Child physical activity as a modifier of the relationship between prenatal exposure to maternal overweight/obesity and neurocognitive outcomes in offspring.
With rising obesity rates among pregnant women, more children are exposed in utero to maternal obesity. In prior epidemiological studies, exposure to maternal obesity was associated with lower intelligence quotient (IQ) scores and worse cognitive abilities in offspring. Further studies have shown that offspring exposed to maternal obesity, exhibit differences in the white matter microstructure properties, fractional anisotropy (FA) and mean diffusivity (MD). In contrast, physical activity was shown to improve cognition and white matter microstructure during childhood. We examined if child physical activity levels modify the relationship between prenatal exposure to maternal obesity with IQ and white matter microstructure in offspring. One hundred children (59% girls) age 7-11 years underwent brain magnetic resonance imaging and IQ testing. Maternal pre-pregnancy BMI was abstracted from electronic medical records. White matter was assessed using diffusion tensor imaging with the measures, global FA, MD. The 3-day physical activity recall was used to measure moderate-to-vigorous physical activity and vigorous physical activity (VPA). Linear regression was used to test for interactions between prenatal exposure to maternal overweight/obesity and child PA levels on child IQ and global FA/MD. The relationship between prenatal exposure to maternal overweight/obesity and child IQ and global FA varied by child VPA levels. Children exposed to mothers with overweight/obesity who engaged in more VPA had higher IQ scores and global FA compared to exposed children who engaged in less VPA. Associations were independent of child age, sex, BMI Z-score and socioeconomic status. Children born to normal-weight mothers did not differ in either IQ or global FA by time in VPA. Our findings support findings in rodent models and suggest that VPA during childhood modifies the relationship between prenatal exposure to maternal obesity and child IQ and white matter microstructure.


First identification of a ranavirus from green pythons (Chondropython viridis).
Ten juvenile green pythons (Chondropython viridis) died or were euthanized shortly after having been illegally imported into Australia from Indonesia in 1998. Histologic examination of two of the three snakes that died revealed moderately severe chronic ulceration of the nasal mucosa and focal or periacinar degeneration and necrosis of the liver. In addition there was severe necrotizing inflammation of the pharyngeal submucosa accompanied by numerous macrophages, heterophils, and edema. An iridovirus was isolated in culture from several tissues and characterized by immunohistochemistry, electron microscopy, enzyme-linked immunosorbent Assay, polyacrylamide gel electrophoresis, polymerase chain reaction and sequence analysis, restriction endonuclease digestion, and DNA hybridization. This is the first report of a systemic ranavirus infection in any species of snake and is a new member of the genus, Ranavirus.


Studies of the ground and excited-state surfaces of the retinal chromophore using CAM-B3LYP.
The isomerization of the 11-cis isomer (PSB11) of the retinal chromophore to its all-trans isomer (PSBT) is examined. Optimized structures on both the ground state and the excited state are calculated, and the dependence on torsional angles in the carbon chain is investigated. Time-dependent density functional theory is used to produce excitation energies and the excited-state surface. To avoid problems with the description of excited states that can arise with standard DFT methods, the CAM-B3LYP functional was used. Comparing CAM-B3LYP with B3LYP results indicates that the former is significantly more accurate, as a consequence of which detailed cross sections of the retinal excited-state surface are obtained.


Treatment of Antipsychotic-Related Akathisia Revisited: The Role of Serotonin 2A Receptor Antagonists.
Akathisia remains a prevalent, clinically significant, and therapeutically challenging adverse event associated with antipsychotic treatment. Compelling evidence supports therapeutic efficacy and clinical utility of agents with marked serotonin 2A receptor antagonism, primarily low-dose mirtazapine, as an effective and well-tolerated antiakathisia treatment.


Weighted pooling--practical and cost-effective techniques for pooled high-throughput sequencing.
Despite the rapid decline in sequencing costs, sequencing large cohorts of individuals is still prohibitively expensive. Recently, several sophisticated pooling designs were suggested that can identify carriers of rare alleles in large cohorts with a significantly smaller number of pools, thus dramatically reducing the cost of such large-scale sequencing projects. These approaches use combinatorial pooling designs where each individual is either present or absent from a pool. One can then infer the number of carriers in a pool, and by combining information across pools, reconstruct the identity of the carriers. We show that one can gain further efficiency and cost reduction by using 'weighted' designs, in which different individuals donate different amounts of DNA to the pools. Intuitively, in this situation, the number of mutant reads in a pool does not only indicate the number of carriers, but also their identity. We describe and study a powerful example of such weighted designs, using non-overlapping pools. We demonstrate that this approach is not only easier to implement and analyze but is also competitive in terms of accuracy with combinatorial designs when identifying rare variants, and is superior when sequencing common variants. We then discuss how weighting can be incorporated into existing combinatorial designs to increase their accuracy and demonstrate the resulting improvement using simulations. Finally, we argue that weighted designs have enough power to facilitate detection of common alleles, so they can be used as a cornerstone of whole-exome sequencing projects.


[Inhibition of NK activity by oses: effect of interleukin 2 (author's transl)].
Several sugars can strongly inhibit the natural cytotoxicity (NK) exhibited by peripheral blood lymphocytes (PBL) against tumour cells. The inhibition of NK cytotoxicity mediated by mannose, glucose, galactose and saccharose was tested in human PBL. All these sugars significantly blocked (P less than 0.01 at 50 mM concentration) the NK cytotoxicity. The blocking is dose-dependent in a linear pattern. The sole preincubation of the attacking (NK) population is required for inhibition of cytotoxicity; no influence of the sugars were noticed on the K562 alone. In contrast, the NK cytotoxicity of PBL primed in mixed lymphocyte reaction and further cultured in presence of conditioned medium (CM), showed, aside of a clear increase (average 40% increase of specific 51Cr release, P less than 0.05) a full insensitivity to the tested sugars. Phytohaemagglutinin (PHA), interferon (IF) and an interleukin 2 (Il2) are contained in the CM. We showed that neither the PHA nor the IF preincubation of the cells can induce the insensitivity of NK for the sugars, thus our data strongly suggest that Il2 is implicated in the sugar insensitivity of the cytotoxicity of lymphocytes cultured with CM.


Mitochondrial Dynamics of Bcl-2 Family Proteins during 17-β-Estradiol-Induced Apoptosis Correlate with the Malignancy of Endometrial Cancer Cells.
Excessive fat intake leads to an increase in cholesterol. Overexposure to estrogen derived from cholesterol is known to contribute to the malignancy of endometrial adenocarcinomas. However, it is not well understood the relationship between the exposure to estrogen and the malignancy of endometrial adenocarcinomas. We investigated how estrogen affected the malignancy of endometrial cancer cells, specifically HEC1 cells (a moderately differentiated adenocarcinoma) and HEC50B cells (a poorly differentiated adenocarcinoma). Cell viability was decreased by exogenous 17-β-estradiol (E2) in a concentration-dependent manner. E2 disturbed the mitochondrial membrane potentials by changing the localization of the B-cell lymphoma 2 (Bcl-2) family protein; however, there were significant differences in the localization of Bcl-2 family proteins between HEC1 and HEC50B cells. In HEC1 cells, E2 increased the expression of B-cell lymphoma-extra large (Bcl-XL) and the Bcl-2-associated X protein (Bax) and decreased Bcl-2 and Bcl-2-associated death promoter (Bad) expression on the outer mitochondrial membrane. Conversely, E2 increased the expression of Bad and Bax, and it decreased Bcl-2 and Bcl-XL expressions on the outer mitochondrial membrane in HEC50B cells. The disturbance of the mitochondrial membrane potential led to the release of cytochrome c from the mitochondria to the cytosolic space followed by activating caspase-9. After that, caspase-3 was activated and induced apoptosis. These results suggested that the localization of the Bcl-2 family protein observed under E2-induced apoptosis is related to the malignancy of endometrial cancer cells. We hope that the dynamics of Bcl-2 family proteins such as Bcl-XL and Bad will be used to diagnose malignant endometrial adenocarcinomas.


[Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3].
To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.


Stenting for acute cerebral venous sinus thrombosis in the superior sagittal sinus.
Endovascular treatment for superior sagittal sinus (SSS) thrombosis is not always successful because of difficult access and long thrombus lesions. We report the first two cases of patients with acute cerebral venous sinus thrombosis at the SSS that was not recanalized by anticoagulation, mechanical thrombectomy, or thrombolysis, but was successfully treated by stent placement. Case 1 was a 37-year-old woman with bilateral subdural hematomas. Digital subtraction angiography showed obstruction of the sinus from the SSS to the right transverse sinus. Recanalization was achieved by selective thrombolysis using urokinase followed by balloon angioplasty, but re-occlusion occurred on the next day of treatment. Repeated endovascular treatment including balloon angioplasty, thrombus aspiration and thrombolysis using recombinant tissue plasminogen activator failed to achieve recanalization. We thus placed intracranial stents in the SSS, which did achieve recanalization. Case 2 was a 69-year-old woman with a small infarction in the left parietal lobe. Digital subtraction angiography showed sinus obliteration from the SSS to the bilateral transverse sinuses. Recanalization was not achieved by balloon angioplasty, thrombus aspiration and selective thrombolysis. We thus placed intracranial stents in the SSS, which did achieve recanalization. Postoperative course was uneventful in both cases and venous sinus patency was confirmed by venography >1.5 years after treatment. When conventional endovascular strategies have been unsuccessful, placement of intracranial stents, which can easily gain access to the distal part of the SSS as compared with carotid stents, may be a useful treatment option for the acute sinus thrombosis in this region.


c-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish.
Neutrophils are the key effectors for generating innate immunity in response to pathogenic infection and tissue injury in vertebrates. Dysregulation of neutrophil development and function is known to associate with various human disorders. Yet, the genetic network that orchestrates lineage commitment, differentiation, and maturation of neutrophils remains incompletely defined. Here, we present an in vivo study to delineate the genetic program underlying neutrophil development during zebrafish embryonic myelopoiesis. We show that loss of c-Myb function has no effect on macrophages but severely impairs neutrophil terminal differentiation, resulting in the accumulation of neutrophils with unsegmented nuclei and scant granule. This neutrophilic defect, which resembles the neutrophil-specific granule deficiency (SGD) caused by the mutations in CCAAT/enhancer-binding protein ε (C/EBPε) in humans, is attributed, at least in part, to the downregulation of the granule protein transcription. Likewise, genetic inactivation of Cebp1, the zebrafish functional homolog of mammalian C/EBPε, also leads to a similar SGD-like phenotype in zebrafish. Genetic epistasis and biochemical analysis further reveals that c-Myb and Cebp1 act in parallel and cooperatively to control neutrophil differentiation by directly regulating granule protein gene transcription. Our study indicates that c-MYB is an intrinsic master regulator for neutrophil terminal differentiation and a potential target in SGD patients.


