Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.
Recent increasing evidence suggests that the currently-used platforms in vitro IKr and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/), based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes in drug safety evaluation. The main goal of the CSAHi HEART team has been to propose comprehensive screening strategies to predict a diverse range of cardiotoxicities by using recently introduced platforms (multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging [MFI], and Ca transient systems) while identifying the strengths and weaknesses of each. Our study shows that hiPS-CMs used in these platforms have pharmacological responses more relevant to humans in comparison with existent hERG, APD or Langendorff (MAPD/contraction) assays, and not only MEA but also other methods such as impedance, MFI, and Ca transient systems would offer paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. Furthermore, we propose a potential multi-parametric platform in which field potential (MEA)-Ca transient-contraction (MFI) could be evaluated simultaneously as an ideal novel platform for predicting a diversity of cardiac toxicities, namely whole effects on the excitation-contraction cascade.


Antiedematogenic activity of two thiazolidine derivatives: N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28).
The search for new anti-inflammatory drugs has been constant in several research centers. The use of the Bioisostery concept allows the elaboration of new bioactive compounds with different properties through the introduction of substitute groups in one or more positions of a main molecule with known biological activity. Preliminary works accomplished at our laboratory with 2,4-thiazolidinedione isosters demonstrated inhibitory activity on edema formation for N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26). We verified the antiedematogenic and ulcerogenic activity of these two compounds in Wistar rats. The carrageenan induced paw edema suffered significant (p<0.05) inhibition (28.36% on average) for GS28 (100 mg/kg; v.o.) during the entire time of the experiment. GS26 (50 and 100 mg/kg; v.o.) significantly inhibited (p<0.05) the paw edema dextran induced (22.1 and 27.8%, for the respective doses) after 180 min. The compounds GS26 and GS28 did not show ulcerogenic activity on gastric mucous. The results suggest antiedematogenic action for both compounds without the appearance of gastric lesions.


Phase I safety and pharmacokinetics study of rovalpituzumab tesirine in Japanese patients with advanced, recurrent small cell lung cancer.
Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.


Continuity and discontinuity of attachment patterns: a short-term longitudinal pilot study using a sample of late-adopted children and their adoptive mothers.
This study analysed the attachment patterns of 28 late-adopted children (placed when they were between four and seven years of age) and their adoptive mothers. The change in the children's internal working models (IWMs) within seven to eight months of their placement was evaluated. In addition, we wanted to observe the influence of a secure-autonomous maternal state of mind in facilitating the change in the children's IWMs and the possible associations between the maternal IWMs and the children's IWMs in the adoptive dyads. The separation-reunion procedure (SRP) was used for the late-adopted children in order to assess their attachment behavioural patterns, and the Manchester Child Attachment Story Task (MCAST) was used to evaluate their attachment narrative patterns. The adoptive mothers completed the Adult Attachment Interview (AAI) in order to classify their state of mind with regard to attachment. The results showed a significant change in the attachment behavioural patterns of late-adopted children, from insecure to secure (p = .002). Furthermore, the children who presented this change were predominantly placed with secure-autonomous adoptive mothers (p = .047), although the link between the adoptive mothers' representations of their attachment history and their adopted children's completed narratives was not significant. In conclusion, it seems possible to revise the attachment behaviour of late-adopted children but, for about one-third of children, the adverse history will persist at a narrative/representational level.


Selective attention modulates early human evoked potentials during emotional face-voice processing.
Recent findings on multisensory integration suggest that selective attention influences cross-sensory interactions from an early processing stage. Yet, in the field of emotional face-voice integration, the hypothesis prevails that facial and vocal emotional information interacts preattentively. Using ERPs, we investigated the influence of selective attention on the perception of congruent versus incongruent combinations of neutral and angry facial and vocal expressions. Attention was manipulated via four tasks that directed participants to (i) the facial expression, (ii) the vocal expression, (iii) the emotional congruence between the face and the voice, and (iv) the synchrony between lip movement and speech onset. Our results revealed early interactions between facial and vocal emotional expressions, manifested as modulations of the auditory N1 and P2 amplitude by incongruent emotional face-voice combinations. Although audiovisual emotional interactions within the N1 time window were affected by the attentional manipulations, interactions within the P2 modulation showed no such attentional influence. Thus, we propose that the N1 and P2 are functionally dissociated in terms of emotional face-voice processing and discuss evidence in support of the notion that the N1 is associated with cross-sensory prediction, whereas the P2 relates to the derivation of an emotional percept. Essentially, our findings put the integration of facial and vocal emotional expressions into a new perspective-one that regards the integration process as a composite of multiple, possibly independent subprocesses, some of which are susceptible to attentional modulation, whereas others may be influenced by additional factors.


Lifetime reproductive success, selection on lifespan, and multiple sexual ornaments in male European barn swallows.
Natural and sexual selection arise when individual fitness varies according to focal traits. Extra-pair paternities (EPPs) can affect the intensity of selection by influencing variance in fitness among individuals. Studies of selection require that individual fitness is estimated using proxies of lifetime reproductive success (LRS). However, estimating LRS is difficult in large, open populations where EPPs cause reallocation of biological paternity. Here, we used extensive field sampling to estimate LRS in a population of barn swallows (Hirundo rustica) to estimate selection on lifespan and ornamental traits of males. We found selection on lifespan mediated both by within- and extra-pair fertilization success and selection on tail length mediated by within- but not extra-pair fertilization success. In addition, we found selection on tail white spots via extra-pair fertilization success after controlling for selection on other traits. These results were not confounded by factors that hamper studies of LRS, including nonexhaustive sampling of offspring and biased sampling of males. Hence, natural and sexual selection mediated by LRS operates on lifespan, tail length, and size of the tail white spots in barn swallows.


Enhancing the Potency of F508del Correction: A Multi-Layer Combinational Approach to Drug Discovery for Cystic Fibrosis.
With better understanding of the cellular and molecular pathophysiology underlying cystic fibrosis (CF), novel drugs are being developed that specifically target the molecular defects of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel on the plasma membrane that causes CF. Starting with cell-based high-throughput screening, small molecules have been identified that are able to fix specific molecular defects of various disease-causing CFTR mutants. With the successful development of ivacaftor, a "potentiator" that enhances CFTR chloride channel activity, new types of small-molecule compounds that "correct" the misfolding and misprocessing of the most common CF-causing mutation, F508del, are actively being sought for. Recent studies focused on the potential mechanisms of action of some of the investigational CFTR "correctors" shed new light on how the F508del mutant can be targeted in an attempt to ameliorate the clinical symptoms associated with CF. A multi-layer combinational approach has been proposed to achieve the high-potency correction necessary for significant clinical outcome. The mechanistic insights obtained from such studies will shape the future therapeutics development for the vast majority of CF patients.


The effects of alprazolam on corticotropin-releasing factor neurons in the rat brain: acute time course, chronic treatment and abrupt withdrawal.
Considerable evidence indicates that corticotropin-releasing factor (CRF) is responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress. We have investigated the time course of action of the anxiolytic triazolobenzodiazepine, alprazolam, on the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of CRF neurons after acute and chronic administration. In addition, because many of the signs and symptoms observed in animals and humans after abrupt discontinuation of benzodiazepines resemble the stress response, we examined the effect of alprazolam withdrawal on CRF neurons and HPA axis activity. Alprazolam decreases CRF concentrations in the locus coeruleus between 0.5 and 3.0 h following acute injection. The half-life of alprazolam in rats is less than 1 h in both plasma and brain. Similarly, chronic (14 days) alprazolam administration also results in decreased CRF concentrations in the locus coeruleus. CRF concentrations return to control values 24 h after abrupt withdrawal. Moreover, abrupt alprazolam withdrawal results in increased plasma adrenocorticotrophic hormone and corticosterone concentrations and decreased anterior pituitary CRF receptor concentrations 24 h after drug discontinuation. These indices return to control values by 48 h postwithdrawal. These results support the hypothesis that both acute and chronic alprazolam administration alters CRF-containing neurons innervating the locus coeruleus. Additionally, abrupt alprazolam withdrawal profoundly activates the HPA axis.


Method validation and analysis of nine dithiocarbamates in fruits and vegetables by LC-MS/MS.
An analytical method for separation and quantitative determination of nine dithiocarbamates (DTCs) in fruits and vegetables by using LC-MS/MS was developed, validated and applied to samples purchased in local supermarkets. The nine DTCs were ziram, ferbam, thiram, maneb, zineb, nabam, metiram, mancozeb and propineb. Validation parameters of mean recovery for two matrices at two concentration levels, relative repeatability (RSDr), relative within-laboratory reproducibility (RSDR) and LOD were obtained for the nine DTCs. The results from the analysis of fruits and vegetables served as the basis for an exposure assessment within the given commodities and a risk assessment by comparing the calculated exposure to the acceptable daily intake and acute reference dose for various exposure groups. The analysis indicated positive findings of DTCs in apples, pears, plums, table grapes, papaya and broccoli at concentrations ranging from 0.03 mg/kg to 2.69 mg/kg expressed as the equivalent amount of CS2. None of the values exceeded the Maximum residue level (MRL) set by the European Union, and furthermore, it was not possible to state whether illegal use had taken place or not, because a clear differentiation between the various DTCs in the LC-MS/MS analysis was lacking. The exposure and risk assessment showed that only for maneb in the case of apples and apple juice, the acute reference dose was exceeded for infants in the United Kingdom and for children in Germany, respectively.


