Evaluation of the Sagittal Saw Blade as an Intraoperative Fomite During Diabetic Foot Surgery.
Surgical site infection is a major potential complication of all operative interventions, and the diabetic foot is particularly at risk for bacterial recontamination and infectious sequelae. The objective of this study was to identify whether the sagittal saw blade used during partial foot amputations and diabetic foot debridements carries the potential to serve as a bacterial fomite. We physically cultured the sagittal saw blade during 20 foot debridements involving the resection of bone in patients diagnosed with a diabetic foot infection. The culture was taken after the initial debridement and during the irrigation phase of the procedure. We observed 16 positive routine intraoperative culture results, with positive saw blade culture results in 15 (93.8%; 15/16) of these cases. In 14 (93.3%; 14/15) of these cases, the saw blade culture grew at least one of the same bacteria as our other routine intraoperative cultures. We observed 4 negative routine intraoperative culture results, with negative saw blade culture results in 3 (75.0%; 3/4) of these cases. This results in agreement between routine intraoperative cultures and saw blade culture of 85.0% (17/20). The results of this investigation demonstrate that the sagittal saw blade used for osseous resection during diabetic foot debridements and partial foot amputations carries the potential for intraoperative bacterial transmission. We recommend changing at least the sagittal saw blade if more bone is resected following irrigation, particularly if it is used to obtain a "clean margin" for microbiological or histological examination. Therapeutic, Level IV: Case series.


Umbelliprenin isolated from Ferula sinkiangensis inhibits tumor growth and migration through the disturbance of Wnt signaling pathway in gastric cancer.
The traditional herb medicine Ferula sinkiangensis K. M. Shen (F. sinkiangensis) has been used to treat stomach disorders in Xinjiang District for centuries. Umbelliprenin is the effective component isolated from F. sinkiangensis which is particularly found in plants of the family Ferula. We previously reported the promising effects of Umbelliprenin against gastric cancer cells, but its anti-migration effect remained unknown. Here we investigated the anti-migration effect and mechanism of Umbelliprenin in human gastric cancer cells. In SRB assay, Umbelliprenin showed cytotoxic activities in the gastric cancer cell lines AGS and BGC-823 in a dose-and-time-dependent manner, while it showed lower cytotoxic activity in the normal gastric epithelium cell line GES-1. During transwell, scratch and colony assays, the migration of tumor cells was inhibited by Umbelliprenin treatment. In gelatin zymography assay, Umbelliprenin could inhibit the expression of MMP2 and MMP9 in tumor cells The expression levels of the Wnt-associated signaling pathway proteins were analyzed with western blots, and the results showed that Umbelliprenin decreased the expression levels of proteins of the Wnt signalling pathway, such as Wnt-2, β-catenin, GSK-3β, p-GSK-3β, Survivin and c-myc. The translocation of β-catenin to the nucleus was also inhibited by Umbelliprenin treatment. In TCF reporter assay, the transcriptional activity of T-cell factor/lymphoid enhancer factor (TCF/LEF) was decreased after Umbelliprenin treatment. The in vivo results suggested that Umbelliprenin induced little to no harm in the lung, heart and kidney. Overall, these data provided evidence that Umbelliprenin may inhibit the growth, invasion and migration of gastric cancer cells by disturbing the Wnt signaling pathway.


Neoadjuvant Therapy for Prostate Cancer: An Oncologist's Perspective.
With increasing use of prostate-specific antigen as a screening tool, diagnosis of prostate cancer has undergone a stage migration toward early-stage disease. Although this has increased the proportion of men who are candidates for definitive, potentially curative therapy, it has also made clear the limitations of our current standard of care. Specifically, despite adequate local therapy, a significant proportion of men go on to develop progressive disease. Neoadjuvant systemic therapy is one approach that continues to be studied as a way to maximize cure rates in the setting of early-stage disease. This article reviews the current data regarding neoadjuvant therapy, both hormonal and chemotherapy, and discusses which men are appropriate candidates for this option.


Pressure ulcer prevention in care home settings.
Pressure ulcer prevention in the care home setting can be challenging and is often compromised by a lack of access to education and resources. There are measures that have been shown to consistently improve outcomes in pressure ulcer prevention including assessment of the patient and their individual risks, delivery of a consistent plan of care that meets patients' needs, and regular evaluation to identify shortfalls. In addition, there should be a robust approach to investigating events that lead to a person developing a pressure ulcer and that information should be used to improve future practice. Pressure ulcer prevention in care homes is achievable and nurses should all be aware of the necessary measures detailed in this article.


Exosomes as Targeted Delivery Platform of CRISPR/Cas9 for Therapeutic Genome Editing.
Therapeutic genome editing harnesses the power of genome editing tools to correct erroneous genes associated with disease pathology. To bring the CRISPR/Cas9 tool from the bench to the bedside, a critical hurdle is the safe and efficient delivery of this nucleic acid tool to the desired type of cells in patients. This review discusses the use of natural carriers, extracellular vesicles (EVs), in particular exosomes, to fill the gap. Exosomes are lipid-containing nanovesicle released by various types of cells to mediate cell-cell communications. Their inherent long-distance transportation capability, biocompatibility, and engineerability have made EVs potential vehicles for delivering therapeutic drugs. We summarize the recent progress of harnessing exosomes as delivery vehicles for the CRISPR/Cas system to achieve therapeutic gene editing for disease treatment, with a focus on various strategies to achieve selective delivery to a particular type of cell and efficient packaging of the genome editing tools in the vesicles. Critical issues and possible solutions in the design and engineering of the targeting vehicles are highlighted. Taken together, we demonstrate EV/exosome-mediated packaging of the nucleic acid/protein tools and the cell/tissue-targeted delivery to be a viable way towards the clinical translation of the CRISPR/Cas9 technology.


[Towards personalized treatment of type 2 diabetes].
The purpose of type 2 diabetes treatment is to reduce the risk of diabetic complications and, as a result, improve the quality and, possibly, quantity of life. This requires control of blood glucose levels and cardiovascular risk factor management in a patient-centred approach. Careful consideration of patient factors and preferences helps the process of individualising treatment strategies and goals. With respect to medication management, the Dutch College of General Practitioners (NHG) recently updated the practice guideline on how to reach these goals. Although this guideline promotes individualised glycaemic targets for patients based on comorbidities, propensity for hypoglycaemia, and capacity to carry out the treatment plan, a more profound shift seems necessary. Based on recent trials, optimal treatment should target specific complications and inherent risks besides glycaemic targets. Patients at high risk for cardiovascular disease may benefit from treatment with drugs that lower this risk.


Influence of artificial fat emulsions on the composition of serum lipoproteins in humans.
Infusions of about 50 g soya oil, emulsified with egg lecithin (Intralipid) or soya lecithin (Lipofundin) have different effects on the composition of serum lipoprotein fractions in volunteers (n = 6). Triglycerides are altered in all lipoprotein fractions most in lowest density classes but also in LDL and HDL. Differences in maximal concentrations (higher during Intralipid) and differences in removal rate of triglycerides (faster with Lipofundin) are due to different emulsifiers. Cholesterol increase in VLDL and decrease in HDL3 are independent from emulsifier. Intralipid produces an increase of phospholipids in all lipoprotein fractions, Lipofundin only in VLDL. Linoleic acid in lecithin fatty acids of lipoprotein fractions is increased by Lipofundin and decreased by Intralipid. Apolipoprotein A-I and A-II decrease in HDL3 and slightly increase in HDL2. During both infusions apolipoprotein C-II increases significantly after Intralipid.


Quantitative proteomics identified a novel invasion biomarker associated with EMT in pituitary adenomas.
Complete resection of invasive pituitary adenoma is usually difficult, resulting in a high recurrence rate. Therefore, it is needed to find potential diagnostic markers and therapeutic targets for invasive pituitary adenoma. We collected samples from patients with invasive and non-invasive pituitary adenomas from Beijing Tiantan Hospital for protein extraction and quantitative analysis. We identified differential proteins (DEPs) by differential analysis of the two groups. The intersection of differential proteins related to invasion and epithelial-mesenchymal transition (EMT) in the GeneCards database was identified as EMT-DEPs. The protein network of EMT-DEPs was analyzed using the STRING database and Cytoscape software, and the hub EMT-DEPs were obtained by the MCC algorithm of the cytoHubba plugin. Correlation analysis was used to obtain the interpairing proteins among EMT-DEPs, and core EMT-DEPs were identified based on the number of paired proteins. The Venn program was used to identify the intersection of hub EMT-DEPs and core EMT-DEPs as key EMT-DEPs. Finally, a series of analyses plus experiments were used to verify the correlation of the target protein with invasion and EMT in pituitary adenoma. Quantitative comparison of proteins between invasive and non-invasive pituitary adenomas indicated 833 differential proteins. The overlaps of EMT-related proteins and differential proteins consisted of 46 EMT-DEPs. There were 6 intersections between the hub EMT-DEPs and core EMT-DEPs. Using quantitative protein data and GSE169498 chip, we found that solute carrier family 2 member 1 (SLC2A1) was our target protein. SLC2A1 was significantly correlated with the invasiveness of pituitary adenoma, and the ROC curve was satisfactory. The functions and pathways of SLC2A1 and paired protein enrichment were closely linked to the EMT. Consistently, SLC2A1 expression was significantly and positively correlated with the expression of classical markers of EMT. The final experiment revealed that SLC2A1 was significantly upregulated in invasive pituitary adenoma. SLC2A1 is significantly upregulated in invasive pituitary adenoma with satisfactory predictive value. It may regulate EMT. It may be a potential diagnostic marker for invasive pituitary adenoma.


