Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system.
To increase hepatoselectivity of HMG-CoA reductase inhibitors by using the specific bile acid transport systems, deoxycholic acid-derived inhibitors 9 and 11 have been synthesized, on the basis of the concept of combining in one molecule structural requirements for specific inhibition of the HMG-CoA reductase and specific recognition by the ileal bile acid transport system. The 1-methyl-3-carboxylpropyl subunit of deoxycholic acid was replaced by the 3,5-dihydroxyheptanoic acid lactone of lovastatin, and position 12-OH was esterified with 2-methylbutyric acid. Compounds 9 and 11 were evaluated for their inhibitory activity on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 cells, and [3H]taurocholate uptake in rabbit brush border membrane vesicles and compared with methyl derivatives 8 and 10. The steroidal 21-CH3 group affects both activity on HMG-CoA reductase and recognition by the ileal bile acid transport system.


Genome-Wide Analysis Characterization and Evolution of SBP Genes in Fragaria vesca, Pyrus bretschneideri, Prunus persica and Prunus mume.
The SQUAMOSA promoter binding protein (SBP)-box proteins are plant-specific transcriptional factors in plants. SBP TFs are known to play important functions in a diverse development process and also related in the process of evolutionary novelties. SBP gene family has been characterized in several plant species, but little is known about molecular evolution, functional divergence and comprehensive study of SBP gene family in Rosacea. We carried out genome-wide investigations and identified 14, 32, 17, and 17 SBP genes from four Rosacea species (Fragaria vesca, Pyrus bretschneideri, Prunus persica and Prunus mume, respectively). According to phylogenetic analysis arranged the SBP protein sequences in seven groups. Localization of SBP genes presented an uneven distribution on corresponding chromosomes of Rosacea species. Our analyses designated that the SBP genes duplication events (segmental and tandem) and divergence. In addition, due to highly conserved structure pattern of SBP genes, recommended that highly conserved region of microsyneteny in the Rosacea species. Type I and II functional divergence was detected among various amino acids in SBP proteins, while there was no positive selection according to substitutional model analysis using PMAL software. These results recommended that the purifying selection might be leading force during the evolution process and dominate conservation of SBP genes in Rosacea species according to environmental selection pressure analysis. Our results will provide basic understanding and foundation for future research insights on the evolution of the SBP genes in Rosacea.


Transcriptome analysis of Arabidopsis colonized by a plant-growth promoting rhizobacterium reveals a general effect on disease resistance.
RNA transcript levels of Arabidopsis plants, infected by the rhizobacterium Pseudomonas thivervalensis (strain MLG45), and axenic control plants were compared using cDNA microarrays representing approximately 14 300 genes. The analysis revealed an increase of defence-related transcripts in the shoots of bacterized plants relative to control (axenic) plants. These modifications of transcript levels were confirmed by physiological experiments. Plants infected with P. thivervalensis were more resistant to subsequent infections by the virulent pathogen P. syringae pv. tomato (strain DC3000) than control plants. In addition, photosynthesis rates were repressed consistently with the reduced growth of plants colonized by P. thivervalensis. These results highlight the value of molecular phenotyping to predict physiological changes.


Isolation of Shiga toxin-resistant Vero cells and their use for easy identification of the toxin.
Shiga toxin-resistant Vero cells were isolated by treatment of the cells with nitrosoguanidine. These mutant cells were not affected by Shiga toxin at more than 1 microgram/ml, although the parent Vero cells were sensitive to 25 pg of the toxin per ml. Immunofluorescence studies showed that all the mutant cells had lost toxin-binding capacity. The cytotoxic activities of various bacterial cultures against the parent and mutant cells were compared. All samples from 10 strains of Shigella dysenteriae type 1 and all three strains of Escherichia coli O157:H7 tested showed cytotoxicity to the parent cells but not to the mutant cells. Samples from other organisms, such as Shigella flexneri, Shigella sonnei, Clostridium difficile, Aeromonas hydrophila, Aeromonas sobria, and other E. coli strains, either had no effect or were cytotoxic on both the parent and mutant cells. Thus, these mutant cells could be used to identify Shiga-like toxin and distinguish it from other cytotoxins. The results also suggest the presence of a receptor for Shiga-like toxin on Vero cells that is essential for expression of the cytotoxicity of Shiga toxin but is not essential for growth of Vero cells.


Progression of chronic kidney disease in children - role of glomerular hemodynamics and interstitial fibrosis.
The aim of this review is to provide an overview of the current advances in the understanding of the mechanisms involved in the progression of chronic kidney disease (CKD) with emphasis on the role of glomerular hemodynamics and tubulointerstitial fibrosis. Despite the varied causes of CKD, the progressive destruction of renal tissue processes through a complex common pathway. Current studies have highlighted both the role of the abnormal intrarenal hemodynamics and of the activation of fibrogenic biochemical pathway in the replacement of normal renal structure by extracellular matrix and ultimately by fibrosis. Molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney has been identified. There is a clear need to understand and elucidate the mechanisms of progression of CKD to develop efficient therapeutic strategies to halt decline of renal function in children.