High-resolution, vacuum-ultraviolet absorption spectrum of boron trifluoride.
In the course of investigations of thermal neutron detection based on mixtures of (10)BF3 with other gases, knowledge was required of the photoabsorption cross sections of (10)BF3 for wavelengths between 135 and 205 nm. Large discrepancies in the values reported in existing literature led to the absolute measurements reported in this communication. The measurements were made at the SURF III Synchrotron Ultraviolet Radiation Facility at the National Institute of Standards and Technology. The measured absorption cross sections vary from 10(-20) cm(2) at 135 nm to less than 10(-21) cm(2) in the region from 165 to 205 nm. Three previously unreported absorption features with resolvable structure were found in the regions 135-145 nm, 150-165 nm, and 190-205 nm. Quantum mechanical calculations, using the TD-B3LYP/aug-cc-pVDZ variant of time-dependent density functional theory implemented in Gaussian 09, suggest that the observed absorption features arise from symmetry-changing adiabatic transitions.


Drug utilization in the pediatric intensive care unit: monitoring prescribing trends and establishing prioritization of pharmacotherapeutic evaluation of critically ill children.
The primary objective of this study was to characterize the drug exposure for children hospitalized in the authors' institution's pediatric intensive care unit for the year 2002. Secondary objectives included the examination of drug utilization differences among various age criteria and the suitability of the most prevalent resources for pediatric dosing guidance. Many of the most commonly prescribed agents in the pediatric intensive care unit fall into the broad categories of pain management/sedation and anti-infectives. Based on the generally narrow windows afforded by each of these drug classes, it is obvious that more, well-defined investigations in critically ill children are warranted. The existing dosing guidance for many of these agents is neither generalizable nor sufficient to accommodate the diversity in pediatric intensive care unit patients, and the current drug monographs fall short of any practical dosing information.


Broadband second-harmonic generation in step-chirped periodically poled lithium niobate waveguides.
Periodically poled lithium niobate (PPLN) structures on a chip enable efficient second-order nonlinear optical effects, benefiting from the tight light confinement and the utilization of d33. Here, we report a broadband second-harmonic (SH) generation in a step-chirped PPLN waveguide on X-cut lithium niobate on insulator (LNOI). The high fidelity of the poling period is demonstrated over the whole length of 7 mm using a non-destructive technique of piezoresponse force microscopy. The SH signal was continuously observed in the step-chirped PPLN waveguides while scanning the wavelength of the pump laser from 1550 nm to 1660 nm. The SH conversion efficiency was measured to be 9.6 % W-1 cm-2 at 1642 nm. This work will benefit wavelength conversions of light sources with wideband spectra.


The beginnings of chronic airflow obstruction.
Recent follow-up studies have provided convincing evidence that the foundations of chronic airflow obstruction (CAO) are laid in utero and early childhood. Men born in Hertfordshire and Derbyshire, England, were more likely to have impaired lung function at 60-70 years of age if they had been lighter at birth and if they had had lower respiratory tract infection (LRTI) in the first 2 years of life. Furthermore, they were more likely to have died from chronic obstructive pulmonary disease if they had been lighter at 1 year of age. These findings suggest that impairment of pulmonary growth in utero and early childhood, as a consequence of undernutrition and LRTI, plays an important part in the development of CAO in late adult life. This may be of particular importance for the future respiratory health of developing nations as the additive effects of smoking take hold.


One-year supplementation with Lactobacillus reuteri ATCC PTA 6475 counteracts a degradation of gut microbiota in older women with low bone mineral density.
Recent studies have shown that probiotic supplementation has beneficial effects on bone metabolism. In a randomized controlled trial (RCT) we demonstrated that supplementation of Lactobacillus reuteri ATCC PTA 6475 reduced bone loss in older women with low bone mineral density. To investigate the mechanisms underlying the effect of L. reuteri ATCC PTA 6475 on bone metabolism, 20 women with the highest changes (good responders) and the lowest changes (poor responders) in tibia total volumetric BMD after one-year supplementation were selected from our previous RCT. In the current study we characterized the gut microbiome composition and function as well as serum metabolome in good responders and poor responders to the probiotic treatment as a secondary analysis. Although there were no significant differences in the microbial composition at high taxonomic levels, gene richness of the gut microbiota was significantly higher (P < 0.01 by the Wilcoxon rank-sum test) and inflammatory state was improved (P < 0.05 by the Wilcoxon signed-rank test) in the good responders at the end of the 12-month daily supplementation. Moreover, detrimental changes including the enrichment of E. coli (adjusted P < 0.05 by DESeq2) and its biofilm formation (P < 0.05 by GSA) observed in the poor responders were alleviated in the good responders by the treatment. Our results indicate that L. reuteri ATCC PTA 6475 supplementation has the potential to prevent a deterioration of the gut microbiota and inflammatory status in elderly women with low bone mineral density, which might have beneficial effects on bone metabolism.


Comparison of pregnancy outcome after amniocentesis for previous neural tube defect or raised maternal serum alphafetoprotein.
Amniocentesis was performed in 219 pregnancies because a previous pregnancy produced a fetus with neural tube defect (NTD) and in 212 pregnancies in which the indication for amniocentesis was a high maternal serum alphafetoprotein (AFP) level. The proportion of abnormal fetuses, the frequency of low birth weight infants, and the frequency of undesired fetal loss were significantly greater in the group with high maternal serum AFP, in which there was also a significant excess of male births. It is concluded that maternal serum AFP screening defines a group of high risk pregnancies. The greater fetal loss and low birth weight associated with high maternal serum AFP levels were not the result of amniocentesis but were an inherent feature of these pregnancies.


Pharmacological characterization of indacaterol, a novel once daily inhaled 2 adrenoceptor agonist, on small airways in human and rat precision-cut lung slices.
Indacaterol is a novel once daily inhaled beta(2) adrenoceptor agonist in clinical development. This study compared the properties of indacaterol with salmeterol, formoterol, and albuterol on small airways in precision-cut lung slices from human and rat contracted with carbachol and serotonin, respectively. In human lung slices, the rank order of potency was formoterol >/= salmeterol > indacaterol > albuterol, respectively. Indacaterol had similar intrinsic efficacy to formoterol, followed by albuterol and salmeterol. The onset of action was fast for albuterol, formoterol, and indacaterol, whereas it was significantly slower for salmeterol. The duration of action ranking was indacaterol > salmeterol > formoterol > albuterol. When compared with human lung slices, in the rat lung slices, similar potency, intrinsic efficacy, and onset of action were observed for indacaterol, formoterol, and salmeterol. Albuterol had an increased potency when compared with human lung slices and a slower onset of action. In conclusion, our results show that the human lung slice system seems to be a good model to study the clinical properties of inhaled long-acting beta(2) adrenoceptor agonists and that caution is needed extrapolating from rat model to humans. Finally, using the human lung slice model, we have characterized indacaterol as a fast acting compound with a longer duration of action than salmeterol and formoterol.


Venetoclax Data Prompt Rethink of CLL Therapy.
The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly-in combinations and as a first-line therapy-for other patients with the disease.


Between- and within-person associations between negative life events and alcohol outcomes in adolescents with ADHD.
Escalations in alcohol use during adolescence may be linked with exposure to negative life events, but most of this research has focused on between-person associations. Moreover, adolescents with attention-deficit hyperactivity disorder (ADHD) may be an especially vulnerable population, reporting more life events and alcohol involvement and may even be more sensitive to the effects of life events on alcohol outcomes compared with those without ADHD. We tested the between- and within-person effects of the number and perceptions of negative life events on the development of alcohol use outcomes from age 14 to 17 years in 259 adolescents with and without ADHD using generalized estimating equations. Between-person differences in exposure to negative life events across adolescence, but not the perception of those events, were associated with a higher likelihood of alcohol use and drunkenness at age 17 years. Within-person differences in life events were associated with alcohol use above and beyond that predicted by an adolescents' typical trajectory over time. Parent- and teacher-reported ADHD symptoms were associated with more negative perceptions of life events and with greater alcohol use and drunkenness at age 17 years, but symptoms did not moderate the life event-alcohol association. Interventions should consider the variables that produce vulnerability to life events as well as the immediate impact of life events. That the accumulation of life events, rather than their perceived negativity, was associated with alcohol outcomes indicates that interventions targeting the reduction of negative events, rather than emotional response, may be more protective against alcohol use in adolescence. (PsycINFO Database Record


Engineering the Quaternary Hydrotalcite-Derived Ce-Promoted Ni-Based Catalysts for Enhanced Low-Temperature CO2 Hydrogenation into Methane.
Ce-promoted NiMgAl mixed-oxide (NiCex-C, x = 0, 1, 5, 10) catalysts were prepared from the quaternary hydrotalcite precursors for CO2 hydrogenation to methane. By engineering the Ce contents, NiCe5-C showed its prior catalytic performance in low-temperature CO2 hydrogenation, being about three times higher than that of the Ce-free NiCe0-C catalyst (turnover frequency of NiCe5-C and NiCe0-C: 11.9 h-1 vs. 3.9 h-1 @ 225 °C). With extensive characterization, it was found that Ce dopants promoted the reduction of NiO by adjusting the interaction between Ni and Mg(Ce)AlOx support. The highest ratio of surface Ni0/(Ni2+ + Ni0) was obtained over NiCe5-C. Meanwhile, the surface basicity was tailored with Ce dopants. The strongest medium-strength basicity and highest capacity of CO2 adsorption was achieved on NiCe5-C with 5 wt.% Ce content. The TOF tests indicated a good correlation with medium-strength basicity over the NiCex-C samples. The results showed that the high medium-strength and Ce-promoted surface Ni0 species endows the enhanced low-temperature catalytic performance in CO2 hydrogenation to methane.


