Investigation for a multi-silique trait in Brassica napus by alternative splicing analysis.
Flower and fruit development are vital stages of the angiosperm lifecycle. We previously investigated the multi-silique trait in the rapeseed (Brassica napus) line zws-ms on a genomic and transcriptomic level, leading to the identification of two genomic regions and several candidate genes associated with this trait. However, some events on the transcriptome level, like alternative splicing, were poorly understood. Plants from zws-ms and its near-isogenic line (NIL) zws-217 were both grown in Xindu with normal conditions and a colder area Ma'erkang. Buds from the two lines were sampled and RNA was isolated to perform the transcriptomic sequencing. The numbers and types of alternative splicing (AS) events from the two lines were counted and classified. Genes with AS events and expressed differentially between the two lines, as well as genes with AS events which occurred in only one line were emphasized. Their annotations were further studied. From the plants in Xindu District, an average of 205,496 AS events, which could be sorted into five AS types, were identified. zws-ms and zws-217 shared highly similar ratios of each AS type: The alternative 5' and 3' splice site types were the most common, while the exon skipping type was observed least often. Eleven differentially expressed AS genes were identified, of which four were upregulated and seven were downregulated in zws-ms. Their annotations implied that five of these genes were directly associated with the multi-silique trait. While samples from colder area Ma'erkang generated generally reduced number of each type of AS events except for Intron Retention; but the number of differentially expressed AS genes increased significantly. Further analysis found that among the 11 differentially expressed AS genes from Xindu, three of them maintained the same expression models, while the other eight genes did not show significant difference between the two lines in expression level. Additionally, the 205 line-specific expressed AS genes were analyzed, of which 187 could be annotated, and two were considered to be important. This study provides new insights into the molecular mechanism of the agronomically important multi-silique trait in rapeseed on the transcriptome level and screens out some environment-responding candidate genes.


The narrative approach as an effective single intervention in functional somatic symptoms in a multi-disciplinary referral clinic for primary care frequent attenders.
Mental health problems are underdiagnosed in general practice, primarily because they are often somatized and the patient reports only physical symptoms. These somatized symptoms are responsible for a large percentage of the frequent attenders in general practice. Palpitations are among those somatized symptoms. Here we present the theoretical background and the process of assessment and treatment of patients referred to a special counselling clinic for frequent attenders, through the report of a patient with palpitations. It illustrates the use of the narrative approach and the possible mode of action of this specific intervention.


Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas.
Pancreatic ductal adenocarcinoma carries a poor prognosis with annual deaths almost matching the reported incidence rates. Surgical resection offers the only potential cure. Yet, even among patients that undergo tumor resection, recurrence rates are high and long-term survival is scarce. Various tumor-related factors have been identified as predictors of survival after potentially curative resection. These factors include tumor size, lymph node disease, tumor grade, vascular invasion, perineural invasion and surgical resection margin. This article will re-evaluate the importance of these factors based on recent publications on the topic, with potential implications for treatment and outcome in patients with pancreatic cancer.


Breastfeeding in Infancy and Lipid Profile in Adolescence.
Breast milk has higher cholesterol than formula. Infants who are breastfed have different cholesterol synthesis and metabolism in infancy than infants who are formula fed. Little is known as to whether breastfeeding is associated with subsequent lipid profile, independent of adiposity. We assessed the association of breastfeeding in early infancy with lipid profile and adiposity at ∼17.5 years in a setting where exclusive breastfeeding is not associated with higher socioeconomic position. We used multivariable linear regression with multiple imputation and inverse probability weighting to examine the associations of contemporaneously reported feeding in the first 3 months of life (exclusive breastfeeding [7.5%], mixed feeding [40%], or always formula feeding [52%]) with lipids and adiposity at ∼17.5 years in 3261 participants in the Hong Kong Chinese birth cohort Children of 1997, adjusting for sex, birth weight, gestational weeks, parity, pregnancy characteristics, parents' highest education, mother's place of birth, and age at follow-up. Exclusive breastfeeding, but not mixed feeding at 0 to 3 months, compared with formula feeding was associated with lower total cholesterol and low-density lipoprotein cholesterol but not with high-density lipoprotein cholesterol at ∼17.5 years. BMI and fat percentage measured by bioimpedance did not differ by type of infant feeding. Exclusive breastfeeding in early infancy may promote a healthier lipid profile in late adolescence through mechanisms unrelated to adiposity, implicating its potential long-term benefits for cardiovascular health.


Genome assemblies of three closely related leaf beetle species (Galerucella spp.).
Galerucella (Coleoptera: Chrysomelidae) is a leaf beetle genus that has been extensively used for ecological and evolutionary studies. It has also been used as biological control agent against invading purple loosestrife in North America, with large effects on biodiversity. Here, we report genome assembly and annotation of three closely related Galerucella species: G. calmariensis, G. pusilla, and G. tenella. The three assemblies have a genome size ranging from 460 to 588 Mbp, with N50 from 31,588 to 79,674 kbp, containing 29,202 to 40,929 scaffolds. Using an ab initio evidence-driven approach, 30,302 to 33,794 protein-coding genes were identified and functionally annotated. These draft genomes will contribute to the understanding of host-parasitoid interactions, evolutionary comparisons of leaf beetle species and future population genomics studies.


Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress.
Although social environment variables such as socioeconomic status (SES) have been linked to childhood asthma, little is known about the psychobiological mechanisms underlying this relationship. The goal of this study was to investigate relationships among SES, psychological stress, and immune processes implicated in asthma. Thirty-seven children ages 9 to 18 years, physician-diagnosed with asthma, and 39 healthy children participated. Families were interviewed about chronic life stress, perceptions of threat, and SES. Blood samples were drawn from children to assess stimulated production of cytokines implicated in asthma (IL-4, IL-5, IL-13) and eosinophil counts. In children with asthma, lower SES was associated with heightened production of IL-5 and IL-13 and higher eosinophil counts (P values < .05). Lower SES also was associated with higher chronic stress and perceived threat (both groups: P values < .05). Higher levels of stress and threat perception were associated with heightened production of IL-5 and IL-13, and higher eosinophil counts in children with asthma (P values < .05). Statistical mediation tests revealed that chronic stress and threat perception represented statistically significant pathways between SES and immune processes in children with asthma (P values < .05). In healthy children, associations were in the opposite direction from the asthma group, though generally not significant. This is one of the first studies to document empirically a psychobiological explanation for the epidemiologic relationship between low SES and poor asthma outcomes. Associations among SES, psychological stress, and immune pathways suggest that the experience of stress, particularly among lower SES children, has implications for childhood asthma morbidity.


Variations of Median Nerve Formation in North Indian Population.
The median nerve is usually formed by two roots contributed from the medial and lateral cords of the brachial plexus. Morphological variations of the median nerve can have clinical implications from the anesthetic and surgical points of view. In this cadaveric observation study, we report the variations of median nerve formation in the North Indian population. We observed the formation of the median nerve in 40 human cadaveric upper limb specimens. The specimens belonged to 20 right and 20 left upper limbs. Variations in the formation of the median nerve were noted. Of the 40 dissected specimens, six (15%) had triple roots including a supernumerary root contributing to the medial nerve formation. The supernumerary root was a branch of the lateral cord in five cases, and it had an additional contribution from the medial cord in one case. The median nerve formation and continuation were located anterior or laterally in 39 specimens (97.5%) and medial in one (2.5%) in relation to the axillary artery. We observed supernumerary roots of varying morphology contributing to the median nerve formation. These variations should be considered during the administration of regional anesthesia and during the management of brachial plexus injuries. Further large multi-region studies will help in a better understanding of these variations.


Stent graft repair of visceral artery aneurysms.
Endovascular techniques with coil embolization have been used in certain visceral aneurysm cases, often resulting in sacrifice of the involved visceral vessel and end-organ thrombosis. We describe two cases in which stent grafts were used to treat these aneurysms, allowing preservation of visceral artery and end-organ flow while completely excluding the aneurysm. Case 1 was a 50-year-old morbidly obese woman with a history of multiple abdominal operations for renal cell carcinoma who was found to have a large splenic artery aneurysm. A 12-mm x 50-mm Wallgraft endoprosthesis (Boston Scientific, Watertown, Mass) was placed across the aneurysm from a femoral approach. The aneurysm was completely excluded, and splenic artery flow was preserved. A subsequent computed tomographic scan showed complete aneurysm exclusion and preserved flow to the spleen. Case 2 was a 73-year-old man with hypertension with back pain who was found with computed tomographic scan to have an 8-cm hepatic artery aneurysm. Arteriography showed a large saccular aneurysm arising from the mid portion of the common hepatic artery. Two 5-mm x 26-mm Jostent stent grafts (Jomed, Alpharetta, Ga) were placed across the aneurysm neck, completely excluding the aneurysm and preserving hepatic artery flow. The patient became pain free, and subsequent duplex ultrasound scan showed a thrombosed aneurysm with normal hepatic artery flow. Stent graft techniques show early promise as a safe and effective treatment of visceral artery aneurysms in selected patients at high risk. Endografts, unlike coil embolization, exclude the aneurysm and preserve end organ perfusion. Determining the durability of this type of therapy will require further study.


