the TCM wastewater after non-thermal plasma treatment. The degradation ratio of the main toxic component was 87.77% after 60min treatment with oxygen used as feed gas and it was 99.59% when the initial pH value was 8.0. High discharge voltage and alkaline solution environment were beneficial for improving the degradation ratio. The treatment process was found to be capable of reducing the toxicity of the wastewater to a low level or even render it non-toxic. These experimental results suggested that the DBD plasma method may be a competitive technology for primary decomposition of biologically undegradable toxic organic pollutants in TCM wastewater.


Cognitive function of older adults engaging in physical activity.
Physical activity can be classified as open-skilled or closed-skilled. Open-skilled physical activity, such as tennis, require participants to perform within a dynamic setting and respond to unpredictable and frequent environmental changes throughout the activity. Closed-skilled types of physical activity, such as swimming, are predictable and self-directed. However, the benefits of cognitive function in these two types of physical activities to older adults are unknown. This study examined the effects of participation in open- and closed-skilled physical activity on the cognitive function of older adults. The study recruited a total of 61 participants aged 65 years and over. Participant recruitment was achieved by distributing flyers asking for volunteers in various sports venues. Participants self-reported to be without medical conditions affecting their physical and cognitive function. All participants underwent a two-hour assessment session involving the completion of seven standardised cognitive function assessments, which were used to assess a range of cognitive function. Overall mean scores across all of the assessments showed superior performance for the open- or closed-skilled participants when compared with the no-physical-activity group. The results of 61 adults who participated in this study showed that closed-skilled physical activity was associated with better selective attention and visuospatial function while open-skilled physical activity was associated with better inhibition and cognitive flexibility function. No significant difference in self-regulation ability was found between the open- or closed-skilled groups. Open-skilled physical activity was associated with better inhibition, visual tracking, and cognitive flexibility while closed-skilled physical activity was associated with better selective attention and visuospatial perception. The findings have important practical implications for the health and quality of life of ageing populations, knowing which particular types of physical activity might affect the cognitive function.


Violent patients. Are you prepared to deal with them?
The medical community is becoming increasingly concerned about violent patients in healthcare settings. Healthcare professionals should be trained to deal with aggressive patients, and they should have access to a room free of dangerous objects for evaluation and examination. Having security personnel stand by may be appropriate in some cases. Verbal intervention is the key to dealing with violent patients. The safest and most effective pharmacologic intervention is use of benzodiazepines, either alone or in conjunction with antipsychotic agents when indicated. Seclusion or restraint may be needed for some violent patients; in such situations, close patient monitoring and explicit documentation are essential. Physicians can be held liable for injuries patients sustain while being restrained, so staff members should receive instruction in safe physical intervention techniques.


Osmolality of Commercially Available Oral Rehydration Solutions: Impact of Brand, Storage Time, and Temperature.
Oral rehydration solutions (ORS) are specifically formulated with an osmolality to optimize fluid absorption. However, it is unclear how many ORS products comply with current World Health Organization (WHO) osmolality guidelines and the osmotic shelf-life stability is not known. Therefore, the purpose of this investigation was to examine the within and between ORS product osmolality variation in both pre-mixed and reconstituted powders. Additionally, the osmotic stability was examined over time. The osmolality of five different pre-mixed solutions and six powdered ORS products were measured. Pre-mixed solutions were stored at room temperatures and elevated temperatures (31 °C) for two months to examine osmotic shelf stability. Results demonstrated that only one pre-mixed ORS product was in compliance with the current guidelines both before and after the prolonged storage. Five of the six powdered ORS products were in compliance with minimal inter-packet variation observed within the given formulations. This investigation demonstrates that many commercially available pre-mixed ORS products do not currently adhere to the WHO recommended osmolality guidelines. Additionally, due to the presence of particular sugars and possibly other ingredients, the shelf-life stability of osmolality for certain ORS products may be questioned. These findings should be carefully considered in the design of future ORS products.


Cross-cultural differences in user-centred research: An international living lab survey.
Digital health applications and interactive technologies increasingly allow organisations to transcend national boundaries and expand the provision of tools and services to communities across the world. Making the transfer beyond the context in which applications were originally conceptualized is challenging, as these have to be tailored towards local end-user needs and regulations. Such information is not always readily available, which risks successful uptake in novel settings. Living labs help to bridge this gap, by performing user experience research and supporting user-centred design for cross-border projects. Dissimilarities in recruitment and participation of end users could however influence study outcomes. Therefore, this study explores to what extent living labs are aware of potential cross-cultural differences. The sample consists of 36 living labs from 20 countries, most focusing on health and care, the silver economy and information technology. Regional differences are reported on participants' motivation and on the impact of gender, age, professional status and socio-economic status on participants' contribution. Awareness of potential differences during recruitment and grouping and supporting equal contribution in sessions could improve the quality of user-centred research in international contexts, while still maintaining sufficient standardisation. Further research with larger international samples is needed to replicate and extend these findings.


[An immunohistochemical study of the expression of the oncoprotein p53 in astrocytic gliomas of the cerebral hemispheres].
p53 oncoprotein was studied in 80 astrocytic gliomas of the hemispheres and nuclear expression of this oncoprotein was found in 90% of the tumors this indicating high specificity of the reaction. A tendency to growing oncoprotein expression was found at different stages of malignant transformation showing feasibility of clonal expansion of cells with gene p53 mutation. High variability of the oncoprotein p53 immunoreactivity is characteristic of glioblastomas this suggesting genotypic polymorphism of gliomas of high grade malignancy. The lowest expression of the p53 oncoprotein was in gliosarcomas suggesting mechanism other than mutation. A stable link between the p53 oncoprotein expression and the proliferating cells nuclei antigen was not observed. This finding confirms an independent character of various progression features of the tumor.


Molecular cloning, functional expression and characterization of d-limonene synthase from Agastache rugosa.
We cloned the gene of d-limonene synthase (ArLMS) from Agastache rugosa (Labiatae). The function of ArLMS was elucidated by the preparation of recombinant protein and subsequent enzyme assay. ArLMS consisted of 2077 nucleotides including 1839 bp of coding sequence that encodes a protein of 613 amino acids. This protein has a 60 kDa molecular weight, which is identical to that of d-limonene synthase from Schizonepeta tenuifolia (Labiatae). The deduced amino acid sequence of ArLMS shows high homology with the known d- and l-limonene synthases from Labiatae plants. Here, we discussed the amino acid residues responsible for the stereochemical regulation in limonene biosynthesis.