Developing a State University System Model to Diversify Faculty in the Biomedical Sciences.
Amid increasing demands from students and the public, universities have recently reinvigorated their efforts to increase the number of faculty from underrepresented populations. Although a myriad of piecemeal programs targeting individual recruitment and development have been piloted at several institutions, overall growth in faculty diversity remains almost negligible and highly localized. To bring about genuine change, we hypothesize a consortia approach that links individuals to hiring opportunities within a state university system might be more effective. Here we present a case study describing the progress of the NSF-funded Alliances for Graduate Education and the Professoriate (AGEP) PROMISE Academy Alliance, a consortium within the University System of Maryland (USM) collaborating to develop, implement, self-study, evaluate, and disseminate a unique postdoc-to-faculty conversion model in the biomedical sciences. The initiative centers on diversifying faculty across five institutions in the USM, including teaching-focused institutions, comprehensive universities, research institutions, and professional schools. Components of this approach include (1) enhanced recruiting and hiring practices to attract outstanding postdoctoral scholars from underrepresented backgrounds, (2) multi-institutional networking and professional development, and (3) facilitated processes to transition (or "convert") postdocs into tenure-track positions at their postdoctoral institution or another institution in the state system. This model is distinct from more deficit-based approaches because it goes beyond focusing on building the individual's skills to enter the professoriate. This program restructures the traditionally short-term nature of postdoctoral employment and incorporates a pathway to a tenure-track professorship at the same institution or within the same statewide system where the postdoc is trained. This multi-institutional model leverages collaboration and distinct institutional strengths to create cross-institutional support, advocacy, and policy. Importantly, it uses a decentralized financial structure that makes this approach distinctly replicable. Recognizing the immediate need for more collaborative approaches to diversify faculty and a lack of literature about such approaches, this case study describes the development of, and potential benefits of, a state university system, as well as the qualitative lessons learned from self-study, internal evaluation, external evaluation, and NSF site visits. The AGEP PROMISE Academy can serve as a model for replication at other university systems hoping to diversify their faculty.


Human papillomavirus and circumcision: a meta-analysis.
Determine the relationship of circumcision status to the risk for genital infection with human papillomavirus (HPV). A MEDLINE search and a review of references in published articles were used to identify publications from peer-reviewed journals in Index Medicus with data on circumcision status in patients with and without HPV infections. Inclusion criteria included diagnosis by culture, biopsy, or PCR, determination of circumcision status by physical examination, and multiple site sampling including the shaft of the penis. A meta-analysis was performed with sensitivity analyses. Sixteen articles contained data on circumcision status in patients with and without HPV infections. Eight studies used accurate diagnostic methods. Only three articles satisfied the strict inclusion criteria. There was no significant association between circumcision status and HPV infection (random-effects model summary effect OR=1.20, 95%CI=0.80-1.79) in these three studies. If the eight studies using accurate diagnostic methods are adjusted for the method of determining circumcision status and failure to sample the penile shaft using meta-regression the summary effects odds ratio is 1.25 (95%CI=0.95-1.67). The medical literature does not support the claim that circumcision reduces the risk for genital HPV infection. To correctly assess the risk of HPV infection in circumcised males, the penile shaft needs to be sampled for HPV infection.


Impact of p73 gene polymorphism on cancer susceptibility: a meta analysis.
Previous studies examining the association between p73 G4A and gastric cancer risk have produced inconsistent results. The objective of this study was to clarify whether p73 G4A plays a major role in the development of gastric cancer. Studies that had examined the association between p73 G4A and gastric cancer risk were identified through PubMed, Science Direct, and CNKI. We selected eligible studies based on inclusion criteria. Odds ratios were estimated using distinct genetic models, and the heterogeneity between studies was explored using Cochran's Q statistic along with the I(2) statistic. Overall, we found no evidence of a significant association between p73 G4A and risk of gastric cancer. A same trend was also indicated in subgroup analysis by ethnicity. The heterogeneity tests revealed that there was no significant heterogeneity across studies. Our meta-analysis indicates that p73 G4A might not have a major effect on risk of gastric cancer. A much larger study is required to validate our findings.


Alternative splicing and its regulatory role in woody plants.
Alternative splicing (AS) is an important post-transcriptional process to enhance proteome diversity in eukaryotic organisms. In plants, numerous reports have primarily focused on AS analysis in model plant species or herbaceous plants, leading to a notable lack of research on AS in woody plants. More importantly, emerging evidence indicates that many important traits, including wood formation and stress resistance, in woody plants are controlled by AS. In this review article, we summarize the current progress of all kinds of AS studies in different tree species at various stages of development and in response to various stresses, revealing the significant role played by AS in woody plants, as well as the similar properties and differential regulation within their herbaceous counterparts. Furthermore, we propose several potential strategies to facilitate the functional characterization of splicing factors in woody plants and evaluate a general pipeline for the systematic characterization of splicing isoforms in a complex AS regulatory network. The utilization of genetic studies and high-throughput omics integration approaches to analyze AS genes and splicing factors is likely to further advance our understanding of AS modulation in woody plants.


Utility of Central 10 Degrees Visual Field Test with Size V Stimulus in End-stage Glaucoma.
In end-stage glaucoma, the central 10 degrees visual field test with a size V stimulus provided useful information, including the number of points with detectable retinal sensitivity threshold values and retinal sensitivity threshold values. To evaluate the clinical utility of the central 10 degrees visual field test with a size V stimulus in end-stage glaucoma. A total of 73 eyes with end-stage glaucoma (visual field limited to a radius of less than 10 degrees from fixation) were included. Central 10 degrees visual field tests were performed using both size III and V stimuli. Reliability indices, test duration, number of points with detectable retinal sensitivity threshold values, and retinal sensitivity threshold values at four central points, four quadrants, and three clusters (papillomacular area, superior half, and inferior half) were compared between the test results using size III and V stimuli. When the size V stimulus was used, the mean test duration increased from 7.8 to 13.3 minutes (P < 0.001), the mean number of test points with detectable retinal sensitivity threshold values in total area increased from 19.0 to 37.3 (P < 0.001), and the mean retinal sensitivity threshold values in total area increased from 3.9 to 9.3 dB (P < 0.001) compared with the test results with the size III stimulus. Significant increase in the visual field parameters was found in all quadrants and clusters (P < 0.001) and a greater increase was associated with better visual acuity and greater mean deviation of the visual field (P < 0.05). The central 10 degrees visual field test with a size V stimulus provided more information than the test with a size III stimulus in end-stage glaucoma.