Leu8 and Pro8 oxytocin agonism differs across human, macaque, and marmoset vasopressin 1a receptors.
Oxytocin (OXT) is an important neuromodulator of social behaviors via activation of both oxytocin receptors (OXTR) and vasopressin (AVP) 1a receptors (AVPR1a). Marmosets are neotropical primates with a modified OXT ligand (Pro8-OXT), and this ligand shows significant coevolution with traits including social monogamy and litter size. Pro8-OXT produces more potent and efficacious responses at primate OXTR and stronger behavioral effects than the consensus mammalian OXT ligand (Leu8-OXT). Here, we tested whether OXT/AVP ligands show differential levels of crosstalk at primate AVPR1a. We measured binding affinities and Ca2+ signaling responses of AVP, Pro8-OXT and Leu8-OXT at human, macaque, and marmoset AVPR1a. We found that AVP binds with higher affinity than OXT across AVPR1a, and marmoset AVPR1a show a 10-fold lower OXT binding affinity compared to human and macaque AVPR1a. Both Leu8-OXT and Pro8-OXT produce a less efficacious response than AVP at human AVPR1a and higher efficacious response than AVP at marmoset AVPR1a. These data suggest that OXT might partially antagonize endogenous human AVPR1a signaling and enhance marmoset AVPR1a signaling. These findings aid in further understanding inconsistencies observed following systemic intranasal administration of OXT and provide important insights into taxon-specific differences in nonapeptide ligand/receptor coevolution and behavior.


Kyoto classification risk scoring system and endoscopic grading of gastric intestinal metaplasia for gastric cancer: Multicenter observation study in Japan.
The usefulness of endoscopic and histological risk assessment for gastric cancer (GC) has not been fully investigated in Japanese clinical practice. In this multicenter observation study, GC and non-GC patients were prospectively enrolled in 10 Japanese facilities. The Kyoto classification risk scoring system, the Kimura-Takemoto endoscopic atrophy classification, the endoscopic grading of gastric intestinal metaplasia (EGGIM), the operative link on gastritis assessment (OLGA) and the operative link on gastric intestinal metaplasia assessment (OLGIM) were applied to all patients. The strength of an association with GC risk was compared. In addition, important endoscopic findings in the Kyoto classification were identified. Overall, 115 GC and 265 non-GC patients were analyzed. Each risk stratification method had a significant association with GC risk in univariate analysis. In multivariate analysis, OLGIM stage III/IV (odds ratio [OR] 2.8 [95% CI 1.5-5.3]), high EGGIM score (OR 1.8 [1.0-3.1]) and opened-type Kimura-Takemoto (OR 2.5 [1.4-4.5]) had significant associations with GC risk. In the Kyoto classification, opened-type endoscopic atrophy, invisible regular arrangement of collecting venules (RAC), extensive (>30%) intestinal metaplasia in the corpus in image-enhanced endoscopy, and map-like redness in the corpus were independent high-risk endoscopic findings. The modified Kyoto classification risk scoring system using these four findings demonstrated a better area under the receiver operating characteristic curve value (0.750, P = 0.052) than that of the original Kyoto classification (0.706). The OLGIM stage III/IV, high EGGIM score and open-typed Kimura-Takemoto had strong association with GC risk in Japanese patients. The modified Kyoto classification risk scoring system may be useful for GC risk assessment, which warrants further validation. (UMIN000027023).


Micro RNA Expression after Ingestion of Fucoidan; A Clinical Study.
Fucoidans are a class of fucose-rich sulfated polysaccharides derived from brown macroalgae that exert a range of biological activities in vitro and in vivo. To generate an unbiased assessment of pathways and processes affected by fucoidan, a placebo-controlled double-blind pilot study was performed in healthy volunteers. Blood samples were taken immediately before and 24 h after ingestion of a single dose of 1 g of Undaria pinnatifida fucoidan (UPF) or placebo. Levels of isolated miRNAs were analyzed using Taqman Open Array Human MicroRNA panels. Out of 754 miRNAs screened, UPF affected a total of 53 miRNAs. Pathway analysis using the TALOS data analysis tool predicted 29 different pathways and processes that were largely grouped into cell surface receptor signaling, cancer-related pathways, the majority of which were previously associated with fucoidans. However, this analysis also identified nine pathways and processes that have not been associated with fucoidans before. Overall, this study illustrates that even a single dose of fucoidans has the potential to affect the expression of genes related to fundamental cellular processes. Moreover, it confirms previous data that fucoidans influence immunity, cancer cells, inflammation, and neurological function.


Antibacterial soap use impacts skin microbial communities in rural Madagascar.
The skin harbors diverse communities of microorganisms, and alterations to these communities can impact the effectiveness of the skin as a barrier to infectious organisms or injury. As the global availability and adoption of antibacterial products increases, it is important to understand how these products affect skin microbial communities of people living in rural areas of developing countries, where risks of infection and injury often differ from urban populations in developed countries. We investigated the effect of antibacterial soap on skin microbial communities in a rural Malagasy population that practices subsistence agriculture in the absence of electricity and running water. We quantified the amount of soap used by each participant and obtained skin swab samples at three time points: prior to soap use, immediately after one week of soap use, and two weeks after soap use was discontinued. Soap use did not significantly impact ecological measures of diversity and richness (alpha diversity). However, the amount of soap used was a predictor of community-level change (beta diversity), with changes persisting for at least two weeks after subjects stopped using soap. Our results indicate that the overall species richness of skin microbial communities may be resistant to short-term use of antibacterial soap in settings characterized by regular contact with the natural environment, yet these communities may undergo shifts in microbial composition. Lifestyle changes associated with the use of antibacterial soap may therefore cause rapid alterations in skin microbial communities, with the potential for effects on skin health.


Screening for hypertension among older adults: a primary care "high risk" approach.
Recommendations for early detection and management of elevated blood pressure through opportunistic clinic-based screening may be inadequate for the rural population in India as access to health facilities is limited. Sixteen Health Aides (trained primary care workers) were trained to measure blood pressure using a standardized training procedure. Six of those assessed competent in initial evaluation were allotted a stratified random sample of about 150 persons each, 50 years or over, in the village under their care to measure blood pressures during their regular scheduled visits. 14/16 of the health aides (83%) met the stipulated criteria for the simulation study using a module from British Hypertension Society. In the field survey of 920 individuals where 20% of the population was evaluated by a blinded investigator, the weighted Kappa for agreement, using normal, pre-hypertension and hypertension as categories, ranged between 62% and 89%. Only 75/286 (25%) of those detected to be hypertensive knew their status prior to the study. All those detected with hypertension were referred to a physician at a referral facility. 70% of those referred were evaluated at the referral facility and 64% of them initiated on treatment for hypertension within 3 months. Using primary care workers to screen for hypertension through the model suggested here will ensure that the population over 50 years of age will be screened once every 2 years without burdening the worker. This screening process will enable the health system to identify and cater to needs of this vulnerable population.


[Study of bone marrow in patients with breast cancer to detect tumor cells and their complexes].
The article presents results of the research of bone marrow of patients with breast cancer (BC) for the presence of tumor cells and their complexes using cytological and immunological methods of diagnostics. The results were compared with the works of foreign scientists working in oncology and it correlates with them. Quite a large percentage of detection of tumor cells in bone marrow even under I-II and III stages of the disease and a clear relationship with the clinical course: local recurrence, bone and visceral metastasis indicate that these data can be used in complex examination of patients with BC and take into account when planning the tactics of the treatment and follow-up during systemic polychemotherapy and hormonal therapy.


Associations between maternal stress and smoking: findings from a population-based prospective cohort study.
To investigate associations between maternal stress and smoking prior to, during and 6 months after the pregnancy. A prospective population-based cohort study. Norway. A total of 71 757 women in the Norwegian Mother and Child Cohort Study (MoBa) participating twice during pregnancy and at 6 months postpartum. Respondents' estimates of anxiety and depression, relationship discord and negative life events were measured, along with self-reports of smoking behaviour and demographic variables. Smoking was assessed at gestation weeks 17 and 30 and at 6 months postpartum. Of the 27.5% women who smoked at conception, 55.8% quit smoking during pregnancy. At 6 months postpartum, 28.9% of quitters had relapsed to smoking. In total, 12.9% of the sample reported smoking during the pregnancy. Adjusted for well-known risk factors, women reporting high levels of anxiety and depression had a decreased likelihood of quitting smoking during pregnancy [odds ratio (OR) 0.80, 95% confidence interval (CI): 0.73, 0.88) and an increased likelihood of relapsing after delivery (OR 1.26, 95% CI: 1.11, 1.44). Both relationship discord (OR 0.82, 95% CI: 0.75, 0.90) and exposure to negative life events (OR 0.93, 95%: CI 0.90, 0.96) had a negative influence on quitting smoking during pregnancy but had no influence on relapse to smoking postpartum. Maternal stress and relationship discord may inhibit smoking cessation during pregnancy and promote resumption of smoking after pregnancy in women who have achieved abstinence.


Geometry-invariant texture retrieval using a dual-output pulse-coupled neural network.
This letter proposes a novel dual-output pulse coupled neural network model (DPCNN). The new model is applied to obtain a more stable texture description in the face of the geometric transformation. Time series, which are computed from output binary images of DPCNN, are employed as translation-, rotation-, scale-, and distortion-invariant texture features. In the experiments, DPCNN has been well tested by using Brodatz's album and the VisTex database. Several existing models are compared with the proposed DPCNN model. The experimental results, based on different testing data sets for images with different translations, orientations, scales, and affine transformations, show that our proposed model outperforms existing models in geometry-invariant texture retrieval. Furthermore, the robustness of DPCNN to noisy data is examined in the experiments.