Patient satisfaction following a switch from treat-and-extend to observe-and-plan regimen in age-related macular degeneration.
Standard treatment of neovascular age-related macular degeneration (nAMD) is intravitreal injections (IVI) of antivascular endothelial growth factor (anti-VEGF) according to treat-and-extend (TnE). Observe-and-plan (OnP), a new regimen based on each individual's relapse interval lead to fewer clinical visits and has so far shown to be safe in treatment-naïve patients. In this study, we explore patient satisfaction and safety in nAMD when switching from TnE to OnP. 38 participants treated acording to TnE for ≥12 months were included and switched from TnE to OnP with their last stable interval. Main outcome was patient satisfaction (Leeds Satisfaction Questionnaire). Secondary outcomes were best-corrected visual acuity (BCVA), central retinal thickness (CRT) before and 12 months after switch and number of monitoring visits and injections of anti-VEGF 12 months prior to and following switch. Mean patient satisfaction was higher (3.7±0.5 SD) at 12 months after switch from TnE to OnP than before (3.6±0.5 SD, p=0.009, response rate 76%). BCVA and CRT were unchanged. Number of monitoring visits and injections were lower in the 12 months following than prior to switch (p<0.001). A switch from TnE to OnP in a non-treatment-naïve population resulted in higher patient satisfaction, while maintaining stable BCVA. This indicates that OnP may be applicable in the large group of nAMD patients that have received IVI for several years. OnP may alleviate the treatment burden on both individual and society of frequent clinical visits while increasing patient satisfaction.


Comparison of agar-gel precipitin responses among strains of fowl adenovirus using antigens prepared from chorioallantoic membranes and chicken kidney cell cultures.
Agar-gel precipitin responses obtained for serologically different strains of fowl adenovirus (FAV) in tests using antigens prepared from FAV-infected chorioallantoic membranes (CAM antigen) and chicken kidney cell cultures (CKC antigen) were compared. Findings showed that both types of antigens exhibited less sensitivity to heterologous than to homologous antisera and that quantitative differences in sensitivity were present between serotypes. CAM antigens were more sensitive than CKC antigens to heterologous antisera. Polyvalent CAM antigens containing 2 or 3 antigens increased sensitivity in testing of field serum samples, resulting in a higher rate of detection.


Living-related liver transplantation for biliary atresia associated with polysplenia syndrome.
This report describes a 1-yr-old boy with biliary atresia (BA) and polysplenia syndrome (PS) who underwent successful living-related liver transplantation (LTx). At the time of initial hepatic portoenterostomy, he was noticed to have a preduodenal portal vein (PV), non-rotation of the intestine, and polysplenia. Because he did not achieve good bile excretion, he underwent a living-related LTx (using a left lateral segment from his mother) at the age of 14 months. Evaluation of the vascular anatomy was made by angiography, magnetic resonance imaging (MRI), computerized tomography (CT), and Doppler ultrasound. The PV was stenotic from the confluence of the superior mesenteric vein (SMV) and splenic vein (SpV) to the hepatic hilum. The retrohepatic inferior vena cava (IVC) was deficient cranially to the renal vein and was connected to the azygous vein. The supra-hepatic IVC was detected below the diaphragm and was connected to three hepatic veins. The common hepatic artery (HA) originated from the superior mesenteric artery. At LTx, the PV was dissected to the level of confluence of the SMV and the SpV, from which the venous graft was interposed using the donor's ovarian vein. Three hepatic veins were plastied into one orifice, which was anastomosed to the graft's hepatic vein under the diaphragm. The graft vascularity and function has been good for 1 yr after LTx. In the present case, sufficient pre-LTx evaluation of vascular anomalies seemed to help performance of the successful LTx.


[Machado-Joseph disease in a family of Spanish origin].
The clinical observations in five patients, of a family of catalan origin (NE of Spain), affected with Machado-Joseph disease are reported. The pedigree showed the presence of 22 members affected (15 men, 7 women) over six generations. The symptoms and signs were variable among the patients and also variable in a same patient during the course of the disease. However, the main neurological alterations were ataxia, akinesia, distal amyotrophy, progressive external ophthalmoplegia, facial and lingual fasciculations and bulging eyes. The neuropathological examination performed in one patient disclosed degeneration of the posterior and spinocerebellar tracts in the spinal cord, marked nerve cell loss in Clarke's column and anterior horns and axonal degeneration of the peripheral nerves, in addition to nerve cell loss in the nuclei of the III, IV and VII cranial nerves and neuronal depletion in the substantia nigra. No other structures, including the striate complex and dentate nucleus, were significantly affected.


Nutrients against Glucocorticoid-Induced Muscle Atrophy.
Glucocorticoid excess is a critical factor contributing to muscle atrophy. Both endogenous and exogenous glucocorticoids negatively affect the preservation of muscle mass and function. To date, the most effective intervention to prevent muscle atrophy is to apply a mechanical load in the form of resistance exercise. However, glucocorticoid-induced skeletal muscle atrophy easily causes fatigue in daily physical activities, such as climbing stairs and walking at a brisk pace, and reduces body movements to cause a decreased ability to perform physical activity. Therefore, providing adequate nutrients in these circumstances is a key factor in limiting muscle wasting and improving muscle mass recovery. The present review will provide an up-to-date review of the effects of various nutrients, including amino acids such as branched-chain amino acids (BCAAs) and β-hydroxy β-methylbutyrate (HMB), fatty acids such as omega-3, and vitamins and their derivates on the prevention and improvement of glucocorticoid-induced muscle atrophy.


Dopaminergic modulation of glutamate-activated channels in the central nervous system.
Modulation of glutamate-activated currents by dopamine was studied in identified central neurons, alpha-motoneurons of the chick and horizontal cells of the perch. This modulation is mediated by a cAMP-dependent protein phosphorylation. The activation and desensitization time constants of glutamate currents were determined before and after incubation with dopamine. In the horizontal cells ultrafast glutamate (AMPA or quisqualate) application prior to the the dopamine incubation gives rise to fast transient current responses which desensitize within less than 100 ms. Kainate produced higher steady state currents. After incubation of the cells with dopamine (100 nM) for 30s the desensitization was dramatically reduced, but the amplitudes of the steady state currents were similar to the transient control currents. Kainate activated currents were not affected. In alpha-motoneurons the exposure to dopamine (100 nM) for 1 min was sufficient to increase the peak and steady state amplitudes but not the desensitization time constant of glutamate activated currents. Here enhancement was specific to the kainate component of glutamate activated currents; the decreased variance of currents reflects increased kainate channel activation. Measurements of motoneuronal cAMP concentrations showed an increase following addition of dopamine. mRNA encoding both D1 and D2 dopamine receptor subtypes was detected. We conclude that the dopamine dependent modulation which is mediated by a protein phosphorylation is due to an alteration of the desensitization of AMPA type receptors in horizontal cells and of the activation of kainate type receptors in motoneurons.


The mental state of arsonists as determined by forensic psychiatric examinations.
In this study we evaluated whether arsonists (n = 98) differ from homicide offenders (n = 55) in regard to psychiatric disorders, suicidality, and criminal responsibility in the context of forensic psychiatric pretrial examinations. Arsonists were mainly male, poorly educated, unemployed, and living in rural areas. Eighty-four percent of the arsonists and 62 percent of the homicide offenders had an alcohol abuse problem. This difference was statistically significant (p = .002). The arsonists more commonly had suicidal thoughts and attempted suicides. Over one-third of the arsonists used fire-setting as a suicide attempt. In comparing the arsonists with the control group, there was a statistically significant difference in the variables that indicate suicidality. Arsonists more commonly had diagnosed psychiatric diseases (p = .008). The incidence of psychoses was fourfold, chronic or severe depression about threefold, and mental retardation twofold when compared with the homicide offenders. Eighty-five percent of the arsonists had received psychiatric care before the crime was committed. The arsonists were more often found to be not criminally responsible for the crime committed (p = .01).


[The spread and inhibition of epileptic processes, findings with the kindling model in the cat].
The study was undertaken to describe some characteristics of subcortical brain activity during the development of an experimentally induced seizure disorder in the cat, as well as to test inhibitory effects of caudate counterstimulation. A further objective was to assess the use of closed circuit TV monitoring for the evaluation of clinical symptoms in an experimental model of limbic epilepsy. The analysis of event related potentials, spectral coherences and phases was especially suitable in order to detect a gradual lowering of the seizure threshold during the establishment of a unilateral Nucl. amygdalae epileptic focus. The results demonstrated evidence for the proceeding importance of hippocampal involvement during the development of seizure activity originating in the ipsilateral amygdala. No evidence, however, could be found for the existence of inhibitory functions triggered by stimulation of the ipsilateral caudate nucleus. The simultaneous split-screen TV monitoring of EEG and partial complex symptoms proved to be a valuable tool for the documentation of seizure patterns during the kindling procedure.


Biochemical and molecular epidemiology of cancer.
Examples of practical approaches to molecular epidemiology of human cancer are described. Biomarkers of carcinogen exposure or inherited host factors for cancer susceptibility are discussed. Major advances have been made in the detection of carcinogenmacromolecular adducts through the use of high performance liquid chromatography, immunoaffinity chromatography, the 32P-postlabeling assay, enzyme immunoassays, gas chromatography/mass spectroscopy and synchronous spectrophotofluorimetry. The polycyclic aromatic hydrocarbon-DNA adducts are the most extensively studied in this field and together with antibodies to these adducts found in human serum, they have become useful indicators of exposure to carcinogens. Assays for various kinds of alkyl-DNA adducts have also been developed and the presence of these adducts have been documented in human tissues. Carcinogen-protein adducts have proven to be useful molecular dosimeters of carcinogen exposure. For example, 4-aminobiphenyl hemoglobin adducts are highly correlated with exposure to tobacco smoke. The study of the molecular aspects of interindividual differences in the metabolism and activation of xenobiotics and other genetic markers [DNA-restriction fragment length polymorphisms (RFLPs), mutations, and functional loss of specific genes in carcinogenesis] is an emerging new field that is discussed in the context of genetic susceptibility to cancer. The cytochrome P450 phenotypes and acetylation phenotype are examples of genetic markers that indicate an individual's potential for metabolism of exogenous substances. Further, inherited genetic polymorphic markers, e.g., DNA-RFLPs at protooncogene loci (HRAS-1 and L-myc) have been examined in a case-control study of lung cancer. Data concerning mutations of protooncogenes (H-, K-, and N-RAS) and tumor suppressor genes (retinoblastoma and p53 genes) in various common cancers are providing evidence of multiple genetic lesions that occur during the multistage process of carcinogenesis.


Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses.
This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination. This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of > or = 3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (< 12%) but statistically significant (P = 0.02) increase in donepezil C(max) was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the t(max) or AUC(0-24 h) of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported during the study. Some digestive system AEs tended to occur more frequently during combination treatment than with either treatment alone, but there was no statistically significant increase in the incidence of any individual AE. The most common AEs during the combination therapy were nausea and diarrhoea, which were rated as mild or moderate in severity. These AEs were also reported during the administration of each drug alone. The co-administration of once-daily oral donepezil HCl 5 mg for 15 days and once-daily oral sertraline HCl (50 mg for 5 days increased to 100 mg for 10 days) did not result in any clinically meaningful pharmacokinetic interactions, and no unexpected AEs were observed.


Neonatal herpes simplex pneumonia.
A neonate with herpes simplex pneumonia is described. Herpes simplex infection should be considered in the differential diagnosis of pneumonia in newborn infants, even in the absence of clinically apparent herpes in the mother.


Glial cell mitogens bFGF and PDGF differentially regulate development of O4+GalC- oligodendrocyte progenitors.
The oligodendrocyte lineage in cerebrum is characterized by the expression of immunologically identified surface antigens resulting in the sequential appearance of three distinct phenotypes, A2B5+O4-, O4+GalC-, and O4+GalC+. In the present study we have placed O4+GalC- progenitors immunopanned from premyelinating rat cerebrum into a basal, defined medium that by itself does not support well either their proliferation or survival. The response of these progenitor cells to platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) was then examined. The results demonstrate that both PDGF and bFGF stimulated proliferation and short-term survival of newly cultured cells, but that their effect on the course of O4+GalC- differentiation was strikingly different. PDGF delayed postmitotic development by transiently reverting (ED50 = 3 ng/ml) O4+GalC- progenitors to A2B5+O4- preprogenitor-like cells that subsequently differentiated even in the continued presence of PDGF. bFGF restored mitogenic activity of the O4+GalC- progenitors to a saturable level at low doses (ED50 = 1 ng/ml); doses of bFGF > or = 10 ng/ml impaired differentiation of the progenitors into GalC+ cells and were also mitogenic for newly differentiated GalC+ oligodendrocytes. These data imply that bFGF supplants PDGF as a mitogen during lineage progression from A2B5+O4- to O4+GalC- progenitors. Lineage reversion of O4+GalC- cells in response to PDGF is suggested as a mechanism for facilitating remyelination by triggering the proliferative expansion of O4+GalC- progenitor-like cells persisting into adulthood.


Cyclone Nargis in Myanmar: lessons for public health preparedness for cyclones.
Recent natural disasters such as the 2004 tsunami, 2008 Sichuan earthquake, and the 2008 Myanmar cyclone have killed more than 100,000 people each. Mortality and morbidity associated with natural disasters are a growing concern, especially because extreme climate events are likely to get increasingly frequent. The authors comment on Cyclone Nargis, claiming an extraordinarily high death toll during its devastating track through the Irrawaddy delta in Myanmar on May 2, 2008 and analyze how and why its mortality pattern differs from other typical postdisaster situations. Underlying factors and preconditions are described and the specificity of the Myanmese context is presented. This leads to lessons how excess mortality can be reduced in future high-ranked cyclones, whose recurrence in this region will only be a matter of time.


Independent structural domains in paramyxovirus polymerase protein.
All enzymatic activities required for genomic replication and transcription of nonsegmented negative strand RNA viruses (or Mononegavirales) are believed to be concentrated in the viral polymerase (L) protein. However, our insight into the organization of these different enzymatic activities into a bioactive tertiary structure remains rudimentary. Fragments of Mononegavirales polymerases analyzed to date cannot restore bioactivity through trans-complementation, unlike the related L proteins of segmented NSVs. We investigated the domain organization of phylogenetically diverse Paramyxovirus L proteins derived from measles virus (MeV), Nipah virus (NiV), and respiratory syncytial virus (RSV). Through a comprehensive in silico and experimental analysis of domain intersections, we defined MeV L position 615 as an interdomain candidate in addition to the previously reported residue 1708. Only position 1708 of MeV and the homologous positions in NiV and RSV L also tolerated the insertion of epitope tags. Splitting of MeV L at residue 1708 created fragments that were unable to physically interact and trans-complement, but strikingly, these activities were reconstituted by the addition of dimerization tags to the fragments. Equivalently split fragments of NiV, RSV, and MeV L oligomerized with comparable efficiency in all homo- and heterotypic combinations, but only the homotypic pairs were able to trans-complement. These results demonstrate that synthesis as a single polypeptide is not required for the Mononegavirales polymerases to adopt a proper tertiary conformation. Paramyxovirus polymerases are composed of at least two truly independent folding domains that lack a traditional interface but require molecular compatibility for bioactivity. The functional probing of the L domain architecture through trans-complementation is anticipated to be applicable to all Mononegavirales polymerases.


[Involvement of trisynaptic hippocampal pathway in generation of neural representations of object-place associations (analytical review)].
A review. Possible mechanisms for generation of neural representations of object-place associations (NROPA) are analyzed in different parts of a neural network which include the hippocampus and parahippocampal complex. Streams of spatial and non-spatial information arrive to the hippocampus from the parahippocampal complex consisting of perirhinal, postrhinal and entorhinal cortical areas. We assume that, due to the absence of connections between lateral and medial areas of the entorhinal cortex, object-place associations are mostly formed in the hippocampus, but can also be generated in the perirhinal cortex due to existence of input from the postrhinal cortex. As both information streams converge on neurons of the dentate fascia and field CA3, a trisynaptic pathway through the hippocampus can play the basic role in the NROPA generation. Since the spatial information arrives in the neocortex and, therefore, reaches the parahippocampal complex and hippocampus approximately by 20 ms earlier than the "non-spatial" stream, only spatial information is processed firstly in the dentate fascia and field CA3. Generation of NROPA in the dentate fascia starts later, due to returning excitation from field CA3c. In the dentate fascia, signals from the NROPA are transferred into field CA3, where the activated neuronal pattern is superimposed by information arriving from the entorhinal cortex. As a result, more complex NROPA are formed in field CA3 and send signals to field CA1. In the dorsal (ventral) part of the field CA1, the activated neuronal pattern is superimposed by non-spatial (spatial) information arriving from the lateral (medial) part of the entorhinal cortex. As a result, a higher-order NROPA are generated. In the parahippocampal cortex, the generation ofNROPA can be a consequence of the activity transferred from the dorsal part of the hippocampal CA1 field.


Why variability facilitates spinal learning.
Spinal Wistar Hannover rats trained to step bipedally on a treadmill with manual assistance of the hindlimbs have been shown to improve their stepping ability. Given the improvement in motor performance with practice and the ability of the spinal cord circuitry to learn to step more effectively when the mode of training allows variability, we examined why this intrinsic variability is an important factor. Intramuscular EMG electrodes were implanted to monitor and compare the patterns of activation of flexor (tibialis anterior) and extensor (soleus) muscles associated with a fixed-trajectory and assist-as-needed (AAN) step training paradigms in rats after a complete midthoracic (T8-T9) spinal cord transection. Both methods involved a robotic arm attached to each ankle of the rat to provide guidance during stepping. The fixed trajectory allowed little variance between steps, and the AAN provided guidance only when the ankle deviated a specified distance from the programmed trajectory. We hypothesized that an AAN paradigm would impose fewer disruptions of the control strategies intrinsic to the spinal locomotor circuitry compared with a fixed trajectory. Intrathecal injections of quipazine were given to each rat to facilitate stepping. Analysis confirmed that there were more corrections within a fixed-trajectory step cycle and consequently there was less coactivation of agonist and antagonist muscles during the AAN paradigm. These data suggest that some critical level of variation in the specific circuitry activated and the resulting kinematics reflect a fundamental feature of the neural control mechanisms even in a highly repetitive motor task.


Introduction to the law.
To provide an introduction to the legal concepts that are involved in negligence suits involving oncology nurses. Medline, Lexis, Westlaw, legal literature and texts. To avoid liability and guard against negligence or malpractice suits, the oncology nurse must be aware of the legal responsibilities of each aspect of the nursing role. Protecting yourself against medical malpractice begins by understanding terms and concepts that are essential in instituting legal action against the nurse and incorporating the appropriate risk reduction practices into daily practice.


Analysis of Macular Retinal Thickness and Microvascular System Changes in Children with Monocular Hyperopic Anisometropia and Severe Amblyopia.
To study the changes of macular retinal thickness and microvascular system in children with monocular hyperopic anisometropia and severe amblyopia using optical coherence tomography angiography (OCTA) and to explore the value of OCTA in the diagnosis and treatment of amblyopia. Thirty-two children with monocular hyperopic anisometropia and severe amblyopia who were treated in the Department of Ophthalmology of the First Affiliated Hospital of Gannan Medical College from January 2020 to December 2020 were included in the study. Eyes with amblyopia (n = 32) served as the experimental group, and the contralateral healthy eyes (n = 32 eyes) served as the control group. All children underwent comprehensive ophthalmological examination including slit lamp, eye position, visual acuity, optometry, eye movement, intraocular pressure, ocular axis, and fundus examination to rule out organic lesions. Macular 6 mm × 6 mm scans were performed on both eyes of all subjects by the same experienced clinician using an OCTA instrument. After ImageJ processing, the vessel density, inner layer, and full-layer retinal thickness (RT) of superficial retinal capillary plexus (SCP) were obtained. All data were analyzed by SPSS21.0 software, and a paired t-test was used for comparison between groups. P < 0.05 was considered to indicate statistical significance. The vessel densities of macular SCP in the amblyopia and control groups were 47.66 ± 2.36% and 50.37 ± 2.24% in the outer superior, 49.19 ± 2.64% and 51.44 ± 2.44% in the inner inferior, 49.63 ± 2.51% and 51.41 ± 3.03% in the outer inferior, and 45.56 ± 3.44% and 50.44 ± 3.52% in the outer temporal regions, respectively. The vessel density of macular SCP in the amblyopia group was significantly lower than that in contralateral healthy eyes in the outer superior, inner inferior, outer inferior, outer temporal, and central regions. There was no significant difference between the two groups in the inner superior, inner nasal, outer nasal, and inner temporal regions. The macular RT in the amblyopia group and the control group is 90.38 ± 6.09 μm and 87.56 ± 5.55 μm in the outer temporal, respectively. The RT in the macular inner layer in the outer temporal region of the amblyopia group was thicker than that of the control group (P < 0.05). There was no significant difference in the other eight regions between the two groups. The whole macular RT in the amblyopia group was thicker than that in the control group in nine regions, and the central area of macular RT in the amblyopia and control groups was 229.06 ± 6.70 μm and 214.50 ± 10.36 μm, respectively. The OCTA results showed the overall RT of macula in 9 areas in the amblyopia group was thicker than that in the control group, which could show that the macular retinal thickness can be a potential way to distinguish the children with monocular hyperopic anisometropia and severe amblyopia.