Melatonin, advanced oxidation protein products and total antioxidant capacity as seminal parameters of prooxidant-antioxidant balance and their connection with expression of metalloproteinases in context of male fertility.
Currently, in highly developed, industrialized countries male factors are identified as the primary cause of infertility in about 60% of childless couples. Standard semen analysis parameters, such as sperm morphology, number and motility, are important in predicting the fertility of large populations, but they are not sufficient to fully specify a particular donor sperm's ability to fertilize the egg. The semen also comprises components, which may also affect sperm fertilizing ability and which have thus far remained little explored: the biochemical parameters of the seminal plasma secreted by the testis, the seminiferous tubules and the prostate gland, such as: matrix metalloproteinases (MMP-2 and MMP-9) and their specific tissue inhibitors (TIMP-1 and TIMP-2). We highlight the need for a better determination of prooxidant-antioxidant balance parameters such as: melatonin, advanced oxidation protein products (AOPPs) and total antioxidant capacity (TAC) in human semen when establishing the diagnostics of male subfertility or infertility. We also discuss their connection with seminal plasma metalloproteinases and their inhibitors. In particular, we believe that the cumulative and synergic effects of the sperm redox parameters on male fertility need to be better explored and we suggest that they should be studied in conjunction with other biologically active parameters of the ejaculate such as the expression of metalloproteinases and their tissue inhibitors. This will enable a better understanding of how their correlated effects impact semen condition.


Elevated levels of fetal hemoglobin synthesis in infants with bronchopulmonary dysplasia.
A study was devised to determine whether levels of fetal hemoglobin (HbF) synthesis are elevated in infants with bronchopulmonary dysplasia (BPD) when compared with the levels of HbF synthesis found in normal control infants. Twelve infants with BPD, whose postconceptional ages ranged from 40 to 62 weeks, were studied. The mean (+/- SD) gestational age and birth weight was 29 +/- 1.9 weeks and 1289 +/- 376 g, respectively. Elevation infants matched for birth weight, gestational age, and postnatal age served as the control subjects. Blood samples were incubated in an amino acid mixture containing [14C]leucine. The adult hemoglobin and HbF were then separated by column chromatography on diethylaminoethyl-Sephadex. The results demonstrated that the mean (+/- SD) level of HbF synthesis in infants with BPD was significantly higher than that in the control infants (42.6 +/- 22.9% vs 18.8 +/- 12.8%; P less than .01). When levels of HbF synthesis in the infants with BPD and the control infants were compared with data previously reported in normal infants, 7 of the 12 infants with BPD, but none of the control infants, were synthesizing amounts of HbF greater than would be expected for their postconceptional age. The results suggest that cardiopulmonary insufficiency could stimulate HbF synthesis during the first year of life as a result of an erythropoietic response to hypoxemia.


Atypical Chondroid Syringoma of the Toe.
Although chondroid syringoma rarely occurs outside the head and neck, the majority of malignant chondroid syringomas are identified in the extremities. Here, we present a case of atypical chondroid syringoma in the fifth toe. Diagnosis of chondroid syringoma with atypical cells was made following initial excisional biopsy and histology, necessitating repeated surgery for positive margins. In this case report, we examine the radiopathologic correlation of this diagnosis, detail the imaging findings of benign and malignant chondroid syringomas, and highlight how magnetic resonance imaging can be used to guide surgical planning and treatment course of this potentially malignant tumor.


Adaptive Immune Responses during Salmonella Infection.
The interaction betweenSalmonella and its host is complex and dynamic: the host mounts an immune defense against the pathogen, which in turn acts to reduce, evade, or exploit these responses to successfully colonize the host. Although the exact mechanisms mediating protective immunity are poorly understood, it is known that T cells are a critical component of immunity to Salmonella infection, and a robust T-cell response is required for both clearance of primary infection and resistance to subsequent challenge. B-cell functions, including but not limited to antibody production, are also required for generation of protective immunity. Additionally, interactions among host cells are essential. For example, antigen-presenting cells (including B cells) express cytokines that participate in CD4+ T cell activation and differentiation. Differentiated CD4+ T cells secrete cytokines that have both autocrine and paracrine functions, including recruitment and activation of phagocytes, and stimulation of B cell isotype class switching and affinity maturation. Multiple bacterium-directed mechanisms, including altered antigen expression and bioavailability and interference with antigen-presenting cell activation and function, combine to modify Salmonella's "pathogenic signature" in order to minimize its susceptibility to host immune surveillance. Therefore, a more complete understanding of adaptive immune responses may provide insights into pathogenic bacterial functions. Continued identification of adaptive immune targets will guide rational vaccine development, provide insights into host functions required to resist Salmonella infection, and correspondingly provide valuable reagents for defining the critical pathogenic capabilities of Salmonella that contribute to their success in causing acute and chronic infections.


MMPI indices of childhood trauma among 110 female outpatients.
This study investigated MMPI characteristics of adult female outpatients in a behavior therapy clinic (N = 110). Those reporting histories of childhood sexual or physical abuse or both differed from those who did not on global Minnesota Multiphasic Personality Inventory (MMPI; Hathaway & McKinley, 1943) indices of psychopathology and on Scales F, K, L, 4, 7, and 8. Subjects reporting abuse also reported high rates of other early traumas: witnessing family violence, parental alcohol abuse, and parental divorce. Physical abuse history was the best predictor of adult maladjustment as assessed by the MMPI. Findings suggest the potential utility of the MMPI for assessing long-range trauma effects and highlight the importance of considering multiple early-risk factors for the development of psychological disturbance.


[Analysis of the clinical state and disease course in patients with acute stroke and reversed blood flow in the ophthalmic artery].
Fifty-four patients with acute stroke and reversed flow in the ophthalmic artery were analysed. Fifty-three had ischaemic stroke and one had subarachnoid haemorrhage. Reversed blood flow in the ophthalmic artery in stroke was more frequent in men (76%) and the mean age of men was significantly lower that of women--59.5 and 64.8 years respectively. In the acute phase of stroke (30 days) no patient died, and most (61.1%) improvement.


The loss of antibody productivity in continuous culture of hybridoma cells.
Two hybridoma lines, HB8178 and AFP-27, were grown in continuous culture. The concentrations of viable cells as well as those of various nutrients and metabolites reached steady-state values. The concentrations of either total IgG or antigen-specific antibody, however, failed to reach steady-state values but rather continuously decreased over the course of the cultures. The fraction of antibody-producing cells in the total cellular population also continuously decreased in the AFP-27 cultures. Comparison of the specific antibody productivity based on either the entire population or the antibody-producing fraction of the population over time suggests that the decrease in productivity was at least partly due to the occurrence of a nonproducing subpopulation of cells.