[Abolishment of allogeneic inhibition of colony formation with the aid of various RNA classes].
The authors analysed the capacity of various temperature fractions of RNA isolated from the spleen of donors of the bone marrow cells (of mice C57BL/6I) and recipients--hybrids (CBA X C57BL/6I) F1 to abolish the depression of colony formation in the nonsyngenous organism. In the administration of bone marrow cells of mice of parental genotype C57BL/6I of the irradiated recipients F1 there is observed a sharp depression of the number of colony forming units in the spleen F1. This depression can be eliminated by preliminary incubation of the bone marrow cells of mice of parental genotype with a 63 degrees fraction of the recipient's RNA. Preliminary inculation of the bone marrow cells of mice of parental genotype with 85 degrees and cytoplasmic fractions of recipient's RNA led to a partial restoration of colony formation only. The 45 degrees and 55 degrees RNA fractions of the recipient's RNA produced no restoring action. None of the temperature RNA fractions of the RNA of donor bone marrow cells were capable of abolishment of the colony formation depression in the nonsyngenous organism. It is supposed that restoration of the colony forming capacity in the nonsyngenous organism was connected with the activity of matrix RNA of the 63 degrees fraction obtained from the recipient's spleen.


Characterization and expression of codon optimized soybean phytase gene in E. coli.
Phytic acid, the major storage form of phosphorus in plant seeds is degraded by the phytases to yield inositol and free phosphate, contributing thereby to the improved bioavailability of phytate phosphorus and essential minerals in plant foods and simultaneous reduction in phosphorus pollution of the terrestrial and aquatic ecosystems. As a possible strategy for altering seed phytate levels, the approach involving reduction of phytate content by ectopically expressing endogenous phytase gene during seed development of soybean (Glycine max L. cv. Pusa-20) was attempted in the present study. Semi-quantitative RT-PCR revealed the maximum expression of phytase gene transcripts in germinating cotyledons (approximately 10 days after germinations), compared to other vegetative tissues. A full-length phytase cDNA was amplified from the germinating seedlings by splicing by overlap extension (SOE)-PCR and its sequence analysis revealed an open-reading-frame of 1644 bp, including an N terminal signal peptide of 28 amino acids. Predicted amino acid sequence (547-aa) of molecular mass 62 kDa on alignment with related purple acid phosphatases in other plants shared five conserved domains and seven invariant amino acids involved in coordination of the metals in the binuclear center of purple acid phosphatases. Owing to a large number of E. coli low-usage codons in soybean phytase gene, the modified gene was cloned into a prokaryotic expression vector pET-28a (+) and its expression in E. coli was confirmed by SDS-PAGE and Western blot analysis. Bioassay of the crude expression product in E. coli revealed a functional phytase gene, showing a great potential for developing low phytate transgenic soybean through its seed-specific overexpression in the early stages of seed development.


Optical Coherence Tomography-Guided Robotic Ophthalmic Microsurgery via Reinforcement Learning from Demonstration.
Ophthalmic microsurgery is technically difficult because the scale of required surgical tool manipulations challenge the limits of the surgeon's visual acuity, sensory perception, and physical dexterity. Intraoperative optical coherence tomography (OCT) imaging with micrometer-scale resolution is increasingly being used to monitor and provide enhanced real-time visualization of ophthalmic surgical maneuvers, but surgeons still face physical limitations when manipulating instruments inside the eye. Autonomously controlled robots are one avenue for overcoming these physical limitations. We demonstrate the feasibility of using learning from demonstration and reinforcement learning with an industrial robot to perform OCT-guided corneal needle insertions in an ex vivo model of deep anterior lamellar keratoplasty (DALK) surgery. Our reinforcement learning agent trained on ex vivo human corneas, then outperformed surgical fellows in reaching a target needle insertion depth in mock corneal surgery trials. This work shows the combination of learning from demonstration and reinforcement learning is a viable option for performing OCT guided robotic ophthalmic surgery.


Food-borne illnesses during pregnancy: prevention and treatment.
After hearing about outbreaks of illness resulting from Listeria and Salmonella, many of my patients are wondering about the risks of food-borne illnesses during pregnancy and what they can do to reduce their chances of contracting them. Although heating or cooking food is the best way to inactivate food-borne pathogens, improved standards and surveillance have reduced the prevalence of contaminated foods at grocery stores. Therefore, it is no longer necessary for pregnant women to avoid foods like deli meats and soft cheeses (associated with Listeria); soft-cooked eggs (associated with Salmonella); or sushi and sashimi. Regardless of whether seafood is raw or cooked, pregnant women should choose low mercury seafood (eg, salmon and shrimp) over higher mercury varieties (eg, fresh tuna). Pregnant women should ensure that their food is obtained from reputable establishments; stored, handled, and cooked properly; and consumed within a couple of days of purchasing.


Tissue distribution of 3H-corticosterone in response to stress.
The level and distribution of 3H-corticosterone (3H-B) was investigated in adult male Sprague-Dawley rats in response to diethyl ether stress, epinephrine (EP) and/or dexamethasone (DXM) administration. Diethyl ether stress caused a significant increase in the 3H-B counts by some of the body tissues and brain regions studied. Plasma 3H-B counts in the stressed rats were found to be twice as much as in the control animals. When EP (1.0 mg/kg) was injected, the tissue-plasma ratios(TPR) of 3H-B were significantly lower (P less than 0.05) than those of the dexamethasone (1.0 mg/kg) treated animals or the control group. The high 3H-B count in the plasma in response to diethyl ether stress or EP may indicate a decline in rate of corticosterone metabolism.


Inhibition of the cardiovascular response to stress by systemic 5-HT1A activation: sympathoinhibition or anxiolysis?
5-HT(1A) agonists given systemically are known to produce anxiolytic effects. In addition, a growing body of research is showing that those compounds also have central sympathoinhibitory properties. Since emotional arousal gives rise to sympathetic activation, it is not clear whether systemic treatment with a 5-HT(1A) agonist reduces the sympathetic response to emotional stress primarily by a direct action on sympathetic-related sites in the brain or indirectly through reducing anxiety. To test this, we compared the effect of intraperitoneal injections of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.05 and 0.25 mg/kg), a preferential 5-HT(1A) agonist, or vehicle on the cardiovascular responses to four stressors known to produce sympathetic activation, three being emotional stressors, and one physiological. In conscious rats, 30-min exposure to either a neutral context, a fear-conditioned context, or to restraint stress led to increases in heart rate and blood pressure, which were attenuated by 8-OH-DPAT. In contrast, the same treatment did not reduce the cardiovascular response to 30-min cold exposure (4 degrees C). The results suggest that 8-OH-DPAT acts preferentially on limbic, rather than central, autonomic sites. Hence, doses of 5-HT(1A) agonists, which are just sufficient to produce anxiolysis, are not enough to cause true sympathoinhibition.


H2 Oxidation over Supported Au Nanoparticle Catalysts: Evidence for Heterolytic H2 Activation at the Metal-Support Interface.
Water adsorbed at the metal-support interface (MSI) plays an important role in multiple reactions. Due to its importance in CO preferential oxidation (PrOx), we examined H2 oxidation kinetics in the presence of water over Au/TiO2 and Au/Al2O3 catalysts, reaching the following mechanistic conclusions: (i) O2 activation follows a similar mechanism to that proposed in CO oxidation catalysis; (ii) weakly adsorbed H2O is a strong reaction inhibitor; (iii) fast H2 activation occurs at the MSI, and (iv) H2 activation kinetics are inconsistent with traditional dissociative H2 chemisorption on metals. Density functional theory (DFT) calculations using a supported Au nanorod model suggest H2 activation proceeds through a heterolytic dissociation mechanism, resulting in a formal hydride residing on the Au and a proton bound to a surface TiOH group. This potential mechanism was supported by infrared spectroscopy experiments during H2 adsorption on a deuterated Au/TiO2 surface, which showed rapid H-D scrambling with surface hydroxyl groups. DFT calculations suggest that the reaction proceeds largely through proton-mediated pathways and that typical Brønsted-Evans Polanyi behavior is broken by introducing weak acid/base sites at the MSI. The kinetics data were successfully reinterpreted in the context of the heterolytic H2 activation mechanism, tying together the experimental and computational evidence and rationalizing the observed inhibition by physiorbed water on the support as blocking the MSI sites required for heterolytic H2 activation. In addition to providing evidence for this unusual H2 activation mechanism, these results offer additional insight into why water dramatically improves CO PrOx catalysis over Au.