Fibronectin and laminin distribution in bovine eye.
Using immunofluorescent techniques we have examined the distribution of the glycoproteins, fibronectin and laminin, in bovine eyes. As expected, both fibronectin and laminin were present in blood vessel walls and in all basement membranes, including the internal limiting membrane of the retina. Fibronectin, but not laminin, was observed arranged in fine fibrillar arrays within the vitreous body. The presence of fibronectin in the vitreous cortex and the occurrence of both proteins in the internal limiting membrane of the retina provide a morphologic suggestion of a role for fibronectin and laminin in vitreoretinal adhesion.


[Improving the quality of washed and buffy coat-free erythrocyte concentrates].
Washing buffy-coat free erythrocyte concentrates three times in bottles used for blood storage will diminish their leukocyte content to 0.22 +/- 0.11 x 10(9) per TE (= 9% of the initial value in whole blood, and the thrombocyte content to 0.3 +/- 0.5 x 10(9) per day (= 2% of the initial value in whole blood). Even 50% of leukocytes (mainly lymphocytes) and 80% of thrombocytes are eliminated simply by buffy coat separation. 30% of erythrocytes are lost by the washing process. Due to increasing haemolysis (0.22%) a subsequent storage of 24 hours should not be exceeded for washed erythrocyte concentrates. Further quality parameters, such as morphological index, pH, ATP, 2,3-P2G and K+ and Na+, were investigated. As far as selected quality parameters are concerned, washing erythrocyte concentrates three times in bottles for blood storage may be compared with washing them once in blood bags. The present findings confirm the conclusion that the washing of erythrocyte concentrates with a solution of sodium chloride in order to eliminate leukocytes may for the most part exclude non-haemolytic febrile transfusion reactions, but not immunization. More effective procedures of eliminating leukocytes, such as filtration, TTK or even glycerin, treatment of erythrocyte concentrates without cryoconservation, are indispensable.


The effect of continuous nursing intervention guided by chronotherapeutics on ambulatory blood pressure of older hypertensive patients in the community.
To explore the effect of continuous nursing intervention guided by chronotherapeutics so as to provide the easy, noninvasive, effective and acceptable intervention for older hypertensive patients in the community. Many researchers studied the effect of administration at different times on blood pressure control and circadian rhythm. However, the individual administrative time was set ambiguously in previous studies. A semi-experimental study. In the study, 90 eligible patients were recruited and separated into three groups randomly, which were the control group, intervention group A (behaviour and chronotherapy intervention) and intervention group B (behaviour intervention). At 6 and 12 months after the study, the intervention groups were measured 24-hour ambulatory blood pressure monitoring. There were significant differences in ambulatory blood pressure monitoring parameters of the two intervention groups at different measurement times, and there were interaction between measurement time and different groups. The number of patients with dipper increased and reverse dipper decreased in group A as the intervention applied. There were statistical differences between two groups. The number of patients with morning surge in group A decreased more, and there were statistical differences between two groups at six months after the intervention. The behaviour and chronotherapy intervention based on the patients' ambulatory blood pressure monitoring can control casual blood pressure much better and last longer, which can also improve patients' indexes of ambulatory blood pressure monitoring better than behaviour intervention only. The behaviour and chronotherapy intervention can increase patients' nocturnal blood pressure drop, increase the number of patients with dipper and decrease reverse dipper, and improve blood pressure surge in the morning. Nurses can use continuous nursing intervention guided by chronotherapeutics to help improve hypertension of older patients better in the community.


Aberrant Expression of TET2 Accounts for DNA Hypomethylation in Varicocele.
Epigenetic modifications such as DNA methylation play a key role in male infertility etiology. This study aimed to explore the global DNA methylation status in testicular spermatogenic cells of varicocele-induced rats and consider their semen quality, with a focus on key epigenetic marks, namely 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC), as well as the mRNA and proteins of ten-eleven translocation (TET) methylcytosine dioxygenases 1-3. In this experimental study, 24 mature male Wistar rats (8 in each group) were assigned amongst the control, sham, and varicocele groups. Sperm quality was assessed, and DNA methylation patterns of testicular spermatogenic cells were investigated using reverse transcription-polymerase chain reaction (RT-PCR), western blot, and immunofluorescence techniques. Sperm parameters, chromatin and DNA integrity were significantly lower, and sperm lipid peroxidation significantly increased in varicocele-induced rats in comparison with control rats. During spermatogenesis in rat testis, 5-mC and 5-hmC epigenetic marks, and TET1-3 mRNA and proteins were expressed. In contrast to the 5-mC fluorescent signal which was presented in all testicular cells, the 5-hmC fluorescent signal was presented exclusively in spermatogonia and a few spermatids. In varicocele-induced rats, the 5-mC signal decreased in all cells within the tubules, whereas a strong signal of 5-hmC was detected in seminiferous tubules compared to the control group. As well, the levels of TET2 mRNA and protein expression were significantly upregulated in varicocele-induced rats in comparison with the control group. Also, our results showed that the varicocele-induced animals exhibited strong fluorescent signals of TET1-3 in testicular cells, whereas weak fluorescent signals were identified in the seminiferous tubules of the control animals. Consequently, we showed TET2 upregulation and the 5-hmC gain at testicular levels are associated with varicocele and sperm quality decline, and therefore they can be exploited as potential biomarkers of spermatogenesis.


Fluorescence array detector for large-field quantitative fluorescence cytometry.
A prototypic fluorescence array detector (FAD) has been designed and constructed which is capable of quantifying single-cell fluorescence emissions from a statistically significant population of cell-sized objects (over 10(3)) on a solid substrate. The system is comprised of a cryogenically cooled CCD, 50 mW air-cooled argon ion laser, and optics that image a large (1 x 1 cm) field at 1:1 (no magnification). The CCD is effectively treated as a two-dimensional array of 2.7 x 10(5) independent 20 x 20 microns photodetectors, with each cell-sized object imaged across only a few CCD pixels. Algorithms have been developed for focusing, image segmentation, shading correction, and noise rejection; performance data for the FAD with fluorescent calibration beads are presented. The FAD is a simple alternative to microscope-based imaging cytometry, allowing large-field imaging without a scanning stage.