A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay.
Executive functions (EF) are a complex set of neurodevelopmental, higher-ordered processes that are especially salient during adolescence. Disruptions to these processes are predictive of psychiatric problems in later adolescence and adulthood. The objectives of the current study were to characterize the latent structure of EF using bifactor analysis and to investigate the independent and interactive effects of genes and environments on EF during adolescence. Using a representative young adolescent sample, we tested the interaction of a polymorphism in the serotonin transporter gene (5-HTTLPR) and parental supervision for EF through hierarchical linear regression. To account for the possibility of a hierarchical factor structure for EF, a bifactor analysis was conducted on the eight subtests of the Delis-Kaplan Executive Functions System (D-KEFS). The bifactor analysis revealed the presence of a general EF construct and three EF subdomains (i.e., conceptual flexibility, inhibition, and fluency). A significant 5-HTTLPR by parental supervision interaction was found for conceptual flexibility, but not for general EF, fluency or inhibition. Specifically, youth with the L/L genotype had significantly lower conceptual flexibility scores compared to youth with S/S or S/L genotypes given low levels of parental supervision. Our findings indicate that adolescents with the L/L genotype were especially vulnerable to poor parental supervision on EF. This vulnerability may be amenable to preventive interventions.


The Yugoslavia cardiovascular disease study. II. Factors in the incidence of coronary heart disease.
In a 7-year follow-up of 11,121 Yugoslav men first examined in 1964-1965 when they were 35-62 years old, it was found that the incidence of coronary heart disease (CHD) was one-fourth that of a comparable Framingham (USA) group. Incidence in rural men was only 59% of urban men. In both urban and rural groups, men with higher blood pressures had greater CHD incidence, and cigarette smoking was also associated with greater incidence. In the urban but not the rural groups serum cholesterol and weight/height were also CHD risk factors. Levels of serum cholesterol and weight were lower in urban Yugoslavia than Framingham and lowest in rural Yugoslavia. At the same levels of these characteristics Framingham incidence was 3 times that in Yugoslavia. At the very low rural levels of weight and blood pressure CHD incidence was the same in urban as rural Yugoslav groups.


A microfluidic chip containing multiple 3D nanofibrous scaffolds for culturing human pluripotent stem cells.
In microfluidics-based lab-on-a-chip systems, which are used for investigating the effect of drugs and growth factors on cells, the latter are usually cultured within the device's channels in two-dimensional, and not in their optimal three-dimensional (3D) microenvironment. Herein, we address this shortfall by designing a microfluidic system, comprised of two layers. The upper layer of the system consists of multiple channels generating a gradient of soluble factors. The lower layer is comprised of multiple wells, each deposited with 3D, nanofibrous scaffold. We first used a mathematical model to characterize the fluid flow within the system. We then show that induced pluripotent stem cells can be seeded within the 3D scaffolds and be exposed to a well-mixed gradient of soluble factors. We believe that utilizing such system may enable in the future to identify new differentiation factors, investigate drug toxicity, and eventually allow to perform analyses on patient-specific tissues, in order to fit the appropriate combination and concentration of drugs.


Two distinct mechanisms of chromatin interaction by the Isw2 chromatin remodeling complex in vivo.
We have previously shown that Saccharomyces cerevisiae Isw2 complex slides nucleosomes to remodel chromatin in vivo. Our data suggested a model in which Isw2 complex binds the histone octamer and DNA separately to generate the force necessary for nucleosome movement. Here we find that the histone H4 "basic patch" is the only portion of any amino-terminal histone tail required for both target-specific association of Isw2 complex with chromatin and chromatin remodeling in vivo, whereas it is dispensable for basal levels of chromatin binding. Similarly, we find that nonremodeled chromatin structure and integrity of Isw2 complex are required only for target-specific association of Isw2 with chromatin. These data demonstrate fundamental differences between the target-specific and basal modes of chromatin binding by Isw2 complex in vivo and suggest that only the former involves contributions from DNA, histone H4, and sequence-specific DNA binding proteins. We propose a model for target recognition and chromatin remodeling by Isw2 complex in vivo.


Selection of salvage cryotherapy patients.
Radiation therapy is a main form of therapy for patients with localized prostate cancer. Despite advances in delivering radiation beams to the gland, urologists will be faced with managing patients with rising prostate-specific antigen values and radiation-recurrent cancer. If the cancer is detected early, salvage therapy can be initiated. Recent modifications in the technique of salvage cryosurgery have led to the ability to eradicate these tumors with a decrease in morbidity. The management and selection of these patients, as well as the results of salvage cryoablation, are discussed in this article.


The quality of school lunch consumed reflects overall eating patterns in 11-16-year-old schoolchildren in Finland.
To explore how the quality of school lunch consumed reflected overall eating patterns in school-aged children. Children filled in an Internet-based questionnaire about their eating patterns. The children were then divided into balanced and imbalanced school lunch eaters on the basis of their responses in the questionnaire. A balanced school lunch consisted of, by the definition used in the present study, a main dish, salad and bread. Eleven primary schools and one middle school in eastern Finland. A total of 531 schoolchildren (247 boys and 284 girls) aged 11-16 years. The school lunch was balanced in 46·5% of children. Eating a balanced school lunch was associated with overall healthier eating patterns outside school. Children who ate a balanced school lunch had more regular meal times and consumed healthier snacks. They ate fruit or berries and vegetables, dairy products and wholegrain foods more often, consumed fewer salty snacks, pizzas, meat pies and drank fewer soft drinks and energy drinks. Their eating patterns at home were also healthier, with vegetables being offered at every family dinner and fruit being offered daily, whereas soft drinks were offered seldom. The choices made by children in their school lunch reflect the overall eating patterns among school-aged children. Eating a balanced school lunch is associated with more regular meal patterns, the availability of healthier foods at home and an overall healthier diet, suggesting that healthy eating patterns are learnt at home.


Subcorneal pustular dermatosis with seronegative polyarthritis.
A 55-year-old woman presented with acute onset of subcorneal pustular dermatosis and a seronegative polyarthritis. There have been a few reports of subcorneal pustular dermatosis associated with arthritis.


[Associations of HLA-DR 4, DR 2, DRw 9 with clinical findings in rheumatoid arthritis].
HLA-DR antigens were determined in 128 patients with classical or definite rheumatoid arthritis (RA) according to American Rheumatism Association criteria (1957). HLA-DR 4 was significantly (p less than 0.01) increased in patients with RA (60%) compared with Japanese control (40%). In radiological changes, the frequency of stage II to IV were significantly greater in DR 4 positive patients (87.1% (67/77)) than in negative patients (70.6%) (36/51)). An early onset of disease was significantly (p less than 0.05) associated with DR 4 positive patients with duration of 4 years or more. Erythrocyte sedimentation rate was significantly (p less than 0.05) less in DR 2 positive patients (8.0% +/- 8.6 (39)) than DR 2 negative patients (12.2 +/- 11.9 (84)). Frequency of Sjogren's syndrome was more in DR 2 positive patients (41.3% (12/29)) than in DR 2 negative (29.2% (19/65)), and less in DR 4 positive (25.4% (15/59)) than in DR 4 negative (45.7% (16/35)), so the complication of Sjogren's syndrome showed a trend against the severity of RA. There were no associations between rheumatoid factor and HLA-DR phenotypes, but the frequency of anti-nuclear anti-nuclear antibody was significantly (p less than 0.01) lower in DRw 9 positive patients (38.4% (15/39)) than in DRw 9 negative (62.7% (54/86)). In both DR 4 and DRw 9 positive patients (16 cases), onset of disease (38.9 years-old +/- 15.9 (16)) was significantly earlier and frequency of Sjogren's syndrome (10.0% (1/10)) was significantly lower than those in DR 4 negative patients (48.5 years-old +/- 12.5 (51): 45.7% (15/35) respectively). The frequency of HLA-DRw 9 was greater in Japanese than people in the other countries and there was the close association between pathogenesis of RA and HLA-DRw 9 as well as DR 4 and DR 2 in Japan.


KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation.
Endotoxin-induced inflammation alters the hepatic expression of the drug efflux transporter genes mdr1b (Abcb1b) and mrp3 (Abcc3) in rats. In this study, we identified a novel kruppel-like zinc finger protein 6 (KLF6) cis-element on the rat mdr1b promoter which is important for basal activity and IL-1beta and endotoxin-mediated induction in gene transcription. Interestingly, KLF6 also functioned as a negative transcriptional regulator, inhibiting TNF-alpha-mediated induction of mdr1b. Furthermore, novel CCAAT/enhancer binding protein beta (C/EBPbeta) and heat shock factor 4 (HSF4) transcription binding sites were identified on the rat mrp3 promoter. Deletion of the HSF4 element significantly increased transcriptional activity of the mrp3 gene when exposed to TNF-alpha. Endotoxin treatment significantly affected transcriptional activity only in C/EBPbeta and HSF4 double deletion mrp3 promoter constructs. In summary, KLF6 and HSF4 are stimuli-specific regulatory elements which may be important in the control of the rat mdr1b and mrp3 genes during health and disease.


Disclosure of competing financial interests and role of sponsors in phase III cancer trials.
Financial relationships between industry, researchers and academic institutions are becoming increasingly complex, raising concern about sponsors' involvement in the conduct of biomedical research. A review of published randomised trials (RCTs) in cancer research was performed to assess adherence to the 1997 disclosure requirements and to document the nature of the disclosed interests. Source(s) of study support, author-sponsor relationships and the role of the study sponsor were assessed for all RCTs published between 1999 and 2003 in 12 international journals. A total of 655 cancer RCTs were identified. Of these, 516 (78.8%) disclosed the source of sponsorship. The nature of the relationship between the authors and the study sponsor was included in 219 of the 227 industry-sponsored studies. The most commonly cited relationships were (131 studies had multiple relations): grants (93.6%); employment (39.2%); consultant/honorarium (12.7%) and stock ownership and participation in a speaker's bureau (12, 5.5% each). Only 41 (18%) of the 227 industry-sponsored RCTs reported the role of the sponsor. Of these, 20 explicitly stated that the sponsor had no role in the study. Twenty-one papers described the sponsor's role, the degree of sponsor involvement was variable and usually described vaguely. Among these papers, four stated that researchers had full access to all data, one that the researchers had no limits on publication and one that 'the decision to submit the paper for publication was determined by the study sponsor'. In conclusion, no researcher should be expected to produce 'findings' without full access to the data, freedom from interference in analysis and interpretation and liberty to publish all results, however disappointing to the stakeholder they may be. In the meantime, researchers do well to arm themselves with the rules for research partnerships and editors to take on the role of watchdog.