Kinetics and fate of IgA-IgG aggregates as a model of naturally occurring immune complexes in IgA nephropathy.
The characteristic granular IgA immunofluorescent pattern in the kidneys of IgA nephropathy patients is consistent with immune complex pathogenesis. The possibility of a delayed clearance of IgA-containing immune complexes from circulation in IgA nephropathy patients is still under discussion. Since pure IgA immune complexes are probably nonphlogistic, (in contrast to IgG-containing IgA immune complexes), the in vivo clearance of a mixture of heat-aggregated IgA/G purified from pooled human sera was analyzed. The test probe was efficiently labeled with 123I and the time course of radioactivity was measured by a gamma-camera. Both the liver and the spleen were found to be involved in the disappearance of IgA/G complexes. Liver accumulation, which was markedly predominant, closely approximates a gamma-variate function which allowed determination of a mean transit time of 34.37 minutes, range 29.8 to 42.2, in 8 normal and 37.54 minutes, range 30.9 to 50.7 in 17 patients (p less than 0.04). At 2 hours, segmental gut accumulation was found, which demonstrated removal by hepatobiliary system as well. Compartmental analysis in patients indicated 3 major compartments represented by vascular bed, hepatobiliary and reticuloendothelial systems (including both liver and spleen phagocytes). Blood clearance rate, representing the final result of multiorgan removal of the test probe from the blood stream, was found to be significantly delayed in IgA nephropathy patients with a slope (0.035 min-1, range 0.019 to 0.052) significantly less negative compared with controls (0.047 min-1, range 0.038 to 0.053, p less than 0.01). This test probe was able to reproduce both removal routes (macrophages cells and hepatobiliary system) hypothesized for IgA-containing immune complexes in humans.


[Efficacy and complications of topical cocaine anesthesia in functional endoscopic sinus surgery].
A 4% cocaine (total dose; 200 mg) solution with 1 mg epinephrine was used as a topical anesthetic for 178 cases undergoing functional endoscopic sinus surgery. Complications were investigated before and during surgery. Bleeding amount and operative duration were compared between patients with and without topical cocaine application. Tachycardia (26 cases) was the only complication encountered in this study. Tachycardia occurred at a high incidence in cases which used atropine as a premedication. Total bleeding amount did no differ significantly between those with and without topical cocaine. However, minimum bleeding cases (less than 20 ml) were found in the cocaine group more frequently than in the non-cocaine group. Operative durations of cases with cocaine anesthesia were significantly shorter than cases without cocaine anesthesia. Those findings suggest that cocaine is effective for prevention of bleeding from micro-vessels and/or mucosal oozing, whereas bleeding from macro-vessels was not controlled by topical cocaine application. Topical cocaine anesthesia produced no major complications, even at 200 mg, in the presence of 1 mg epinephrine and when atropine use was avoided.


Study on the Hemostasis Characteristics of Biomaterial Frustules Obtained from Diatom Navicula australoshetlandica sp.
Diatoms, known as photosynthetic unicellular algae, can produce natural biosilica frustules that exhibit great biocompatibility, superhydrophilicity, and superhemophilicity. In our study, the diatom Navicula australoshetlandica sp. was isolated from aquaculture wastewater and pretreated to obtain frustules so as to explore their hemostasis characteristics. A special "porous web" (6-8 nm) substructure in the ordered nanopores (165-350 nm) of boat-shaped diatom frustule was observed in Navicula australoshetlandica sp. using SEM and TEM analysis. Moreover, X-ray, N2 adsorption-desorption isotherms, and BET analysis showed that the diatom frustule is a mesoporous material with a surface area of 401.45 m2 g-1 amorphous silica. FTIR analysis showed that Navicula australoshetlandica sp. frustules possessed abundant OH functional groups. A low hemolysis ratio was observed for 1-5 mg mL-1 diatom frustules that did not exceed 1.55 ± 0.06%, which indicates favorable hemocompatibility. The diatom frustules exhibited the shortest clotting time (134.99 ± 7.00 s) with a hemostasis material/blood (mg/μL) ratio of 1:100, which is 1.83 times (112.32 s) shorter than that of chitosan. The activated partial thromboplastin time (aPTT) of diatom frustule was also 44.53 s shorter than the control. Our results demonstrate the potential of Navicula australoshetlandica sp. diatom frustules to be used as medical hemostasis material.


Isolation, Characterization and Structural Elucidation of Polybutylene Terephthalate Cyclic Oligomers and Purity Assessment Using a ¹H qNMR Method.
The use of polybutylene terephthalate (PBT) as a food contact material is increasing over the last years. Typical contaminations in the final PBT product include its cyclic oligomers, which are allowed as additives in food contact plastics according to Regulation (EU) No. 10/2011. Their investigation is currently limited by the lack of analytical standards and physical-chemical information. Therefore, four PBT cyclic oligomers have been isolated and purified from a PBT raw material with an automated preparative HPLC-DAD system. Comprehensive characterization of the compounds was performed using Ultra-High Performance Liquid Chromatography (UHPLC) with high resolution time-of-flight mass spectrometry, Fourier-Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Nuclear Magnetic Resonance (NMR) spectroscopy. The purity of each oligomer was assessed using a ¹H qNMR method and ranged from 96.1% to 97.0% for PBT tetramer and trimer respectively. The availability of pure and well characterized PBT cyclic oligomer standards will facilitate future studies of release from plastic food packaging materials.


Implementation of parallel transmit beamforming using orthogonal frequency division multiplexing--achievable resolution and interbeam interference.
The speed of sound in the human body limits the achievable data acquisition rate of pulsed ultrasound scanners. To overcome this limitation, parallel beamforming techniques are used in ultrasound 2-D and 3-D imaging systems. Different parallel beamforming approaches have been proposed. They may be grouped into two major categories: parallel beamforming in reception and parallel beamforming in transmission. The first category is not optimal for harmonic imaging; the second category may be more easily applied to harmonic imaging. However, inter-beam interference represents an issue. To overcome these shortcomings and exploit the benefit of combining harmonic imaging and high data acquisition rate, a new approach has been recently presented which relies on orthogonal frequency division multiplexing (OFDM) to perform parallel beamforming in transmission. In this paper, parallel transmit beamforming using OFDM is implemented for the first time on an ultrasound scanner. An advanced open platform for ultrasound research is used to investigate the axial resolution and interbeam interference achievable with parallel transmit beamforming using OFDM. Both fundamental and second-harmonic imaging modalities have been considered. Results show that, for fundamental imaging, axial resolution in the order of 2 mm can be achieved in combination with interbeam interference in the order of -30 dB. For second-harmonic imaging, axial resolution in the order of 1 mm can be achieved in combination with interbeam interference in the order of -35 dB.


The effect of smoking on caries-related microorganisms.
Epidemiological studies have shown a close relationship between smoking and dental caries. Bacteria are one of the essential factors of caries formation. The imbalance of cariogenic bacteria and commensal bacteria in dental plaque results in higher production of acid that can corrode dental hard tissue. The aim of our review is to summarize the effect of smoking on caries-related bacteria. English articles available in Pubmed and ScienceDirect databases and published before December 2018 were searched. A variety of evidence was collected including not only the influence of cigarette products on bacteria strains in vitro but also their effect on bacterial composition in saliva and dental plaque in vivo. We particularly emphasize the mechanisms by which nicotine acts on oral bacteria. The components of cigarettes promote the growth of cariogenic microorganisms. The mechanisms of how nicotine enhances Streptococcus mutans, Lactobacilli, Streptococcus gordonii, Actinomyces and Candida albicans are described separately in detail. The commensal bacteria, Streptococcus sanguinis, show less competitive capability in the presence of nicotine. Smoking influences saliva by lowering the buffer capability, altering its chemical agent and bacterial components, and therefore promotes the formation of a caries-susceptible environment. Cigarette smoking and nicotine exposure promote the cariogenic activity of oral microorganisms and the formation of a caries-susceptible environment. This suggests that smokers should quit smoking, amongst other health reasons, also for their oral health.