Virulent and avirulent encapsulated variants of Staphyococcus aureus.
There are at least two serologically distinct capsular types of coagulase-positive Staphylococcus aureus. Until now, unequivocal evidence for encapsulation of the Smith diffuse variant was lacking. However, the data presented in this paper provide definitive details of encapsulation of the Smith strain. A marked difference in ld(50) values for the two serologically distinct capsular types of S. aureus was demonstrated. The paradoxical behavior of these two strains suggested that the host was resistant to one and was susceptible to the other. A survey of the carriage incidence in mice for staphylococci and staphylococcal capsular antibodies disclosed the presence of staphylococci and capsular antibodies in these animals. The capsular antibodies detected were reactive against only one of the capsular types of S. aureus. None of the sera from the mice surveyed possessed capsular antibodies against the Smith diffuse variant, but the average incidence for the capsular antibodies against the wound mucoid type was 46%. We postulated that the susceptibility of the mice to the Smith diffuse variant was caused by the absence of protective, type-specific capsular antibodies. Conversely, the resistance of the mice to the wound mucoid staphylococci may have been a result of the presence of type-specific capsular antibodies.


[Relationship between facilitatory effect of piracetam on memory and glutamate receptors].
By Y-maze method, repeated administrations of sodium glutamate 400 mg.kg-1.d-1 ip for 5 d before training remarkably reduced the number of trials from 45.3 +/- 15.5 of the control to 20.0 +/- 6.9 in mouse of anisodine-induced memory impairment. Ketamine (10 mg.kg-1, ip), a selective NMDA receptor antagonist, inhibited the anti-amnesic activity of piracetam. The number of memory errors was raised from 1.9 +/- 1.5 to 2.6 +/- 2.1 in mouse step-down test. Piracetam 500 mg.kg-1.d-1 ip for 3 d caused a decrease in mouse brain glutamate content and glutamate/GABA rate from 7.07 +/- 0.83 mumol.g-1 to 5.69 +/- 0.60 mumol.g-1 and 4.98 +/- 0.63 to 4.52 +/- 0.81, respectively. These results suggest that facilitatory effect of piracetam on memory may be mediated by glutamate receptor.


Characteristics of pulmonary arterial hypertension in affected carriers of a mutation located in the cytoplasmic tail of bone morphogenetic protein receptor type 2.
Mutations in BMPR2 encoding bone morphogenetic protein receptor type 2 (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling. This cohort study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain. We identified 171 carriers affected with PAH with a mutated BMPR2. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared with other BMPR2 mutation carriers (43.2 ± 12.1 years and 35.7 ± 14.6 years, P = .040), a lower pulmonary vascular resistance (13.3 ± 3.5 and 17.4 ± 6.7, P = .023), and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, P = .02). No statistically significant differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain. Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared with other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of these BMPR2 mutations in BMPRII signaling pathways and their possible role in pulmonary arterial remodeling.


Immunocytochemical localization of nerve growth factor: effects of fixation.
The fixation dependence of immunocytochemically demonstrable nerve growth factor (NGF) was investigated. Several commonly used fixation methods have been employed, including buffered formaldehyde, Bouin's fluid, and chloroform-methanol, as well as freezing and cryostat sectioning. The immunostaining technique was an immunoenzyme bridge procedure on either paraffin sections or frozen sections. Of those methods tested, fixation for 1 hr in a buffered formaldehyde appeared to provide optimal preservation and localization of immunoreactive material. Using this method, reaction product was localized in granules of the granular tubule cells of the male mouse submandibular gland. Prolonged fixation in buffered formaldehyde resulted in a diffuse background staining and loss of granule immunoreactivity. In frozen sections and in tissues fixed with either Bouin's solution, chloroform-methanol, or buffered paraformaldehyde-glutaraldehyde increased cytoplasmic background staining and loss of granule immunoreactivity were observed. It was concluded that, for the localization of NGF at the light microscopic level, a brief (1 hr) buffered formaldehyde fixation is optimal.


Saturation of adrenomedullin receptors plays an important role in reducing pulmonary clearance of adrenomedullin during the late stage of sepsis.
Adrenomedullin (AM) is a potent vasodilator that plays a major role in the cardiovascular response during the progression of sepsis. Although pulmonary clearance of AM (i.e., the primary site of AM clearance) is reduced during the late, hypodynamic stage of sepsis, the role of AM receptors under such conditions remains unclear. This study was carried out to test the hypothesis that saturation of AM receptors is responsible for the decreased clearance of AM in the lungs during sepsis. Polymicrobial sepsis was induced in male adult rats by cecal ligation and puncture (CLP). At 20 h after CLP (i.e., the late phase), 125I-labeled rat AM was administered through the jugular vein, both with (+) and without (-) pre-injection of the human AM fragment AM(22-52) (an AM receptor antagonist). Pulmonary tissue samples were harvested after 30 min and the radioactivity was determined. In addition, lung levels of AM were determined at 5 and 20 h after CLP by radioimmunoassay. Alterations in gene expression of the recently identified AM receptor subunits calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-2 and -3 (RAMP-2 and -3) were assessed in the lungs by reverse transcription-polymerase chain reaction (RT-PCR) at 5 and 20 h after CLP. The results indicate that there was a significant decrease in pulmonary [125I]AM clearance at 20 h in -AM(22-52) CLP animals. Lung clearance in +AM(22-52) sham animals was significantly lower than in -AM(22-52) sham animals and was not statistically different from the -AM(22-52) CLP group. There was no statistical difference between +AM(22-52) and -AM(22-52) CLP groups. However, there was a significant increase in lung AM levels at 20 but not 5 h after CLP. In addition, RAMP-3 expression was significantly upregulated at 5 but not 20 h after CLP. There were no alterations in the expression of CRLR or RAMP-2 at either time point. These results suggest that pulmonary AM receptors become saturated as more AM enters the bloodstream, thereby reducing the ability of the lungs to clear this peptide during late sepsis. Early upregulation of RAMP-3 may be a compensatory mechanism to help clear the upregulated AM from the bloodstream. The lack of upregulation of RAMP-3 during late sepsis could also contribute to the decreased clearance observed during this phase.