Bronchoscopy of symptom free patients infected with human immunodeficiency virus for detection of pneumocystosis.
No evidence of Pneumocystis carinii infection was found in eight symptom free patients who were positive for the human immunodeficiency virus and who underwent bronchoscopy, bronchoalveolar lavage, and brush biopsy. This suggests that the presence of Pneumocystis carinii in bronchoscopy material is likely to indicate pneumocystis infection.


In vivo quantitation using SPECT of radiopharmaceutical uptake by human meningiomas.
A single photon emission computed tomographic method was designed for the measurement of radiopharmaceutical uptake in brain tumors. Results of phantom studies showed a correlation coefficient of .99 when measured volume was compared with actual volume. The correlation coefficient for measured radioactivity concentration compared with the actual concentration was .97. In 13 meningiomas the correlation between in vivo SPECT measurements of uptake and in vitro measurements in samples of the same tumors removed surgically was .84; when two tumors that contained regions of necrosis and fibrosis were excluded it was .93. This method can be used for in vivo quantitative assessment of pharmacokinetics of labeled drug uptake in human brain tumors.


A chemical screen identifies novel compounds that overcome glial-mediated inhibition of neuronal regeneration.
A major barrier to regeneration of CNS axons is the presence of growth-inhibitory proteins associated with myelin and the glial scar. To identify chemical compounds with the ability to overcome the inhibition of regeneration, we screened a novel triazine library, based on the ability of compounds to increase neurite outgrowth from cerebellar neurons on inhibitory myelin substrates. The screen produced four "hit compounds," which act with nanomolar potency on several different neuronal types and on several distinct substrates relevant to glial inhibition. Moreover, the compounds selectively overcome inhibition rather than promote growth in general. The compounds do not affect neuronal cAMP levels, PKC activity, or EGFR (epidermal growth factor receptor) activation. Interestingly, one of the compounds alters microtubule dynamics and increases microtubule density in both fibroblasts and neurons. This same compound promotes regeneration of dorsal column axons after acute lesions and potentiates regeneration of optic nerve axons after nerve crush in vivo. These compounds should provide insight into the mechanisms through which glial-derived inhibitors of regeneration act, and could lead to the development of novel therapies for CNS injury.


Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies.
Genome-wide association (GWA) studies identified novel gene variants that are associated with type 2 diabetes. However, results were not always consistent across different populations. Thus, the aims of this study were (i) to replicate findings from previous GWA studies in mainly Northern European populations using data from the German KORA 500 K diabetes project and (ii) to assess the impact of BMI on associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. The KORA 500 K diabetes project includes 433 cases with validated type 2 diabetes and 1 438 nondiabetic controls from two population-based KORA surveys. Genotyping was performed using the Affymetrix GeneChip Human Mapping 500 K Array Set. We investigated associations between SNPs and type 2 diabetes in 10 genes that have been reported to increase the risk of type 2 diabetes or were in complete or near-complete linkage disequilibrium with these variants. SNPs in the CDKAL1 gene showed the strongest association with type 2 diabetes [range of age and sex-adjusted odds ratios (OR): 1.30-1.39, p-values 0.0008-0.0004]. In addition, we found evidence for association of SNPs in the genes PPARG, IGF2BP2, HHEX, TCF7L2, and FTO with type 2 diabetes in the same directions as previously described (p<0.05), but not for WFS1, CDKN2A/B, KCNJ11, or EXT2. Adjustment for BMI slightly strengthened the link between CDKAL1 and type 2 diabetes, but had almost no impact on the other associations. We conclude that gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. These associations appear to be independent of BMI.


Differential expression and tissue compartmentalization of the inflammatory response following thermal injury.
Studies have shown that both animal tissue-fixed immune cells and human peripheral blood mononuclear cell (PBMC) functions are altered after burn injury. Additional studies suggest that the burn injury-induced alterations in these divergent cell populations from different species are similar. It remains unknown, however, whether the observed changes in animal tissue-fixed immune cell function following thermal injury also occurs to a similar extent in the PBMC population. The aim of our study was to compare PBMC and tissue-fixed immune cell functions from the same animal using a murine burn model. At 7 days post-burn, mice were more susceptible to sepsis and delayed type hypersensitivity responses were suppressed. Splenocytes isolated from injured mice displayed suppressed proliferation and increased IL-10 production. In contrast, PBMC from injured mice displayed suppressed proliferation, IL-2 and IFN-gamma production. Splenic macrophage nitric oxide, PGE(2), TNF-alpha, IL-6 and IL-10 production was enhanced post-burn and IL-12 production was suppressed. PBMC from such animals displayed enhanced PGE(2) production and suppressed IL-6 and IL-12 production. These results indicate that while an immunosuppressive Th(2) phenotype (increased IL-10 and/or suppressed IL-2, IFN-gamma) was induced in both the splenic and PBMC compartments post-injury, differential expression and dimorphism in the response also exists. Thus, the assessment of only PBMC function in burn patients may not accurately reflect the patient's actual immune status at the tissue level.