Expression of Pregnancy Up-regulated Non-ubiquitous Calmodulin Kinase (PNCK) in Hepatocellular Carcinoma.
Pregnancy up-regulated non-ubiquitous calmodulin kinase (PNCK) is a member of calmodulin kinase, and overexpression of PNCK with involvement in carcinogenesis have been reported in HER-2 amplified breast cancer, clear cell renal cell carcinoma and nasopharygeal carcinoma. However, the expression of PNCK and its clinical implication have not been elucidated in hepatocellular carcinoma (HCC). We investigated PNCK expression at both the protein and mRNA level using immunohistochemistry (IHC) and microarray gene expression profiling in HCC tissue samples, and evaluated its association with clinicopathological parameters and their potential prognostic significance. High PNCK protein expression and high PNCK mRNA level was observed in 61.7% and 34.7% of total HCC cases, respectively. PNCK mRNA level was higher in tumor tissues than in background non-tumor tissues, and significantly correlated with protein expression by IHC. High PNCK expression was associated with higher Edmondson grade, intrahepatic metastasis, microvascular invasion and higher AFP levels. Patients with high PNCK expression showed shorter recurrence-free survival and disease-specific survival, and high mRNA expression of PNCK was an independent prognostic factor in disease-specific survival. Up-regulation of PNCK expression as well as its association with poor prognosis was demonstrated in HCC. PNCK might be a prognostic biomarker of HCC, and could be a potential candidate therapeutic target.


Comparison of ovarian cancer markers in endometriosis favours HE4 over CA125.
Endometriosis is a gynaecological condition with an associated chronic inflammatory response. The ectopic growth of 'lesions', consisting of endometrial cells outside the uterine cavity, stimulates an inflammatory response initiating the activation of macrophages, and resulting in increased cytokine and growth factor concentrations in the peritoneal fluid (PF). Endometriosis‑associated inflammation is chronic and long lasting. In patients with endometriosis, the risk of developing ovarian cancer within 10 years, particularly of the endometrioid or clear cell subtype, is increased 2.5‑4 times. Endometriosis creates a peritoneal environment that exposes the affected endometriotic and the normal ovarian surface epithelial cells to agents that have been suggested to be involved in the pathogenesis of cancer. Concentrations of several cytokines and growth factors were increased in the PF of patients with endometriosis. The ovarian cancer marker, CA125, was one such growth factor; however, this remains to be confirmed. Human epididymis protein 4 (HE4) was detected at high concentrations in patients with ovarian cancer and was identified as the best biomarker for the detection of ovarian cancer. The present study determined the levels of HE4 and CA125 in the peritoneal fluid of 258 patients with and 100 control individuals without endometriosis attending the Department of Obstetrics and Gynaecology, University of Berne (Berne, Switzerland) between 2007 and 2014. The cases were subdivided into groups without hormonal treatment (n=107), or treated with combined oral contraceptives (n=45), continuous gestagens (n=56) or GnRH agonists (n=50). Both of these markers were significantly increased in the non‑treated endometriosis samples compared with the control group. Hormone treatment with either of the three agents mentioned resulted in the concentration of CA125 returning to the control levels and the concentration of HE4 decreasing to below the control levels. CA125, however not HE4, significantly differed between the proliferative and secretory cycle phases. Since HE4 is sensitive to hormonal treatment and robust towards menstrual cycle variation, HE4 is potentially superior to CA125 as an endometriosis marker and therefore has greater potential as a marker for the identification of women at risk of developing ovarian cancer.


Expectations, Task Persistence, and Attributions in Children with Mental Retardation During Integrated Physical Education.
The purpose was to study expectations, persistence, and posttask attributions in 33 children (ages 9 to 15 years) with mental retardation (MR) and 40 children (ages 10 to 13 years) without disabilities during integrated physical education classes. Each of the participants (34 male and 39 females) viewed a video of another child successfully completing a game, responded to a question about expectations, and engaged in this same game alongside a peer. Results indicated that expectations did not differ between children with and without MR, χ2(1) = .35, p > .05. Following each child's request to stop playing, a video of individual performance was displayed and an interview was conducted to determine posttask attributions. Learners with MR were less persistent than peers without disabilities, F(1, 68) = 4.60, p < .5, η2 = .06. Although less persistent, children with MR did not differ on posttask attributions from peers without disabilities, χ2(2) = 3.64, p > .05; χ2(2) = 1.74, p > .05.


A rare cause of graft dysfunction after a heart transplant.
A 39-year-old man with a dilated cardiomyopathy was treated for recurrent life threatening ventricular arrhythmias with an automatic defibrillator and multiple antiarrhythmic agents. After transplant, the donor heart was asystolic probably secondary to these agents. A biventricular paracorporeal device supported the patient for four days and the heart recovered. He remains NYHA class I seven years later.


A selective nanosensor device for exhaled breath analysis.
This paper describes a novel concept of a three-nanosensor array microsystem that may potentially serve as a coarse diagnostic tool handheld breath analyzer to provide a first detection device. The specification and performance of a simple metal oxide nanosensor operating between three distinct temperatures are discussed, focusing on the need for a noninvasive blood cholesterol monitor. Interfacing the sensor array to an integrated circuit for electrical readout and temperature control provides a complete microsystem capable of capturing a single exhaled breath and analyzing it with respect to the relative content of isoprene, carbon dioxide and ammonia gas. This inexpensive sensor technology may be used as a personalized medical diagnostics tool in the near future.


Experimental observations of active invariance striations in a tank environment.
The waveguide invariant in shallow water environments has been widely studied in the context of passive sonar. The invariant provides a relationship between the frequency content of a moving broadband source and the distance to the receiver, and this relationship is not strongly affected by small perturbations in environment parameters such as sound speed or bottom features. Recent experiments in shallow water suggest that a similar range-frequency structure manifested as striations in the spectrogram exists for active sonar, and this property has the potential to enhance the performance of target tracking algorithms. Nevertheless, field experiments with active sonar have not been conclusive on how the invariant is affected by the scattering kernel of the target and the sonar configuration (monostatic vs bistatic). The experimental work presented in this paper addresses those issues by showing the active invariance for known scatterers under controlled conditions of bathymetry, sound speed profile and high SNR. Quantification of the results is achieved by introducing an automatic image processing approach inspired on the Hough transform for extraction of the invariant from spectrograms. Normal mode simulations are shown to be in agreement with the experimental results.


Investigation on epitaxial lateral overgrowth of InGaN/GaN multi-quantum-well nanowires.
To achieve semipolar InGaN/GaN multi-quantum-well (MQW) structure, we fabricate InGaN/GaN MQW nanowires by using a combination of selectively epitaxial lateral overgrowth and patterned GaN/sapphire substrate techniques. Basing on the SEM observations, the nanowires along different crystal orientation of GaN substrate have various surface morphologies. Furthermore, cathodoluminescence measurements exhibit the dependence of the emission peaks of InGaN quantum wells on the axial direction of nanowires, being mainly attributed to the change of the morphology situation of the side facet. The shift of the peaks is larger than 30 nm as the axial direction of a nanowire varies between [1120] and [1100].


The effect of age on the racing speed of Thoroughbred racehorses.
The running performance of Thoroughbred racehorses has been reported to peak when they are between 4 and 5 years old. However, changes in their racing speed by month or season have not been reported. The purposes of this study were to reveal the average racing speed of Thoroughbreds, and observe changes in their average speed with age. The surveyed races were flat races on turf and dirt tracks with firm or standard track conditions held by the Japan Racing Association from January 1st, 2002 to December 31st, 2010. The racing speed of each horse was calculated by dividing the race distance (m) by the horse's final time (sec). Average speeds per month for each age and distance condition were calculated for each gender group when there were 30 or more starters per month for each age and distance condition for each gender group. The common characteristic change for all conditions was an average speed increase up until the first half of the age of 4 years old. The effect of increased carry weight on average speed was small, and average speed increased with the growth of the horse. After the latter half of the age of 4 years old, the horses' average speed remained almost constant, with little variation. It is speculated that decreases in the weight carried; and the retirement of less well performing horses; are responsible for the maintenance of average speed.


Integrated optical grating scale readout employing a double grating.
A reading head empolying a double grating in a monomode waveguide for the interferometric readout of grating scales is proposed and demonstrated. A theoretical analysis employing a ray-tracing programthat includes wave-front data output shows promising insensitivity to deviations from the design data for this device. Experimental results for a laboratory setup are presented.


Surgical correction of mandibular prognathism in Norway, 1975-1984. A national survey.
The estimated need for surgical correction of mandibular prognathism in Norway is 500 patients each year. A questionnaire sent to the maxillofacial surgical units performing orthognathic surgery in Norway showed that in the decade from 1975 to 1985 altogether 1169 patients underwent surgical correction of mandibular prognathism; that is, only 117 patients were treated yearly [corrected]. Extraoral vertical subcondylar osteotomy of the mandibular ramus was the preferred surgical technique, performed on 57% of the patients. Intraoral vertical subcondylar osteotomy of the ramus increased in use and thus seems to be taking over for the extraoral technique. Sagittal split osteotomy was used on 25% of the patients. The different units showed great variation in their preference for the different surgical techniques. Preoperative orthodontics was widely used, on a mean of 77% of the patients. The average hospital stay was 8.5 days, somewhat longer than reported from other countries; however, geographical conditions should be taken into consideration.


Human glucagon receptor antagonists with thiazole cores. A novel series with superior pharmacokinetic properties.
The aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained.


Total synthesis of (3R,3'R,6'R)-lutein and its stereoisomers.
(3R,3'R,6'R)-lutein (1) is a major dietary carotenoid that is abundant in most fruits and vegetables commonly consumed in the U.S. and that accumulates in the human plasma, major organs, and ocular tissues. Numerous epidemiological and experimental studies have shown that 1 has important biological activities and may play an important role in the prevention of age-related macular degeneration (AMD). While the total synthesis of 1 has been previously reported in a poor overall yield, the total synthesis of the other seven stereoisomers of lutein has not yet been accomplished. We have developed a relatively straightforward methodology for the total synthesis of 1 and three of its stereoisomers, (3R,3'S,6'S)-lutein (2), (3R,3'S,6'R)-lutein or 3'-epilutein (3), and (3R,3'R,6'S)-lutein (4) by C(15) + C(10) + C(15) Wittig coupling reactions. Employing this methodology, the other four stereoisomers of lutein that are enantiomeric to the aforementioned lutein isomers can be similarly prepared. One of the important features of this strategy is its application to the total synthesis of (13)C-labeled luteins and their metabolites with appropriate stereochemistry for metabolic studies in animals and humans. This synthesis also provides access to the C(15)-precursors of optically active carotenoids with a 3-hydroxy-epsilon end group that are otherwise difficult to synthesize.