The syngeneic mixed leukocyte reaction represents polyclonal activation of antigen-specific T lymphocytes with receptors for self-Ia antigens.
We used a combination of positive and negative selection techniques to evaluate the relationship between the T cell that responds to self-Ia antigens in the SMLR and the T cells that respond to foreign antigen in association with self-Ia. BudR and light treatment of T cells proliferating in the SMLR abolished their subsequent primary and secondary proliferative response to antigen but had little effect on their response to allogeneic Ia. F1 cells that had been positively selected in the SMLR with stimulator cells from 1 parental strain demonstrated a markedly enhanced proliferative response to antigen in association with the parental strain used in the SMLR selection culture. The observed genetic restriction on the antigen responses of SMLR primed F1 T cells was not the result of haplotype-specific help or suppression and most likely represents direct activation of antigen-specific T cell clones by unmodified Ia antigens.


Propofol infusion for sedation of patients with head injury in intensive care. A preliminary report.
Propofol was given by continuous intravenous infusion to 10 patients with severe head injuries in the intensive care unit. Heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, pupil size and arterial carbon dioxide tension were recorded throughout the study period. A mean infusion rate of 2.88 mg/kg/hour provided satisfactory sedation, and recovery from the propofol was often rapid. Cerebral perfusion pressure was significantly increased at 24 hours.


Refractive index measurements of ten germanium samples.
The refractive index of germanium was measured for ten samples, covering the various crystal types, over the 8-14-microm wavelength range. Samples were obtained from several suppliers, and differences between samples in the index values reported were not significant compared with the estimated index uncertainties of +/-0.0003. Three samples were examined at two laboratories to act as a check on the absolute values obtained. A temperature coefficient index of 0.00040 degrees C(-1) was obtained for the 20-25-C range.


Preparation and characterization of latent alpha 1-antitrypsin.
Members of the serine proteinase inhibitor or serpin superfamily have a common molecular architecture based on a dominant five-membered A beta-pleated sheet and a mobile reactive center loop. The reactive center loop has been shown to adopt a range of conformations from the three turn alpha-helix of ovalbumin to the cleaved or latent inhibitor in which the reactive center loop is fully inserted into the A sheet of the molecule. While the cleaved state can be achieved in all inhibitory serpins only plasminogen activator inhibitor-1 and, more recently, antithrombin have been shown to adopt the latent conformation. We show here that the archetypal serpin, alpha 1-antitrypsin, can also be induced to adopt the latent conformation by heating at high temperatures in 0.7 M citrate for 12 h. The resulting species elutes at a lower sodium chloride concentration on an anion-exchange column and has a more cathodal electrophoretic mobility on non-denaturing polyacrylamide gel electrophoresis and isoelectric focusing than native M antitrypsin. Latent antitrypsin is inactive as an inhibitor of bovine alpha-chymotrypsin, is stable to unfolding with 8 M urea, and is more resistant to heat-induced loop-sheet polymerization than native but less resistant than cleaved antitrypsin. The reactive center loop of latent antitrypsin is inaccessible to proteolytic cleavage, and its occupancy of the A sheet prevents the molecule accepting an exogenous reactive center loop peptide. The activity of latent antitrypsin may be increased from < 1% to approximately 35% by refolding from 6 M guanidinium chloride.


Volatile emissions from Aesculus hippocastanum induced by mining of larval stages of Cameraria ohridella influence oviposition by conspecific females.
Larval stages of the horse chestnut leafminer Cameraria ohridella can completely destroy the surface of horse chestnut leaves, Aesculus hippocastanum. This study investigated the effect of the degree of leaf browning caused by the insect's larvae on olfactory detection, aggregation, and oviposition of C. ohridella adults. The influence of A. hippocastanum flower scent on oviposition of the first generation was also evaluated. Utilizing gas chromatography coupled with parallel detection by mass spectrometry and electroantennography (GC-MS/EAD), more than 30 compounds eliciting responses from antennae of C. ohridella were detected. Oviposition and mining by C. ohridella caused significant changes in the profile of leaf volatiles of A. hippocastanum. After oviposition and subsequent mining by early larval stages (L1-L3), substances such as benzaldehyde, 1,8-cineole, benzyl alcohol, 2-phenylethanol, methyl salicylate, (E)-beta-caryophyllene, and (E,E)-alpha-farnesene were emitted in addition to the compounds emitted by uninfested leaves. Insects were able to detect these compounds. The emitted amount of these substances increased with progressive larval development. During late larval stages (L4, L5) and severe loss of green leaf area, (E,E)-2,4-hexadienal, (E/Z)-linalool oxide (furanoid), nonanal, and decanal were also released by leaves. These alterations of the profile of volatiles caused modifications in aggregation of C. ohridella on leaves. In choice tests, leaves in early infestation stages showed no significant effect on aggregation, whereas insects avoided leaves in late infestation stages. Further choice tests with leaves treated with single compounds led to the identification of substances mediating an increase or decrease in oviposition.


Nanophase segregation and water dynamics in hydrated Nafion: molecular modeling and experimental validation.
Reported results of coarse-grained molecular dynamics simulations rationalize the effect of water on the phase-segregated morphology of Nafion ionomers. We analyzed density maps and radial distribution functions and correlated them with domain structures, distributions of protogenic side chains, and water transport properties. The mesoscopic structures exhibit spongelike morphologies. Hydrophilic domains of water, protons, and anionic side chains form a random three-dimensional network, which is embedded in a matrix of hydrophobic backbone aggregates. Sizes of hydrophilic domains increase from 1 to 3 nm upon water uptake. At low water content, hydrophilic domains are roughly spherical and poorly connected. At higher water content, they convert into elongated cylindrical shapes with high connectivity. Further structural analysis provides a reasonable estimate of the percolation threshold. Radial distribution functions from coarse-grained and atomistic molecular dynamics models exhibit a good agreement. Water cluster size distributions from coarse-grained molecular dynamics and dissipative particle dynamics are consistent with small angle x-ray scattering data. Moreover, we calculated the water diffusivity by molecular dynamics methods and corroborated the results by comparison with pulsed field gradient NMR.