Epithelioid angiosarcoma of the spine: A case report of a rare bone tumor.
Epithelioid angiosarcoma (EA) is an extremely rare subtype of angiosarcoma, which is characterized by large cells with an epithelioid morphology. EA typically arises in deep soft tissues, including the adrenal gland, skin and thyroid, however, EA rarely arises in the spine. The current study presents a case of osteolytic lesions involving the fourth lumbar (L4) level of the spine. Preoperatively, the patient was misdiagnosed with metastatic carcinoma, however, a radiological examination detected the presence of osteolytic or destructive lesions in the vertebrae, which extended into the pedicles. Histopathological and immunohistochemical evaluations were performed on the tumor tissue obtained from a decompression specimen of the L4 vertebra. A bone lesion composed of sheet-like malignant cells exhibiting atypical epithelioid morphology with vascular formation was observed. The presence of anastomosing vascular channels lined by epithelioid endothelial cells also indicated that focal endothelial differentiation had occurred. In addition, immunohistochemistry assays revealed that the lesion was positive for the endothelial cell markers, CD31, CD34 and vimentin. The tumor was treated with decompression of the L4 vertebra, followed by posterior stabilization. The patient subsequently refused chemotherapy and radiotherapy but completed six months of follow-up. At the time of writing, the tumor remains under control and the patient is asymptomatic. This case highlights the difficulty of diagnosing EA, which requires careful pathological examination and immunophenotype labeling. At present, CD31 is the most sensitive marker for detecting EA.


First-principles theory of atomic-scale friction explored by an intuitive charge density fluctuation surface.
Atomic-scale friction theory, and even superlubricity, is inseparable from charge redistribution, but lacks a bridge to establish the potential link between them. Here, we first report a quantized charge density fluctuation surface (CDFS) by assembling silicene/graphene and germanene/graphene heterostructures and their corresponding homogeneous bilayers for DFT calculations. By observing the PES morphology, we see that it exhibits a decrease in friction by more than two orders of magnitude. A crucial physical quantity controlling the friction was found to be the charge density fluctuation during the friction process via analyzing the CDFSs. Such CDFS holds a universal applicability in van der Waals materials, and is recommended to explore the friction cooperating with PES. This will be a new idea for exploring whether friction is related to electrical properties by defining the conversion factor K for a wide series of interactions, including metallic, covalent, and van der Waals bonding. In particular, the same conversion factor K exists for van der Waals bonding, and a mutual identification between the CDFS and PES can be achieved.


Expanding the Phenotype of TRMT10A Mutations: Case Report and a Review of the Existing Cases
The tRNA methyltransferase 10 homologue A (TRMT10A) gene encodes tRNA methyl transferase, and biallelic loss of function mutations cause a recessive syndrome of intellectual disability, microcephaly, short stature and diabetes. A case with intellectual disability and distinctive features including microcephaly was admitted. She was diagnosed with epilepsy at 2.5 years old. At 3.6 years of age, severe short stature related to growth hormone (GH) deficiency was detected. She had an incidental diagnosis of diabetes at age 11.4 years which was negative for diabetes antibodies with persistent C-peptide level and she was treated with metformin. Spontaneous puberty did not begin until 15.7 years of age and she was found to have primary ovarian failure. A homozygous p.Arg127* mutation in TRMT10A was detected. In addition to the typical clinical features which characterize TRMT10A syndrome, we observed an unusual form of impaired glucose metabolism which presented in early childhood with hypoglycemia followed by diabetes in late childhood. GH deficiency and primary ovarian failure may also be additional findings of this syndrome. Patients with slow onset diabetes who are negative for auto-antibodies and have extra-pancreatic features should be tested for all known subtypes of monogenic diabetes.


[Problem of fracture of the radius head in the child].
Guidelines for the choice of conservative or operative treatment of fractures of the proximal radius are derived from a study comprising 21 children. Postoperative complications and long-term failures are specifically stressed. True intraarticular fractures of the radial head are rarely observed in children. Major problems arise in the treatment of comminuted fractures of the radial head associated with dislocation of the elbow, since these show the worst prognosis. Displaced marginal fractures below 3 mm are suited for early functional treatment using conservative procedures. 18 patients suffered a fracture of the radial neck type III and IV (Judet). Despite low failure rates of the operative therapy, we have recently been refraining from the operation.


Single-photon tomographic determination of regional cerebral blood flow in epilepsy.
Using a single-photon emission computed tomographic scanner (SPECT) the authors determined regional cerebral blood flow (rCBF) with inhaled xenon-133, a noninvasive procedure. Studies were performed in 40 normal individuals, and these were compared with rCBF determinations in 51 patients with seizure disorders. Although positive results were obtained in 15 of 16 patients with mass lesions, the group of principal interest comprised 25 patients suffering from "temporal lobe" epilepsy. Only one of these had a positive x-ray computed tomogram, but 16 had positive findings on rCBF study. These findings included increased local blood flow in the ictal state and reduced flow interictally.


The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.
Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic coronavirus named SARS-CoV-2 (previously known as 2019-nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS-CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. The most characteristic symptom of patients with COVID-19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID-19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS-CoV and SARS-CoV2, it remains to make clear whether the potential invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of patients with COVID-19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS-CoV-2-induced respiratory failure.


[Primary study on infection of Epstein Barr virus in malignant tumors of oral and maxillofacial regions]
OBJECTIVE:To indicate the relationship between infection of the Epstein-Barr virus and malignant tumors of oral and maxillofacial regions.METHODS:The Epstein-Barr virus DNA was measured in tissues and saliva of 18 patients with malignant tumors of oral and maxillofacial regions by polymerase chain reaction (PCR).RESULTS:It showed that DNAs of EB virus fragment were amplified in tissues and saliva of 3 patients with salivary carcinoma,but negative in controls and squamous cell carcinomas and sarcomas.CONCLUSION:It indicated that there was association between Epstein-Barr virus and salivary carcinoma.


Color vision devices for color vision deficiency patients: A systematic review and meta-analysis.
There is insufficient evidence to support that using electronic or optical color vision devices improve color perception with current advanced technology. The purpose of this study is to compare and analyze the different color vision devices available for patients with color vision deficiency (CVD) and evaluate whether these devices improved their color perception. This review included randomized, experimental, comparative studies, as well as narrative reviews, prototype and innovation studies, and translational studies, followed by case-control and clinical trials with nonsurgical interventions studies, that is, electronic color vision devices, optical devices, and contact lens-based studies, with standardized inclusion and exclusion criteria. The primary outcome studied was the performance of color vision devices, both objective and subjective. Secondary outcomes included the ease of use and accessibility of color vision devices and technology. The grading of recommendation, assessment, development, and evaluation framework was used to develop a systematic approach for consideration and clinical practice recommendation for CVD devices for color-deficient populations. We incorporated meta-analysis reports from a total of n = 16 studies that met the criteria which consisted of case-control studies, prototype and innovation studies, comparative studies, pre- and post-clinical trial studies, case studies, and narrative reviews. Proportion and standard errors, as well as correlations, were calculated from the meta-analysis for various available color vision devices. This review concludes that commercially available color vision devices, such as EnChroma Glasses, Chromagen filters, and EnChroma Cx-14 do not provide clinically significant evidence that subjective color perception has improved. As a result, recommending these color vision devices to the CVD population may not prove high beneficial/be counterproductive. However, only a few color shades can be perceived differently. This systematic review and analysis will aid future research and development in color vision devices.


Problems in the reporting of acne clinical trials: a spot check from the 2009 Annual Evidence Update on Acne Vulgaris.
In the course of producing the 2009 NHS Evidence--skin disorders Annual Evidence Update on Acne Vulgaris, 25 randomised controlled trials were examined. From these, at least 12 potentially serious problems of trial reporting were identified. Several trials concluded no effect of a treatment yet they were insufficiently powered to exclude potentially useful benefits. There were examples of duplicate publication and "salami publication", as well as two trials being combined and reported as one. In some cases, an incorrect "within-groups" statistical comparison was made and one trial report omitted original efficacy data and included only P values. Both of the non-inferiority studies examined failed to pre-specify a non-inferiority margin. Trials reported as "double-blind" compared treatments that were dissimilar in appearance or had differing adverse effect profiles. In one case an intention-to-treat analysis was not performed and there was a failure to account for all of the randomized participants. Trial results were made to sound more impressive by selective outcome reporting, emphasizing the statistical significance of treatment effects that were clinically insignificant, and by the use of larger-sounding odds ratios rather than rate ratios for common events. Most of the reporting problems could have been avoided by use of the CONSORT guidelines and prospective trial registration on a public clinical trials database.


Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing's sarcoma.
Many poor-risk neuroblastomas and tumours of the Ewing's sarcoma family (ET) recur despite autologous transplants. Recurrence may be due to tumor cells contained in the BM harvests or PBSC harvests. The objectives of this prospective study were to: (1) determine the incidence and degree of tumor cell contamination in paired BM and PBSC harvests; and (2) determine the efficacy of tumor cell purging by immunomagnetic CD34+ cell selection. 198 samples from 11 consecutive patients with neuroblastoma or Ewing's sarcoma were analyzed. We assayed tumor contamination by RT-PCR assay for PGP 9.5, plus immunohistochemistry for neuroblastoma-specific antigens (the latter in neuroblastoma only). None of these patients had tumor cells detected in their BM by clinical histology immediately before BM or PBSC harvests. However, 82% of PBSC and 89% of backup BM harvests were contaminated with tumor by RT-PCR and/or immunocytochemistry assays. Unselected PBSC and BM harvests contained similar quantities of tumor cells (median, approximately 200000 cells). Cyclophosphamide plus G-CSF mobilization did not affect the incidence or level of contamination in PBSC harvests, as compared to blood obtained before mobilization. Immunomagnetic CD34+ cell selection depleted tumor cells by a median of 3.0 logs for PBSC, and 2.6 logs for BM harvests.