MiR-361-3p inhibits β-amyloid accumulation and attenuates cognitive deficits through targeting BACE1 in Alzheimer's disease.
The role of miR-361-3p in the pathology of Alzheimer's disease is unknown. The target scan was used to screen potential target genes of miR-361-3p, and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) was emphasized. Results from western blotting and reverse transcription-quantitative polymerase chain reaction (RT-PCR) showed that down-regulated miR-361-3p was correlated with up-regulated BACE1 in Alzheimer's disease patients' brains. Luciferase assay confirmed that miR-361-3p directly targets BACE1. MiR-361-3p overexpression and knockdown experiments were performed and found that miR-361-3p could regulate the expression of BACE1, and the accumulation of APP-β in APPswe transfected SH-SY5Y cell. A Morris water maze test was performed and showed that overexpression of miR-361-3p improved cognitive deficits in APP/PS1 mice. We found miR-361-3p inhibited β-amyloid accumulation by targeting BACE1, which thus weakened cognitive deficits in Alzheimer's disease.


Effects of Bait Presence and Type of Preservative Fluid on Ground and Carrion Beetle Samples Collected by Pitfall Trapping.
Pitfall trapping is a sampling technique frequently used by entomologists around the world. However, there exist sampling biases linked to particular trapping designs, which require investigation. In this study, we compared the effects of the type of preservative fluid (propylene glycol or formaldehyde) and the presence of fish bait in pitfall traps on the number of specimens (individuals) collected, the species richness, and the species composition of carabid (Coleoptera: Carabidae) and silphid (Coleoptera: Silphidae) beetle assemblages. Traps containing propylene glycol collected a substantially higher number of individuals of both taxa and a higher number of silphid species compared with traps containing formaldehyde. The use of fish bait in the traps increased the number of individuals collected and the number of species collected for silphid beetles but had no effect on the collection parameters for carabids. The species composition of the carabid assemblages was minimally affected by the presence of fish bait or the type of preservative fluid, whereas the fish bait had a substantial effect on the species composition of silphids. The silphid species that feed directly on vertebrate carcasses were almost completely absent in the nonbaited traps. The results suggest that pitfall traps baited with fish and containing propylene glycol as a preservative fluid are optimal for the simultaneous sampling of carabid and silphid beetles, which both provide important ecosystem services (e.g., predation of pests and decomposition of vertebrate carcasses) and are therefore interesting for ecological research.


Potential sites of virus latency associated with indigenous pseudorabies viruses in feral swine.
Free-ranging feral swine (Sus scrofa) are known to be present in at least 32 states of the USA and are continuously expanding their range. Infection with pseudorabies virus (PRV) occurs in feral swine and the primary route of transmission in free-living conditions seems to be venereal. Between 1995 and 1999, naturally infected feral swine and experimentally infected hybrid progeny of feral and domestic swine, were kept in isolation and evaluated for occurrence of latent PRV indigenous to feral swine in sacral and trigeminal ganglia and tonsil. Sacral ganglia were shown, by polymerase chain reaction (PCR) amplification of the thymidine kinase (TK) gene of PRV, to be the most frequent sites of latency of PRV. Nine (56%) of 16 sacral ganglia, seven (44%) of 16 trigeminal ganglia, and five (39%) of 13 tonsils from naturally infected feral swine were positive for PCR amplification of TK sequences of PRV. These tissues were negative for PRV when viral isolation was attempted in Vero cells. DNA sequencing of cloned TK fragments from the sacral ganglia of two feral swine, showed only one nucleotide difference between the two fragments and extensive sequence homology to fragment sequences from various domestic swine PRV strains from China, Northern Ireland, and the USA. The hybrid feral domestic swine, experimentally inoculated with an indigenous feral swine PRV isolate by either the genital or respiratory route, acquired the infection but showed no clinical signs of pseudorabies. Virus inoculated into either the genital or respiratory tract could, at times, be isolated from both these sites. The most common latency sites were the sacral ganglia, regardless of the route and dose of infection in these experimentally infected hybrids. Nine of 10 sacral ganglia, six of 10 trigeminal ganglia, and three of 10 tonsils were positive for PCR amplification of TK sequences. No virus was isolated from these tissues in Vero cells. The demonstration of the sacral ganglia as the most common sites of latency of pseudorabies viruses indigenous to feral swine, supports the hypothesis that these viruses are primarily transmitted venereally, and not by the respiratory route as is common in domestic swine, in which the trigeminal ganglia are the predominant sites of virus latency.


Assessing Smoothness of Arm Movements With Jerk: A Comparison of Laterality, Contraction Mode and Plane of Elevation. A Pilot Study.
Measuring the quality of movement is a need and a challenge for clinicians. Jerk, defined as the quantity of acceleration variation, is a kinematic parameter used to assess the smoothness of movement. We aimed to assess and compare jerk metrics in asymptomatic participants for 3 important movement characteristics that are considered by clinicians during shoulder examination: dominant and non-dominant side, concentric and eccentric contraction mode, and arm elevation plane. In this pilot study, we measured jerk metrics by using Xsens® inertial measurement units strapped to the wrists for 11 different active arm movements (ascending and lowering phases): 3 bilateral maximal arm elevations in sagittal, scapular and frontal plane; 2 unilateral functional movements (hair combing and low back washing); and 2 unilateral maximal arm elevations in sagittal and scapular plane, performed with both arms alternately, right arm first. Each arm movement was repeated 3 times successively and the whole procedure was performed 3 times on different days. The recorded time series was segmented with semi-supervised algorithms. Comparisons involved the Wilcoxon signed rank test (p < 0.05) with Bonferroni correction. We included 30 right-handed asymptomatic individuals [17 men, mean (SD) age 31.9 (11.4) years]. Right jerk was significantly less than left jerk for bilateral arm elevations in all planes (all p < 0.05) and for functional movement (p < 0.05). Jerk was significantly reduced during the concentric (ascending) phase than eccentric (lowering) phase for bilateral and unilateral right and left arm elevations in all planes (all p < 0.05). Jerk during bilateral arm elevation was significantly reduced in the sagittal and scapular planes versus the frontal plane (both p < 0.01) and in the sagittal versus scapular plane (p < 0.05). Jerk during unilateral left arm elevation was significantly reduced in the sagittal versus scapular plane (p < 0.05). Jerk metrics did not differ between sagittal and scapular unilateral right arm elevation. Using inertial measurement units, jerk metrics can well describe differences between the dominant and non-dominant arm, concentric and eccentric modes and planes in arm elevation. Jerk metrics were reduced during arm movements performed with the dominant right arm during the concentric phase and in the sagittal plane. Using IMUs, jerk metrics are a promising method to assess the quality of basic shoulder movement.


Headspace sampling and detection of cocaine, MDMA, and marijuana via volatile markers in the presence of potential interferences by solid phase microextraction-ion mobility spectrometry (SPME-IMS).
The successful air sampling and detection of cocaine, methylenedioxymethylamphetamine (MDMA), and marijuana using SPME-IMS achieved by targeting their volatile markers (methyl benzoate, piperonal, and terpenes, respectively) is presented. Conventional methods of direct air sampling for drugs are ineffective because the parent compounds of these drugs have very low vapor pressures, making them unavailable for headspace sampling. Instead of targeting the parent drugs, IMS was set at the optimal operating conditions (determined in previous work) in order to detect their volatile chemical markers. SPME is an effective and rapid air sampling technique for the preconcentration of analytes which is especially useful in confined spaces such as cargo containers, where the volatile marker compounds of drugs can be found in sufficient concentrations. By sampling the air using a 100 microm polydimethyl siloxane (PDMS) SPME fiber for as little as one minute, enough mass of the targeted volatile markers in the headspace of a quart-sized metal paint can (gallon, approximately 1101 cm(3)) which contained sub-gram quantities of the drug samples was recovered for IMS detection. Additionally, several potentially interfering compounds found in goods commonly shipped in cargo containers were tested individually as well as in mixtures with the drugs. No peak interferences were observed for MDMA or marijuana, and minimal peak interferences were found for cocaine.


Combining Techniques to Treat Isolated Deep Recession-Type Defects: A Case Report with Long-Term Stability.
The purpose of this case report was to show the clinical long-term stability of a successful two-step root coverage procedure. A combination of two single techniques was used to treat an isolated deep-wide defect. Case Presentation. A 28-year-old female patient was referred in order to treat a single recession defect at #22. Due to her fear of dental procedures and a poor economic situation, the team developed an alternative solution. They used a modified apically repositioned flap (MARF) to increase the donor area and then a laterally positioned flap (LPF) to treat the root defect. Clinical evaluation at the three-year follow-up revealed complete resolution of the defect, a gain in clinical attachment, excellent esthetic results, and minor morbidity to the patient. The combination of the MARF and the LPF procedures was able to successfully treat a single deep recession defect with some advantages over traditional techniques such as simplicity, ideal color match of tissues, and the absence of palatal donor tissue.