Clinical implications of lipid peroxidation in acne vulgaris: old wine in new bottles.
Acne vulgaris is a common dermatological disorder, one that is frequently associated with depression, anxiety and other psychological sequelae. In recent years there has been an increasing focus on the extent to which oxidative stress is involved in the pathophysiology of acne. Emerging studies have shown that patients with acne are under increased cutaneous and systemic oxidative stress. Indeed, there are indications that lipid peroxidation itself is a match that lights an inflammatory cascade in acne. The notion that lipid peroxidation is a 'starter gun' in acne is not a new one; here we review the nearly 50-year-old lipid peroxidation theory and provide a historical perspective to the contemporary investigations and clinical implications.In addition, we present a novel hypothesis in which lipid peroxidation may be priming an increased susceptibility to co-morbid depression and anxiety in those with acne. The emerging research on the systemic burden of oxidative stress in acne sheds further light on the brain-skin axis. The recent findings also suggest potential avenues of approach for the treatment of acne via specific nutrients, dietary modifications, oral and topical interventions.


Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells.
Pluripotent mesenchymal cells form a population of precursors to a variety of cell types, including osteoblasts and adipocytes. Aging tilts the balance in favor of adipocyte differentiation at the expense of osteoblast differentiation, resulting in reduced bone formation and osteopenic disorders, including osteoporosis, in humans and animals. Understanding the mechanisms involved in causing this apparent shift in differentiation and identifying factors that stimulate osteoblast formation while inhibiting adipogenesis are of great therapeutic interest. In this study we report that specific, naturally occurring oxysterols, previously shown to direct pluripotent mesenchymal cells toward an osteoblast lineage, exert their osteoinductive effects through activation of Hedgehog signaling pathway. This was demonstrated by 1) oxysterol-induced expression of the Hh target genes Gli-1 and Patched, 2) oxysterol-induced activation of a luciferase reporter driven by a multimerized Gli-responsive element, 3) inhibition of oxysterol effects by the hedgehog pathway inhibitor, cyclopamine, and 4) unresponsiveness of Smoothened-/- mouse embryonic fibroblasts to oxysterols. Using Patched-/- cells that possess high baseline Gli activity, we found that oxysterols did not dramatically shift the IC50 concentration of cyclopamine needed to inhibit Gli activity in these cells. Furthermore, binding studies showed that oxysterols did not compete with fluorescently labeled cyclopamine, BODIPY-cyclopamine, for direct binding to Smoothened. These findings demonstrate that oxysterols stimulate hedgehog pathway activity by indirectly activating the seven-transmembrane pathway component Smoothened. Osteoinductive oxysterols are, therefore, novel activators of the hedgehog pathway in pluripotent mesenchymal cells, and they may be important modulators of this critical signaling pathway that regulates numerous developmental and post-developmental processes.


[Standardization of production of process Notopterygii Rhizoma et Radix slices].
Notopterol, isoimperatorin, volatile oil and extract (water and ethanol) were used as the research objects in this study to investigate the effects of different softening method, slice thickness and drying methods on the quality of Notopterygii Rhizoma et Radix slices, and the experimental data were analyzed by homogeneous distance evaluation method. The results showed that different softening, cutting and drying processes could affect the content of five components in Notopterygii Rhizoma et Radix incisum. The best processing technology of Notopterygii Rhizoma et Radix slices was as follows: non-medicinal parts were removed; mildewed and rot as well as moth-eaten parts were removed; washed by the flowing drinking water; stacked in the drug pool; moistening method was used for softening, where 1/8 volume of water was sprayed for every 1 kg of herbs every 2 h; upper part of herbs covered with clean and moist cotton, and cut into thick slices (2-4 mm) after 12 h moistening until appropriate softness, then received blast drying for 4 h at 50 ℃, and turned over for 2 times during the drying. The process is practical and provides the experimental basis for the standardization of the processing of Notopterygii Rhizoma et Radix, with great significance to improve the quality of Notopterygii Rhizoma et Radix slices.


Presence of albumin-positive cells in the liver of analbuminemic rats and their increase on treatment with hepatocarcinogens.
The analbuminemic rat is a mutant in which albumin mRNA processing is blocked owing to a seven-base-pair deletion in the 9th intron of the albumin gene. A small amount of albumin is detected in the serum of this rat. Production of serum albumin in the liver of this mutant rat was studied by an immunohistochemical method. The results showed that a few albumin-positive cells were present in the liver of the mutant rat, whereas all the hepatocytes in normal rat liver were albumin-positive. In the mutant the number of albumin-positive cells increased with age: their frequency was 10(-5) at birth and 6 X 10(-3) at 45 weeks of age. On administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) and 2-acetylaminofluorene, albumin-positive cells increased dramatically. Their numbers were 7 to 10 times those of untreated rats after 10 to 16 weeks of carcinogen treatment. The number of albumin-positive cells did not decrease after 3'-Me-DAB feeding was discontinued. In regenerating liver after partial hepatectomy, clusters of albumin-positive cells increased while the number of singlet albumin-positive cells decreased. These observations suggest that the appearance of albumin-positive cells in analbuminemic rat liver may be due to a somatic mutation of the hepatocytes.


Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model.
Normal cells are dependent on exogenous, receptor-mediated growth stimulation for cell cycle entry and progression, providing a critical homeostatic mechanism regulating cellular proliferation. In contrast, tumor cells acquire some degree of growth signal autonomy, often through their ability to produce growth factors as well as their receptors (autocrine signaling). Recently, data have begun to emerge implicating heterotypic signaling between diverse cell types within a tumor in the genesis and progression of cancer; however, current experimental approaches in vivo have not adequately addressed this critical relationship. Here we used transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF), or its growth antagonist NK2, as genetically modified hosts for transplantation of tumor cells expressing their receptor, c-Met, to directly assess the contribution of heterotypic signaling to metastatic colonization. We demonstrate that metastatic potential under nonautocrine signaling conditions (i.e., where tumor cells expressing c-Met are transplanted into transgenic hosts producing HGF/SF) rivaled that observed under conditions of autocrine signaling (i.e., where tumor cells expressing both HGF/SF and c-Met are transplanted into wild-type hosts). HGF/SF and NK2 were not functionally equivalent in vivo. Attenuation of NK2-associated growth inhibition by the presence of an HGF/SF-Met autocrine loop uncovered a shift in metastatic site preference from lung to liver only in NK2-transgenic hosts, a qualitative behavioral alteration likely detectable only through the genetic approach used here. Our data demonstrate that growth factors not intrinsic to malignant cells can have profound effects on metastatic efficiency in vivo and provide experimental support of a role for heterotypic signaling in tumor progression.


Systematic review and comparison of pharmacologic therapies for neuropathic pain associated with spinal cord injury.
Management of neuropathic pain (NeP) associated with spinal cord injury (SCI) is difficult. This report presents a systematic literature review and comparison of the efficacy and safety of pharmacologic therapies for treating SCI-associated NeP. Medline, Embase, Cochrane, and Database of Abstracts of Reviews of Effects were searched through December 2011 for randomized, blinded, and controlled clinical trials of SCI-associated NeP meeting predefined inclusion criteria. Efficacy outcomes of interest were pain reduction on the 11-point numeric rating scale (NRS) or 100 mm visual analog scale and proportion of patients achieving ≥30% or ≥50% pain reduction. Discontinuations and adverse events (AEs) were also assessed, for which Bayesian meta-analytic indirect comparisons were performed. Of the nine studies included in the analysis, samples were <100 patients, except for one pregabalin study (n = 136). Standard errors for the NRS outcome were often not reported, precluding quantitative comparisons across treatments. Estimated 11-point NRS pain reduction relative to placebo was -1.72 for pregabalin, -1.65 for amitriptyline, -1.0 for duloxetine, -1 (median) for levetiracetam, -0.27 for gabapentin, 1 (median) for lamotrigine, and 2 for dronabinol. Risk ratios relative to placebo for 30% improvement were 0.71 for levetiracetam and 2.56 for pregabalin, and 0.94 and 2.91, respectively, for 50% improvement. Meta-analytic comparisons showed significantly more AEs with pregabalin and tramadol compared with placebo, and no differences between placebo and any treatment for discontinuations. Studies of SCI-associated NeP were few, small, and reported insufficient data for quantitative comparisons of efficacy. However, available data suggested pregabalin was associated with more favorable efficacy for all outcome measures examined, and that the risks of AEs and discontinuations were found to be similar among the therapies.


Intracranial hemorrhage and subsequent ischemic stroke in patients with atrial fibrillation: a nationwide cohort study.
The risk of ischemic stroke/thromboembolic events after an intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF) who are on warfarin treatment is poorly characterized. The aim of this study was to assess the association between the risk of ischemic stroke/thromboembolic events and ICH. Linkage of three Danish nationwide administrative registries in the period between 1999 and 2012 identified patients with AF on warfarin treatment. Event-rate ratios of stroke/thromboembolic events, major bleeding, and all-cause mortality stratified by ICH were calculated, and Cox proportional hazard models were used to compare event rates among ICH survivors. A matched OR was calculated for ICH occurrences within 0 to 3 months relative to the 3 to 6 months prior to a stroke/thromboembolic event. A rate ratio of claimed warfarin prescriptions in a 3-month period pre- and post-ICH was also calculated. We studied 58,815 patients with AF (median age, 72.6 years; 60% men). When compared with the non-ICH group, the ICH group was at increased risk for stroke/systemic embolism/transient ischemic attack (TIA) (rate ratio, 3.67; 95% CI, 3.12-4.31) and mortality (rate ratio, 5.55; 95% CI, 5.20-5.92), but not for major bleeding (rate ratio, 1.06; 95% CI, 0.81-1.39). The matched OR of ICH occurrences prior to a stroke/systemic embolism/TIA was 4.33 (95% CI, 2.44-8.15). The rate ratio of claimed warfarin prescriptions post- and pre-ICH event was 0.28 (95% CI, 0.24-0.33). In this large-scale study of patients with AF treated with warfarin, first-time ICH was associated with an increased rate of ischemic stroke/systemic embolism/TIA and mortality compared with the non-ICH group. There was a decrease in the warfarin-prescription purchase rate in the post-ICH period compared with pre-ICH, which may partly explain the excess risk.