Mental Health and Immigrant Detainees in the United States: Competency and Self-Representation.
Most immigrant detainees held in U.S. Immigration and Customs Enforcement (ICE) facilities do not have legal representation, because immigration proceedings are a matter of civil, not criminal, law. In 2005, Mr. Franco, an immigrant from Mexico with an IQ between 35 and 55, was found incompetent to stand trial, but was not appointed an attorney for his immigration proceedings. This failure led to a class action lawsuit, known as the Franco litigation, and in April 2013, a federal judge ordered the U. S. government to provide legal representation for immigrant detainees in California, Arizona, and Washington who are incompetent to represent themselves due to a mental disorder or defect. This development has implications for forensic evaluators, because there is likely to be an increase in the number of competency examinations requested by courts for immigrant detainees. Furthermore, forensic evaluators must understand that an evaluation for competency of an immigrant detainee includes both the Dusky criteria and capacity for self-representation. In this article, we explore the legal context and ethics concerns related to the Franco litigation.


Current trends in the production of biodegradable bioplastics: The case of polyhydroxyalkanoates.
The global pollution caused by plastics and microplastics is stimulating intense research towards more environmentally friendly materials, preserving the remarkable application characteristics of the currently available polymers. Among these, polyhydroxyalkanoates (PHAs) have been hailed as the solution to replace conventional, oil-based plastics. Given their biodegradable nature and mechanical properties, their use can be envisioned in a wide range of applications reducing the environmental footprint. Several types of processes have been proposed for their production, which can be grouped in three main classes: (i) microbiological, (ii) enzymatic and (iii) chemical processes. Given the significant amount of literature available on this topic, this review aims to critically analyse what has been proposed so far in each of these classes, with specific reference to their potential to provide bioplastics that can actually replace the currently available materials. A comparison is made, based on the following aspects: achievable molecular structures (such as molecular weight and composition distributions), raw-material and production costs and availability of large-scale production technologies. Finally, some considerations and ideas on what should be further investigated and implemented to realize the economically sustainable production of PHA are brought forward.


Epidemiological trends in acute pancreatitis: A retrospective cohort in a tertiary center over a seven year period.
Acute pancreatitis (AP) remains a major cause of hospitalization and mortality with important health-related costs worldwide. Using an electronic database of a large tertiary center, we estimated the incidence, etiology, severity and costs of hospitalized AP cases in southern Romania. To estimate the incidence, cost and tobacco usage of hospitalized AP cases in southern Romania and to update and upgrade the knowledge we have on the etiology, severity (in regard to Revised Atlanta Classification), outcome, morphology and local complications of AP. We performed an electronic health care records search on AP patients treated at Emergency University Hospital of Bucharest (Spitalul Universitar de Urgență București) between 2015 and 2022. The incidence, etiology, and severity were calculated; potential risk factors were evaluated, and the hospitalization costs of AP were documented and analyzed. The cohort of this study is part of the BUCharest - Acute Pancreatitis Index registry. A total of 947 consecutive episodes of AP where the patients were hospitalized in the gastroenterology department were analyzed, with 79.45% as 1st episode and the rest recurrent. The majority of the patients were males (68.9%). Alcoholic (45.7%), idiopathic (16.4%) and biliary (15.2%) were the main causes. The incidence was estimated at 29.2 episodes/100000 people. The median length of stay was 7 d. The median daily cost was 747.96 RON (165 EUR). There was a high prevalence of active tobacco smokers (68.5%). The prevalence of severe disease was 11.1%. The admission rate to the intensive care unit was 4.6%, with a mortality rate of 38.6%. The overall mortality was 5.5%. We estimated the incidence of AP at 29.2 episodes that required hospitalization per 100000 people. The majority of our cases were found in males (68.9%) and were related to alcohol abuse (45.7%). Out of the cases we were able to find data regarding tobacco usage, the majority were active smokers (68.5%). Most patients had a mild course (54.4%), with a mortality rate of 5.5%. Interstitial AP prevailed (45.3%). The median daily cost of hospitalization was 747.96 RON (165 EUR).


Structure of a Multilayer Nanofilm To Increase the Encapsulation Efficiency of Basic Fibroblast Growth Factor.
In this study, we established the structure of a multilayer nanofilm that more efficiently encapsulates basic fibroblast growth factor (bFGF). First, a positively charged layer material was selected from biocompatible polymers such as collagen (Col), poly(beta-amino ester) (Poly2), and chitosan (Chi), while considering the film thickness. We then investigated the change in bFGF encapsulation efficiency when the multilayer structure was changed from a tetralayer to a trilayer. As a result, we obtained a highly improved bFGF encapsulation efficiency in the nanofilm using a positively charged layer formed by a blend of Col and Poly2 and a negatively charged poly(acrylic acid) (PAA) layer within a trilayered structure. In particular, we found that a significant amount of adsorbed bFGF was desorbed again during the film fabrication process of a tetralayered nanofilm. In the conventional nanofilm, bFGF was regarded as a polycation and formed a multilayer nanofilm that was composed of a tetralayered structure and was represented as (polycation/polyanion/bFGF/polyanion) n where n = number of repeated tetralayers. Here, we suggested that bFGF should not be considered a polycation, rather it should be considered as a small quantity of molecule that exists between the polyanion and polycation layers. In this case, the nanofilm is composed of repeating units of (polycation/polyanion/bFGF/polycation/polyanion), because the amount of adsorbed bFGF is considerably lower than that of other building blocks.


Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells.
Zika virus (ZIKV) is a mosquito-transmitted flavivirus with a causative link to microcephaly, a condition resulting in reduced cranial size and brain abnormalities. Despite recent progress, there is a current lack of in vivo models that permit the study of systemic virus on human neurons in a developing organism that replicates the pathophysiology of human disease. Furthermore, no treatment to date has been reported to reduce ZIKV-induced microcephaly. We tested the effects of ZIKV on human induced neural stem cells (hiNSCs) in vitro and found that infected hiNSCs secrete inflammatory cytokines, display altered differentiation, and become apoptotic. We also utilized this in vitro system to assess the therapeutic effects of niclosamide, an FDA-approved anthelminthic, and found that it decreases ZIKV production, partially restores differentiation, and prevents apoptosis in hiNSCs. We intracranially injected hiNSCs into developing chicks, subjected them to systemic ZIKV infection via the chorioallantoic membrane (CAM), a tissue similar in structure and function to the mammalian placenta, and found that humanized ZIKV-infected embryos developed severe microcephaly including smaller crania, decreased forebrain volume and enlarged ventricles. Lastly, we utilized this humanized model to show that CAM-delivery of niclosamide can partially rescue ZIKV-induced microcephaly and attenuate infection of hiNSCs in vivoThis article has an associated First Person interview with the first author of the paper.