Metabolic engineering for betaine accumulation in microbes and plants.
Plants accumulate a variety of osmoprotectants that improve their ability to combat abiotic stresses. Among them, betaine appears to play an important role in conferring resistance to stresses. Betaine is synthesized via either choline oxidation or glycine methylation. An increased betaine level in transgenic plants is one of the potential strategies to generate stress-tolerant crop plants. Here, we showed that an exogenous supply of serine or glycine to a halotolerant cyanobacterium Aphanothece halophytica, which synthesizes betaine from glycine by a three-step methylation, elevated intracellular accumulation of betaine under salt stress. The gene encoding 3-phosphoglycerate dehydrogenase (PGDH), which catalyzes the first step of the phosphorylated pathway of serine biosynthesis, was isolated from A. halophytica. Expression of the Aphanothece PGDH gene in Escherichia coli caused an increase in levels of betaine as well as glycine and serine. Expression of the Aphanothece PGDH gene in Arabidopsis plants, in which the betaine synthetic pathway was introduced via glycine methylation, further increased betaine levels and improved the stress tolerance. These results demonstrate that PGDH enhances the levels of betaine by providing the precursor serine for both choline oxidation and glycine methylation pathways.


Evaluation of cell membrane integrity of spermatozoa by hypoosmotic swelling test - "water test" in mice after intraperitoneal daidzein administration.
The functional integrity of the cell membrane of the mice sperm after daidzein administration intraperitoneal was assessed by studying the swelling reaction of the sperm when suspended in distilled water. The results obtained in water test indicate that daidzein, one of the phytoestrogens, decreases the number of normal and live sperm (swollen) in the samples obtaining from vas deferens. This effect was statistically significant in the mice after 7 and 14 days of daidzein administration. In mice treated with daidzein the number of dead (unswollen) sperm was increased, especially in animals after 14 days of experiment.


Combining Solid and Liquid Biopsy for Therapy Monitoring in Esophageal Cancer.
Esophageal cancer (EC) has one of the highest mortality rates among cancers, making it imperative that therapies are optimized and dynamically adapted to individuals. In this regard, liquid biopsy is an increasingly important method for residual disease monitoring. However, conflicting detection rates (14% versus 60%) and varying cell-free circulating tumor DNA (ctDNA) levels (0.07% versus 0.5%) have been observed in previous studies. Here, we aim to resolve this discrepancy. For 19 EC patients, a complete set of cell-free DNA (cfDNA), formalin-fixed paraffin-embedded tumor tissue (TT) DNA and leukocyte DNA was sequenced (139 libraries). cfDNA was examined in biological duplicates and/or longitudinally, and TT DNA was examined in technical duplicates. In baseline cfDNA, mutations were detected in 12 out of 19 patients (63%); the median ctDNA level was 0.4%. Longitudinal ctDNA changes were consistent with clinical presentation. Considerable mutational diversity was observed in TT, with fewer mutations in cfDNA. The most recurrently mutated genes in TT were TP53, SMAD4, TSHZ3, and SETBP1, with SETBP1 being reported for the first time. ctDNA in blood can be used for therapy monitoring of EC patients. However, a combination of solid and liquid samples should be used to help guide individualized EC therapy.


Challenging integration: clinicians' perspectives of communicating collaboration in a center for integrative medicine.
A shift has occurred in the provision of health care to include a focus not just on biology and disease but also on the whole person, preventative care, and an array of healing modalities based on systems of beliefs and values not typically included within biomedical practice. This approach to health care, termed integrative medicine (IM), blends biomedicine with a broader understanding of patients and their illnesses, including elements of mind, body, and spirit that may be contributing to an ailment. While the use of integrative medicine has increased and centers for integrative medicine have proliferated within conventional health care organizations, distinct tensions arise from this amalgamation. The tensions between IM and biomedical clinicians often center on their differing training and philosophies, as well as on a larger system of health care that privileges biomedicine. As a result, this research is designed to explore the challenges IM clinicians face in collaborating with conventional practitioners to provide patient care. Analysis of interviews with 14 clinicians at one center for integrative medicine revealed four specific challenges they face in their attempt to co-practice IM with conventional medicine. The four challenges include (a) challenges to collaboration, (b) challenges to legitimacy, (c) challenges to consistency, and (d) challenges to unification. Future research should investigate the ways in which these challenges can be addressed so that collaboration throughout the system is facilitated. The professional training of clinicians, the structuring and institutionalization of integrative medicine, and enhanced systems for communicating patient information all play a significant role in this transformation.


[Maxillofacial imaging in the aid of the clinician].
The rapidly changing field of maxillofacial diagnostic imaging provides the clinician with tools for superior diagnostic capabilities and improved treatment planning improving and thus patient's outcome. There are currently growing number of imaging modalities available in the maxillofacial region, of which a choice must be made according to the least invasive and the most diagnostic option. The introduction of Cone-Beam-Computerized Tomography (CBCT) allows for 3-dimensional imaging volume with improved spatial resolution, along with increased responsibilities of the referring clinician. As various papers showed numerous incidental findings which may be encountered in the imaging data, international organizations advocated the need of both precise, justified and restricted referrals for advanced imaging as well as a need for a radiologic report based on a thorough examination of the entire volume. This paper aims to demonstrate some of the current themes in maxillofacial imaging. it describes the CBCT modality in the maxillofacial region, its application and the various output options. In addition, it introduces the possibility of an imaging consult service. This can be done by either referral of the patient for radiology consult pertaining to findings detected within the region of interest (ROI )or outside the ROI that were not the reason for referral (incidental findings) or by requesting for a written report for an imaging scan.


Stimulation of human peripheral lymphocytes with endotoxin and radiodetoxified endotoxin.
The effects of parent endotoxin and radiodetoxified endotoxin on human peripheral lymphocytes were compared in experiments in vitro. Radiodetoxified endotoxin is able to exceed the degree of the stimulation induced by parent endotoxin and its stimulatory effect. At the same time, no change was observed in the presence of autologous serum. Radiodetoxified endotoxin did not inhibit the phytohaemagglutinin-induced proliferative response.


UDP-glycosyltransferase gene SlUGT73C1 from Solanum lycopersicum regulates salt and drought tolerance in Arabidopsis thaliana L.
Among abiotic stresses, plants are the most vulnerable to salt and drought stresses. These stresses affect plant growth and development. Glycosyltransferases are involved in the responses of plants to abiotic stresses. In this study, a UDP-glycosyltransferase gene (SlUGT73C1) from Solanum lycopersicum was isolated and identified, which exhibited induction under salt or drought stress. The full length of SlUGT73C1 was 1485 bp, encoding 494 amino acids. Stress-related cis-acting elements were present in the promoter sequence of SlUGT73C1, such as ARE, LTR, and GC motifs. Compared with the wild-type plants, Arabidopsis thaliana overexpressing SlUGT73C1 exhibited increased seed germination rate and SOD and POD activities, decreased MDA content, and increased expression levels of osmotic stress regulators genes, rate-limiting enzymes genes in the proline synthesis pathway, Na+/K+ reverse transporter genes, and rate-limiting genes in the ABA biosynthesis pathway under salt or drought stress. These results indicated that SlUGT73C1 plays an important role in regulating salt and drought tolerance in plants.


Concise approach to the carbocyclic core of the naturally occurring sphingomyelinase inhibitor scyphostatin.
A flexible strategy toward the carbocyclic core of the naturally occurring sphingomyelinase inhibitor scyphostatin, from the readily available Diels-Alder adducts of cyclopentadiene and 2-allyl-p-benzoquinone, has been devised. This approach leverages the stereochemical predisposition of the norbornyl-fused scaffolds to generate the desired stereochemical pattern and leads to a concise synthesis of the epoxycyclohexenoid core of scyphostatin with a manipulable allyl side arm.


Synergistic doping of fullerene electron transport layer and colloidal quantum dot solids enhances solar cell performance.
The spatial location of the predominant source of performance-limiting recombination in today's best colloidal quantum dot (CQD) cells is identified, pinpointing the TiO2:CQD junction; then, a highly n-doped PCBM layer is introduced at the CQD:TiO2 heterointerface. An n-doped PCBM layer is essential to maintain the depletion region and allow for efficient current extraction, thereby producing a record 8.9% in overall power conversion efficiency.


Directionally biased sidestepping of Kip3/kinesin-8 is regulated by ATP waiting time and motor-microtubule interaction strength.
Kinesin-8 motors, which move in a highly processive manner toward microtubule plus ends where they act as depolymerases, are essential regulators of microtubule dynamics in cells. To understand their navigation strategy on the microtubule lattice, we studied the 3D motion of single yeast kinesin-8 motors, Kip3, on freely suspended microtubules in vitro. We observed short-pitch, left-handed helical trajectories indicating that kinesin-8 motors frequently switch protofilaments in a directionally biased manner. Intriguingly, sidestepping was not directly coupled to forward stepping but rather depended on the average dwell time per forward step under limiting ATP concentrations. Based on our experimental findings and numerical simulations we propose that effective sidestepping toward the left is regulated by a bifurcation in the Kip3 step cycle, involving a transition from a two-head-bound to a one-head-bound conformation in the ATP-waiting state. Results from a kinesin-1 mutant with extended neck linker hint toward a generic sidestepping mechanism for processive kinesins, facilitating the circumvention of intracellular obstacles on the microtubule surface.


Chronic Intermittent Hypoxia-Induced Aberrant Neural Activities in the Hippocampus of Male Rats Revealed by Long-Term in vivo Recording.
Chronic intermittent hypoxia (CIH) occurs in obstructive sleep apnea (OSA), a common sleep-disordered breathing associated with malfunctions in multiple organs including the brain. How OSA-associated CIH impacts on brain activities and functions leading to neurocognitive impairment is virtually unknown. Here, by means of in vivo electrophysiological recordings via chronically implanted multi-electrode arrays in male rat model of OSA, we found that both putative pyramidal neurons and putative interneurons in the hippocampal CA1 subfield were hyper-excitable during the first week of CIH treatment and followed by progressive suppression of neural firing in the longer term. Partial recovery of the neuronal activities was found after normoxia treatment but only in putative pyramidal neurons. These findings correlated well to abnormalities in dendritic spine morphogenesis of these neurons. The results reveal that hippocampal neurons respond to CIH in a complex biphasic and bidirectional manner eventually leading to suppression of firing activities. Importantly, these changes are attributed to a larger extent to impaired functions of putative interneurons than putative pyramidal neurons. Our findings therefore revealed functional and structural damages in central neurons in OSA subjects.