Nanoparticle Delivery of MnO2 and Antiangiogenic Therapy to Overcome Hypoxia-Driven Tumor Escape and Suppress Hepatocellular Carcinoma.
Antiangiogenic therapy is widely administered in many cancers, and the antiangiogenic drug sorafenib offers moderate benefits in advanced hepatocellular carcinoma (HCC). However, antiangiogenic therapy can also lead to hypoxia-driven angiogenesis and immunosuppression in the tumor microenvironment (TME) and metastasis. Here, we report the synthesis and evaluation of NanoMnSor, a tumor-targeted, nanoparticle drug carrier that efficiently codelivers oxygen-generating MnO2 and sorafenib into HCC. We found that MnO2 not only alleviates hypoxia by catalyzing the decomposition of H2O2 to oxygen but also enhances pH/redox-responsive T1-weighted magnetic resonance imaging and drug-release properties upon decomposition into Mn2+ ions in the TME. Moreover, macrophages exposed to MnO2 displayed increased mRNA associated with the immunostimulatory M1 phenotype. We further show that NanoMnSor treatment leads to sorafenib-induced decrease in tumor vascularization and significantly suppresses primary tumor growth and distal metastasis, resulting in improved overall survival in a mouse orthotopic HCC model. Furthermore, NanoMnSor reprograms the immunosuppressive TME by reducing the hypoxia-induced tumor infiltration of tumor-associated macrophages, promoting macrophage polarization toward the immunostimulatory M1 phenotype, and increasing the number of CD8+ cytotoxic T cells in tumors, thereby augmenting the efficacy of anti-PD-1 antibody and whole-cell cancer vaccine immunotherapies. Our study demonstrates the potential of oxygen-generating nanoparticles to deliver antiangiogenic agents, efficiently modulate the hypoxic TME, and overcome hypoxia-driven drug resistance, thereby providing therapeutic benefit in cancer.


Effects of iontophoretically applied naloxone, picrotoxin and strychnine on dorsal horn neuron activities treated with high frequency conditioning stimulation in cats.
Transcutaneous electrical nerve stimulation(TENS), acupuncture-needling, and electroacupuncture are useful non-ablative methods in medical practice for relief of pain. These procedures appear to work by causing an increased discharge in afferent nerve fibers which in turn modifies the transmission of impulses in pain pathways. It is known that the mechanism of analagesic effect via these maneuvers are variable depending on the stimulating parameters. For example, the endogenous opioid system is profoundly related to the mechanism when a peripheral nerve stimulation is applied with parameters of low frequency and high intensity. However, when stimulated with parameters of high frequency and high intensity, the reduced activity of dorsal horn neurons is only slightly reversed by a systemic administration of naloxone, a specific opiate antagonist. Thus, the present study was performed to investigate the neurotransmitter that concerns the mechanism of peripheral nerve stimulation with parameters of high frequency and high intensity. We used an iontophoretic application of antagonists of possible related neurotransmitters. The dorsal horn neuron activity which was evoked by squeezing the peripheral cutaneous receptive field, was recorded as an index of pain with a microelectrode at the lumbo-sacral spinal cord. Naloxone, picrotoxin and strychnine were applied at 200nA during a period of conditioning nerve stimulation. We observed the effects of these drugs on the change of dorsal horn neuron activities. The main results of the experiment can be summarized as follows. The spontaneous activity of dorsal horn neurons increased in the presence of glutamate and decreased with GABA. It did not change with naloxone, picrotoxin or strychnine. When naloxone was applied iontophoretically during peripheral nerve stimulation, there was no statistically significant analgesic effect compared with that of the control group. When picrotoxin was applied iontophoretically during peripheral nerve stimulation, the analgesic effect was reduced. When strychnine was applied, the analgesic effect was reduced but did not show a statistically significant difference with the control group. These results suggested that the GABAergic system may have been partially related in the analgesic action of peripheral nerve stimulation with parameters of high frequency and high intensity.


NDVI Changes Show Warming Increases the Length of the Green Season at Tundra Communities in Northern Alaska: A Fine-Scale Analysis.
A warming Arctic has been associated with increases in aboveground plant biomass, specifically shrubs, and changes in vegetation cover. However, the magnitude and direction of changes in NDVI have not been consistent across different tundra types. Here we examine the responsiveness of fine-scale NDVI values to experimental warming at eight sites in northern Alaska, United States. Warming in our eight sites ranged in duration from 2‑23 seasons. Dry, wet and moist tundra communities were monitored for canopy surface temperatures and NDVI in ambient and experimentally-warmed plots at near-daily frequencies during the summer of 2017 to assess the impact of the warming treatment on the magnitude and timing of greening. Experimental warming increased canopy-level surface temperatures across all sites (+0.47 to +3.14˚C), with the strongest warming effect occurring during June and July and for the southernmost sites. Green-up was accelerated by warming at six sites, and autumn senescence was delayed at five sites. Warming increased the magnitude of peak NDVI values at five sites, decreased it at one site, and at two sites it did not change. Warming resulted in earlier peak NDVI at three sites and no significant change in the other sites. Shrub and graminoid cover was positively correlated with the magnitude of peak NDVI (r=0.37 to 0.60) while cryptogam influence was mixed. The magnitude and timing of peak NDVI showed considerable variability across sites. Warming extended the duration of the summer green season at most sites due to accelerated greening in the spring and delayed senescence in the autumn. We show that in a warmer Arctic (as simulated by our experiment) the timing and total period of carbon gain may change. Our results suggest these changes are dependent on community composition and abundance of specific growth forms and therefore will likely impact net primary productivity and trophic interactions.


Nyamiviridae: proposal for a new family in the order Mononegavirales.
Nyamanini virus (NYMV) and Midway virus (MIDWV) are unclassified tick-borne agents that infect land birds and seabirds, respectively. The recent molecular characterization of both viruses confirmed their already known close serological relationship and revealed them to be nonsegmented, single- and negative-stranded RNA viruses that are clearly related to, but quite distinct from, members of the order Mononegavirales (bornaviruses, filoviruses, paramyxoviruses, and rhabdoviruses). A third agent, soybean cyst nematode virus 1 (SbCNV-1, previously named soybean cyst nematode nyavirus), was recently found to be an additional member of this new virus group. Here, we review the current knowledge about all three viruses and propose classifying them as members of a new mononegaviral family, Nyamiviridae.


Predictors of antidepressant prescription and early use among depressed outpatients.
The rates of antidepressant recommendation and use were determined in outpatients with major depression receiving services in mental health clinics. Site of service and the patients' sociodemographic and clinical characteristics were investigated as possible predictors. Patients admitted to six outpatient clinics were recruited through a two-stage sampling procedure. Patients with major depressive disorder (N = 124) according to the Structured Clinical Interview for DSM-IV--Patient Edition were assessed at admission and 3 months later. Drug therapy was recommended for most patients (71%), and minimal use (at least 1 week) was recorded for 59% of the subjects. White patients were nearly three times as likely to receive a recommendation for antidepressants. Antidepressant recommendation was also associated with severity of depressed mood, recent medication use, and clinic type. Recent antidepressant use was the only variable that predicted whether the patient actually took the recommended medication. Many patients with depression seeking treatment at community mental health clinics do not receive antidepressant drug therapy. The offer of medication is predicted by patient ethnicity, clinic type, and symptom severity. Minority patients are less likely to be offered antidepressant treatment.


Predicting physician burnout using clinical activity logs: Model performance and lessons learned.
Burnout is a significant public health concern affecting more than half of the healthcare workforce; however, passive screening tools to detect burnout are lacking. We investigated the ability of machine learning (ML) techniques to identify burnout using passively collected electronic health record (EHR)-based audit log data. Physician trainees participated in a longitudinal study where they completed monthly burnout surveys and provided access to their EHR-based audit logs. Using the monthly burnout scores as the target outcome, we trained ML models using combinations of features derived from audit log data-aggregate measures of clinical workload, time series-based temporal measures of EHR use, and the baseline burnout score. Five ML models were constructed to predict burnout as a continuous score: penalized linear regression, support vector machine, neural network, random forest, and gradient boosting machine. 88 trainee physicians participated and completed 416 surveys; greater than10 million audit log actions were collected (Mean [Standard Deviation] = 25,691 [14,331] actions per month, per physician). The workload feature set predicted burnout score with a mean absolute error (MAE) of 0.602 (95% Confidence Interval (CI), 0.412-0.826), and was able to predict burnout status with an average AUROC of 0.595 (95% CI 0.355-0.808) and average accuracy 0.567 (95% CI 0.393-0.742). The temporal feature set had a similar performance, with MAE 0.596 (95% CI 0.391-0.826), and AUROC 0.581 (95% CI 0.343-0.790). The addition of the baseline burnout score to the workload features improved the model performance to a mean AUROC of 0.829 (95% CI 0.607-0.996) and mean accuracy of 0.781 (95% CI 0.587-0.936); however, this performance was not meaningfully different than using the baseline burnout score alone. Current findings illustrate the complexities of predicting burnout exclusively based on clinical work activities as captured in the EHR, highlighting its multi-factorial and individualized nature. Future prediction studies of burnout should account for individual factors (e.g., resilience, physiological measurements such as sleep) and associated system-level factors (e.g., leadership).