CtBP impedes JNK- and Upd/STAT-driven cell fate misspecifications in regenerating Drosophila imaginal discs.
Regeneration following tissue damage often necessitates a mechanism for cellular re-programming, so that surviving cells can give rise to all cell types originally found in the damaged tissue. This process, if unchecked, can also generate cell types that are inappropriate for a given location. We conducted a screen for genes that negatively regulate the frequency of notum-to-wing transformations following genetic ablation and regeneration of the wing pouch, from which we identified mutations in the transcriptional co-repressor C-terminal Binding Protein (CtBP). When CtBP function is reduced, ablation of the pouch can activate the JNK/AP-1 and JAK/STAT pathways in the notum to destabilize cell fates. Ectopic expression of Wingless and Dilp8 precede the formation of the ectopic pouch, which is subsequently generated by recruitment of both anterior and posterior cells near the compartment boundary. Thus, CtBP stabilizes cell fates following damage by opposing the destabilizing effects of the JNK/AP-1 and JAK/STAT pathways.


Ni-Catalyzed Site-Selective Dicarboxylation of 1,3-Dienes with CO2.
A site-selective catalytic incorporation of multiple CO2 molecules into 1,3-dienes en route to adipic acids is described. This protocol is characterized by its mild conditions, excellent chemo- and regioselectivity and ease of execution under CO2 (1 atm), including the use of bulk butadiene and/or isoprene feedstocks.


Familial-Environmental Risk Factors in South African Children With Attention-Deficit Hyperactivity Disorder (ADHD): A Case-Control Study.
We investigated familial and environmental risk factors in a cohort of South African children diagnosed with attention-deficit hyperactivity disorder (ADHD). A prospective, hospital-based case control study was conducted comprising 50 children diagnosed with ADHD and 50 matched non-ADHD controls. The adjusted effect of familial-environmental risk factors on ADHD was determined by systematic assessment. Birth complications, parental psychiatric disorder, maternal ADHD, early childhood trauma, and nonmaternal child care were significant risk factors for ADHD. Prolonged breastfeeding was found to be protective. In a multivariable logistic regression model, 5 criteria (birth complications, breastfeeding <3 months, at least 1 parent with tertiary education, presence of parental psychiatric disorder, and nonmaternal primary caregiver) differentiated ADHD from non-ADHD controls with a sensitivity and specificity of 74% and 86%, respectively. We found a correlation between certain familial and environmental risk factors and ADHD. A 5-criterion multivariable logistic regression model may offer clinical guidance in ADHD diagnosis.


Changes of IgG N-Glycosylation in Thyroid Autoimmunity: The Modulatory Effect of Methimazole in Graves' Disease and the Association With the Severity of Inflammation in Hashimoto's Thyroiditis.
The N-glycome of immunoglobulin G (IgG), the most abundant glycoprotein in human blood serum, reflects pathological conditions of autoimmunity and is sensitive to medicines applied in disease therapy. Due to the high sensitivity of N-glycosylation, the IgG N-glycan profile may serve as an indicator of an ongoing inflammatory process. The IgG structure and its effector functions are strongly dependent on the composition of N-glycans attached to the Fc fragment, and the binding of antigens is regulated by Fab sugar moieties. Because of the crucial role of N-glycans in IgG function, remodeling of its N-oligosaccharides can induce pathological changes that ultimately contribute to the development of autoimmunity; restoration of their physiological structure is critical to the reduction of disease symptoms. Our recently published data have shown that the pathology of autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is accompanied by alterations of the composition of IgG N-glycans. The present study is a more in-depth investigation of IgG glycosylation in both AITDs, designed to determine the relationship between the severity of thyroid inflammation and IgG N-glycan structures in HT, and to assess the impact of immunosuppressive therapy on the N-glycan profile in GD patients. The study material consisted of human serum samples collected from donors with elevated anti-thyroglobulin (Tg) and/or anti-thyroperoxidase (TPO) IgGs without symptoms of hypothyroidism (n=68), HT patients characterized by high autoantibody titers and advanced destruction of the thyroid gland (n=113), GD patients with up-regulated IgG against thyroid-stimulating hormone receptor (TSHR) before (n=62) and after (n=47) stabilization of TSH level as a result of methimazole therapy (study groups), and healthy donors (control group, n=90). IgG was isolated from blood serum using protein G affinity chromatography. N-glycans were released from IgG by PNGase F digestion and analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) after 2-aminobenzamide (2-AB) labeling. UPLC-MS chromatograms were integrated into 25 peaks (GP) in the Waters UNIFI Scientific Information System, and N-glycans were assigned based on the glucose unit values and mass-to-charge ratios (m/z) of the detected ions. The Kruskal-Wallis non-parametric test was used to determine the statistical significance of the results (p<0.05). The obtained results suggest that modifications of IgG sialylation, galactosylation and core-fucosylation are associated with the severity of HT symptoms. Methimazole therapy implemented in GD patients affected the IgG N-glycan profile; as a result, the content of the sialylated and galactosylated oligosaccharides with core fucose differed after treatment. Our results suggest that N-glycosylation of IgG undergoes dynamic changes during the intensification of thyroiditis in HT, and that in GD autoimmunity it is affected significantly by immunosuppressive therapy.


Rationale and Study Design of the TSOC-Fully Organized Registry for the Management of Symptomatic ACS Study (T-FORMOSA Study).
Successful implementation of practice guidelines has been challenging in the treatment of acute coronary syndrome (ACS), leaving room for improvement. A nationwide registry can provide more information than that recorded in the National Health Insurance Research Database (NHIRD). We conducted a prospective, nationwide, multi-center ACS full spectrum registry involving 3600 patients admitted to hospitals within 24 hours of the onset of myocardial infarction with ST-segment elevation or ACS without ST-segment elevation. In total, 41 sites including medical centers and regional hospitals were selected across Taiwan. The data for each patient are collected at 3 time points for the main study: during hospitalization, 6 months, and 12 months after the discharge. The milestone for first patient in was reached on January 7, 2022, and complete enrollment is expected before October 2023. The primary aims of the main study are to determine the degree of guideline-directed medical therapies and to identify prognostic predictors associated with 1-year composite outcomes, including death, myocardial infarction, stroke, and unplanned coronary revascularization in ACS patients. Thereafter, the patient data will be analyzed every 3 to 5 years for up to 20 years after discharge using the NHIRD in the extended study. We hypothesized that a greater increase in the implementation of guideline-directed medical therapies can be observed. The results of the current study will add new and important information regarding a broad spectrum of ACS to drive further investigations.


Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn's Disease.
Ustekinumab, an inhibitor of the p40 subunit of interleukins 12 and 23, is an effective treatment for patients with Crohn's disease (CD). Trough concentrations of tumor necrosis factor (TNF) antagonists and presence of anti-drug antibodies are associated with important clinical and endoscopic outcomes. We investigated associations between trough concentrations of ustekinumab and clinical, biomarker, and endoscopic outcomes of real-world patients with CD. We recruited 62 patients with CD who were either refractory or intolerant to TNF antagonists, treated with ustekinumab from April 2014 to September 2015. Patients received 90 mg of ustekinumab subcutaneously at weeks 0, 1, and 2 during induction and 90 mg every 4 or 8 weeks during maintenance. Clinical, biomarker, and endoscopic outcomes, trough concentrations of ustekinumab, and anti-drug antibodies were assessed at both week 10 postinduction therapy and at week 26 or later during maintenance therapy in a prospective longitudinal patient cohort or at week 26 or later during maintenance therapy in a cross-sectional patient cohort. Analysis was performed on data combined from both maintenance cohorts, which had similar outcomes at week 26 or later. A primary analysis determined if ustekinumab drug trough concentrations were associated with clinical response (reduction in Harvey Bradshaw Index score of 3 or greater), clinical remission (Harvey Bradshaw Index score <5), steroid-free clinical remission, biomarker (serum level of C-reactive protein [CRP] or level of fecal calprotectin) reduction, biomarker normalization (serum level of CRP below 5 mg/L or level of fecal calprotectin below 200 μg/g), endoscopic response (simple endoscopic score for CD reduced by 50% or more), or endoscopic remission (simple endoscopic score for CD of 2 or less). At week 26 or beyond, 80.7% of patients had a clinical response, 66.1% were in clinical remission, 50.0% were in steroid-free clinical remission, 58.9% had an endoscopic response, and 19.6% were in endoscopic remission. The mean trough concentration of ustekinumab at this time point was higher in patients with an endoscopic response (4.7 μg/mL) than without (3.8 ug/mL; P = .03). An optimal ustekinumab threshold trough concentration at week 26 or later was found to be 4.5 μg/mL (area under the curve, 0.67). A greater proportion of patients with trough concentrations of ustekinumab above 4.5 μg/mL at week 26 or later had an endoscopic response (75.9%) than did patients with trough concentrations below this level (40.7%; P = .008). Patients with trough concentrations of ustekinumab above 4.5 μg/mL at week 26 or later also had a lower mean level of CRP (12.6 mg/L) than did patients with trough concentrations below this level (mean level of CRP, 23.9 mg/L; P = .04). We did not detect antibodies against ustekinumab in any patient. Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist. Maintenance trough concentrations of ustekinumab above 4.5 μg/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response.


Protective effect of baicalein against endotoxic shock in rats in vivo and in vitro.
Dried roots of Scutellaria baicalensis Georgi (Huang qin) are widely used in traditional Chinese medicine. Baicalein is a major bioactive flavonoid component of H. qin that shows a wide range of biological activities, including antioxidant and anti-inflammatory actions. We evaluated therapeutic effects and possible mechanisms of action of baicalein on circulatory failure and vascular dysfunction during sepsis induced by lipopolysaccharide (LPS; 10 mg/kg, i.v.) in anesthetized rats. Treatment of the rats with baicalein (20 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes of hypotension and tachycardia caused by LPS and significantly inhibited the elevation of plasma tumor necrosis factor alpha (TNF-alpha). Baicalein also decreased levels of inducible nitric oxide synthase (iNOS) and the overproduction of NO and superoxide anions caused by LPS. It also increased the survival rate of ICR mice (25-30 g) challenged by LPS (60 mg/kg). Moreover, infiltration of neutrophils into the liver and lungs of rats 6h after treatment with LPS was also reduced by baicalein. To investigate the mechanism of action of baicalein on sepsis, RAW 264.7 cells were used as a model. Baicalein inhibited iNOS protein production, and suppressed LPS-induced degradation of IkappaBalpha, the formation of a nuclear factor kappa B (NF-kappaB)-DNA complex and NF-kappaB-dependent reporter gene expression. Thus, the therapeutic effects of baicalein were associated with reductions in TNF-alpha and superoxide anion levels during sepsis. The inhibitory effects of baicalein on iNOS production may be mediated by inhibition of the activation of NF-kappaB. Baicalein may thus prove a potential agent against endotoxemia.


Facile syntheses of all possible diastereomers of conduritol and various derivatives of inositol stereoisomers in high enantiopurity from myo-inositol.
Phosphoinositide-based signaling processes are crucially important in intracellular signal transduction events. Inositol phosphate analogues have been useful in probing the structure-activity relationships between inositol phosphates and biomacromolecules, and in studying biological functions of newly found inositol phosphates. Thus, a systematic and ready access to inositol stereoisomers is highly desirable. And practical and convenient syntheses of conduritols and related compounds are also important because of their biological activities and their synthetic utilities in the preparation of other bioactive molecules. We herein report the first syntheses of all possible diastereomers of conduritol and various derivatives of eight inositol stereoisomers in high enantiopurity from myo-inositol, which involve efficient enzymatic resolution of the intermediates conduritol B and C derivatives, followed by oxidation-reduction or the Mitsunobu reaction, and cis-dihydroxylation in stereo- and regioselective manners.