The clinical spectrum of narcolepsy with cataplexy: a reappraisal.
In the absence of a golden standard for the diagnosis of narcolepsy, the clinical spectrum of disorder remains controversial. The aims of this study were (1) to determine frequency and characteristics of sleep-wake symptoms in patients with narcolepsy with cataplexy, (2) to compare clinical characteristics with results of ancillary tests, and (3) to identify factors that discriminate narcolepsy from other conditions with excessive daytime sleepiness (EDS). We prospectively studied 57 narcoleptics with cataplexy, 56 patients with non-narcoleptic hypersomnia (H), and 40 normal controls (No). Based on suggested and published criteria, we differentiated between narcoleptics with definite cataplexy (N) and narcoleptics without definite cataplexy (possible cataplexy, NpC). Assessment consisted of questionnaires [all patients and controls, including the Ullanlinna Narcolepsy Score (UNS)], polysomnography (all patients), multiple sleep latency test (MSLT) and human leukocyte antigen typing (in most narcoleptics). A new narcolepsy score based on five questions was developed. Data were compared with those of 12 hypocretin-deficient narcoleptics (N-hd). There were significant differences between N and NpC (including mean sleep latency on MSLT), but none between N and N-hd. A score of sleep propensity during active situations (SPAS) and the frequency of sleep paralysis/hallucinations at sleep onset, dreams of flying, and history of sleep shouting discriminated N from H and No (P < 0.001). Cataplexy-like symptoms in H (18%) and No (8%) could be discriminated from 'true' cataplexy in N on the basis of topography of motor effects, triggering emotions and triggering situations (P < 0.001). Our narcolepsy score had a similar sensitivity (96% versus 98%) but a higher specificity (98% versus 56%) than the UNS. Analysis of co-occurring symptoms in narcolepsy revealed two symptom complexes: EDS, cataplexy, automatic behaviors; and sleep paralysis, hallucinations, parasomnias. Low/undetectable cerebrospinal fluid hypocretin-1 levels and a history of definite cataplexy identify similar subgroups of narcoleptics. Specific questions on severity of EDS (SPAS score) and characteristics of cataplexy allow the recognition of subgroups of narcoleptics and their differentiation from non-narcoleptic EDS patients, including those reporting cataplexy-like episodes. The existence of co-occurring symptoms supports the hypothesis of a distinct pathophysiology of single narcoleptic symptoms.


[Post mortem dissections -the legal status in Israel].
Forensic medicine is the application of science to the medical disciplines to answer questions related to criminal law. Most forensic practitioners are physicians with expertise in pathology. In the field of post mortem surgeries, the extensive area of the encounter between the law and medicine is compLicated. The doctor who is responsible for the procedure needs to take decisions on the cause of death, as well as considerations of Legal and religious issues. Furthermore, the doctor needs to take into consideration the requests of the family of the deceased. This article aims to reveal the legal, medical and moral complexity of post mortem surgeries, especially in the last few years during which new imaging techniques developed may pose as reasonable alternatives for such surgeries.


[Study on the relationship between mental health and overweight, obesity, different sex among junior middle school students].
To examine the relationships between overweight, obesity and indices as satisfaction of life, trait anxiety, depression, self concept etc. in male and female junior middle school students. A questionnaire survey was administered to 1818 participants in a middle school in Hefei city, Anhui province. This contents of survey would include Multidimensional Students' Life Satisfaction Scale (MSLSS), Center for Epidemiologic Studies Depression Scale (CES-D), Trait Anxiety Inventory (TAI), and Piers-Harris Children's Self Concept Scale (PHSCS). Anthropometric measures were taken together with the calculation of body mass index (BMI). The students were divided into normal-weight, overweight and obesity groups by BMI separate criteria. Gender differences of mental health status and group differences of mental health among normal-weight, overweight obesity students were analyzed. Relationships between BMI and the scores of MSLSS, CES-D, TAI, PHSCS were estimated among boys and girls respectively. The prevalence rates of overweight and obesity of boys (21.5%, 7.7%) were significantly higher than in girls (8.0%, 2.8%). Difference of the MSLSS scores in gender was significant among normal-weight group (P = 0.002). The difference of the CES-D scores in gender was significant among overweight group (P = 0.046). There were significant group differences of the CES-D scores, TAI scores, and PHSCS scores among normal-weight, overweight and obese girls (P < 0.05). Both the CES-D score and TAI score of obese girls were higher than normal-weight girls (P = 0.012 and P = 0.035). The PHSCS score of obese girls was lower than normal-weight girls (P = 0.014) and the group difference of the CES-D score was also significant between overweight and normal-weight girls (P = 0.025). Both prevalence rates of overweight and obesity of boys were higher than that in girls. Nevertheless, level of mental health level among girls with overweight and obesity were lower than that in boys.


Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes.
Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction. To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation. Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy. Pathological changes in sural nerve. Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum). Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).


Insulin gene profile cycles with season of birth of future diabetic children and their relatives.
HLA class II gene pattern and IA-2A antibody positivity, revealing selected risks for prediction of type 1 diabetes mellitus (DM1), were previously shown to be cycling roughly in parallel with seasonally fluctuating frequencies of births of future diabetic children. Is this also true for insulin genotyping? Is this also true for births of the healthy close relatives of children with DM1? In 98 Slovak children with DM1 and in 60 healthy parents and siblings, two single nucleotide polymorphisms of the insulin gene (-23 Hph I; +1127 Pst I) were typed. Results were expressed as score 0 (maximal risk) up to 2 (minimal risk or protection), or 0-4 for the sum of both scores. Birth seasonality of these risk scores was tested by Halberg cosinor regression. Results were similar for the two alleles; therefore, the summed risk score was evaluated. The DM1 risk from the insulin gene pattern in births of future diabetics cycled significantly semi-annually, with maxima around the spring and autumn equinoxes. In the relatives, a significant annual and extremely pronounced quarterly peaking rhythm was found, with maximum risk in births around the autumn equinox and shortly after the winter solstice. Significant protection peaks are present in late winter, spring and summer. The highest frequency of Coxsackie infections in the Slovakian child population, and of 'diabetic' births and manifestations, found earlier together with maximal risks from HLA II and IA-2A antibodies in late summer and early autumn, is now confirmed also for the insulin gene pattern in diabetic children and even also for their healthy close relatives.


Visuomotor optimality and its utility in parametrization of response.
We present a method of characterizing visuomotor response by inferring subject-specific physiologically meaningful parameters within the framework of optimal control theory. The characterization of visuomotor response is of interest in the assessment of impairment and rehabilitation, the analysis of man-machine systems, and sensorimotor research. We model the visuomotor response as a linear quadratic Gaussian (LQG) controller, a Bayesian optimal state estimator in series with a linear quadratic regulator. Subjects used a modified computer mouse to attempt to keep a displayed cursor at a fixed desired location despite a Gaussian random disturbance and simple cursor dynamics. Nearly all subjects' behavior was consistent with the hypothesized optimality. Experimental data were used to fit an LQG model whose assumptions are simple and consistent with other sensorimotor work. The parametrization is parsimonious and yields quantities of clear physiological meaning: noise intensity, level of exertion, delay, and noise bandwidth. Significant variations in response were observed, consistent with signal-dependent noise and changes in exerted effort. This is a novel example of the role of optimal control theory in explaining variance in human visuomotor response. We also present technical improvements on the use of LQG in human operator modeling.


Interleukin-22 ameliorated acetaminophen-induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses.
Acetaminophen (APAP) overdose can lead to acute, severe kidney injury, which has recently attracted considerable attention among researchers and clinicians. Unfortunately, there are no well-established treatments for APAP-induced renal injury, and the molecular mechanism of APAP-induced kidney injury is still unclear. Herein, we explored the protective effects of interleukin (IL)-22 on APAP-induced renal injury and the underlying molecular basis. We found that IL-22 could significantly alleviate the accumulation of reactive oxygen species (ROS) and ameliorate mitochondrial dysfunction, reducing APAP-induced renal tubular epithelial cell (TEC) death in vitro and in vivo. Furthermore, IL-22 could downregulate the APAP-induced NLRP3 inflammasome activation and mature IL-1β release in kidney injury. Additionally, the APAP-mediated upregulation of the serum levels of IL-18, TNF-α, IL-6, and IL-1β was obviously decreased, suggesting IL-22 has inhibitory effects on inflammatory responses. Conclusively, our study demonstrated that IL-22 exerted ameliorative effects on APAP-induced kidney injury by alleviating mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that IL-22 represents a potential therapeutic approach to treat APAP-induced kidney injury. KEY POINTS: • IL-22 could ameliorate APAP that triggered oxidative stress and mitochondrial dysfunction. • IL-22 could reduce APAP that caused inflammatory responses. Graphical abstract.