Acalculous cholecystitis: its role as a complication of major burn injury.
The authors present four cases of acute acalculous cholecystitis complicating major burn injury and review the recent literature on acalculous cholecystitis. All patients were men and ranged in age from 22 to 40 years. The mean extent of the burn was 50% of the total body surface area, with an average 29% third-degree component. All four patients survived. Because of their severity, major burn injuries expose patients to many risks, including acute acalculous cholecystitis. Recent experimental evidence supports a vascular insult through the activation of Factor XII pathways as the initial event. A diagnosis is made on clinical grounds, supported by laboratory and ultrasonographic findings, in a patient with a burn covering more than 30% of the total body surface area and who has signs of acute cholecystitis. Cholecystectomy is the treatment of choice; tube cholecystostomy is reserved for critically ill patients.


The state of vaccine safety science: systematic reviews of the evidence.
This Review updates the scientific evidence assessing possible causal associations of adverse events following immunisation (AEFI) compiled in the 2012 report from the Institute of Medicine and the 2014 report from the Agency for Healthcare Research and Quality. For 12 of 46 AEFI examined, a causal relationship has been established with at least one vaccine currently routinely recommended to the general USA population: anaphylaxis, arthralgia or arthritis (mild, acute, and transient, not chronic), deltoid bursitis (when vaccine is administered improperly), disseminated varicella infection (in immune deficient individuals for whom the varicella vaccine is contraindicated), encephalitis, febrile seizures, Guillain-Barré syndrome, hepatitis (in immune deficient individuals for whom the varicella vaccine is contraindicated), herpes zoster, immune thrombocytopenic purpura, meningitis, and syncope. Other than mild acute and transient arthralgia or arthritis, which is very common in adult women after rubella vaccine, these adverse reactions are rare or very rare. Vaccines have an excellent safety profile overall and provide protection against infectious diseases to individuals and the general population.


Spatial cognition and motor development: a study of children with spina bifida.
The purpose of this study was to examine the relation between motor development and spatial cognition. The sample was 20 children with Spina bifida (M age: 11.4 yr., SD = 1.7) and 20 healthy children as controls (M age: 11.8, SD = 1.8 yr.). An experimental assessment of motor development in spatial cognition in a simulated virtual maze by school-age children is lacking. In this study children with Spina bifida, who were impaired in walking since birth, completed four visuospatial tasks in a small-scale space (Mental Rotation, Water-Level Task, Embedded Figures Test, Visual Short-term Memory Test), and a spatial behaviour and knowledge task in a virtual maze. These children showed poorer performance than children in the control group on most measures. The results are discussed with respect to theoretical implications and further research.


Quantitative analysis of the flavonoids in raw propolis from northern Croatia.
Spectrometric analyses of flavonoids in twenty propolis samples, collected from ten different geographic localities in northern Croatia using two complementary methods, are reported. Flavones and flavonols were determined using aluminum chloride and expressed as quercetine equivalent while flavanones were determined using 2,4-dinitrophenylhydrazine and expressed as naringenin. Contents of flavones and flavonols were similar for most samples and ranged from 2 to 2.3%, except for one sample with a concentration of 1.3% and one sample in which it was not possible to detect flavones and flavonols. The content of flavanones in propolis samples is very variable. 55% of samples contained flavanones between 15 and 24% and 45% of samples between 4 and 14%. Total levels of flavonoids in raw propolis samples ranged between 5 and 26%; for the majority of samples (75%), the total level of flavonoids ranged between 15 and 25.9%. The high variability of flavanone concentration will affect the biological activity of propolis preparations.


Clinically useful predictors for premature mortality among psychiatric patients visiting a psychiatric emergency room.
The aim of this study was to examine changes in the distribution of causes of death and mortality rates among psychiatric patients visiting a psychiatric emergency room (PER), to determine clinically useful predictors for avoiding premature mortality among these patients and to discuss possible interventions. The study was designed as a historical prospective record linkage study of patients with at least one visit to a Danish PER in 1995-2007. Five consecutive 3-year cohorts of individuals aged 20 to <80 years were identified. Data from the Danish Civil Registration System were linked to the Cause of Death Register and the Central Psychiatric Research Register, and logistic predictor analyses for premature death were performed. The standardised mortality ratio (SMR) of all visitors compared to the general Danish population was approximately 5. Overall, patients with drug and/or alcohol use disorder experienced at least a twofold increase in SMR compared to patients without substance use disorder. In the case of patients with schizophrenia and a concurrent substance use disorder, the SMR increased considerably. During the period, substance use disorder was the strongest predictor of premature death among visitors to a PER (odds ratio (OR) = 1.8; 95% confidence interval (CI) = 1.5, 2.2). Persons visiting the PER had an increased SMR and substance use disorders were the strongest predictor of premature death within 3 years. However, death caused by substance use disorder is preventable, and PERs are ideal points of early intervention. Systematic screening for substance use disorder at the PER and/or crisis intervention teams may be effective intervention strategies.


Cytotoxic effect of galvanically coupled magnesium-titanium particles on Escherichia coli.
Orthopedic device-related infections (ODRIs) are difficult to control due to microbial biofilm formation and associated with high-level resistance to conventional antibiotics. In many cases, the only treatment option for ODRI is explantation. Previous studies have shown that application of cathodic potentials at the metal surface can eradicate biofilms, and Mg and Mg-Ti particles have the same effect as cathodic potentials. This study investigated the effects of Mg and Mg-Ti particles on established biofilms and planktonic cells E. coli. Bacterial cultures with developed biofilms or planktonic cells were treated with Mg or Mg-Ti particles, and the viability were assessed using flow cytometry or visual assessment methods (i.e., observation from SEM images and opacity of the solution). It was found that viability of biofilms treated with 16.67 mg/ml of Mg was 2.8 ± 0.96% at the end of 6-hr killing compared to untreated controls. This extent of killing was more significant compared to 24-hr grown biofilms treated with ofloxacin, an antibiotic known to be effective against these bacteria. Biofilms treated with 50 and 100 μg/ml of ofloxacin had 62 ± 4.6% and 52 ± 19.3% survival, respectively, where ofloxacin at these concentrations is known to kill planktonic counterparts very effectively. Inhibition zone tests revealed that biofilms within 2 mm of Mg or Mg-Ti particle clusters were effectively killed. These results demonstrated the potential of Mg or Mg-Ti particles in killing microbial biofilms and potential for controlling ODRI.


Allowing for never and episodic consumers when correcting for error in food record measurements of dietary intake.
Food records, including 24-hour recalls and diet diaries, are considered to provide generally superior measures of long-term dietary intake relative to questionnaire-based methods. Despite the expense of processing food records, they are increasingly used as the main dietary measurement in nutritional epidemiology, in particular in sub-studies nested within prospective cohorts. Food records are, however, subject to excess reports of zero intake. Measurement error is a serious problem in nutritional epidemiology because of the lack of gold standard measurements and results in biased estimated diet-disease associations. In this paper, a 3-part measurement error model, which we call the never and episodic consumers (NEC) model, is outlined for food records. It allows for both real zeros, due to never consumers, and excess zeros, due to episodic consumers (EC). Repeated measurements are required for some study participants to fit the model. Simulation studies are used to compare the results from using the proposed model to correct for measurement error with the results from 3 alternative approaches: a crude approach using the mean of repeated food record measurements as the exposure, a linear regression calibration (RC) approach, and an EC model which does not allow real zeros. The crude approach results in badly attenuated odds ratio estimates, except in the unlikely situation in which a large number of repeat measurements is available for all participants. Where repeat measurements are available for all participants, the 3 correction methods perform equally well. However, when only a subset of the study population has repeat measurements, the NEC model appears to provide the best method for correcting for measurement error, with the 2 alternative correction methods, in particular the linear RC approach, resulting in greater bias and loss of coverage. The NEC model is extended to include adjustment for measurements from food frequency questionnaires, enabling better estimation of the proportion of never consumers when the number of repeat measurements is small. The methods are applied to 7-day diary measurements of alcohol intake in the EPIC-Norfolk study.


Steroid treatment in young MRL.MpJ-Fas(lpr) autoimmune mice prevents cochlear dysfunction.
Corticosteroid therapy reverses clinical autoimmune sensorineural hearing loss, although little is known of how steroids restore normal auditory function. If suppression of systemic autoimmune processes underlies hearing restoration, then preventing autoimmune symptoms from developing should prevent cochlear dysfunction. MRL. MpJ-Fas(lpr) autoimmune mice were used to test this potential mechanism by initiating oral prednisolone treatment at 6 weeks of age, prior to autoimmune disease and hearing loss onset. The steroid treatment group was given prednisolone in their drinking water, while untreated controls were given tap water. Treatment continued for 7 months with periodic evaluations of cochlear function with auditory brainstem response (ABR) audiometry. Autoimmune mice given the steroid lived longer and did not develop levels of serum immune complexes seen in their untreated controls. Also, their ABR thresholds remained near normal throughout the 7 months of treatment, while untreated controls showed progressive threshold elevations typical for autoimmune disease. This correlation of suppressed systemic autoimmune activity and maintenance of normal cochlear function identifies one potential mechanism for autoimmune hearing loss and hearing restoration with steroid therapy. The autoimmune mouse should serve as a valuable model for future studies of the cochlear mechanisms responsive to steroid treatment in autoimmune hearing loss.