Oxidative damage to macromolecules in human Parkinson disease and the rotenone model.
Parkinson disease (PD), the most common neurodegenerative movement disorder, is associated with selective degeneration of nigrostriatal dopamine neurons. Although the underlying mechanisms contributing to neurodegeneration in PD seem to be multifactorial, mitochondrial impairment and oxidative stress are widely considered to be central to many forms of the disease. Whether oxidative stress is a cause or a consequence of dopaminergic death, there is substantial evidence for oxidative stress both in human PD patients and in animal models of PD, especially using rotenone, a complex I inhibitor. There are many indices of oxidative stress, but this review covers the recent evidence for oxidative damage to nucleic acids, lipids, and proteins in both the brain and the peripheral tissues in human PD and in the rotenone model. Limitations of the existing literature and future perspectives are discussed. Understanding how each particular macromolecule is damaged by oxidative stress and the interplay of secondary damage to other biomolecules may help us design better targets for the treatment of PD.


Collective interactions, collaborative inhibition, and shared spatial knowledge.
Research on spatial mental representations focuses on individual mental maps and spatial knowledge. This exploratory study investigates instead collective interactions, collaborative memory, and the sharing of spatial knowledge. Based on the principle of collaborative inhibition (i.e., people recall information less effectively in groups), we posed the following research question: How do collective interactions, occurring during environmental exploration and group drawing sessions, affect collaborative inhibition, and the quality of sketch maps designed collectively? We conducted in situ explorations in Plaine St-Denis (France) with real-time tracking, followed by individual and group drawing sessions. This experiment involved 118 participants divided into three groups: (1) solo explorations without devices; (2) solo explorations with a mobile mapping application; (3) collective explorations using the same application enhanced with interaction features (viewing collective routes and photos of visited places). The comparison of the total number of entities found on individual mental maps with those included in collective sketch maps reveals that collaborative inhibition applies to spatial memory. Additional findings indicate that the use of a map, combined with collective interactions, mitigates collaborative inhibition and increases the accuracy of the sketch maps. However, the effect of such interactions on group dynamics remains unclear as of now.


Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol.
Previous investigations have shown that abnormalities in the postheparin plasma levels of the lipolytic enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are correlated with variations in plasma high-density lipoprotein cholesterol (HDL-C) levels. The present study was performed to determine correlations between the postheparin plasma activities of these two enzymes and HDL levels in a sizable number of subjects with low HDL-C levels. Two types of low-HDL subjects were investigated: 159 male subjects with low HDL-C (< 40 mg/dL) and normal triglyceride (< 250 mg/dL) levels (the low-HDL group) and 80 male subjects with low HDL-C (< 40 mg/dL) and elevated triglyceride (> or = 250 mg/dL) levels (the low-HDL/high-TG group). Postheparin plasma activities of LPL and HTGL were determined in these two groups, and these levels were compared with those obtained from 51 normolipidemic (normal-HDL) male subjects. Postheparin LPL activities were significantly lower in the low-HDL and low-HDL/high-TG groups (mean +/- SD, 9.9 +/- 2.9 and 10.4 +/- 3.0 mmol/h per liter, respectively; P < .001 for both) compared with the normal-HDL group (12.5 +/- 3.7 mmol/h per liter). Conversely, postheparin HTGL activities were significantly higher in the low-HDL and low-HDL/high-TG groups (39.3 +/- 16.2 and 44.4 +/- 16.7 mmol/h per liter, respectively; P < .001 for both) compared with the normal-HDL group (29.7 +/- 11.3 mmol/h per liter). Consequently, mean LPL/HTGL ratios were markedly lower in the two low-HDL groups compared with the normal-HDL group.(ABSTRACT TRUNCATED AT 250 WORDS)


How Do Mines Explode? Understanding Risk in European Mining Doctrine, 1803-1906.
Historians of risk and disaster have paid little attention to coal mining-an industry characterized by extreme risks and disasters-even though coal mine operators were concerned with the causes of explosions throughout the nineteenth and early twentieth centuries. This article goes beyond nationally oriented mining scholarship on coal mine safety and regulations to examine one form of industrial risk: how did European researchers understand the role of coal dust in mine explosions. It describes the complex factors involved in applying science and technology methodologies to solve industrial risk in this dangerous sector. It traces European countries shifting after 1882 to new types of mine experimentation sponsored by the state and mine owners to better mimic real-life situations, while French mining researchers continued to defend work in laboratory settings. French researchers converged methodologically with their colleagues only after the French Courrières mine catastrophe in 1906.


Potential moderators of day-to-day variability in children's physical activity patterns.
Little is known about whether physical activity compensation occurs and, if so, what are potential moderators of such responses. This study examined whether children's physical activity, sedentary time and energy expenditure on one day was associated with these behaviours the following day, and what factors may moderate observed associations. One hundred and twenty-seven children (8-11 years) wore an ActiGraph accelerometer for eight days. Time spent in sedentary time and physical activity was obtained. Daily energy expenditure was also assessed using a SenseWear Armband (n=98). Moderators examined were sex, age, BMI, fitness, and fundamental movement skills (FMS). Multilevel analyses were conducted using generalized mixed models. On any given day, every additional 10 minutes spent in moderate-to-vigorous physical activity (MVPA) was associated with 9.3 minutes less MVPA the following day. Every additional 10kcal expended on one day was associated with 2.9 fewer kcal expended the following day. Additional time spent sedentary on any given day was associated with less light physical activity the following day in children with lower FMS. The results are largely consistent with the compensation hypothesis, with children appearing to compensate their activity between days. Strategies to minimise potential compensatory changes may be needed for children overall rather than for specific population sub-groups.


Corticomotor threshold to magnetic stimulation: normal values and repeatability.
The threshold for corticomotor excitation by magnetic stimuli is a clinically important parameter in the assessment of central motor conduction. Hitherto, arbitrary criteria have been adopted to define threshold and there are few published data using a figure of eight coil. A new method is described in which the highest stimulus intensity evoking responses in the relaxed first dorsal interosseous muscle with a probability of zero [lower threshold (LT)] and the lowest intensity evoking responses with a probability of one [upper threshold (UT)] have been determined. The method, which utilizes a coil located and optimally oriented over hand motor cortex, minimizes the number of stimuli needed. Both LT and UT are normally distributed and are independent of age, gender, and hemisphere. In 102 healthy hands of 55 control subjects 23-84 years of age, mean +/- SD UT was 46.6 +/- 9.4% and LT was 38.0 +/- 8.6% maximum stimulator output. Repeatability estimates indicated an absolute change of more than 13% or 11% in UT or LT respectively in the same individual over 1-3 months was significant at the 5% level.