Estimation of pulmonary artery pressure with transesophageal echocardiography: An observer-blinded test accuracy study.
With the declining use of the pulmonary artery catheter (PAC), transesophageal echocardiography (TEE) has become an appealing alternative to obtain pulmonary artery pressure non-invasively using the simplified Bernoulli equation. The validation of this method in the perioperative setting has been scarce with no clear recommendations about which view is the most accurate to estimate right ventricular systolic pressure (RVSP).Therefore, we performed a prospective, observer-blinded, diagnostic test accuracy study to assess the difference in systolic pulmonary artery pressure (sysPAP) measuring both, invasively sysPAP and estimated RVSP with TEE in 3 different views: the mid-esophageal (ME) 4Chamber, the ME right ventricular (RV) inflow-outflow and the ME modified bicaval view.To show a clinically significant difference of at least 10% in RVSP, we included 40 cardiac surgical patients divided into 3 subgroups: Patients with mild to moderate tricuspid regurgitation (TR) and mean PAP <25 mm Hg, patients with mild to moderate TR and mean PAP≥ 25 mm Hg, and patients with severe TR.For the whole cohort, bias of estimated RVSP compared to measured sysPAP was 5.27 mm Hg, precision was 7.96 mm Hg, limits of agreement were -10.66 to 21.19 mm Hg. The best agreement between the 2 methods was found in patients with severe TR and in the ME RV inflow-outflow and the modified bicaval view. Good Doppler signals were available in 35% and 46% in these views, and in 20% in the ME 4 chamber view.The estimation of the sysPAP by TEE cannot be considered reliable in the clinical perioperative setting. Only measurements that provide a full Doppler envelope show sufficient precision to provide accurate estimations.


Utility of Dermoscopy Training in Improving Diagnostic Accuracy of Skin Lesions Among Physician Assistant Students.
Patients often first present to their primary care provider for skin lesion concerns, and dermoscopy is a tool that enhances diagnostic acumen of both malignant and benign skin lesions. Physician assistants (PAs) frequently serve as primary care and dermatology providers, but to our knowledge, no current research on dermoscopy expertise with PAs exists. We hypothesize that PA students could be taught dermoscopy based on the triage amalgamated dermoscopic algorithm (TADA) to increase their diagnostic skill, as previously shown with medical students. Dermoscopy was taught to first-year PA students at all 5 PA programs in the state of Minnesota. The training was 50 minutes in length and focused on the fundamentals of the TADA method. Physician assistant students participated in a pretraining and post-training test, consisting of 30 dermoscopic images. A total of 139/151 (92%) PA students completed both the pretraining and post-training tests. Overall, mean scores for all students increased significantly (P < .0001) after dermoscopy training was given (18.5 ± 7.1 vs. 23.8 ± 6.7). Our study demonstrates that after TADA training, PA students improved their ability to assess dermoscopy images of both skin cancer and benign lesions accurately, suggesting that PAs can be trained as novice dermoscopists and provide better dermatologic care to patients. We strongly encourage integration of dermoscopy into didactic education across PA programs. Implementing a dermoscopy curriculum in established PA programs will enable future PAs to provide better clinical care when evaluating skin lesions.


Synaptotagmins 1 and 7 in vesicle release from rods of mouse retina.
Synaptotagmins are the primary Ca2+ sensors for synaptic exocytosis. Previous work suggested synaptotagmin-1 (Syt1) mediates evoked vesicle release from cone photoreceptor cells in the vertebrate retina whereas release from rods may involve another sensor in addition to Syt1. We found immunohistochemical evidence for syntaptotagmin-7 (Syt7) in mouse rod terminals and so performed electroretinograms (ERG) and single-cell recordings using mice in which Syt1 and/or Syt7 were conditionally removed from rods and/or cones. Synaptic release was measured in mouse rods by recording presynaptic anion currents activated during glutamate re-uptake and from exocytotic membrane capacitance changes. Deleting Syt1 from rods reduced glutamate release evoked by short depolarizing steps but not long steps whereas deleting Syt7 from rods reduced release evoked by long but not short steps. Deleting both sensors completely abolished depolarization-evoked release from rods. Effects of various intracellular Ca2+ buffers showed that Syt1-mediated release from rods involves vesicles close to ribbon-associated Ca2+ channels whereas Syt7-mediated release evoked by longer steps involves more distant release sites. Spontaneous release from rods was unaffected by eliminating Syt7. While whole animal knockout of Syt7 slightly reduced ERG b-waves and oscillatory potentials, selective elimination of Syt7 from rods had no effect on ERGs. Furthermore, eliminating Syt1 from rods and cones abolished ERG b-waves and additional elimination of Syt7 had no further effect. These results show that while Syt7 contributes to slow non-ribbon release from rods, Syt1 is the principal sensor shaping rod and cone inputs to bipolar cells in response to light flashes.


A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators.
G protein-coupled receptors (GPCRs) are of great importance to the pharmaceutical industry as they are involved in many human diseases and include well-validated targets for therapeutic intervention. Discovery of lead compounds, including small synthetic molecules, that specifically inhibit the receptor's function, is an important initial step in drug development and relies on sensitive, specific, and robust cell-based assays. Here, we describe a kinetic cellular assay with a fluorescent readout primarily designed to identify receptor-specific antagonists that inhibit the intracellular Ca2+ release evoked upon the activation of the CXC chemokine receptor 4 (CXCR4) by its endogenous ligand, the CXC chemokine ligand 12 (CXCL12). A key advantage of this method is that it also enables screening of compounds endowed with intrinsic agonistic properties (i.e., compounds eliciting an increase in intracellular Ca2+ concentration in the absence of CXCL12) or compounds modulating the receptor's function via interaction with allosteric binding sites (i.e., positive and negative allosteric modulators (PAMs and NAMs, respectively)). On the down side, autofluorescent compounds might interfere with the assay's readout, thereby hampering reliable data interpretation. Most likely this assay can be implemented, with minimal adaptations, as a generic drug discovery assay for many other GPCRs of which the activation leads to a release of intracellular Ca2+.


The role of CD4 in regulating homeostasis of T helper cells.
Intrathymic T cell selection and peripheral activation of mature T cells are crucial for self-recognition and the general immune response to viral, bacterial, and tumor antigens. The T cell coreceptors, CD4 and CD8, contribute to the regulation of these processes. The importance of interactions between CD4 and molecules encoded by the class II major histocompatibility complex (MHC) for thymic T cell selection has been clearly established, however, the role of CD4-MHC class II interactions in T helper (TH) cell differentiation, in the maintenance of homeostasis in the peripheral immune system, and in the generation of memory TH cells is largely unclear. Here, we present evidence for a role of CD4 in controlling homeostasis in the peripheral immune system. We also demonstrate the importance of CD4-MHC class II interactions in inducing these previously not recognized functions of CD4.


Cirrhotic cardiomyopathy: does it contribute to chronic fatigue and decreased health-related quality of life in cirrhosis?
Diminished health-related quality of life (HRQoL) and fatigue have been reported in patients with cirrhosis. The presence of cirrhotic cardiomyopathy and the attendant poor cardiac response to physical stress may affect HRQoL and contribute to fatigue in these patients. To evaluate the contribution of cirrhotic cardiomyopathy to HRQoL and fatigue in ambulatory cirrhotic patients. Thirty ambulatory cirrhotic patients (14 preascitic, Child-Pugh score 5.6 +/- 0.3; 16 ascitic, Child-Pugh score 9.1 +/- 0.5) underwent cardiopulmonary exercise testing and assessment of HRQoL, fatigue and depressive symptomatology. HRQoL and fatigue scores were correlated with liver disease severity, depressive symptomatology and parameters of cardiac function and exercise physiology. Subscales of all HRQoL measuring the effect of disease on the ability to perform physical, social and emotional roles were significantly impaired when compared with controls (P<0.001). The impact of fatigue, as assessed by the Fatigue Assessment Inventory, was greater in cirrhotics (4.46 versus 2.53 in healthy age-matched controls, P<0.01). Diminished HRQoL, impact of fatigue and vitality were related to depressive symptoms rather than to cardiac structural and functional abnormalities, which were present in cirrhotic patients. Poorer physical quality of life scores correlated with diminished mental health. Depression, rather than the presence of cirrhotic cardiomyopathy, may have contributed to the diminished HRQoL and vitality in patients with cirrhosis with or without ascites.


The early effect of sublethal X-irradiation of phagocytic cells in mouse blood and the influence of cystamine as measured by chemiluminescence.
The metabolic burst accompanying phagocytosis of granulocytes (PMN) leads to the generation of activated oxygen species such as O-2, H2O2, 1O2 and OH; which give rise to chemiluminescence (CL) in the presence of luminol. Reliable CL-measurements of stimulated PMN can be carried out in freshly drawn mouse blood, when photon counts are related to the number of PMN. Effects of low dose total body X-irradiation were studied using C57B1/6 mice. It was found that 24 and 48 hours after irradiation (0.24-0.95 Gy) CL of whole blood was slightly decreased. If however CL-counts were related to the number of PMN, an enhanced CL per single granulocyte was recorded. The administration of cystamine leads to an immune stimulating effect of unirradiated animals. In animals, who received 0.95 Gy a distinct radioprotective effect of cystamine can be observed.


Chiropractic patients in Denmark: a short description of basic characteristics.
The vast majority of information on chiropractic and chiropractic patients originates from English-speaking countries. Lately, however, reports describing chiropractic patients and practice in other European countries have emerged. To describe basic characteristics of Danish chiropractic patients. Survey questionnaire. All chiropractic clinics in Denmark were asked to collect information on new patients during 1 randomly assigned week in 1999. Private chiropractic practice and a nonprofit research institution. Age and sex, location and duration of chief complaint, pain intensity, limitation of activities of daily living from chief complaint, and mode of referral. Eighty-eight percent of all chiropractic clinics in Denmark participated in the study. Out of 2020 patients from the participating clinics, 1897 (94%) filled out a self-administered questionnaire. The mean age of participants was 42 years, and slightly more women than men returned the questionnaire. By far the most frequent area of complaint was pain related to the lower back (50%) followed by pain related to the neck (15%). The majority of patients had complaints in the subacute or chronic category (duration 1-6 months). Patients with sciatica had significantly higher pain scores and limitation in activities of daily living (ADL) than any other group, whereas patients with neck pain tended to score lower. Patients in the subacute category had the highest pain scores and limitation in ADL. For complaints lasting more than 6 months, limitation in ADL remained constant at a low level. Twenty-three percent of all patients were referred to the chiropractor, most frequently by a general medical practitioner. More than half of all patients had previously been treated for the same or similar problems, most frequently by a chiropractor. Fifty-one percent had also received chiropractic care for other types of problems. Most Danish chiropractic patients complain of pain related to the low back or neck of between 1 and 6 months' duration. This study confirms that chiropractic is fairly well integrated in the Danish primary health care system. There are differences between the chiropractic patient population in Denmark compared with that of Sweden and Holland.