A novel method for the detection of necrotic lesions in human cancers.
Data are presented in support of the hypothesis that malignant tumors, containing abnormally permeable, degenerating cells, can be selectively detected using monoclonal antibodies to intracellular antigens. Biodistribution, imaging, and autoradiographic studies were performed in nude mice transplanted with four different human tumor cell lines to demonstrate the binding of radiolabeled antinuclear monoclonal antibodies within bulky tumors containing necrotic lesions. For these studies, two monoclonal antibodies, designated TNT-1 (IgG2a) and TNT-2 (IgM) were chosen since they were found to bind to abundant nuclear antigens which are retained in permeable, dying cells. F(ab')2 fragments prepared by pepsin digestion were radiolabeled with iodine-125 or iodine-131 by the iodogen method for i.v. administration. Biodistribution studies in nontumor-bearing BALB/c mice at various time intervals revealed normal patterns of antibody excretion with no accumulation of antibody in healthy organs. In contrast, biodistribution studies performed on Day 3 in tumor-bearing nude mice showed high tumor to organ ratios in those animals bearing necrotic tumors. Necrotic regions dissected at necropsy gave tumor to blood ratios as high as 131:1. Transplants having little demonstrable necrosis were found to have low tumor to blood ratios (0.4:1). Sequential imaging studies confirmed the high tumor-to-organ ratios and showed positive tumor imaging as early as 4 h. Autoradiographic studies of excised tumors showed the presence of label selectively in necrotic areas with preferential labeling over the nuclei of degenerating cells. Because of the universal presence of these nuclear antigens and the known prevalence of necrosis in tumors, this approach may be of value for the imaging and treatment of a wide variety of cancers in humans.


Nodule detection in a lung region that's segmented with using genetic cellular neural networks and 3D template matching with fuzzy rule based thresholding.
The purpose of this study was to develop a new method for automated lung nodule detection in serial section CT images with using the characteristics of the 3D appearance of the nodules that distinguish themselves from the vessels. Lung nodules were detected in four steps. First, to reduce the number of region of interests (ROIs) and the computation time, the lung regions of the CTs were segmented using Genetic Cellular Neural Networks (G-CNN). Then, for each lung region, ROIs were specified with using the 8 directional search; +1 or -1 values were assigned to each voxel. The 3D ROI image was obtained by combining all the 2-Dimensional (2D) ROI images. A 3D template was created to find the nodule-like structures on the 3D ROI image. Convolution of the 3D ROI image with the proposed template strengthens the shapes that are similar to those of the template and it weakens the other ones. Finally, fuzzy rule based thresholding was applied and the ROI's were found. To test the system's efficiency, we used 16 cases with a total of 425 slices, which were taken from the Lung Image Database Consortium (LIDC) dataset. The computer aided diagnosis (CAD) system achieved 100% sensitivity with 13.375 FPs per case when the nodule thickness was greater than or equal to 5.625 mm. Our results indicate that the detection performance of our algorithm is satisfactory, and this may well improve the performance of computer-aided detection of lung nodules.


Susceptibility of lung epithelium to neutrophil elastase: protection by native inhibitors.
The development of emphysema is thought to be due to an imbalance of proteases (especially neutrophil elastase [NE]) and antiproteases with loosening of the respiratory epithelium as an early event. We investigated the effect of NE on respiratory epithelial cell adherence in vitro , in the presence of varying concentrations and combinations of native inhibitors, alpha-1-proteinase inhibitor (PI) and secretory leukoprotease inhibitor (SLPI). SLPI was two to 12 times more effective than PI at preventing the effects of NE, especially when enzyme:inhibitor ratios were almost equivalent. Even when the concentration of SLPI was only 10% of the total (as in normal peripheral lung secretions), it gave greater protection than PI alone. This suggests that SLPI plays an important role in controlling neutrophil elastaseinduced inflammation and tissue damage.


The somatodendritic endosomal regulator NEEP21 facilitates axonal targeting of L1/NgCAM.
Correct targeting of proteins to axons and dendrites is crucial for neuronal function. We showed previously that axonal accumulation of the cell adhesion molecule L1/neuron-glia cell adhesion molecule (NgCAM) depends on endocytosis (Wisco, D., E.D. Anderson, M.C. Chang, C. Norden, T. Boiko, H. Folsch, and B. Winckler. 2003. J. Cell Biol. 162:1317-1328). Two endocytosis-dependent pathways to the axon have been proposed: transcytosis and selective retrieval/retention. We show here that axonal accumulation of L1/NgCAM occurs via nondegradative somatodendritic endosomes and subsequent anterograde axonal transport, which is consistent with transcytosis. Additionally, we identify the neuronal-specific endosomal protein NEEP21 (neuron-enriched endosomal protein of 21 kD) as a regulator of L1/NgCAM sorting in somatodendritic endosomes. Down-regulation of NEEP21 leads to missorting of L1/NgCAM to the somatodendritic surface as well as to lysosomes. Importantly, the axonal accumulation of endogenous L1 in young neurons is also sensitive to NEEP21 depletion. We propose that small endosomal carriers derived from somatodendritic recycling endosomes can serve to redistribute a distinct set of membrane proteins from dendrites to axons.


Catalase, a remarkable enzyme: targeting the oldest antioxidant enzyme to find a new cancer treatment approach.
This review is centered on the antioxidant enzyme catalase and will present different aspects of this particular protein. Among them: historical discovery, biological functions, types of catalases and recent data with regard to molecular mechanisms regulating its expression. The main goal is to understand the biological consequences of chronic exposure of cells to hydrogen peroxide leading to cellular adaptation. Such issues are of the utmost importance with potential therapeutic extrapolation for various pathologies. Catalase is a key enzyme in the metabolism of H2O2 and reactive nitrogen species, and its expression and localization is markedly altered in tumors. The molecular mechanisms regulating the expression of catalase, the oldest known and first discovered antioxidant enzyme, are not completely elucidated. As cancer cells are characterized by an increased production of reactive oxygen species (ROS) and a rather altered expression of antioxidant enzymes, these characteristics represent an advantage in terms of cell proliferation. Meanwhile, they render cancer cells particularly sensitive to an oxidant insult. In this context, targeting the redox status of cancer cells by modulating catalase expression is emerging as a novel approach to potentiate chemotherapy.


Pain control with ibandronate for bone marrow oedema of the knee.
Bone marrow oedema is a disabling disease characterised by severe bone pain (with or without prior trauma), insufficient response to analgesics, and reduction of weight bearing. Several studies showed promising results after using bisphosphonates to inhibit osteoclast activity. The aim of this study was to investigate the association between ibandronate administration and pain relief in patients with bone marrow oedema of the knee, and to precisely describe its presentation in magnetic resonance imaging (MRI). This is a single-centre, retrospective analysis of 18 patients who received intravenous ibandronate due to bone marrow oedema of the knee between April 2012 and February 2016. Information has been extracted from our clinical database and a questionnaire. Furthermore, an experienced radiologist reassessed all MRI diagnoses. Our results showed a significant reduction of pain from 7.4 to 3.8 points on the visual analogue scale (p = 0.0001; median follow-up 41.5 months). Furthermore, the disability in daily life also significantly decreased (p = 0.008); 55.6% of the participants stated to be pain-free in the follow-up, and the same percentage also did not use alternative therapies after completing therapy with ibandronate (e.g., regular use of analgesics, operation, or local infiltration). However, there was no significant correlation between pain and specific radiologic findings. Participants with bone marrow oedema of the knee showed a significant pain reduction after an administration of ibandronate, independently of the severity showed in MRI. If the first administration leads to an insufficient control of pain, the administration of a second dose may be helpful. As bone marrow oedema syndrome is a self-limiting disease, prospective studies with a comparison group are needed to distinguish between the natural course of the disease and the beneficial effects of bisphosphonates. &nbsp.


Articulated rods - a novel class of molecular rods based on oligospiroketals (OSK).
We developed a new type of molecular rods consisting of two (or more) rigid units linked by a flexible joint. Consequently we called these constructs articulated rods (ARs). The syntheses of ARs were carried out by a flexible and modular approach providing access to a number of compounds with various functionalizations in terminal positions. First applications were presented with pyrene, cinnamoyl and anthracenyl labelled ARs.


An auxin-mediated shift toward growth isotropy promotes organ formation at the shoot meristem in Arabidopsis.
To control morphogenesis, molecular regulatory networks have to interfere with the mechanical properties of the individual cells of developing organs and tissues, but how this is achieved is not well known. We study this issue here in the shoot meristem of higher plants, a group of undifferentiated cells where complex changes in growth rates and directions lead to the continuous formation of new organs. Here, we show that the plant hormone auxin plays an important role in this process via a dual, local effect on the extracellular matrix, the cell wall, which determines cell shape. Our study reveals that auxin not only causes a limited reduction in wall stiffness but also directly interferes with wall anisotropy via the regulation of cortical microtubule dynamics. We further show that to induce growth isotropy and organ outgrowth, auxin somehow interferes with the cortical microtubule-ordering activity of a network of proteins, including AUXIN BINDING PROTEIN 1 and KATANIN 1. Numerical simulations further indicate that the induced isotropy is sufficient to amplify the effects of the relatively minor changes in wall stiffness to promote organogenesis and the establishment of new growth axes in a robust manner.