[Influence of tonsillectomy in adults on the concentration and glycosylation profile of acute phase proteins].
Chronic tonsillitis (ch.t.) in adults can have the effect on immunological system and its function. The aims of this study were: 1. the estimation of concentration and glycosylation of acute-phase serum protein (a.ph.s.p.)--C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), alpha 1-antichymotrypsin (ACT), transferrin (Tf) and the concentration of immunoglobulins (Ig) and alpha 2-macroglobulin (alpha 2-M) in adults with ch.t. 2. the influence of tonsillectomy on the concentration and glycosylation a.ph.s.p. in I week and 6-8 months after surgery and determination of normalization estimated parameters. 116 patients with ch.t. and 15 healthy persons were evaluated. In all patients with ch.t. the concentration of acute-phase serum protein, alpha 2-M and immunoglobulins were determined before, in I-II day, VII day and 6-8 months after surgery. In patients with ch.t. were observed the significantly higher the concentration of CRP, AGP, ACT, IgG and the significantly decreased the concentration of serum transferrin before tonsillectomy, as an effects of immunological response on chronic inflammation. Tonsillectomy induced further increases the concentration of a.ph.s.p. and the highest value attained the CRP level. The change of glycosylation of AGP and ACT were results of chronic inflammatory process and analysis the glycosylation of these proteins can be useful in the estimation of activity of inflammatory process. The normalization of the concentration of acute-phase serum protein were observed in 6-8 months after tonsillectomy and confirmed the withdrawal of inflammatory process.


Molybdenum intake influences molybdenum kinetics in men.
The objectives of this study were to determine physiologic adaptations that occur when humans are exposed to a wide range of molybdenum intake levels and to identify the pathways that are influenced by dietary intake. Four males consumed each of 5 daily molybdenum intakes of 22, 72, 121, 467, and 1490 microg/d (0.23, 0.75, 1.3, 4.9, and 15.5 micromol/d) for 24 d each. During each treatment period, oral and intravenous doses of (100)Mo and (97)Mo were administered. Serial plasma, urine, and fecal samples were analyzed for labeled and unlabeled molybdenum. Compartmental modeling was used to determine rates of distribution and elimination at each dietary intake level. Three pathways were sensitive to daily molybdenum intake. With increasing intake, absorption and urinary molybdenum excretion increased, whereas the fraction deposited in tissues decreased. Kinetic analysis suggested a daily intake of 115-120 microg/d (1.20-1.25 micromol/d) would maintain initial plasma molybdenum levels at their prestudy values and that their prestudy dietary intake was well above the Recommended Dietary Allowance of 45 microg/d. The physiological adaptations to changing intake that the model demonstrated may help prevent molybdenum deficiency and toxicity.


Structure, function, and regulation of vertebrate Na+/H+ exchangers.
The Na+/H+ exchangers are vital transmembrane transporters that participate in the regulation of intracellular pH and volume as well as transepithelial ion transport. Several isoforms of these antiporters belonging to the same gene family have been cloned, and they display tissue-specific expression. All these transporters are highly regulated via various stimuli, which can modulate their activity and expression level. Impairments in regulation of the antiporters may contribute to certain pathologic situations. Biochemical techniques and the tools of molecular genetics now provide the means to analyze the different aspects of these transporters at a molecular level.


Identification of novel methylated DNA marker ZNF569 for head and neck squamous cell carcinoma.
Aberrant DNA methylation pattern plays an indispensable role in the initiation and development of head and neck squamous cell carcinoma (HNSCC). It is well recognized that lymph node metastasis is closely with unfavorable prognosis of HNSCC. Therefore, exploring the methylation events accounting for the lymph node metastasis of HNSCC is very important for improving the clinical outcome of HNSCC. Methylation data, RNA-seq data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. MethylMix was use for data analysis by integrating both methylation and gene expression data on HNSCC patients with lymph node metastasis and without lymph node metastasis. Pathway analysis was performed on significantly altered genes using ConsensusPathDB. The role of our interested gene zinc figure protein 569 (ZNF569) in HNSCC was further evaluated. Our results identified many novel hypermethylated/hypomethylated genes that might be closely associated with the lymph node metastasis of HNSCC. Pathway analysis revealed that increase in methylation of genes involved in generic transcription pathway including zinc figure proteins. ZNF569 was hypermethylated in HNSCC tissues especially those with lymph node metastasis. In addition, the expression levels of ZNF569 mRNA and protein were significantly lower in HNSCC tissues and cell lines compared to their respective controls. Moreover, overexpression of ZNF569 inhibited the proliferation, migration and invasion of HNSCC cells. HNSCC patients with lower ZNF569 expression suffered a significantly shorter overall survival than those with higher ZNF569 expression. In conclusion, we have identified many novel differentially methylated genes that might be important for the lymph node metastasis of HNSCC. In addition, ZNF569 might play a tumor suppressive role in carcinogenesis of HNSCC.


The dTDP-4-dehydro-6-deoxyglucose reductase encoding fcd gene is part of the surface layer glycoprotein glycosylation gene cluster of Geobacillus tepidamans GS5-97T.
The glycan chain of the S-layer protein of Geobacillus tepidamans GS5-97(T) consists of disaccharide repeating units composed of L-rhamnose and D-fucose, the latter being a rare constituent of prokaryotic glycoconjugates. Although biosynthesis of nucleotide-activated L-rhamnose is well established, D-fucose biosynthesis is less investigated. The conversion of alpha-D-glucose-1-phosphate into thymidine diphosphate (dTDP)-4-dehydro-6-deoxyglucose by the sequential action of RmlA (glucose-1-phosphate thymidylyltransferase) and RmlB (dTDP-glucose-4,6-dehydratase) is shared between the dTDP-D-fucose and the dTDP-L-rhamnose biosynthesis pathway. This key intermediate is processed by the dTDP-4-dehydro-6-deoxyglucose reductase Fcd to form dTDP-alpha-D-fucose. We identified the fcd gene in G. tepidamans GS5-97(T) by chromosome walking and performed functional characterization of the recombinant 308-amino acid enzyme. The in vitro activity of the enzymatic cascade (RmlB and Fcd) was monitored by high-performance liquid chromatography and the reaction product was confirmed by (1)H and (13)C nuclear magnetic resonance spectroscopy. This is the first characterization of the dTDP-alpha-D-fucopyranose biosynthesis pathway in a Gram-positive organism. fcd was identified as 1 of 20 open reading frames contained in a 17471-bp S-layer glycosylation (slg) gene cluster on the chromosome of G. tepidamans GS5-97(T). The sgtA structural gene is located immediately upstream of the slg gene cluster with an intergenic region of 247 nucleotides. By comparison of the SgtA amino acid sequence with the known glycosylation pattern of the S-layer protein SgsE of Geobacillus stearothermophilus NRS 2004/3a, two out of the proposed three glycosylation sites on SgtA could be identified by electrospray ionization quadrupole-time-of-flight mass spectrometry to be at positions Ser-792 and Thr-583.