Birth Experience Mediates the Association Between Fear of Childbirth and Mother-Child-Bonding Up to 14 Months Postpartum: Findings From the Prospective Cohort Study DREAM.
To explore the longitudinal associations between prepartum fear of childbirth (FOC), birth experience, and postpartum mother-child-bonding, and the potential mediator role of the birth experience. Women from the prospective cohort study DREAM completed questionnaires during pregnancy, 8 weeks, and 14 months after the birth. A community sample of n = 645 pregnant women from a large city in Eastern Germany participated in the study. In a regression analysis, FOC predicted negative birth experience (β = 0.208, p < 0.001) which in turn predicted poorer mother-child-bonding both at 8 weeks (β = 0.312, p < 0.001) and 14 months postpartum (β = 0.200, p < 0.001). FOC also predicted mother-child-bonding at 14 months postpartum (β = 0.098, p < 0.05). Of note, this association was mediated by birth experience both at 8 weeks, indirect effect ab = 0.065, 95% CI [0.036, 0.098], and 14 months postpartum, indirect effect ab = 0.043, 95% CI [0.023, 0.067]. These effects remained stable even when adjusting for potential confounders. This study suggests that the association between FOC and mother-child-bonding is mediated by birth experience, pointing to the importance of a woman's positive subjective experience. Findings reveal two targets for peripartum interventions for women at risk for poor mother-child-bonding, namely the implementation of FOC screenings during pregnancy, and birth experience as mediating factor between FOC and mother-child-bonding. Focusing on the mother's subjective birth experience could aid to identify women at risk for impaired bonding who might need additional support.


Identification of a novel major locus for gray leaf spot resistance in Italian ryegrass (Lolium multiflorum Lam.).
Gray leaf spot (GLS), caused by Magnaporthe oryzae (anamorph Pyricularia oryzae), in ryegrasses is a very serious problem. Heavily infected small seedlings die within a matter of days, and stands of the grasses are seriously damaged by the disease. Thus, the development of GLS-resistant cultivars has become a concern in ryegrass breeding. Phenotypic segregations in a single cross-derived F1 population of Italian ryegrass (Lolium multiflorum Lam.) indicated that the GLS resistance in the population was possibly controlled by one or two dominant genes with 66.5-77.9% of broad-sense heritability. In bulked segregant analyses, two simple sequence repeat (SSR) markers, which have so far been reported to locate on linkage group (LG) 3 of Italian ryegrass, showed specific signals in the resistant parent and resistant bulk, indicating that the resistance gene locus was possibly in the LG 3. We thus constructed a genetic linkage map of the LG 3 covering 133.6 centimorgan with other SSR markers of the LG 3 of Italian ryegrass and grass anchor probes that have previously been assigned to LG 3 of ryegrasses, and with rice expressed sequence tag (EST)-derived markers selected from a rice EST map of chromosome (Chr) 1 since LG 3 of ryegrasses are syntenic to rice Chr 1. Quantitative trait locus (QTL) analysis with the genetic linkage map and phenotypic data of the F1 population detected a major locus for GLS resistance. Proportions of phenotypic variance explained by the QTL at the highest logarithm of odds scores were 61.0-69.5%. A resistance locus was confirmed as novel for GLS resistance, because its genetic position was different from other known loci for GLS resistance. Broad-sense heritability and the proportion of phenotypic variance explained by the QTL were similar, suggesting that most of the genetic factors for the resistance phenotype against GLS in the F1 population can be explained by a function of the single resistance locus. We designated the putative gene for the novel resistance locus as LmPi2. LmPi2 will be useful for future development of GLS-resistant cultivars in combination with other resistance genes.


Genome sequencing of Pseudomonas aeruginosa strain M2 illuminates traits of an opportunistic pathogen of burn wounds.
Pseudomonas aeruginosa is a Gram-negative nosocomial pathogen and one of the most prevalent organisms isolated from burn wounds worldwide. Pseudomonas aeruginosa strain M2 (O5 serotype, type B flagella) is utilized for examining the murine model associated with burns. Pseudomonas aeruginosa M2 is similar in lethality to common laboratory P. aeruginosa strains when infecting CD-1 mice. Conversely, we recently showed that, relative to these strains, P. aeruginosa M2-infected mice are more susceptible to sepsis and demonstrate a 6-log reduction in LD50 from subcutaneous infection at the infection site directly after 10% total body surface area burn. To better understand this striking phenotypic difference from other P. aeruginosa strains employed in burn models, we sequenced the P. aeruginosa M2 genome. A total of 4,136,641 read pairs were obtained, providing an average genome coverage of 97.5X; subsequent assembly yielded a draft genome with 187 contigs comprising 6,360,304 bp with a G + C content of 66.45%. Genome-based phylogeny estimation of 92 P. aeruginosa strains placed P. aeruginosa M2 with P. aeruginosa-12-4-4(59), a nonairway clinical strain isolated from the blood culture of a burn patient. Phylogenomic analyses identified genes shared between P. aeruginosa M2 and P. aeruginosa 14, another strain exhibiting increased lethality in thermal tissues, as well as P. aeruginosa M2 unique genes with diverse functions like degradation of toxic aromatic compounds, iron scavenging, swarming motility and biofilm formation, defense against invasive DNA, and host assault. Predicted lateral gene transfers illuminate proteins heretofore uncharacterized for roles in P. aeruginosa biology. Our work yields a rich resource for assessing P. aeruginosa genes required for increased lethality in burn tissue seroma.


β-adrenoceptor activation increased VAMP-2 and syntaxin-4 in secretory granules are involved in protein secretion of submandibular gland through the PKA/F-actin pathway.
Autologous submandibular gland transplantation is an effective treatment for severe dry eye syndrome. However, the protein secretion in transplanted gland is altered by a mechanism that remains to be elucidated. In the present study, we found that β1-adrenoceptor (β1-AR) and β2-AR expression and the phosphorylation of the downstream molecule protein kinase A (PKA) were elevated in transplanted submandibular glands obtained from epiphora patients. Synaptobrevin/vesicle-associated membrane protein 2 (VAMP-2) interacted with syntaxin-4 and actin in human submandibular gland. The contents of syntaxin-4 and actin interacting with VAMP-2 were increased in transplanted gland. Moreover, VAMP-2 and syntaxin-4 expression in the secretory granule fraction, and VAMP-2 expression in the membrane protein fraction were increased in isoproterenol-treated and transplanted glands. Isoproterenol increased F-actin polymerization in the apical and lateral regions of the cytoplasm in both control and transplanted glands. Inhibiting PKA activity and/or F-actin formation abolished the isoproterenol-enhanced expression of VAMP-2 and syntaxin-4 in the secretory granule fraction and the isoproterenol-enhanced expression of VAMP-2 in the membrane protein fraction. Taken together, these results indicate that the activation of β-ARs induces secretory granules and cell membrane fusion via the interaction of VAMP-2 and syntaxin-4 in a PKA- and F-actin-dependent manner in human submandibular gland. Up-regulated β-ARs might participate in altering protein secretion in transplanted submandibular gland by promoting the interaction of VAMP-2 with syntaxin-4.


Polyclonal immunoglobulin E levels are correlated with hemoglobin values and overall survival in patients with multiple myeloma.
Polyclonal IgG, IgA, and IgM immunoglobulins are often decreased in sera of patients with multiple myeloma (MM), whereas very few data are available on polyclonal IgE levels. We have determined IgE levels in a large series of MM patients at diagnosis and subjects with monoclonal gammopathy of undetermined significance (MGUS) and correlated IgE levels with survival and prognostic factors in MM. IgE were determined with a commercially available ELISA kit in 201 MM patients at diagnosis, 144 subjects with MGUS, and 77 age-matched controls. IgE levels progressively decreased from controls to MGUS and from MGUS to MM (P = 0.001). MM patients with IgE levels of >11.5 IU/mL (median) had a better survival than patients with IgE of <11.5 IU/mL (P = 0.048). The difference was even more significant when MM patients were divided according to clinical cutoff values. Patients with elevated IgE levels (>100 IU/mL) had from 2 to 3 years longer survival than those with low (<10 IU/mL) or intermediate values (10-100 IU/mL; P < 0.01). IgE levels were positively and negatively correlated with hemoglobin (P = 0.006) and beta2-microglobulin levels (P = 0.007), respectively. Univariate and multivariate analyses confirmed that high IgE levels are positive predictors of overall survival (P = 0.03 and 0.08, respectively) and strongly correlated with hemoglobin values. Because IgE levels are dependent on Th(2) responses, these data open new perspectives in the interpretation of antitumor immune responses and pathogenesis of anemia in MM.


Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene.
A 200∼240 kb SH2B1-containing deletion region on 16p11.2 is associated with early-onset obesity and developmental delay. Here, we describe monozygotic twin brothers with discordant clinical presentations. Intrauterine fetal growth restriction was present in both twins. Additionally, twin A exhibited coarctation of aorta, left ventricular noncompaction, atrial septal defect, pericardial effusion, left hydronephrosis, and moderate developmental delay, whereas twin B exhibited single umbilical artery. Chromosome microarray analysis was performed on both twins and their parents. An identical 244 kb microdeletion on 16p11.2 including 9 Refseq genes, including SH2B1, was identified in the twins. The novel findings in monozygotic twins may expand the phenotypic spectrum of 16p11.2 microdeletion. Further studies are needed to strengthen the correlation between genotypes and abnormal clinical features.