Mathematical models for dermal drug absorption.
Mathematical models of dermal transport offer the advantages of being much faster and less expensive than in vitro or in vivo studies. The number of methods used to create such models has been increasing rapidly, probably due to the steady rise in computational power. Although each of the various approaches has its own virtues and limitations, it may be difficult to decide which approach is best suited to address a given problem. Here we outline the basic ideas, drawbacks and advantages of compartmental and quantitative structure-activity relationship models, as well as of analytical and numerical approaches for solving the diffusion equation. Examples of special applications of the different approaches are given. Although some models are sophisticated and might be used in future to predict transport through damaged or diseased skin, the comparatively low availability of suitable and accurate experimental data limits extensive usage of these models and their predictive accuracy. Due to the lack of experimental data, the possibility of validating mathematical models is limited.


Montagna symposium on epidermal stem cells oligonucleotide-directed gene correction in epidermis.
Oligonucleotide-directed gene alteration produces a targeted DNA sequence change in the genome of mammalian cells. The advantage of this approach is that expression of the corrected gene is regulated in the same way as a normal gene. Reliable, sensitive, and standardized assays played a critical role in the measurement of gene correction frequency among different cell types and in evaluating the structure-activity relationship of oligonucleotides. Mechanistic studies using these assays have become critical for understanding the gene repair process and setting realistic expectations on the capability of this technology. The epidermis is an ideal tissue where oligonucleotides can be administered locally and the treated sites can be monitored easily. But given the low frequency of gene correction, general selection procedures and amplification of corrected cells via epidermal stem cells are ultimately needed to make the gene repair technology practical. Recent data suggest that the in vivo application of oligonucleotides may be capable of gene correction in epidermal stem cells and the subsequent expansion of the corrected cells may result in an apparent high-level and long-lasting gene repair. Advances in oligonucleotide delivery and targeting of epidermal stem cells will be required for potential application of oligonucleotides toward treatment of genodermatoses.


Above- and belowground linkages shape responses of mountain vegetation to climate change.
Upward shifts of mountain vegetation lag behind rates of climate warming, partly related to interconnected changes belowground. Here, we unravel above- and belowground linkages by drawing insights from short-term experimental manipulations and elevation gradient studies. Soils will likely gain carbon in early successional ecosystems, while losing carbon as forest expands upward, and the slow, high-elevation soil development will constrain warming-induced vegetation shifts. Current approaches fail to predict the pace of these changes and how much they will be modified by interactions among plants and soil biota. Integrating mountain soils and their biota into monitoring programs, combined with innovative comparative and experimental approaches, will be crucial to overcome the paucity of belowground data and to better understand mountain ecosystem dynamics and their feedbacks to climate.


Chemical composition, antioxidant and antibacterial activities of essential oils from Ferulago angulata.
Ferulago angulata Boiss. (Apiaceae), a perennial aromatic herb, grows wild in Iran. The aerial parts of F. angulata are used as a flavouring in foods, especially dairy foods by indigenous people in western and southwestern Iran. This study investigates variation in chemical compositions, antioxidant and antibacterial activities of the essential oils from F. angulata collected from natural habitats in the alpine regions of southwestern Iran. The antimicrobial activity, minimum inhibitory concentration (MIC) and minimum bactericidal (MBC) of the essential oils were evaluated against four bacteria (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus and Salmonella typhimurium). Antioxidant activity of the oils was determined by DPPH assay. The essential oils were analyzed by GC-FID and GC/MS, which 49 volatile components were identified. There were significant differences between the various populations for oil yield and some main compounds. The major constituents of the essential oils from F. angulata were α-pinene, and cis-β-ocimene. The MICs of the essential oils were within concentration ranges from 62 to 250 μg/mL and the respective MBCs were 125 to > 500 μg/mL. Generally, the oils from F. angulata indicated weak to moderate inhibitory activities against bacteria, especially against Listeria monocytogenes. The highest antioxidant activity was obtained from the oil of the Kallar population (IC50 value = 488 μg/mL) and BHT as positive control (IC50 value = 321 μg/mL). The essential oil of F. angulata could be serving as a potential source of α-pinene and cis-β-ocimene for use in the food, cosmetic and pharmaceutical industries.


[Flow cytometry: is it a novel tool in microbiological diagnostics?].
Direct detection of pathogens is time- and labor-intensive. There is an increasing demand for new rapid microbiological testing methods, which would be faster and more sensitive than the conventional ones. Initially, automated methods were applied for the testing of bacteremia, urinary tract infections, characterization of antimicrobial susceptibility and quantitation of pathogen specific antibodies. Recently the nucleic acid-based detection methods have also become a routine. The molecular biological methods accelerate diagnosis, enhance specificity and provide an opportunity to identify pathogens with potential difficulties in culturing. However, they do not give any information about the immune status of the host. Yet it should also be borne in mind that detection of pathogen-specific nucleic acids is not equivalent to the presence of living microbes. The greatest advantage of FACS against these techniques is the capability to identify individual microbial cells as well. High speed FACS becomes a priority in the characterization of slow-growing microbes and identification of pathogens in mixed infections. Last but not least, it allows the monitoring of immune status and follow up of antimicrobial therapy.


Amyloid beta protein: Abeta40 inhibits Abeta42 oligomerization.
Abeta40 and Abeta42 are peptides that adopt similar random-coil structures in solution. Abeta42, however, is significantly more neurotoxic than Abeta40 and forms amyloid fibrils much more rapidly than Abeta40. Here, mass spectrometry and ion mobility spectrometry are used to investigate a mixture of Abeta40 and Abeta42. The mass spectrum for the mixed solution shows the presence of a heterooligomer composed of equal parts of Abeta40 and Abeta42. Ion mobility results indicate that this mixed species comprises an oligomer distribution extending to tetramers. Abeta40 alone produces such a distribution, whereas Abeta42 alone produces oligomers as large as dodecamers. This indicates that Abeta40 inhibits Abeta42 oligomerization.


Role of microRNA-7 in liver diseases: a comprehensive review of the mechanisms and therapeutic applications.
MicroRNA-7 (miR-7) is a small non-coding RNA, which plays critical roles in regulating gene expression of multiple key cellular processes. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and pancreas. Although it is expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells. In this review, we focus on the mechanisms by which miR-7 controls cell growth, proliferation, invasion, metastasis, metabolism, and inflammation. We also summarize the specific roles of miR-7 in liver diseases. MiR-7 is considered as a tumor suppressor miRNA in hepatocellular carcinoma and is involved in the pathogenesis of hepatic steatosis and hepatitis. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.


Recent advances in asthma biomarker research.
Asthma is characterized by recurrent and reversible airflow obstruction, which is routinely monitored by history and physical examination, spirometry and home peak flow diaries. As airway inflammation is central to asthma pathogenesis, its monitoring should be part of patient management plans. Fractional exhaled nitric oxide level (FeNO) is the most extensively studied biomarker of airway inflammation, and FeNO references were higher in Chinese (Asians) than Whites. Published evidence was inconclusive as to whether FeNO is a useful management strategy for asthma. Other biomarkers include direct (histamine, methacholine) and indirect (adenosine, hypertonic saline) challenges of bronchial hyperresponsiveness (BHR), induced sputum and exhaled breath condensate (EBC). A management strategy that normalized sputum eosinophils among adult patients resulted in reductions of BHR and asthma exacerbations. However, subsequent adult and pediatric studies failed to replicate these benefits. Asthma phenotypes as defined by inflammatory cell populations in sputum were also not stable over a 12-month period. A recent meta-analysis concluded that induced sputum is not accurate enough to be applied in routine monitoring of childhood asthma. There is poor correlation between biomarkers that reflect different asthma dimensions: spirometry (airway caliber), BHR (airway reactivity) and FeNO or induced sputum (airway inflammation). Lastly, EBC is easily obtained noninvasively by cooling expired air. Many biomarkers ranging from acidity (pH), leukotrienes, aldehydes, cytokines to growth factors have been described. However, significant overlap between groups and technical difficulty in measuring low levels of inflammatory molecules are the major obstacles for EBC research. Metabolomics is an emerging analytical method for EBC biomarkers. In conclusion, both FeNO and induced sputum are useful asthma biomarkers. However, they will only form part of the clinical picture. Longitudinal studies with focused hypotheses and well-designed protocols are needed to establish the roles of these biomarkers in asthma management. The measurement of biomarkers in EBC remains a research tool.


Physical-chemical characterization of tungsten carbide nanoparticles as a basis for toxicological investigations.
One task in risk assessment of engineered nanoparticles is toxicological studies. A suitable interpretation of these investigations demands a comprehensive physical-chemical characterization. Here, we present an approach to gain well-dispersed nanoparticles in physiological media. Therefore, a step-by-step procedure is demonstrated on two different tungsten carbide nanopowders which can be transferred to other powders. The procedure includes a comprehensive powder characterization, followed by a preparation of a non-physiologic, electrostatically stable nanoparticle suspension and finally closes with investigations of the particles' behavior in different physiological media. Our study showed that the particles agglomerate in protein-free media. In this context, dependencies of mass- and surface-based nanoparticle concentrations as well as of different physiological media were analyzed. In the presence of bovine serum albumin (BSA) or serum, the agglomeration process is decelerated or, at the appropriate protein amount, prevented.


Teaching college students better learning skills using self-hypnosis.
This paper reports the effects of self-hypnosis used by 51 college students enrolled in a 10-week course on efficient learning skills. All students were administered the Creative Imagination Scale. Subsequently, they learned to enter and deepen alert self-hypnosis. They gave themselves personal suggestions and then studied in hypnosis. They reported their depth of hypnosis and satisfaction with each session. Grades were collected the quarter before, during and after the course. Satisfaction and depth data indicated the students were involved all through the course. Statistical testing showed that students who scored highest on the CIS had the lowest initial GPA, improved most during the course, and significantly increased their GPA in the quarter after.