Synthesis of quinone imine and sulphur-containing compounds with antitumor and trypanocidal activities: redox and biological implications.
Ortho-Quinones represent a special class of redox active compounds associated with a spectrum of pronounced biological activities, including selective cytotoxicity and antimicrobial actions. The modification of the quinone ring by simple nitrogen and sulphur substitutions leads to several new classes of compounds with their own, distinct redox behaviour and equally distinct activities against cancer cell lines and Trypanosoma cruzi. Some of the compounds investigated show activity against T. cruzi at concentrations of 24.3 and 65.6 μM with a selectivity index of around 1. These results demonstrate that simple chemical modifications on the ortho-quinone ring system, in particular, by heteroatoms such as nitrogen and sulphur, transform these simple redox molecules into powerful cytotoxic agents with considerable "potential", not only in synthesis and electrochemistry, but also, in a broader sense, in health sciences.


Interleukin-19 mediates tissue damage in murine ischemic acute kidney injury.
Inflammation and renal tubular injury are major features of acute kidney injury (AKI). Many cytokines and chemokines are released from injured tubular cells and acts as proinflammatory mediators. However, the role of IL-19 in the pathogenesis of AKI is not defined yet. In bilateral renal ischemia/reperfusion injury (IRI)-induced and HgCl2-induced AKI animal models, real-time quantitative (RTQ)-PCR showed that the kidneys, livers, and lungs of AKI mice expressed significantly higher IL-19 and its receptors than did sham control mice. Immunohistochemical staining showed that IL-19 and its receptors were strongly stained in the kidney, liver, and lung tissue of AKI mice. In vitro, IL-19 upregulated MCP-1, TGF-β1, and IL-19, and induced mitochondria-dependent apoptosis in murine renal tubular epithelial M-1 cells. IL-19 upregulated TNF-α and IL-10 in cultured HepG2 cells, and it increased IL-1β and TNF-α expression in cultured A549 cells. In vivo, after renal IRI or a nephrotoxic dose of HgCl2 treatment, IL-20R1-deficient mice (the deficiency blocks IL-19 signaling) showed lower levels of blood urea nitrogen (BUN) in serum and less tubular damage than did wild-type mice. Therefore, we conclude that IL-19 mediates kidney, liver, and lung tissue damage in murine AKI and that blocking IL-19 signaling may provide a potent therapeutic strategy for treating AKI.


Polymer Conjugation to Enhance Cellulase Activity and Preserve Thermal and Functional Stability.
A thermophilic cellulase, FnCel5a, from Fervidobacterium nodosum was conjugated with various functional polymers including cationic, anionic, and strongly and weakly hydrogen bonding polymers. The activity of FnCel5a toward a high-molecular-weight carboxymethyl cellulose substrate was enhanced by polymer conjugation. Activity enhancements of 50% or greater observed for acrylamide and mixed N,N-dimethyl acrylamide-2-(N,N-dimethylamino)ethyl methacrylate polymers, suggesting that the greatest enhancements were caused by polymers capable of noncovalent interactions with the substrate. The conjugates were found to have nearly identical thermodynamic stability to the native enzyme, as assessed by free energy (ΔG), enthalpy (ΔH), and entropy (TΔS) parameters extracted from differential scanning fluorimetry. Polymers tended to confer comparable tolerance to high concentrations of dimethylformamide, with longer polymers typically enabling higher activity relative to shorter polymers. The new FnCel5a conjugates represent an advance in the production of cellulases that maintain activity at high temperatures or in the presence of denaturing organic solvents.


[Establishment of malignant progression associated gene expression profiles in human brain glioma].
To establish malignant progression associated gene expression profiles in human brain glioma. The primary (WHO grade II), recurrent (WHO grade III) and re-recurrent (WHO grade IV) glioma specimens were sequentially collected from one single patient. Gene expression of different tumor specimens and normal brain tissue of the same patient was compared by microarrary techniques. 197 differentially expressed genes with differential ratio > or = 3 were observed when compared with normal brain tissue. When the specimens (3 tumor, 1 normal brain) were paired with each other, 7 groups containing 489 genes (upregulated 193, downregulated 296) were observed. According to the descending frequency of the 109 genes with known function, they were the genes associated with development, metabolism, differentiation, signal transduction, DNA binding transcription, cellular receptor, immunity, ion-channel transportation, protein translation, cell backbone motion, stress, protooncogene and anti-oncogene and cell apoptosis, respectively. From the 197 differentially expressed genes found in one glioma patient experiencing tumor malignant progression, 17 genes screened out by bioinformatics assay, may offer valuable information on molecular mechanisms on genesis and malignant progression of glioma.


Muco-epidermoid carcinoma of the oesophagus: a case report.
Muco-epidermoid carcinomas (MECs) are typically located in the salivary, lacrimal and tracheobronchial glands. However, they can also be present in the oesophagus. Primary MECs of the oesophagus account for 0.05% to 2.2% of all cases of primary oesophageal cancer. Treatment for this tumour has primarily been surgical resection. In this report we present the surgical and pathological findings of a primary MEC of the oesophagus in an 82-year-old woman and review the management options for this tumour.


[A painful collapse: the flat foot management].
Flatfoot is a progressive deformity with a collapse of the foot. Its therapeutic approach has undergone a conceptual shift. Initially focused on posterior tibial tendon insufficiency, it is now defined by a sum of anatomical alterations resulting in a three-dimensional deformity. If the deformity is symptomatic, we look for hindfoot valgus, forefoot abduction and varus, as well as valgus ankle instability. The clinical rigidity of the deformities and the weight-bearing radiological examinations help guide treatment. Although plantar supports and rigid orthoses are sufficient for mild cases, surgical treatment using bone, ligament, tendon or even prosthetics procedures are the final stage of management for severe cases.


Failing to forget: inhibitory-control deficits compromise memory suppression in posttraumatic stress disorder.
Most people have experienced distressing events that they would rather forget. Although memories of such events become less intrusive with time for the majority of people, those with posttraumatic stress disorder (PTSD) are afflicted by vivid, recurrent memories of their trauma. Often triggered by reminders in the daily environment, these memories can cause severe distress and impairment. We propose that difficulties with intrusive memories in PTSD arise in part from a deficit in engaging inhibitory control to suppress episodic retrieval. We tested this hypothesis by adapting the think/no-think paradigm to investigate voluntary memory suppression of aversive scenes cued by naturalistic reminders. Retrieval suppression was compromised significantly in PTSD patients, compared with trauma-exposed control participants. Furthermore, patients with the largest deficits in suppression-induced forgetting were also those with the most severe PTSD symptoms. These results raise the possibility that prefrontal mechanisms supporting inhibitory control over memory are impaired in PTSD.


ROLE OF MULTIPLE FTSZ RINGS IN CHLOROPLAST DIVISION UNDER OLIGOTROPHIC AND EUTROPHIC CONDITIONS IN THE UNICELLULAR GREEN ALGA NANNOCHLORIS BACILLARIS (CHLOROPHYTA, TREBOUXIOPHYCEAE)(1).
Chloroplasts of the unicellular green alga Nannochloris bacillaris Naumann cultured under nutrient-enriched conditions have multiple rings of FtsZ, a prokaryote-derived chloroplast division protein. We previously reported that synthesis of excess chloroplast DNA and formation of multiple FtsZ rings occur simultaneously. To clarify the role of multiple FtsZ rings in chloroplast division, we investigated chloroplast DNA synthesis and ring formation in cells cultured under various culture conditions. Cells transferred from a nutrient-enriched medium to an inorganic medium in the light showed a drop in cell division rate, a reduction in chloroplast DNA content, and changes in the shape of chloroplast nucleoids as cells divided. We then examined DNA synthesis by immunodetecting BrdU incorporated into DNA strands using the anti-BrdU antibody. BrdU-labeled nuclei were clearly observed in cells 48 h after transfer into the inorganic medium, while only weak punctate signals were visible in the chloroplasts. In parallel, the number of FtsZ rings decreased from 6 to only 1. When the cells were transferred from an inorganic medium to a nutrient-enriched medium, the number of cells increased only slightly in the first 12 h after transfer; after this time, however, they started to divide more quickly and increased exponentially. Chloroplast nucleoids changed from punctate to rod-like structures, and active chloroplast DNA synthesis and FtsZ ring formation were observed. On the basis of our results, we conclude that multiple FtsZ ring assembly and chloroplast DNA duplication under nutrient-rich conditions facilitate chloroplast division after transfer to oligotrophic conditions without further duplication of chloroplast DNA and formation of new FtsZ rings.


Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling: DEPENDENCE ON DNA SEQUENCE, MR CONFORMATION, AND AP-1 FAMILY MEMBER EXPRESSION.
Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFκB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFκB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFκB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFκB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.


Single-atom catalysts: a new frontier in heterogeneous catalysis.
Supported metal nanostructures are the most widely used type of heterogeneous catalyst in industrial processes. The size of metal particles is a key factor in determining the performance of such catalysts. In particular, because low-coordinated metal atoms often function as the catalytically active sites, the specific activity per metal atom usually increases with decreasing size of the metal particles. However, the surface free energy of metals increases significantly with decreasing particle size, promoting aggregation of small clusters. Using an appropriate support material that strongly interacts with the metal species prevents this aggregation, creating stable, finely dispersed metal clusters with a high catalytic activity, an approach industry has used for a long time. Nevertheless, practical supported metal catalysts are inhomogeneous and usually consist of a mixture of sizes from nanoparticles to subnanometer clusters. Such heterogeneity not only reduces the metal atom efficiency but also frequently leads to undesired side reactions. It also makes it extremely difficult, if not impossible, to uniquely identify and control the active sites of interest. The ultimate small-size limit for metal particles is the single-atom catalyst (SAC), which contains isolated metal atoms singly dispersed on supports. SACs maximize the efficiency of metal atom use, which is particularly important for supported noble metal catalysts. Moreover, with well-defined and uniform single-atom dispersion, SACs offer great potential for achieving high activity and selectivity. In this Account, we highlight recent advances in preparation, characterization, and catalytic performance of SACs, with a focus on single atoms anchored to metal oxides, metal surfaces, and graphene. We discuss experimental and theoretical studies for a variety of reactions, including oxidation, water gas shift, and hydrogenation. We describe advances in understanding the spatial arrangements and electronic properties of single atoms, as well as their interactions with the support. Single metal atoms on support surfaces provide a unique opportunity to tune active sites and optimize the activity, selectivity, and stability of heterogeneous catalysts, offering the potential for applications in a variety of industrial chemical reactions.