Effect of prolonged gastric distension on motor function of LES and of proximal stomach.
Gastric distension is a potent stimulus of transient lower esophageal sphincter (LES) relaxation. To investigate the time effect of prolonged gastric distension on the rate of transient LES relaxations, LES pressure, and the motor and sensory functions of the proximal stomach, we performed a continuous isobaric distension of the proximal stomach at the 75% threshold pressure for discomfort for 2 h in seven healthy subjects. A multilumen assembly incorporating a sleeve and an electronic barostat was used. The rate of transient LES relaxations (n/30 min) was constant during the first hour [4.1 +/- 1.2 (0-30 min) and 5.4 +/- 1.1 (30-60 min)] but markedly decreased (P < 0.05) in the second hour [2.1 +/- 0.5 (60-90 min) and 2.3 +/- 0.9 (90-120 min)], whereas LES pressure, baseline volume and volume waves within the gastric bag, hunger, and fullness did not change throughout the experiment. It is concluded that the rate of transient LES relaxations decreases with time during prolonged gastric distension, thus suggesting that this type of stimulus should not be used in sequential experimental conditions.


Intractable Acute Pain Related to Fluoroquinolone-Induced Peripheral Neuropathy.
Fluoroquinolones are widely prescribed antibiotics, used for various infectious etiologies. These antibiotics carry the possibility of the serious adverse effect of peripheral neuropathy, with a true incidence not known owing to its rare existence. Recently, the Food and Drug Administration (FDA) has required alterations to drug labels to highlight this adverse effect of fluoroquinolones. This is a case report of a single patient at an inpatient neurology service at an urban academic medical center in the United States. The patient is a 20-year-old male, with well-controlled type 1 diabetes mellitus, presenting with a short duration of bilateral lower extremity pain following a 10-day course of levofloxacin for suspected epididymitis. The patient was initially diagnosed with complex regional pain syndrome and treated with a variety of pain medications, including lidocaine infusions, hydromorphone, methadone, and ketamine infusions. After review of the patient's history and limited response to medical management, the patient's condition was reclassified as an adverse effect from fluoroquinolone treatment. Pain of unknown etiology can be perplexing, both for the physician and the patient. Reporting of similar incidents attributed to medication adverse effects will increase the awareness of this type of neuropathy, avoid future cases of misdiagnosis, and enable early detection and treatment.


Meningioangiomatosis is associated with neurofibromatosis 2 but not with somatic alterations of the NF2 gene.
Meningioangiomatosis occurs sporadically and in patients with neurofibromatosis. The literature, however, is unclear concerning the type of neurofibromatosis associated with meningioangiomatosis. Because determining which form of neurofibromatosis predisposes to meningioangiomatosis would clarify the genetic alterations of this lesion, we reviewed all reported cases of meningioangiomatosis associated with neurofibromatosis in light of current diagnostic criteria for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2). All well-documented cases of meningioangiomatosis occurred in the setting of NF2, implying that germline alterations of the NF2 gene predispose to meningioangiomatosis. To determine whether sporadic (non-NF) cases of meningioangiomatosis arise from somatic alterations of the same gene, we screened the NF2 gene for mutations in 12 sporadic cases of meningioangiomatosis and in constitutional DNA from 6 of these 12 patients. No mutations were found in either the lesional or constitutional DNA, which suggests that sporadic meningioangiomatosis is not a forme fruste of NF2 and that somatic alterations of the NF2 gene do not play a major role in sporadic meningioangiomatosis. For some tumor suppressor genes, germline mutations may predispose to specific tumors, while similar sporadic lesions only rarely suffer somatic mutations in these genes. The present findings suggest a similar dichotomy for the NF2 gene in meningioangiomatosis.


[Effects of root growth on dynamics of microbes and enzyme activities during litter decomposition.]
To understand the influence of roots of understory plant entering litter layer on litter decomposition in forest ecosystems, we examined the effects of different treatments of Lolium multiflorum root biomass on microorganisms and enzyme activities during leaf litter decomposition of Symplocos setchuensis, a dominant species in a mid-subtropical evergreen broad-leaved forest, through a litter bag simulation experiment. Results showed that diversity index of bacterial and fungal communities of leaf litter surface under three treatments, i.e. no root (N), less roots (L), more roots (M), in a 240-day decomposition process showed the following pattern: M > L > N. The effects of these different root biomass treatments on the composition and quantity of fungal community were more significant than those on bacterial community. The biomass of living roots growing in the litter bag gradually decreased at the end of the growing season of L. multiflorum. The impacts of root growth on the composition of the fungal community gradually decreased during decomposition. At the same decomposition stage, the activities of acid phosphatase, β-glucosidase, polyphenol oxidase, and peroxidase on the litter surface were higher in the treatments with roots than that without roots. These results indicated that root growth could change the composition and quantity of microbial communities and increase the extracellular enzyme activities of microbes, and thus stimulating litter decomposition.


Overview and state of the art in the management of lung cancer.
Lung cancer is a major health problem worldwide. Non-small-cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers, while small-cell lung cancer (SCLC) accounts for 15% to 20% of cases. For early-stage and locally advanced NSCLC (stages I through III), a multimodality treatment approach is appropriate because it improves survival. Combination chemotherapy is currently the standard treatment for good performance patients with metastatic disease. Elderly patients (> or = 70 years) with metastatic NSCLC also benefit from treatment. In SCLC, concurrent radiation therapy and chemotherapy is the standard for limited disease, while chemotherapy is the treatment for extensive disease. Novel innovative therapies, which could include molecular targeting agents, are needed to treat both NSCLC and SCLC.


Human rights, bioethics, and mental disorder.
This article considers the international human rights instruments which set minimum standards for the content and use of mental health legislation, and the extent to which they represent 'hard law' (binding and enforceable in domestic or international courts) or 'soft law' which is not strictly binding in the same sense but which may provide persuasive authority or may be used in debate to embarrass a Government into compliance. The article considers the extent to which these various instruments impose both 'negative obligations' on states not to interfere with rights such as physical integrity or protection against arbitrary detention and 'positive' obligations on states to take positive steps to uphold the rights of individuals. The article on the case law under the European Convention on Human Rights showing how 'soft law' sources are increasingly used by the Strasbourg Court as aids to construing the scope of Convention rights. The article concludes by suggesting that whilst mentally disordered people may be afforded different treatment in relation to general bioethics instruments on the international plane, they are also entitled to rights under Disability Conventions which enjoin states to take positive steps to promote equal treatment, social inclusion and protection against discrimination and stigma.


[Osteo-conductive materials: animal experiments and instrumental analysis II].
In daily dental surgery practice, when it is not possible to obtain-enough autogenous bone graft to fill bone defects, bone substitutes can be useful for bone regeneration. After a preliminary microscopic examination of histologic samples obtained from semithin sections of the tibias of rats showing no major differences in the results both for the single material and implant time, further studies on five different osteoconductive materials used in oral clinical practice were carried out with microradiography, SEM and X-ray microanalysis. In experimental animals (rats) bone defects 3 mm large were surgically induced in both tibias: one of the defects was filled by bone substitutes and on the other side the bone defect healed naturally. The findings obtained were studied in depth, and allowed to conclude that the materials tested are suitable for the purpose for which they are marketed. Non-demineralized bovine bone showed the best results with a high degree of osteointegration. However, the results also show that not all the materials tested offer healing advantages over controls.


Modulation of renal baroreceptor function by catecholamines and salt intake in the conscious dog.
We have examined the relationship between plasma renin activity and renal perfusion pressure by determining the stimulus-response curve of the renal baroreceptor in conscious, uninephrectomized dogs, and the modulation induced by catecholamines and varying salt intake. Renal perfusion pressure was controlled by step-wise inflation of a constricting cuff previously implanted around the renal artery. The stimulus-response curve of the renal baroreceptor may be divided into two ranges: a relatively flat portion close to normal pressure (100 mmHg), and a much steeper section below a "threshold" pressure of 75-80 mmHg. Epinephrine (I.V. or I.R.) produced a parallel shift of the curve to the right, i.e., a smaller drop in pressure was needed to reach "threshold." Changing the diet from normal salt intake (80 meq/day) to a low salt intake (10 meq/day) increased the gain of the stimulus-response curve. Thus, the same elevated PRA may be reached either by a shift of the curve to the right, or by increase in gain.


Removal of hexavalent chromium by using red mud activated with cetyltrimethylammonium bromide.
The removal of hexavalent chromium [Cr(VI)] from aqueous solution by using red mud activated with cetyltrimethylammonium bromide (CTAB) was studied. The optimum operation parameters, such as CTAB concentration, pH values, contact time, and initial Cr(VI) concentration, were investigated. The best concentration of CTAB for modifying red mud was found to be 0.50% (mCTAB/VHCl,0.6 mol/L). The lower pH (<2) was found to be much more favourable for the removal of Cr(VI). Red mud activated with CTAB can greatly improve the removal ratio of Cr(VI) as high as four times than that of original red mud. Adsorption equilibrium was reached within 30 min under the initial Cr(VI) concentration of 100 mg L(-1). The isotherm data were analysed using Langmuir and Freundlich models. The adsorption of Cr(VI) on activated red mud fitted well to the Langmuir isotherm model, and the maximum adsorption capacity was estimated as 22.20 mg g(-1) (Cr/red mud). The adsorption process could be well described using the pseudo-second-order model. The result shows that activated red mud is a promising agent for low-cost water treatment.


Perineal impalements in children: distinguishing accident from abuse.
Perineal impalements are uncommon and potentially life-threatening injuries. Medical providers must evaluate the risk of child abuse in all cases of genital or anal trauma. Determination of abuse depends on medical assessment of the mechanism of injury and statements by the child and witnesses, and may require collaboration with police or child protection agencies for scene investigation. To describe circumstances, medical findings, and child protection issues raised in accidental pediatric perineal impalement injuries. Retrospective case series selected from the authors' own practices and from submissions through an international list-serve of child abuse physicians. All cases included were determined to be accidental. Thirty-four cases were identified. Children ranged in age from 13 months to 14 years, 59% were girls. Most injuries occurred in the home (24/34, 71%), and more than one third (13/34, 38%) occurred in the bathroom. Most children had examination under anesthesia (26/34, 77%), many required surgical repair (20/34, 59%), and 4 had bowel perforations. Multidisciplinary assessment regarding child abuse was used in 71% (24/34) of cases. Inspection of the impaling objects or the scene was accomplished by medical providers or police in 50% (17/34) of cases. Ambulatory children can sustain accidental perineal impalement injuries, and severe internal injuries may accompany minor external findings. History from supervising adults and from other child witnesses, examination of the impaling objects, and investigation of the scene may be required to reach the conclusion of accidental injury.