Laser control of collective spontaneous emission.
The collective spontaneous emission of a pair of two coupled three-level radiators in vacuum is investigated in the presence of a possibly intense laser field. The parameters describing the collective interaction along with the population and decay rates of all involved dressed states are shown to be controllable by the applied laser field. In particular, all populations of the collective system may be transferred at will in a reversible way into a subradiant state, allowing effective storage and manipulation of the quantum system.


[Contributions to the mechanism of the Witebsky-test (author's transl)].
The assumption that immune and normal alloantibodies of the ABO system could be distinguished by partial neutralization with soluble specific blood group substance (Witebsky test) has been reexamined. The following results were presented: 1. ABO alloantibodies in both normal and immune sera as well as their IgG and IgM preparations were inhibited by their homologous soluble specific blood group substances. 2. Anti-A and anti-B immune antibodies as well as normal antibodies of the IgG class were found to be strong hemagglutinins in a saline medium; therefore they have to be called "complete" hemagglutinins as have anti-A and anti-B antibodies of the class IgM too. 3. ABO alloantibodies in both IgG and IgM preparations were able to form precipitation pellets with their homologous soluble specific blood group substances. IgM revealed a stronger precipitation power as IgG. 4. Agglutination reaction in saline was inhibited by the 50-200-fold group substance concentration needed for a optimal precipitation reaction, whereas agglutination of enzyme treated erythrocytes or red cells tested with antiglobulin (Coombs) sera was inhibited by a 20,000-80,000-fold concentration of the blood group substances. 5. Soluble antigen-antibody complexes, prepared from solubilized precipitates or from Witebsky test mixtures using chromatography, ultracentrifuge or ultrafiltration for separation were able to agglutinate erythrocytes in the antiglobulin or papain test. Following conclusions were drawn: A. Soluble antigen-antibody complexes are the main component leading to a positive Witebsky test. B. The mechanism of the Witebsky test as it has to be assumed in respect to our findings do not allow the distinguish immune and normal alloantibodies resp. IgG and IgM alloagglutinins in the ABO system.


Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer.
With the surge in therapeutic options for men with castration-resistant prostate cancer (CRPC) comes increasingly complicated treatment decision making, highlighting the need for biomarkers that can identify appropriate patients for specific treatments and accurately assess disease response. Predictive biomarkers are factors related to the disease or the host that are associated with improvements in outcomes, such as survival, due to specific therapies. Such biomarkers have become of paramount importance in oncology to maximize the benefits of novel systemic agents while minimizing harm to individual patients and the costs to society. Given the number of newly approved and expensive systemic therapies, including novel hormonal therapies, chemotherapies, immunotherapies, and bone microenvironment-targeting therapies, predictive biomarkers are needed to give physicians a more rational sense of matching the right patient to the right therapy sequence at a given time. There are currently no validated predictive biomarkers in CRPC. We discuss potential predictive biomarkers in men with CRPC and how these may be developed in the context of therapeutic clinical trials.


The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder.
This study examined the persistence of attention-deficit/hyperactivity disorder (ADHD) into young adulthood using hyperactive (N = 147) and community control (N = 71) children evaluated at ages 19-25 years. ADHD was rare in both groups (5% vs. 0%) based on self-report but was substantially higher using parent reports (46% vs. 1.4%). Using a developmentally referenced criterion (+2 SD), prevalence remained low for self-reports (12% vs. 10%) but rose further for parent reports (66% vs. 8%). Parent reports were more strongly associated with major life activities than were self-reports. Recollections of childhood ADHD showed moderate correlations with actual parent ratings collected in childd hood, which suggests some validity for such recollections. The authors conclude that previous follow-up studies that relied on self-reports might have substantially underestimated the persistence of ADHD into adulthood.


Prevalence of Cochlear Nerve Deficiency and Hearing Device Use in Children With Single-Sided Deafness.
This study aimed to assess the prevalence of cochlear nerve deficiency (CND) in a cohort of pediatric patients with single-sided deafness (SSD). A secondary objective was to investigate trends in intervention and hearing device use in these children. Case series with chart review. Pediatric tertiary care center. Children ages 0 to 21 years with SSD (N = 190) who underwent computerized tomography (CT) and/or magnetic resonance imaging (MRI) were included. Diagnostic criteria for SSD included unilateral severe-to-profound sensorineural hearing loss with normal hearing sensitivity in the contralateral ear. Diagnostic criteria for CND included neuroradiologist report of an "aplastic or hypoplastic nerve" on MRI or a "stenotic cochlear aperture" on CT. The prevalence of CND was 42% for children with CT only, 76% for children with MRI only, and 63% for children with both MRI and CT. Of the children with MRI and CT, there was a 90% concordance across imaging modalities. About 36% of children with SSD had hearing devices that routed sound to the normal hearing ear (ie, bone conduction hearing device/contralateral routing of signal), while only 3% received a cochlear implant. Approximately 40% did not have a hearing device. Hearing device wear time averaged 2.9 hours per day and did not differ based on cochlear nerve status. There is a high prevalence of CND in children with SSD. Cochlear nerve status should be confirmed via MRI in children with SSD. The limited implementation and use of hearing devices observed for children with SSD reinforce the need for increased support for early and continuous intervention.


Immunological mechanisms in the maintenance of pregnancy.
Mmammalian pregnancy involves prolonged, intimate interactions between genetically dissimilar organisms. This dissimilarity evokes an immunological response in the gravida which promotes placental implantation and fetal viability. The nature of the immunological reactions, the factors moderating these responses and the signficance of abnormalities in the responses are discussed.