A systematic review of the quality and scope of economic evaluations in child oral health research.
Economic evaluations provide policy makers with information to facilitate efficient resource allocation. To date, the quality and scope of economic evaluations in the field of child oral health has not been evaluated. Furthermore, whilst the involvement of children in research has been actively encouraged in recent years, the success of this movement in dental health economics has not yet been explored. This review aimed to determine the quality and scope of published economic evaluations applied to children's oral health and to consider the extent of children's involvement. The following databases were searched: CINAHL, Cochrane Library, Econlit, EThOS, MEDLINE, NHS EED, OpenGrey, Scopus, Web of Science. Full economic evaluations, relating to any aspect of child oral health, published after 1997 were included and appraised against the Drummond checklist and the Consolidated Health Economic Evaluation Reporting Standards by a team of four calibrated reviewers. Data were also extracted regarding children's involvement and the outcome measures used. Two thousand seven hundred fifteen studies were identified, of which 46 met the inclusion criteria. The majority (n = 38, 82%) were cost-effectiveness studies, with most focusing on the prevention or management of dental caries (n = 42, 91%). One study quantified outcomes in Quality Adjusted Life Years (QALYs), and one study utilised a child-reported outcome measure. The mean percentage of applicable Drummond checklist criteria met by the studies in this review was 48% (median = 50%, range = 0-100%) with key methodological weaknesses noted in relation to discounting of costs and outcomes. The mean percentage of applicable CHEERS criteria met by each study was 77% (median = 83%, range = 33-100%), with limited reporting of conflicts of interest. Children's engagement was largely overlooked. There is a paucity of high-quality economic evaluations in the field of child oral health. This deficiency could be addressed through the endorsement of standardised economic evaluation guidelines by dental journals. The development of a child-centred utility measure for use in paediatric oral health would enable researchers to quantify outcomes in terms of quality adjusted life years (QALYs) whilst promoting child-centred research.


Diagnostic values of sonography for assessment of sternal fractures compared with conventional radiography and bone scans.
This study was prospectively undertaken to evaluate the diagnostic value of sonography for detection of sternal fractures. We compared sonographic, conventional radiographic, and bone scan examinations of sternal fractures. Fifty consecutive patients (26 male and 24 female; mean age, 45.2 years) were evaluated. Conventional radiography and sonography were performed in all patients, and bone scans were performed in 39 patients. All patients had acute pain and tenderness in anterior midline chest areas. Sonography was performed by 2 musculoskeletal radiologists within 1 to 2 days after admission. Patients underwent conventional radiography at admission and bone scans within 4 to 7 days after admission. Two radiologists reviewed all imaging findings by means of consensus. In addition, sonography was performed in 20 asymptomatic patients in a normal control group. Conventional radiography depicted sternal fractures in 12 of 50 patients. Sternal fractures were detected in 31 of 50 patients on sonography. Fractures on sonography were located in the manubrium (8 cases), upper sternal body (11 cases), mid sternal body (5 cases), and lower sternal body (7 cases). Bone scans showed sternal hot uptakes (accumulations of the radionuclide used) in 18 of 39 patients. In the control group, there were no bony defects or abnormal contours. We could detect sternal fractures more effectively with sonography than with conventional radiography and bone scans. In addition, sternal fracture locations showed relatively even distributions, and focal fractures in the manubrium were not easily detected on bone scans.


Thrombogenicity and reoperation of the St. Jude Medical Silzone valve: a comparison with the conventional St. Jude Medical valve.
The St. Jude Medical Silzone valve was withdrawn from the market after an interim analysis of the AVERT study revealed a 2.76% incidence of paravalvar leakage leading to valve re-replacement, compared with only 1.02% in the control group. Additionally, an increased risk for thromboembolic complications was reported in different series of patients. To monitor the consistency of these reports, the incidence of thromboembolic complications and paravalvar leakage was investigated in 113 patients who received a Silzone valve at the authors' institution, compared with 101 patients who, immediately prior to the Silzone group, received a conventional valve. No difference was found in the incidence of either thromboembolism or paravalvar leakage after either Silzone or conventional valve replacement. Differences between the AVERT study and the present study might reflect differences in operative technique or in patient groups, but this as yet is unknown. To clarify the prospects of the estimated 36,000 patients with Silzone valves world wide, further research should aim at identifying possible unique features of patient groups with a higher risk of paravalvar leakage leading to valve explantation. In brief, an increased rate of paravalvar leakage and/or thromboembolism does not apply to either valve replacement groups.


Using a 3D handheld scanner to capture trochlear groove shape: proof of concept study.
Trochleoplasty is a surgical procedure used to treat patellar instability by modifying the trochlear groove. Analysis of the groove with a handheld scanner would enable accurate real-time planning and facilitate tailormade correction. We aimed to measure trochlear depth, sulcus angle, trochlear facet ratio, trochlear angle and lateral trochlear inclination angle and to establish inter- and intra-rater reliability for knee models to determine reliability and repeatability. The trochlear grooves of three knee models were scanned by two investigators. Three-dimensional reference models were created and surface-matched. Custom software was used to determine the desired parameters. The intraclass correlation coefficient (ICC) was used to determine test-retest reliability and the parameter results for each model that showed best reproducibility. There was good interobserver reliability (trochlear depth, 1.0mm; sulcus angle, 2.7°; trochlear angle, 4.0°; lateral trochlear inclination angle, 4.0°), except in the trochlear facet ratio (32.0%) of one knee model. With outliers removed, the ICC was moderate to excellent in 73.34% of measurements, with trochlear depth showing the best reproducibility. This feasibility study showed a handheld scanner in conjunction with supporting software can measure trochlear parameters with good to excellent inter- and intra-observer reliability.


Using PyMOL to Explore the Effects of pH on Noncovalent Interactions between Immunoglobulin G and Protein A: A Guided-Inquiry Biochemistry Activity.
Students' understandings of foundational concepts such as noncovalent interactions, pH and pKa are crucial for success in undergraduate biochemistry courses. We developed a guided-inquiry activity to aid students in making connections between noncovalent interactions and pH/pKa . Students explore these concepts by examining the primary and tertiary structures of immunoglobulin G (IgG) and Protein A. Students use PyMOL, an open source molecular visualization application, to (1) identify hydrogen bonds and salt bridges between and within the proteins at physiological pH and (2) apply their knowledge of pH/pKa to association rate constant data for these proteins at pH 4 and pH 11. The laboratory activity was implemented within a one semester biochemistry laboratory for students majoring in allied health disciplines, engineering, and biological sciences. Several extensions for more advanced students are discussed. Students' overall performance highlighted their ability to successfully complete tasks such as labeling and identifying noncovalent interactions and revealed difficulties with analyzing noncovalent interactions under varying pH/pKa conditions. Students' evaluations after completing the activity indicated they felt challenged but also recognized the potential of the activity to help them gain meaningful understanding of the connections between noncovalent interactions, pH, pKa , and protein structure. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(6):528-536, 2017.


Cancer progression in the transgenic adenocarcinoma of mouse prostate mouse is related to energy balance, body mass, and body composition, but not food intake.
Calorie restriction can inhibit or delay carcinogenesis, reportedly due to a reduction in calorie intake rather than by concurrent changes in body mass and/or composition. Our objective was to test the hypothesis that body mass and/or composition have an important effect, independent of energy intake, on the benefits or hazards associated with calorie restriction or overeating, respectively. In the first experiment, transgenic mice that spontaneously develop prostate cancer [transgenic adenocarcinoma of mouse prostate (TRAMP)] were housed at 27 degrees C or 22 degrees C and pair fed the same diet for 21 weeks (95% of ad libitum intake at 27 degrees C). In the second experiment, TRAMP mice were housed at 27 degrees C or 22 degrees C and fed the same diet ad libitum for 21 weeks. Despite a similar calorie intake, pair-fed mice at 27 degrees C (PF27) were heavier (28.3 +/- 3.3 versus 17.6 +/- 1.6 g at 21 weeks; P < 0.001; mean +/- SD) and had greater fat (6.4 +/- 2.1 versus 1.9 +/- 0.3 g; P < 0.001) and lean mass (P < 0.001) than pair-fed mice at 22 degrees C. Furthermore, PF27 mice had greater levels of serum leptin (P < 0.001), lower levels of adiponectin (P < 0.05), and a greater frequency of prostatic adenocarcinoma (P < 0.05). In contrast, ad libitum-fed mice housed at 22 degrees C consumed approximately 30% more calories than ad libitum-fed mice at 27 degrees C, but there was no difference between groups in body composition or cancer progression. These results imply that the ability of calorie restriction to inhibit or delay cancer incidence and progression is mediated in part by changes in energy balance, body mass, and/or body composition rather than calorie intake per se, suggesting that excess calorie retention, rather than consumption, confers cancer risk.


Enhanced immunosuppression in bursectomized chickens by passive transfer of antibody.
Three trials were conducted using commercial broiler cockerels to determine the immunological consequences of passive transfers of immune sera to bursectomized chickens. The data illustrate that passive transfers of immune sera to juvenile chickens which had been surgically bursectomized immediately after hatching caused a suppression of the primary hemagglutination response which was greater than that caused by bursectomy or passive transfer of immune sera alone. However, when these same birds were given a secondary challenge of antigen the resulting secondary hemagglutination response was normal. These data indicate that the passive transfer of immune sera to bursectomized chickens greatly limits their ability to mount primary humoral responses, while not affecting the ability to develop anamnestic immunity.


Downsizing and prostate cancer.
In the treatment of prostatic carcinoma, neoadjuvant androgen deprivation therapy has been shown to confer several clinical and quality-of-life benefits. Compared with the luteinizing hormone-releasing hormone agonists, gonadotropin-releasing hormone antagonists can achieve castrate levels of testosterone much faster, without the risks associated with testosterone flare. They can provide equal or superior efficacy in apoptosis, radiation sensitization, and prostate volume reduction. Urologists are increasingly employing neoadjuvant androgen deprivation in patients undergoing prostatectomy, radiation, brachytherapy, and cryotherapy.