Statistical analysis of efficient unbalanced factorial designs for two-color microarray experiments.
Experimental designs that efficiently embed a fixed effects treatment structure within a random effects design structure typically require a mixed-model approach to data analyses. Although mixed model software tailored for the analysis of two-color microarray data is increasingly available, much of this software is generally not capable of correctly analyzing the elaborate incomplete block designs that are being increasingly proposed and used for factorial treatment structures. That is, optimized designs are generally unbalanced as it pertains to various treatment comparisons, with different specifications of experimental variability often required for different treatment factors. This paper uses a publicly available microarray dataset, as based upon an efficient experimental design, to demonstrate a proper mixed model analysis of a typical unbalanced factorial design characterized by incomplete blocks and hierarchical levels of variability.


Conformational sampling enhancement of replica exchange molecular dynamics simulations using swarm particle intelligence.
In this paper, we present a new method based on swarm particle social intelligence for use in replica exchange molecular dynamics simulations. In this method, the replicas (representing the different system configurations) are allowed communicating with each other through the individual and social knowledge, in additional to considering them as a collection of real particles interacting through the Newtonian forces. The new method is based on the modification of the equations of motion in such way that the replicas are driven towards the global energy minimum. The method was tested for the Lennard-Jones clusters of N = 4, 5, and 6 atoms. Our results showed that the new method is more efficient than the conventional replica exchange method under the same practical conditions. In particular, the new method performed better on optimizing the distribution of the replicas among the thermostats with time and, in addition, ergodic convergence is observed to be faster. We also introduce a weighted histogram analysis method allowing analyzing the data from simulations by combining data from all of the replicas and rigorously removing the inserted bias.


[The "war neurosis"-- an early model of a pluridimensional outlined trauma-theory in psychiatry].
The war neurosis, mainly observed during the first World War, caused a lively debate on its origin and etiology. In psychiatric history this debate is often portrayed in a somewhat simplifying manner. Namely Oppenheim was considered as the leading exponent of the organic etiology of traumatic neurosis, while others, with growing interest in psychodynamic theories, were thought to favor exclusively psychogenesis of this condition. However, only discussing matters in this way would be too simple. Rather, the controversy was much more differentiated and led to important insights: First, it turned out to be impossible to explain any psychopathological syndrome exclusively in terms of neuropathological, i. e. structural alterations, in particular, a syndrome presenting with a sudden onset of dissociative and conversion symptoms. Secondly, the psychiatric theory of hysteria of Charcot and Freud was developed and extended further. And, last, the etiology of war neurosis was recognized to be multifactorial. Thus, the discourse on this issue was not one-dimensional and favoring a single explanation for a complex disorder, but revealed "pluridimensional" features. Subsequently psychotherapy, for the first time, was widely introduced into clinical practice with a clear indication and well-defined methodological approach. In summary, war neuroses can be addressed as an early model of traumatic stress disorder, such as acute stress disorder or post-traumatic stress disorder.


The Goldilocks Principle in Phase Labeling. Minimalist and Orthogonal Phase Tagging for Chromatography-Free Mitsunobu Reaction.
An inexpensive and chromatography-free Mitsunobu methodology has been developed using low molecular weight and orthogonally phase-tagged reagents, a tert-butyl-tagged highly apolar phosphine, and a water-soluble DIAD analogue. The byproduct of the Mitsunobu reactions can be removed by sequential liquid-liquid extractions using traditional solvents such as hexanes, MeOH, water, and EtOAc. Owing to the orthogonal phase labeling, the spent reagents can be regenerated. This new variant of the Mitsunobu reaction promises to provide an alternative and complementary solution for the well-known separation problem of the Mitsunobu reaction without having to resort to expensive, large molecular weight reagents and chromatography.


Late recurrence of adenoid cystic carcinoma of the prostate.
A 44-year-old patient underwent radical prostatectomy and adjuvant radiotherapy for adenoid cystic carcinoma of the prostate. After 7 years and 3 months he recurred locally and was treated with external beam irradiation. The current follow up comprises 9 years and 5 months at which the patient is asymptomatic with stable disease. Lymph node or distant metastases did never occur and the prostate specific antigen level was always within the normal range.


Prevalence and factors associated with sarcopenia in patients with rheumatoid arthritis.
Objectives: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients. Methods: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses. Results: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker's stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia. Conclusion: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.


Pharmacotherapy for patellofemoral pain syndrome.
Patellofemoral pain syndrome (PFPS) is common among adolescents and young adults. It is characterised by pain behind or around the patella and crepitations, provoked by ascending or descending stairs, squatting, prolonged sitting with flexed knees, running and cycling. The symptoms impede function in daily activities or sports. Pharmacological treatments focus on reducing pain symptoms (non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids), or restoring the assumed underlying pathology (compounds containing glucosamine to stimulate cartilage metabolism, anabolic steroids to increase bone density of the patella and build up supporting muscles). In studies, drugs are usually applied in addition to exercises aimed at building up supporting musculature. This review aims to summarise the evidence of effectiveness of pharmacotherapy in reducing anterior knee pain and improving knee function in people with PFPS. We searched the Cochrane Musculoskeletal Injuries Group and Cochrane Rehabilitation and Related Therapies Field trials registers, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2003), PEDro (up to January 2004), MEDLINE (1966 to January 2004), EMBASE (1988 to January 2004), and CINAHL (1982 to January 2004). Controlled trials (randomised or not) comparing pharmacotherapy with placebo, different types of pharmacotherapy, or pharmacotherapy to other therapies for people with PFPS. The literature search yielded 780 publications. Eight trials were included, of which three were of high quality. Data were analysed qualitatively using best evidence synthesis, because meta-analysis was impeded by differences in route of administration of drugs, care programs and outcome measures. Four trials (163 participants) studied the effect of NSAIDs. Aspirin compared to placebo in a high quality trial produced no significant differences in clinical symptoms and signs. Naproxen produced significant short term pain reduction when compared to placebo, but not when compared to diflunisal. Laser therapy to stimulate blood flow in tender areas led to more satisfied participants than tenoxicam, though not significantly. Two high quality RCTs (84 participants) studied the effect of glycosaminoglycan polysulphate (GAGPS). Twelve intramuscular injections in six weeks led to significantly more participants with a good overall therapeutic effect after one year, and to significantly better pain reduction during one of two activities. Five weekly intra-articular injections of GAGPS and lidocaine were compared with intra-articular injections of saline and lidocaine or no injections, all with concurrent quadriceps training. Injected participants showed better function after six weeks, though only the difference between GAGPS injected participants and non-injected participants was significant. The differences had disappeared after one year. One trial (43 participants) found that intramuscular injections of the anabolic steroid nandrolone phenylpropionate significantly improved both pain and function compared to placebo injections. There is only limited evidence for the effectiveness of NSAIDs for short term pain reduction in PFPS. The evidence for the effect of glycosaminoglycan polysulphate is conflicting and merits further investigation. The anabolic steroid nandrolone may be effective, but is too controversial for treatment of PFPS.


Renal tubular dysfunction in schizophrenic patients treated with antipsychotic drugs.
Several factors have been considered in relation to the free radical formation in schizophrenia, such as the disease itself, drug treatment and smoking. Several chemicals and drugs may cause damage to the renal tubules by different subcellular mechanisms including oxidative stress, and the aim of our study was the investigation of tubular dysfunction in schizophrenic patients. The urinary excretion of beta-N-acetylhexosaminidase (Hex) and its isoenzymes Hex A and Hex B, alpha1-microglobulin, albumin, total proteins and fractionated porphyrins were determined in 45 schizophrenic patients treated with first- and second-generation antipsychotics. In 7 patients, an increase in proteinuria of tubular origin was found, and in one as a result of mixed glomerular/tubular origin. The group of patients had a significantly higher level of excretion than the control group (n = 54) of total Hex (p < 0.001), Hex A (p < 0.05), Hex B (p < 0.001) and the relative proportion of this isoenzyme (p < 0.001). In some cases with normal levels of total Hex and urinary alpha1-microglobulin, the proportion of Hex B was already increased. Significant correlations were found for total Hex and its isoenzymes with alpha1-microglobulin (p < 0.001). Also, the porphyrins had significant correlations with total Hex (p < 0.001), Hex A (p < 0.05), Hex B (p < 0.005) and alpha1-microglobulin (p < 0.001). In the group of patients studied, it was possible to reveal early tubular cell damage (affected structural integrity) with increased excretion of Hex B, possibly mediated by free radicals, previous to the decrease in tubular reabsorption of proteins with low molecular mass filtered by the glomerulus (affected functional integrity).


Synthesis and biological activity of 1beta-methyl-2-[5-(2-N-substituted aminoethylcarbamoyl)pyrrolidin-3-ylthio]carbapenem derivatives.
The synthesis of a new series of 1beta-methylcarbapenems having the substituted aminoethylcarbamoylpyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. In particular, the compound 11g having piperazinyl urea moiety showed the most potent antibacterial activity and 11k exhibited excellent anti-MRSA.


Thematic workshop on fluorescence compensation settings in multicolor flow cytometry.
In his program of thematic one-day workshops, the French Association of Cytometry had organized a workshop dedicated to the fluorescence compensation settings in multicolor flow cytometry. This special day was in honor of our past President Jean Luc D'Hautcourt who has been involved in the quality of the use of flow cytometry in its clinical and research purposes. Review on fluorescence phenomena, compensation rules, settings, and few observed confounding situations were presented.