Changes in lymphocyte subsets, interleukin 2, and soluble interleukin 2 receptor in old and very old age.
In this study, the changes in some of the cellular components of the immune system and the activity of the cytokine interleukin 2, important for immune activation and lymphocyte proliferation, were measured in a large cross-sectional study of all age groups including octogenarian and nonagenarian subjects. In 206 apparently well community-living subjects, the absolute lymphocyte count and T and B cell numbers fell a little in old and very old subjects. Within the T cell compartment, helper/inducer CD4+ T cells, together with their subsets identified as 'naive' (CD4+/CD45RA+) and 'memory' (CD4+/CD45RO+) cells, also showed a decline with increased age. The suppressor/cytotoxic CD8+ subset showed no age-related change. The levels of the cytokine interleukin 2 were very low in octogenarian and nonagenarian subjects, while the soluble interleukin 2 receptor levels increased with increasing age. The interleukin 2 levels were associated with number and percentage of the 'memory' (CD4+/CD45RO+) subset of T cells which mediates the host response to previously met antigens. Since the interleukin 2 values were very low in the oldest groups and were associated with a reduced 'memory' (CD4+/CD45RO+) compartment, this suggests a possible mechanism of why the very elderly subject is more susceptible to morbidity and mortality from infectious or other agents.


Factors Determining Staphylococcus aureus Susceptibility to Photoantimicrobial Chemotherapy: RsbU Activity, Staphyloxanthin Level, and Membrane Fluidity.
Photoantimicrobial chemotherapy (PACT) constitutes a particular type of stress condition, in which bacterial cells induce a pleiotropic and as yet unexplored effect. In light of this, the key master regulators are of putative significance to the overall phototoxic outcome. In Staphylococcus aureus, the alternative sigma factor σ(B) controls the expression of genes involved in the response to environmental stress. We show that aberration of any sigB operon genes in S. aureus USA300 isogenic mutants causes a pronounced sensitization (>5 log10 reduction in CFU drop) to PACT with selected photosensitizers, namely protoporphyrin diarginate, zinc phthalocyanine and rose bengal. This effect is partly due to aberration-coupled staphyloxanthin synthesis inhibition. We identified frequent mutations in RsbU, a σ(B) activator, in PACT-vulnerable clinical isolates of S. aureus, resulting in σ(B) activity impairment. Locations of significant changes in protein structure (IS256 insertion, early STOP codon occurrence, substitutions A230T and A276D) were shown in a theoretical model of S. aureus RsbU. As a phenotypic hallmark of PACT-vulnerable S. aureus strains, we observed an increased fluidity of bacterial cell membrane, which is a result of staphyloxanthin content and other yet unidentified factors. Our research indicates σ(B) as a promising target of adjunctive antimicrobial therapy and suggests that enhanced cell membrane fluidity may be an adjuvant strategy in PACT.


Analyzing excitation forces acting on a plate based on measured acoustic pressure.
This paper presents a theoretical study on "seeing" through an elastic structure to uncover the root cause of sound and vibration by using nearfield acoustical holography (NAH) and normal modes expansion. This approach is of generality because vibro-acoustic responses on the surface of a vibrating structure can always be reconstructed, exactly or approximately. With these vibro-acoustic responses, excitation forces acting on the structure can always be determined, analytically or numerically, given any set of boundary conditions. As an example, the explicit formulations for reconstructing time-harmonic excitation forces, including point, line and surface forces, and their arbitrary combinations acting on a rectangular thin plate in vacuum mounted on an infinite baffle are presented. The reason for choosing this example is that the analytic solutions to vibro-acoustic responses are available, and in-depth analyses of results are possible. Results demonstrate that this approach allows one to identify excitation forces based on measured acoustic pressures and reveal their characteristics such as locations, types and amplitudes, as if one could "see" excitation forces acting behind the plate based on acoustic pressure measured on the opposite side. This approach is extendable to general elastic structures, except that in such circumstance numerical results must be sought.


Treatment effects of Cardiotrophin-1 (CT-1) on streptozotocin-induced memory deficits in mice.
Increasing evidence has shown that diabetes-associated cognitive impairment is correlated with mitochondrial dysfunction and resultant synaptic injury as well as brain insulin resistance. Cardiotrophin-1 (CT-1), a regulator of energy metabolism, has been shown to exhibit impressive neuroprotective effects. In this study, we evaluated the effects of CT-1 on brain pathological features in intracerebroventrical-streptozotocin (ICV-STZ)-treated mouse model, and explored its potential mechanisms. STZ was injected twice (3mg/kg, ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with CT-1 (1μg/day, ICV) starting from the first dose of STZ for 14days showed that CT-1 significantly improved learning and memory deficits, alleviated mitochondrial dysfunction, and increased synaptic density in the CA1 region of the hippocampus in ICV-STZ-treated mice. Moreover, CT-1 significantly enhanced insulin signaling pathway in the hippocampus of ICV-STZ-treated mice when compared with the control. However, all the protective effects including biochemistry, pathological changes and cognitive function could be blocked by an ICV injection of Compound C, a specific AMPK inhibitor. Taken together, these results suggested that CT-1 improves pathological changes and cognitive impairments via AMPK activation in ICV-STZ mice.


Stimulation of prostaglandin EP2 receptors prevents NMDA-induced excitotoxicity.
Prostaglandin E(2) (PGE(2)) plays an important role in inflammation and neurologic disorders. The neuromodulatory effects of PGE(2) are mediated through regulation of four G-protein-coupled receptors known as EP1, EP2, EP3, and EP4. The goal of the current study was to determine whether EP2 receptor activation protects neurons from acute NMDA-mediated excitotoxicity. To examine the effects of EP2 activation, mice were given an injection of the EP2 receptor-selective agonist butaprost (K (i) = 110 nM for EP2 receptor; K (i) > 10,000 for other prostaglandin receptors) in the cerebral ventricle and then an injection of NMDA in the right striatum. After 48 h, a significant reduction in NMDA-induced lesion volume was observed in groups pretreated with butaprost (1-300 nmol/L), with maximal protection at 100 nmol/L (p < 0.001). To determine if EP2-activated protection was specific to neurons, mouse neuronal cultures were treated with butaprost, and cell viability was analyzed after 24 h of NMDA excitotoxicity. The results showed that butaprost significantly increased neuron survival in a dose-dependent fashion. Furthermore, treatment of primary neurons with butaprost significantly increased cAMP levels (p < 0.001). Together, these data reveal that EP2 receptor stimulation mediates neuroprotection against NMDA excitotoxicity both in vivo and in vitro and that butaprost can limit acute brain damage. Development and testing of specific PGE(2) receptor mimetics could lead to a decrease in side effects associated with anti-inflammatory drugs and could help to fight acute and/or chronic neurologic disorders.