Comparative effects of valsartan and enalapril on cardiac sympathetic nerve activity and plasma brain natriuretic peptide in patients with congestive heart failure.
To evaluate the effects of valsartan on cardiac sympathetic nerve activity, plasma brain natriuretic peptide (BNP) concentration, cardiac function, and symptoms in patients with congestive heart failure (CHF) by comparison with those of enalapril. 50 patients with CHF (left ventricular ejection fraction (LVEF) < 40%) were randomly assigned to valsartan (80 mg/day; n = 25) or enalapril (5 mg/day; n = 25). All patients were also treated with a loop diuretic. The delayed heart to mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate were determined from (123)I-meta-iodobenzylguanidine (MIBG) images. Plasma BNP concentrations were measured before and after six months of treatment. The left ventricular end diastolic volume (LVEDV) and LVEF were also determined by echocardiography. In patients receiving valsartan, TDS decreased from a mean (SD) of 43 (8) to 39 (10) (p < 0.01), H/M ratio increased from 1.70 (0.17) to 1.78 (0.22) (p < 0.05), washout rate decreased from 46 (11)% to 41 (10)% (p < 0.05), and plasma BNP concentration decreased from 237 (180) pg/ml to 143 (93) pg/ml (p < 0.05). In addition, LVEDV decreased from 172 (42) ml to 151 (45) ml (p < 0.05) and LVEF increased from 31 (7)% to 39 (10)% (p < 0.001). However, these parameters did not change significantly in patients receiving enalapril. Plasma BNP concentration and (123)I-MIBG scintigraphic and echocardiographic parameters improved significantly after six months of treatment with valsartan. These findings indicate that valsartan can improve cardiac sympathetic nerve activity and left ventricular performance in patients with CHF.


Effectiveness of sanitization protocols in removing or reducing parasites from vegetables: A systematic review with meta-analysis.
Parasitic contamination in vegetables is a reality in several countries and a challenge for food safety. The risk of consumption usually raw, associated with failures in good practices of production, transportation, and preparation further increase the possibility of ingesting contaminated food. Given this, a systematic review was carried out to scientifically demonstrate the effectiveness of sanitization protocols in the parasitic decontamination of plants. This review was conducted following the guidelines of the Cochrane Manual, being registered in the PROSPERO protocol base (CRD42020206929) and reported according to the PRISMA 2020 statement. The review evaluated studies published in the MEDLINE, Embase, Web of Science, FSTA, LILACS, and AGRIS databases, as well as manual searches of related articles, references, and theses and dissertations directories. The meta-analysis was performed using the Revman 5 software program, the bias assessment used the Robins I Tools with some adaptations, and the quality of the evidence was evaluated using GRADE. The review included a total of 31 studies, most of which were carried out in countries with a high incidence of plant parasites, such as Brazil and Iran. Interventions combined with 200ppm chlorination preceded by brushing, rinsing, or immersion in detergent showed the greatest efficiency in parasitic decontamination. Despite the high heterogeneity and risk of bias in the primary studies, this review can inspire the planning of new studies which observe the critical and methodological evaluation for research in the field of food safety.


How does multi-reference computation change the catalysis chemistry? DFT and CASPT2 studies of the Cu-catalysed coupling reactions between aryl iodides and β-diketones.
The molecular mechanism of a Cu-catalysed coupling reaction was theoretically studied using density functional theory (DFT) and the complete active space self-consistent field method followed by the second-order perturbation theory (CASSCF/CASPT2) to investigate the effects of the strong electron correlation of the Cu centre on the reaction profile. Both DFT and CASSCF/CASPT2 calculations showed that the catalytic cycle proceeds via an oxidative addition (OA) reaction, followed by a reductive elimination (RE) reaction, where OA is the rate-determining step. Although the DFT-calculated activation energies of the OA and RE steps are highly dependent on the choice of functionals, the CASSCF/CASPT2 results are less affected by the choice of DFT-optimised geometries. Therefore, with a careful assessment based on the CASSCF/CASPT2 single-point energy evaluation, an optimal choice of the DFT geometry is of good qualitative use for energetics at the CASPT2 level of theory. Based on the changes in the electron populations of the 3d orbitals during the OA and RE steps, the characteristic features of the DFT-calculated electronic structure were qualitatively consistent with those calculated using the CASSCF method. Further electronic structure analysis by the natural orbital occupancy of the CASSCF wavefunction showed that the ground state is almost single-reference in this system and the strong electron correlation effect of the Cu centre can be dealt with using the MP2 or CCSD method, too. However, the slightly smaller occupation numbers of the 3dπ orbital in the course of reactions suggested that the electron correlation effect of the Cu(III) centre appears through the interaction between the 3dπ orbital and the C-I antibonding σ* orbital in the OA step, and between the 3dπ orbital and the Cu-C antibonding σ* orbital in the RE step.


Quality of life and severity of skin changes in the dynamics of psoriasis.
Psoriasis is a chronic skin disease with periods of recurrence and remission. The skin changes which are typical of this disease can have a considerable effect on the patient's psychological state, self-esteem and body image. It can also affect the patient's functioning in all areas of life and quality of life. The present study characterized the patient needs to improve the quality of life in specified areas in patients depending on the severity of psoriatic changes. The study was conducted in two stages on 100 patients aged from 18 to 66. A dermatological examination was conducted in stage one. Patients' dermatological condition was assessed with the Psoriasis Area and Severity Index (PASI). Clinical and socio-economic information was collected in stage two using a questionnaire, a medical interview and a standardized questionnaire measuring quality of life, the WHOQOL-BREF. The following factors had the greatest effect on the general quality of life and quality of health ratings in the studied sample: severity of psoriatic changes, duration of the most recent recurrence and sex. Severity of psoriatic changes had a negative effect on the patient's somatic, psychological, environmental and social functioning. Duration of the most recent recurrence had a negative effect on social functioning. Practical implications of this study allow dermatologists to determine the appropriate therapeutic intervention which improves the quality of life of these patients on the one hand, and will increase patient's involvement in the process of treatment on the other hand. Quality of life is more impaired by more severe chronic skin disease.


Examination of carotid arteries with quantitative color Doppler flow imaging.
The results of conventional duplex scanning were compared with QCDFI. A total of 224 consecutive patients comprising 442 unilateral carotid systems were examined by conventional duplex techniques. MPSV, as determined by QCDFI, were recorded for each of the 442 carotid segments and grouped according to the previously determined degrees of stenosis. The predictive value of QCDFI was confirmed by angiography with an overall accuracy of 91%. Results obtained by duplex scanning correlated with angiography 89% of the time. Based on QCDFI data, a scale to grade carotid stenosis was developed.


Effects of interactions with older males on behavior and reproductive development in first-year male red-winged blackbirds Agelaius phoeniceus.
Male red-winged blackbirds Agelaius phoeniceus in their first year normally do not establish territories or breed. To investigate the possibility that interactions with older males might inhibit reproductive development of young males, we compared the behavior of first-year males in the presence and absence of older males. For three months during the first half of the breeding season, we studied mixed- and single-age groups of three males in standardized outdoor aviaries: two groups of three first-year males (FFF groups), two groups of one older and two first-year males (AFF groups), and one group of three older males (AAA group). In all groups one male established clear dominance, invariably the older male in AFF groups. The dominant male in FFF groups displaced subordinates less frequently than did the dominant older male in AFF groups early in the season, but equally frequently later. In May the largest testies weights of males in FFF groups were significantly lower than those of dominant older males in AFF groups. First-year males in the absence of direct interactions with older males can achieve levels of aggressive behavior comparable to those of a dominant older male in similar social environments but the seasonal development of their aggressive behavior occurs later and their testes in May are smaller than dominant adults'. This delay in the seasonal development of aggressive behavior in first-year males, independent of the immediate social environment, suggests that the age-dependent territoriality of males in this species is not strongly regulated by effects of older males on the development of younger males.


Stroop effect in smartphone addiction among college students.
Smartphone addiction (SPA) affects an increasing number of college students, but it remains poorly understood. This study aimed to explore the psychological mechanism of the decrease in cognitive control ability from cognitive psychology in students with SPA.The smartphone addition tendency scale (MPATS) was used to identify 64 undergraduates with SPA (MPATS > 45) and 64 sex- and age-matched controls (MPATS < 30).The 2 groups were well matched for age and sex distribution. The RT of the SPA group under the conflict state was 628.2±59.2 ms vs 549.4 ± 44.2 ms under the consistent state (P < .005). The RT of the control group under the conflict state was 707.5 ± 66.4 vs 582.0 ± 39.4 ms under the consistent state (P < .005). Under the conflict state, errors made by the SPA group were 8.7 ± 5.4, and that of the control group was 6.6 ± 3.7 (P < .05). The reaction delay of the SPA group was 25.6 ± 49.2 vs 110.0 ± 41.8 ms (P < .05).Correlation analysis showed a clear positive correlation between SPA and the number of mistakes in the conflict state of the Stroop task.


Diversity and survival of artificial lifeforms under sedimentation and random motion.
Cellular automata are often used to explore the numerous possible scenarios of what could have occurred at the origins of life and before, during the prebiotic ages, when very simple molecules started to assemble and organise into larger catalytic or informative structures, or to simulate ecosystems. Artificial self-maintained spatial structures emerge in cellular automata and are often used to represent molecules or living organisms. They converge generally towards homogeneous stationary soups of still-life creatures. It is hard for an observer to believe they are similar to living systems, in particular because nothing is moving anymore within such simulated environments after few computation steps, because they present isotropic spatial organisation, because the diversity of self-maintained morphologies is poor, and because when stationary states are reached the creatures are immortal. Natural living systems, on the contrary, are composed of a high diversity of creatures in interaction having limited lifetimes and generally present a certain anisotropy of their spatial organisation, in particular frontiers and interfaces. In the present work, we propose that the presence of directional weak fields such as gravity may counter-balance the excess of mixing and disorder caused by Brownian motion and favour the appearance of specific regions, i.e. different strata or environmental layers, in which physical-chemical conditions favour the emergence and the survival of self-maintained spatial structures including living systems. We test this hypothesis by way of numerical simulations of a very simplified ecosystem model. We use the well-known Game of Life to which we add rules simulating both sedimentation forces and thermal agitation. We show that this leads to more active (vitality and biodiversity) and robust (survival) dynamics. This effectively suggests that coupling such physical processes to reactive systems allows the separation of environments into different milieux and could constitute a simple mechanism to form ecosystem frontiers or elementary interfaces that would protect and favour the development of fragile auto-poietic systems.