The SAM domains of Anks family proteins are critically involved in modulating the degradation of EphA receptors.
We recently reported that the phosphotyrosine-binding (PTB) domain of Anks family proteins binds to EphA8, thereby positively regulating EphA8-mediated signaling pathways. In the current study, we identified a potential role for the SAM domains of Anks family proteins in EphA signaling. We found that SAM domains of Anks family proteins directly bind to ubiquitin, suggesting that Anks proteins regulate the degradation of ubiquitinated EphA receptors. Consistent with the role of Cbl ubiquitin ligases in the degradation of Eph receptors, our results revealed that the ubiquitin ligase c-Cbl induced the ubiquitination and degradation of EphA8 upon ligand binding. Ubiquitinated EphA8 also bound to the SAM domains of Odin, a member of the Anks family proteins. More importantly, the overexpression of wild-type Odin protected EphA8 and EphA2 from undergoing degradation following ligand stimulation and promoted EphA-mediated inhibition of cell migration. In contrast, a SAM domain deletion mutant of Odin strongly impaired the function of endogenous Odin, suggesting that the mutant functions in a dominant-negative manner. An analysis of Odin-deficient primary embryonic fibroblasts indicated that Odin levels play a critical role in regulating the stability of EphA2 in response to ligand stimulation. Taken together, our studies suggest that the SAM domains of Anks family proteins play a pivotal role in enhancing the stability of EphA receptors by modulating the ubiquitination process.


Utility of Endoscopic Submucosal Dissection in the Remnant Stomach and Clinical Outcomes for Different Reconstruction Methods.
The number of patients with remnant gastric tumor during postoperative follow-up is increasing. We evaluated clinical outcomes to determine the feasibility of endoscopic submucosal dissection (ESD) for early gastric neoplasm in the remnant stomach. We compared 138 lesions of ESD in the remnant stomach after proximal gastrectomy, distal gastrectomy (DG) or pylorus-preserving DG with 3,237 lesions of ESD in the intact stomach. ESD was performed at our hospital between January 2005 and September 2017. Compared with the intact group, the remnant group had significantly longer mean procedure duration and lower rates of curative resection (all p < 0.01). However, complication rates did not differ significantly between the 2 groups. Among the reconstruction techniques after DG, the rate of lesions at the anastomosis site was significantly higher and the mean procedure duration was significantly longer after Billroth II reconstruction (both p < 0.01). Also, curative resection rate was significantly lower after Billroth II (50.0%) than after Billroth I (p < 0.05). Although technically demanding, ESD for early gastric tumor in the remnant stomach was a safe and effective therapeutic method. However, because the curative resection rate was lower for the more frequent lesions occurring at the anastomosis site after Billroth II reconstruction, early detection of remnant stomach tumor is desirable after Billroth II reconstruction following DG.


Effect of melatonin in the prevention of postoperative pericardial adhesion formation.
To evaluate the efficacy of melatonin in preventing postoperative pericardial adhesions, 12 single breed dogs were randomized equally into experimental (melatonin) and control groups. After ketamine anesthesia, a vertical midsternal incision was done and the parietal pericardium of the inferior site of the heart was opened vertically. To promote adhesion formation, abrasions were created on both parietal and visceral pericardial surfaces in an area of 2 cm2 with two vertically reciprocal movements of dry gauze. In the melatonin group, 5% ethanol plus 10 mg/kg melatonin in 10 ml NaCl and, in control group, 10 ml NaCl dilution vehicle containing 5% ethanol was instilled intra-pericardium on to the abrasion sites. After a 6-week recovery period, the animals were evaluated for grading of adhesion formation by an examiner blinded to the groups. The extent of adhesions was graded from 0 (no adhesion) to 3 (total involvement of the traumatized area). The results showed that adhesion scores were significantly lower in melatonin group (1.00+/-0.63) compared with controls (2.66+/-0.51); P=0.001. We conclude that melatonin administration effectively reduced postoperative pericardial adhesions in dogs. The use of melatonin in the prevention of pericardial adhesion formation in human subjects warrants further investigations.


[Pharmacokinetic mechanisms underlying resistance in psychopharmacological treatment. The role of P-glycoprotein].
In the last years efflux transporters, as for example P-glycoprotein, have been shown to play an important role in the regulation of the uptake of drugs in the central nervous system. These transporters are expressed constitutively in the brain capillary endothelial cells which form the brain-blood barrier, but their expression or activity could be inhibited or induced by other compounds or could be modified under pathological conditions. Some antipsychotics (amisulpride, chlorpromazine, fluphenazine, haloperidol, olanzapine, pimozide, prometazine, quetiapine, risperidone, trifluoperazine), antidepressants (amitriptiline, doxepine, nortriptiline, venlafaxine), and antiepileptics (felbamate, gabapentin, lamotrigine, phenobarbital and topiramate) are P-glycoprotein substrates. Interactions that could take place at the P-glycoprotein level may explain some cases of resistance in polimedicated patients. Other factors, yet unknown, could induce the expression of this transporter and therefore decrease the uptake of psychotropic drugs in the central nervous system, affecting their efficacy.


A depth profile of oxidation and gel fraction in gamma-irradiated silane crosslinked and ultra high molecular weight polyethylenes.
The depth profile of oxidation index and gel fraction has been measured for two silane crosslinked poly(ethylene) (SXLPE) acetabular cups (one gamma irradiated in air, and one non-irradiated, both with a shelf-life of 13 years) and for two UHMWPE components (one gamma irradiated in air and one non-irradiated, with shelf-lives of 13 and 7 years, respectively). Only the irradiated UHMWPE exhibited any variation in these properties with depth. The oxidation profile (maximum 1 mm below surface) has been explained to result from reduced levels of diffused oxygen with depth, giving rise to a balance of alkyl and peroxyl radicals (and hence maximum carbonyl production) just below the surface. The gel fraction profile (maximum 4 mm below surface) is also attributed to the lower levels of diffused oxygen with depth, causing crosslinking to dominate in the bulk and chain scission to dominate at the surface. The resistance to oxidative degradation in the non-irradiated SXLPE was attributed to the use of antioxidants in the polymer processing.


Association between perfluoroalkyl substance exposure and thyroid hormone/thyroid antibody levels in maternal and cord blood: The Hokkaido Study.
Thyroid antibodies (TAs) are the most common cause of hypothyroidism during gestation. Although previous studies found that prenatal exposure to perfluoroalkyl substances (PFASs) disrupts thyroid hormones (THs) in humans, their effects on TAs during the perinatal period have not been investigated. To explore the associations between prenatal exposure to eleven different PFASs from two different groups (carboxylates and sulfonates) and the expression of THs and TAs in maternal and cord blood while considering maternal TA status. In a prospective birth cohort (the Hokkaido Study), we included 701 mother‑neonate pairs recruited in 2002-2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFASs were measured in maternal plasma obtained at 28-32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. THs and TAs including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks), and in cord blood at birth. The median levels of TgAb and TPOAb in maternal serum were 15.0 and 6.0 IU/mL, respectively. The median TgAb level in neonates was 38.0 IU/mL, and TPOAb were detected in only 12.3% of samples. Maternal FT3 level was positively associated with PFAS levels in both TA-positive and TA-negative mothers. Maternal perfluorooctanoate was inversely associated with maternal TPOAb. Among boys, some maternal PFASs were associated with higher TSH and lower FT3 levels in maternal TA-negative group, while perfluorodecanoic acid was associated with lower TSH in maternal TA-positive group. Among girls, some PFAS of mothers showed associations with lower TSH and higher FT3 in maternal TA-negative group, while perfluorododecanoic acid was associated with lower FT4 in maternal TA-positive. Maternal PFASs showed associations with boy's TgAb inversely in maternal TA-negative group and with girl's TgAb positively in maternal TA-positive group. Our results suggest thyroid disrupting effects of PFAS exposure and susceptibility vary depending on maternal TA levels.


Application of Doppler spectroscopy in H2 to the prediction of experimental D(d,n)3He reaction rates in an inertial electrostatic confinement device.
In our previous paper, we developed an optical measurement for absolute densities of fast (tens of keV) H ions in an abnormal hollow cathode discharge of hydrogen in the units to tens of mTorr pressure range. We apply this method to a cylindrically symmetric inertial electrostatic confinement (IEC) discharge of hydrogen using the Doppler spectrum of Halpha. We predict neutron production rates for an equivalent discharge of deuterium and compare these with experimental values under the separate conditions of constant deuterium gas pressure (approximately 6 mTorr) and voltage (30 kV). Our predictions capture the variation of production rates with dc current (10-50 mA) and agree with experiment to within an order of magnitude. The applicability of this diagnostic to the cylindrical IEC discharge is thus demonstrated, with our results supporting the theory that the discharge is dominated by energetic neutrals emerging from the cathode apertures.


Contextualising the relevance of specialty-specific electives in dental education: Perspectives of dental and oral hygiene graduates.
Electives have been shown to contribute to both the professional and personal development of students in specific areas of interest outside the standard curriculum. The School of Oral Health Sciences at the University of the Witwatersrand introduced electives as a pedagogy in the Bachelor of Dental Sciences (BDS) and Bachelor of Oral Health Sciences (BOHSc) curricula in 2010 and 2014, respectively. However, since its introduction, the relevance of these electives in the BDS and BOHSc curricula has not been investigated. This research was designed as an evaluation study that used a questionnaire survey administered to 76 dental and oral hygiene graduates (BDS and BOHSc). Of the initial 76 questionnaires that were distributed, 55 (BDS = 38, BOHSc = 17) were returned, giving a response rate of 72.4%. Almost all the participants (92.7%) agreed that the electives enabled them to develop better interpersonal skills; 80.0% and 82.7% agreed that their clinical skills, and knowledge of key concepts in dental practice, respectively, had improved upon completion of the elective. In appraising the elective programme, 87.0% of the graduates agreed that the content and outcome of the elective programme should be reviewed and changed. Obtaining empirical data on the impact of electives on clinical knowledge, skill and behaviour of dental graduates will enhance the relevance of electives in dental education. Findings by this study reveal that the actual impact of the electives on dental graduates was desirable and corresponded with the intended impact. The problematic areas that were identified will inform future planning.