Nurse practitioners in the county correctional facility setting: unique challenges and suggestions for effective health promotion.
The correctional facility practice setting is among the newer practice specialties emerging for nurse practitioners (NPs). As with any new setting, a variety of unique challenges continues to emerge. Because there is a relative paucity of literature regarding NP practice in this particular specialty, those practicing now do not have adequate resources to assist in the development of their practice. This article discusses some of the challenges unique to this area of practice and offers suggestions for incorporating theory-based health promotion interventions. This article is also an effort to begin development of a body of knowledge for NPs providing primary, secondary, and tertiary care to the inmate population of jails and prisons. Hopefully, nurse practitioners in this unique setting will be encouraged to share their own anecdotal and research-based suggestions for improving correctional facility practice.


Occurrence and characteristics of enterotoxigenic Escherichia coli isolated from calves with diarrhea.
Of 1,004 isolates of Escherichia coli obtained during the spring of 1975 in seven different states from calves with diarrhea, 124 isolates were enterotoxigenic based upon ability to cause distention of the calf ligated intestinal segment. Isolates of enterotoxigenic E. coli (ETEC) were obtained from calves in six of the seven states. ETEC were detected in calves in 118 of 355 herds in Montana during the 1974 and 1975 spring beef calving seasons. The occurrence and serotypes of ETEC isolated from calves in states outside Montana were similar to ETEC isolated from calves in Montana. One hundred and fourteen of the 124 isolates of ETEC were placed in one of six different groups upon agglutination in OK antiserum. Serotyping of 35 of the 124 isolates of ETEC indicated the following serotype for isolates in each group: group 1, O9:K35; group 2, O101:K30; group 3, O8:K85; group 4, O20:K?; group 5, O8:K25; and group 6, O101:K28. Determination of the presence of K99 antigen indicated that 28 of 35 isolates of ETEC had K99 antigen, whereas the antigen was not detected in any of the 10 isolates of non-ETEC studied.


Student Experience and Satisfaction with Clinical Nursing Practice in Women's Health Nursing.
The purpose of this study was to identify students' experiences of performance and their satisfaction with clinical nursing practice in Women's health nursing. Data was collected using questionnaire consisting of 104; 89,; and 82 nursing activities with 12; 10; and 7 domains for delivery floor, obstetric, and gynecologic wards retrospectively. Five hundred ninety nursing students from 10 four year and one three year colleges, were recruited and selected for data collection. Site specific core nursing activities among top 15 items of performed experience were: interpreting fetal monitoring; massage for pain reduction; breathing technique; perineal pad change; non stress test; manual check for uterine contraction; and position change for the delivery floor. Experiences of clinical nursing practice for the obstetric ward and the gynecologic ward were identified and ranked as well. Observation of delivery, measurement & test during labor and observation of anesthesia and operation were the highest ranked activity domains of satisfaction for delivery floor, obstetric and gynecologic wards retrospectively. Discussions are needed to standardize curriculum for clinical practice in women's health nursing initiated at the level of Korean Society of Womens' Health Nursing by reflecting this result. Strategic approaches are emphasized in order to enhance a collaboration between clinical fields and colleges.


Testicular biopsy in stallions: diagnostic potential and effects on prospective fertility.
Testicular biopsy was performed as a standing procedure on fertile, mature stallions (n=7) under sedation and local anaesthesia. The 'Biopty' instrument was used to collect three samples from the left testis of each stallion. The oestradiol, testosterone and inhibin content in each testis were assessed by validated radioimmunoassay (RIA); protein concentrations were determined and the testes were prepared histologically for haematoxylin and eosin staining. The fertility status of each stallion was assessed before and after testicular biopsy by semen evaluation, changes in total scrotal width, pregnancy rate per oestrous cycle, serum and seminal plasma antisperm antibody concentrations, and determination of plasma LH, FSH, oestradiol, testosterone and inhibin concentrations once a week by validated RIA. Testicular testosterone (3.85 +/- 1.24 ng mg(-1) protein), oestradiol (3.01 +/- 0.95 ng mg(-1) protein) and inhibin (11.06 +/- 1.69 ng mg(-1) protein) content were measured successfully from tissue samples by RIA. Active spermatogenesis was evident in all histological samples. The mean numbers of progressively motile morphologically normal spermatozoa were not significantly different in the last three ejaculates of the 7 day periods of semen collection before (3.37 +/- 0.48 x 10(9) spermatozoa per ejaculate) and after (3.77 +/- 0.48 x 10(9) spermatozoa per ejaculate) testicular biopsy. Total scrotal width varied within normal ranges throughout the year (from 11.7 +/- 0.3 to 10.0 +/- 0.4 cm). Pregnancy rates per oestrous cycle before (50 +/- 6%) and after (63 +/- 9%) testicular biopsy were not significantly different. The concentration of antisperm antibodies in serum and seminal plasma samples did not vary significantly before and after testicular biopsy. Plasma LH, FSH, oestradiol, testosterone and inhibin concentrations fluctuated within normal ranges after biopsy in the expected seasonal pattern. In conclusion, the present study demonstrates that using the 'Biopty' instrument to obtain testicular biopsy samples from stallions has no apparent detrimental effects on prospective stallion fertility and can be used to evaluate testicular factors and structure.


Public, environmental, and occupational health research activity in Arab countries: bibliometric, citation, and collaboration analysis.
The objective of this study was to analyze quantity, assess quality, and investigate international collaboration in research from Arab countries in the field of public, environmental and occupational health. Original scientific articles and reviews published from the 22 Arab countries in the category "public, environmental & occupational health" during the study period (1900 - 2012) were screened using the ISI Web of Science database. The total number of original and review research articles published in the category of "public, environmental & occupational health" from Arab countries was 4673. Main area of research was tropical medicine (1862; 39.85%). Egypt with 1200 documents (25.86%) ranked first in quantity and ranked first in quality of publications (h-index = 51). The study identified 2036 (43.57%) documents with international collaboration. Arab countries actively collaborated with authors in Western Europe (22.91%) and North America (21.04%). Most of the documents (79.9%) were published in public health related journals while 21% of the documents were published in journals pertaining to prevention medicine, environmental, occupational health and epidemiology. Research in public, environmental and occupational health in Arab countries is in the rise. Public health research was dominant while environmental and occupation health research was relatively low. International collaboration was a good tool for increasing research quantity and quality.


Suppression of LDL oxidation by garlic.
It has been known for several decades that hypercholesterolemia is a major risk factor for atherosclerosis and that lowering of cholesterol can significantly reduce risk for cardiovascular diseases. More recently, oxidation of LDL has been recognized as playing an important role in the initiation and progression of atherosclerosis. Oxidized LDL, but not native LDL, promotes vascular dysfunction by exerting direct cytotoxicity toward endothelial cells, by increasing chemotactic properties for monocytes, by transforming macrophages to foam cells via scavenger-receptors and by enhancing the proliferation of various cell types, e.g., endothelial cells, monocytes and smooth muscle cells; all of these events are recognized as contributing to atherogenesis. In this paper, experimental evidence is presented that shows that several garlic compounds can effectively suppress LDL oxidation in vitro. Short-term supplementation of garlic in human subjects has demonstrated an increased resistance of LDL to oxidation. These data suggest that suppressed LDL oxidation may be one of the powerful mechanisms accounting for the antiatherosclerotic properties of garlic.


Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. The Steps Study Group.
The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.


Curved array photoacoustic tomographic system for small animal imaging.
We present systematic characterization of a photoacoustic imaging system optimized for rapid, high-resolution tomographic imaging of small animals. The system is based on a 128-element ultrasonic transducer array with a 5-MHz center frequency and 80% bandwidth shaped to a quarter circle of 25 mm radius. A 16-channel data-acquisition module and dedicated channel detection electronics enable capture of a 90-deg field-of-view image in less than 1 s and a complete 360-deg scan using sample rotation within 15 s. Measurements on cylindrical phantom targets demonstrate a resolution of better than 200 microm and high-sensitivity detection of 580-microm blood tubing to depths greater than 3 cm in a turbid medium with reduced scattering coefficient mu(s) (')=7.8 cm(-1). The system is used to systematically investigate the effects of target size, orientation, and geometry on tomographic imaging. As a demonstration of these effects and the system imaging capabilities, we present tomographic photoacoustic images of the brain vasculature of an ex vivo mouse with varying measurement aperture. For the first time, according to our knowledge, resolution of sub-200-microm vessels with an overlying turbid medium of greater than 2 cm depth is demonstrated using only intrinsic biological contrast.