Group II intron-mediated deletion of lactate dehydrogenase gene in an isolated 1,3-propanediol producer Hafnia alvei AD27.
Our previous studies showed that glycerol fermentation by Hafnia alvei AD27 strain was accompanied by formation of high quantities of lactate. The ultimate aim of this work was the elimination of excessive lactate production in the 1,3-propanediol producer cultures. Group II intron-mediated deletion of ldh (lactate dehydrogenase) gene in an environmental isolate of H. alvei AD27 strain was conducted. The effect of the Δldh genotype in H. alvei AD27 strain varied depending on the culture medium applied. Under lower initial glycerol concentration (20 gL-1), lactate and 1,3-propanediol production was fully abolished, and the main carbon flux was directed to ethanol synthesis. On the other hand, at higher initial glycerol concentrations (40 gL-1), 1,3-propanediol and lactate production was recovered in the recombinant strain. The final titers of 1,3-propanediol and ethanol were similar for the recombinant and the WT strains, while the Δldh genotype displayed significantly decreased lactate titer. The by-products profile was altered upon ldh gene deletion, while glycerol utilization and biomass accumulation remained unaltered. As indicated by flow-cytometry analyses, the internal pH was not different for the WT and the recombinant Δldh strains over the culture duration, however, the WT strain was characterized by higher redox potential.


Localization of S-antigen by enzyme-labelled antibody method and electron microscopy.
Localization of S-antigen was studied by a direct enzyme-labeled immunohistochemical method with light and electron microscopes. IgG was prepared from rabbits which were sensitized by swine retinal S-antigen and the IgG was conjugated with horseradish peroxidase (HRP). This HRP-labeled IgG was directly applied to normal rabbit retina and the retina was processed to make slides for light and electron microscopic examinations. In light microscopic findings, a clear-cut positive response was noted in the outer segment of photoreceptor cells which was similar to that of Wacker's observation, and a weak response was observed in the inner segment of the photoreceptor cells and the outer nuclear layer. In electron microscopic findings, immunoprecipitates, which were represented by electron-dense particles, were observed on both sides of the disk membrane of the outer segment with evenly distributed particles on both outer and inner surfaces, showing a pattern symmetric to that of the membrane. These immunoprecipitates were also noted in the plasma membrane of the outer segment but there they did not show a pattern similar to that of the disk membrane. A small amount of pinpoint-shaped immunoprecipitates were also noted in the cytoplasm of the inner segment and the connecting cilia. The immunoprecipitates were observed to gradually decrease in number with the phagocytosis of the outer segment by the retinal pigment epithelium, and they finally disappeared as fragments which were completely phagocytized. These findings may suggest a renewal process of S-antigen and a rationalization of this theory was discussed.


Secretion of transforming growth factor-beta isoforms by embryonic stem cells: isoform and latency are dependent on direction of differentiation.
Murine embryonic stem (ES) cells are maintained in an undifferentiated state when cultured in medium conditioned by Buffalo rat liver (BRL) cells. BRL conditioned medium (CM) contains a differentiation inhibitory activity (DIA) that is synonymous with leukemia inhibitory factor (LIF). ES cells in monolayer culture can be induced to differentiate by addition of all-trans retinoic acid (RA) to the BRL CM, when they mainly form cells resembling parietal endoderm, or by culture in medium not conditioned by BRL cells. ES cells thus deprived of LIF/DIA differentiate spontaneously to a cell type that expresses Brachyury (T), a marker of early mesoderm. Northern blot analyses have shown previously that transcripts for transforming growth factor beta 1 (TGF-beta 1) are detected in undifferentiated cells while transcripts for TGF-beta 2 and TGF-beta 3 only become detectable after differentiation. We have now determined levels of TGF-beta protein in CM and in the extracellular matrix (ECM) and have used neutralizing antibodies specific for TGF-beta 1 and TGF-beta 2 that do not react with recombinant human TGF-beta 3 to determine the isoform secreted. Using the growth inhibition of mink lung CCL64 cells as a bioassay for TGF-beta activity, we demonstrate that undifferentiated ES cells secrete latent TGF-beta 1 into the medium but no activity is found in their ECM. Cells induced to differentiate with RA contain TGF-beta 2 in both active and latent forms in their CM. Likewise their ECM contains TGF-beta 2 as the sole isoform. ES cells deprived of LIF/DIA secrete both TGF-beta 1 and TGF-beta 2 isoforms in their CM but TGF-beta-like activity remains after addition of neutralizing antibodies for TGF-beta 1 and TGF-beta 2. This active TGF beta is the major component of the TGF-beta activity in this CM. By contrast, ECM from LIF/DIA deprived cells contains only the TGF-beta 1 and beta 2 isoforms. The remaining activity in CM correlates with high expression of TGF-beta 3 by Northern blot analysis in these cells. We speculate that TGF-beta 3 is secreted by these cells and may be activated more efficiently and/or in a different manner to TGF-beta 1 and TGF-beta 2, since it is present in CM only in its active form.


The effect of chemoreduction on retinoblastoma-induced retinal detachment.
Retinoblastoma with total retinal detachment traditionally has been managed with enucleation. We employed a chemoreduction protocol in an effort to reduce the tumor size to allow for focal treatment and salvage of the eye. A prospective study was performed to assess the effects of a 2-month chemoreduction regimen of vincristine, etoposide, and carboplatin on massive retinoblastoma with total retinal detachment. We treated 17 eyes with total retinal detachment from retinoblastoma in 13 patients over a 14-month period. At the initial examination, the mean tumor base was 15 mm and mean thickness was 10 mm. The eyes were classified as Reese-Ellsworth group V in 16 cases (94%) and group III in one case (6%). The retina was totally detached with serous subretinal fluid in all cases. After 2 months of chemoreduction, all tumors showed a response, and the tumors decreased to a mean base of 10 mm and thickness of 5 mm. Overall, a mean of 33% decrease in base and 47% decrease in thickness was noted. The subretinal fluid had resolved completely in seven eyes (41%), leaving flat retina. In three eyes (18%), partial resolution was achieved; in seven eyes (41%), minimal resolution of the subretinal fluid at the 2-month period was noted. By last follow up, at a mean of 10 months after initiation of chemoreduction, complete resolution of the subretinal fluid occurred in 13 eyes (76%) and partial resolution of subretinal fluid occurred in four eyes (24%). Preliminary observations suggest that chemoreduction may be an important tool in the initial management of retinoblastoma, even for large tumors with total retinal detachment. Tumor shrinkage may be dramatic and subretinal fluid resolution may be complete.


Synthesis and characterization of nitrile functionalized silver(I)-N-heterocyclic carbene complexes: DNA binding, cleavage studies, antibacterial properties and mosquitocidal activity against the dengue vector, Aedes albopictus.
A series of four benzimidazolium based nitrile-functionalized mononuclear-Ag(I)-N-heterocyclic carbene and binuclear-Ag(I)-N-heterocyclic carbene (Ag(I)-NHC) hexafluorophosphate complexes (5b-8b) were synthesized by reacting the corresponding hexafluorophosphate salts (1b-4b) with Ag2O in acetonitrile, respectively. These compounds were characterized by 1H NMR, 13C NMR, IR, UV-visible spectroscopic techniques, elemental analyses and molar conductivity. Additionally, 8b was structurally characterized by single crystal X-ray diffraction technique. Preliminary in vitro antibacterial evaluation was conducted for all the compounds against two standard bacteria; gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacterial strains. Most of the Ag(I)-NHC complexes (5b-8b) showed moderate to good antibacterial activity with MIC values in the range of 12.5-100 μg/mL. Especially, compound 8b exhibited promising anti-Staphylococcus aureus activity with a low MIC value (12.5 μg/mL). However, all the hexafluorophosphate salts (1b-4b) were inactive against the bacteria strains. The preliminary interactive investigation revealed that the most active compound, 8b, could effectively intercalate into DNA to form 8b-DNA complex which shows a better binding ability for DNA (Kb = 3.627 × 106) than the complexes 5b-7b (2.177 × 106, 8.672 × 105 and 6.665 × 105, respectively). Nuclease activity of the complexes on plasmid DNA and Aedes albopictus genomic DNA was time-dependent, although minimal. The complexes were larvicidal to the mosquito, with 5b, 6b and 8b being highly active. Developmental progression from the larval to the adult stage was affected by the complexes, progressively being toxic to the insect's development with increasing concentration. These indicate the potential use of these complexes as control agents against bacteria and the dengue mosquito Ae. albopictus.


Bone marrow-derived mesenchymal stem cells propagate immunosuppressive/anti-inflammatory macrophages in cell-to-cell contact-independent and -dependent manners under hypoxic culture.
Immunosuppressive/anti-inflammatory macrophage (Mφ), M2-Mφ that expressed the typical M2-Mφs marker, CD206, and anti-inflammatory cytokine, interleukin (IL)-10, is beneficial and expected tool for the cytotherapy against inflammatory diseases. Here, we demonstrated that bone marrow-derived lineage-positive (Lin+) blood cells proliferated and differentiated into M2-Mφs by cooperation with the bone marrow-derived mesenchymal stem cells (MSCs) under hypoxic condition: MSCs not only promoted proliferation of undifferentiated M2-Mφs, pre-M2-Mφs, in the Lin+ fraction via a proliferative effect of the MSCs-secreted macrophage colony-stimulating factor, but also promoted M2-Mφ polarization of the pre-M2-Mφs through cell-to-cell contact with the pre-M2-Mφs. Intriguingly, an inhibitor for intercellular adhesion molecule (ICAM)-1 receptor/lymphocyte function-associated antigen (LFA)-1, Rwj50271, partially suppressed expression of CD206 in the Lin+ blood cells but an inhibitor for VCAM-1 receptor/VLA-4, BIO5192, did not, suggesting that the cell-to-cell adhesion through LFA-1 on pre-M2-Mφs and ICAM-1 on MSCs was supposed to promoted the M2-Mφ polarization. Thus, the co-culture system consisting of bone marrow-derived Lin+ blood cells and MSCs under hypoxic condition was a beneficial supplier of a number of M2-Mφs, which could be clinically applicable to inflammatory diseases.