Staphylococcus aureus bacteremia with a mediastinal abscess in a 9-month-old infant: a case report and literature review.
Non-traumatic mediastinal abscesses are very rare in children; we can classify them into 2 types: descending mediastinitis (or mediastinitis by extension or by contiguity) complicating an otorhinolaryngological or esophageal etiology and mediastinitis generated by direct blood inoculation in a context of a septicemia or primary mediastinitis which is exceptional. We describe a case of right pleuropulmonary staphylococcal disease with bilateral mediastinal localization in a previously healthy 9-month-old infant. It was revealed by sepsis with severe respiratory distress. The germ was isolated from the pleural puncture fluid. A thoracic computed tomography was indicated due to a widening mediastinum noted on chest X-ray in addition to pleuropulmonary involvement. Thoracic computed tomography revealed a huge bilateral mediastinal abscess which was curbed thanks to right pleural drainage with adapted antibiotic therapy. Other investigations did not show any immune abnormalities in this infant. Mediastinitis represents a diagnostic and therapeutic emergency; those that are secondary to direct blood or lymphatic dissemination even very rare; should be considered in any context of severe sepsis including staphylococcus or streptococcus pneumonia. Since 1985 only 11 cases of such mediastinal abscesses have been reported.


Stromule geometry allows optimal spatial regulation of organelle interactions in the quasi-2D cytoplasm.
In plant cells, plastids form elongated extensions called stromules, the regulation and purposes of which remain unclear. Here, we quantitatively explore how different stromule structures serve to enhance the ability of a plastid to interact with other organelles: increasing the effective space for interaction and biomolecular exchange between organelles. Interestingly, electron microscopy and confocal imaging showed that the cytoplasm in Arabidopsis thaliana and Nicotiana benthamiana epidermal cells is extremely thin (around 100 nm in regions without organelles), meaning that inter-organelle interactions effectively take place in 2D. We combine these imaging modalities with mathematical modelling and new in planta experiments to demonstrate how different stromule varieties (single or multiple, linear or branching) could be employed to optimise different aspects of inter-organelle interaction capacity in this 2D space. We found that stromule formation and branching provide a proportionally higher benefit to interaction capacity in 2D than in 3D. Additionally, this benefit depends on optimal plastid spacing. We hypothesize that cells can promote the formation of different stromule architectures in the quasi-2D cytoplasm to optimise their interaction interface to meet specific requirements. These results provide new insight into the mechanisms underlying the transition from low to high stromule numbers, the consequences for interaction with smaller organelles, how plastid access and plastid to nucleus signaling are balanced, as well as the impact of plastid density on organelle interaction.


Cardiovascular response to physical stress in offspring of hypertensive parents: Dutch Hypertension and Offspring Study.
Blood pressure (BP) regulatory mechanisms were studied in youngsters with contrasting risks for hypertension, based on parental history, during physical stress. As a static exercise, an isometric handgrip task (22% of maximal force during 5 min) was used and a dynamic exercise task was performed on a bicycle ergometer. At rest and during stress, BP and heart rate were recorded. In order to study the adaptation of the cardiovascular system to physical stress, cardiac output and total peripheral resistance were measured in addition to indices of vagal and sympathetic influences on the heart. Heart rate and cardiac output declined significantly more in offspring of hypertensive parents during static exercise (difference in heart rate: -2.5 +/- 1.2 bpm, P = 0.04; difference in cardiac output: -9.0 +/- 4.6%, P = 0.05). This is most likely the result of a larger increase in the total peripheral resistance in youngsters at risk (difference: 13.2 +/- 6.8%, P = 0.06). No differences between the two groups were found in reactivity of BP or in the indices of sympathetic activation or vagal inhibition of the heart. The offspring of hypertensive parents showed an attenuated increase in stroke volume during the dynamic exercise task (difference at the first cycling level: -11.5 +/- 5.4%, P = 0.04), while no difference in neural activity or heart rate was found. Youngsters with a parental history of hypertension show an enhanced reactivity of total peripheral resistance during static exercise. This does not lead to a higher BP response in this group, most probably because of a larger decrease of the cardiac output. During dynamic exercise the physiological increase in stroke volume is blunted in offspring of hypertensive parents.


Temporal Dysregulation of the Angiopoietin-2/-1 Ratio After Trauma and Associations With Injury Characteristics and Outcomes.
Traumatic injury and hemorrhagic shock result in endothelial cell activation and vascular dysfunction that, if not corrected, can propagate multiorgan failure. Angiopoietin-1 and angiopoietin-2 are important regulators of endothelial cell function, and the ratio of plasma angiopoietin-2-to-1 is a useful indicator of overall vascular health. We therefore characterized plasma angiopoietin-2/-1 ratios over time after trauma in adults in an effort to gain insight into the pathophysiology that may drive post-traumatic vasculopathy and organ injury. We performed a single-center prospective observational study to measure plasma angiopoietin-1 and -2 levels and determine angiopoietin-2/-1 ratios in adult trauma patients upon hospital arrival and after 12, 24, and 48 h. Compared with levels in healthy adults, angiopoietin-1 levels were significantly elevated at hospital arrival, and angiopoietin-2 levels were significantly elevated at 12, 24, and 48 h. These kinetics translated in angiopoietin-2/-1 ratios that were significantly greater than controls at 24 and 48 h. After regression analysis, elevated angiopoietin-2 levels were independently associated with blunt injuries at admission, with coagulopathy at admission and 12 h, and with hemorrhagic shock at 24 and 48 h. Significant correlations were observed between both angiopoietins and 24-h transfusion requirements. Angiopoietin-2/-1 ratios correlated with mechanical ventilation duration and intensive care unit and hospital lengths of stay. In this study, we demonstrate novel temporal associations between angiopoietin dysregulation and blunt injuries, acute coagulopathy, and hemorrhagic shock. Moreover, our findings highlight the presence of endothelial activation following traumatic insults in adults that may contribute to worse clinical outcomes.


Chinese University English Teachers' Professional Learning through Academic Reading on Social Media-A Mixed-Methods Approach.
Teachers' professional learning on social media has received growing attention recently, but research into teachers' academic engagement on social media remains limited. This study aimed to examine what factors motivated university English teachers to engage with academic reading on social media. The determinants of academic reading on social media were identified by semi-structured interviews, which were further validated by quantitative investigation. The results showed that participants' perception of values of content knowledge, pedagogical content knowledge, and students' participation in the classroom affected their intentions toward commitment to academic reading on social media. Additionally, the results revealed that perceived value of pedagogical content knowledge mediated the relationship between perceived value of content knowledge and participants' intentions toward academic reading on social media while also mediating the relationship between perceived value of students' participation in the classroom and the participants' intentions toward academic reading on social media. These findings yield implications for the professional development of university teachers and the development of pedagogical content knowledge.


A novel low molecular weight hemorrhagic toxin from Trimeresurus flavoviridis (Vorojima) venom.
A low molecular weight hemorrhagic toxin, LMHT, was isolated from the venom of Trimeresurus flavoviridis from Yorojima using Q-Sepharose column chromatography. The purified hemorrhagic toxin was homogeneous by disc polyacrylamide gel electrophoresis at pH 8.3, and Ouchterlony immunodiffusion. LMHT has a molecular weight of 16,500 and possesses hemorrhagic activity. It did not show casein, azocasein, azoalbumin, or TAME (tosyl-L-arginine methyl ester hydrochloride) hydrolytic activities. Hemorrhagic activity was inhibited by EDTA, TEP (tetraethylenepentamine), p-APMSF(p-amidinophenylmethanesulfonylfluoride HCl), and N-bromosuccinimide. The minimum hemorrhagic dose of this hemorrhagic toxin was 7.1 microg/mouse. LMHT induced hydrolysis of the Aa and Bbeta chains of bovine fibrinogen.


The characterization of the Olf-1/EBF-like HLH transcription factor family: implications in olfactory gene regulation and neuronal development.
The Olf-1/EBF helix-loop-helix (HLH) transcription factor has been implicated in olfactory gene regulation and in B-cell development. Using homology screening methods, we identified two additional Olf-1/EBF-like cDNAs from a mouse embryonic cDNA library. The Olf-1/EBF-like (O/E) proteins O/E-1, O/E-2, and O/E-3 define a family of transcription factors that share structural similarities and biochemical activities. Although these O/E genes are expressed within olfactory epithelium in an identical pattern, they exhibit different patterns of expression in the developing nervous system. Although O/E-1 mRNA is present in several tissues in addition to olfactory neurons and developing B-cells, O/E-2 and O/E-3 are expressed at high levels only in olfactory tissue. In O/E-1 knock-out animals, the presence of two additional O/E family members in olfactory neurons may provide redundancy and allow normal olfactory neurodevelopment. Further, the identification of the O/E family of HLH transcription factors and their embryonic expression patterns suggest that the O/E proteins may have a more general function in neuronal development.


Anthocyanins from flowers of Cichorium intybus.
From the blue perianth segments of Cichorium intybus we isolated four anthocyanins. The pigments were identified as delphinidin 3,5-di-O-(6-O-malonyl-beta-D-glucoside) and delphinidin 3-O-(6-O-malonyl-beta-D-glucoside)-5-O-beta-D-glucoside and the known compounds were delphinidin 3-O-beta-D-glucoside-5-O-(6-O-malonyl-beta-D-glucoside) and delphinidin 3,5-di-O-beta-D-glucoside. In addition 3-O-p-coumaroyl quinic acid has been identified.


[The prevention of drug substances abuse among schoolchildren].
The drug abuse is one of the most important medical and social problems of the youth. The problems with illegal and dangerous using of psychoactive drugs of different chemical categories by schoolchildren are caused by common social and psychological risk factors. Thus, in many research studies, all drugs and solvent substances are covered by general concept of "narcotic substances". The study purpose is to develop an evidence database related to efficiency of common prevention measures and to development of sound recommendations of its management. The study included sociological survey of representative sampling of 445 schoolchildren aged from 14 to 17 years. The relationship between participation in preventive activities (factorial sign) and development of objective concepts about harm of drug abuse and possibilities of narcology (resulting sign) are studied using calculation of relative risk and its confidence interval. The study proves the positive effect of lecturing of specialists, psychological lessons and trainings, review of thematic video materials. The involvement of schoolchildren into development of agitation materials concerning healthy life-style and into reading of special literature is considered as effective in case of their implementation after target group received initial knowledge about problems of drug abuse and toxicomania. The study proved the negative effect of independent search of information about drugs in Internet, fabrication agitation materials about harm of drugs by adolescents, discussions based on opposite opinions and all forms of communication with patients with drug addiction. The necessity of widespread implementation of target advanced training of managers of preventive measures application.