Abundant DNase I-sensitive bacterial DNA in healthy porcine lungs and its implications for the lung microbiome.
Human lungs are constantly exposed to bacteria in the environment, yet the prevailing dogma is that healthy lungs are sterile. DNA sequencing-based studies of pulmonary bacterial diversity challenge this notion. However, DNA-based microbial analysis currently fails to distinguish between DNA from live bacteria and that from bacteria that have been killed by lung immune mechanisms, potentially causing overestimation of bacterial abundance and diversity. We investigated whether bacterial DNA recovered from lungs represents live or dead bacteria in bronchoalveolar lavage (BAL) fluid and lung samples in young healthy pigs. Live bacterial DNA was DNase I resistant and became DNase I sensitive upon human antimicrobial-mediated killing in vitro. We determined live and total bacterial DNA loads in porcine BAL fluid and lung tissue by comparing DNase I-treated versus untreated samples. In contrast to the case for BAL fluid, we were unable to culture bacteria from most lung homogenates. Surprisingly, total bacterial DNA was abundant in both BAL fluid and lung homogenates. In BAL fluid, 63% was DNase I sensitive. In 6 out of 11 lung homogenates, all bacterial DNA was DNase I sensitive, suggesting a predominance of dead bacteria; in the remaining homogenates, 94% was DNase I sensitive, and bacterial diversity determined by 16S rRNA gene sequencing was similar in DNase I-treated and untreated samples. Healthy pig lungs are mostly sterile yet contain abundant DNase I-sensitive DNA from inhaled and aspirated bacteria killed by pulmonary host defense mechanisms. This approach and conceptual framework will improve analysis of the lung microbiome in disease.


Molecular cloning and sequencing of sulfated glycoprotein-2 cDNA from testis of mouse: implications of two different mRNAs of SGP-2.
We cloned a mouse homolog of sulfated glycoprotein-2 (SGP-2) cDNA by screening a mouse testicular cDNA library and its nucleotide sequence was determined. The predicted amino acid sequence of the cDNA shares 93% identity with that of rat SGP-2. The nucleotide sequences of both cDNAs show extensive homology throughout the open reading frames and 3' untranslated regions. The 5' untranslated regions, however, share homology only up to 28 bp upstream from the start codons; the rest of sequences are quite different. DNA sequence homology search to mouse SGP-2 cDNA through the EMBL/GenBank database and a recent study on the genomic organization of rat TRPM-2 gene suggest a possibility that there are at least two different SGP-2 mRNAs as a result of alternative splicing and/or different promoter usage in mouse.


Oral platelet glycoprotein IIb/IIIa receptor inhibitors--part II.
Although the hypothesis of benefit from prolonged oral IIb/IIIa inhibition was appealing, the large Phase III trials have uniformly shown there was no improvement in outcome. In addition, there was an increased mortality seen in patients treated with the oral IIb/IIIa inhibitor. This latter finding is not adequately explained, but is likely a multifactorial problem of this strategy of platelet inhibition. The trials found that, even with no improvement in efficacy, there was increased bleeding, meaning that for chronic therapy with IIb/IIIa inhibition there does not appear to be a therapeutic window. Accordingly, chronic oral IIb/IIIa inhibition appears to have been well tested but has not worked. Fortunately, there are several other oral antiplatelet agents available that have shown beneficial results, including clopidogrel. In addition, other newer classes of antiplatelet agents are in earlier stages of development. Thus, agents targeted more "upstream" in platelet activation pathways may offer a more tolerable and efficacious approach to long-term antiplatelet therapy.


Palliative stereotactic-endoscopic third ventriculostomy for the treatment of obstructive hydrocephalus from cerebral metastasis.
Endoscopic third ventriculostomy (ETV) is increasingly used in the treatment of obstructive hydrocephalus. The literature supporting its use in the setting of metastatic disease, however, remains limited. Between 2005 and 2010, 16 patients underwent ETV for treatment of obstructive hydrocephalus secondary to cerebral metastasis. Efficacy of symptomatic palliation and associated complications were reviewed. The results were compared to reported data for ventriculoperitoneal shunt placement in adult brain tumor patients. Patient selection criteria for ETV are reviewed. Eleven of the 16 patients experienced symptomatic improvement after ETV (69%). Patients who presented with headache associated with nausea, vomiting, or lethargy were more likely to respond to treatment relative to patients presenting with headache alone. Of the 16 ETV patients, one suffered a wound infection and another underwent external ventricular drainage for assessment of intracranial pressure, yielding an overall complication rate of 12.5%. In select patients with obstructive hydrocephalus related to cerebral metastasis, ETV constitutes a minimally invasive palliative option. The efficacy of ETV in this population is comparable to those reported for obstructive hydrocephalus secondary to primary cerebral neoplasm or other non-neoplastic causes. Patients receiving chemotherapy close to the time of ETV may be at increased risk for infection.


Magnitude of negative interpretation bias depends on severity of depression.
The present study investigated the hypothesis that the magnitude of negative interpretation bias displayed by those with depression is related to the degree of depression they experience. Seventy one depressed participants (scoring 14 and above on the Beck Depression Inventory II) completed tasks spanning three domains of possible negative interpretations: semantic ambiguity; nonverbal ambiguity and situational ambiguity. Regression analyses revealed that just under half of the variance in depressive symptom severity was explained by the combination of negative interpretation bias tasks, with the strongest predictor of depressive symptom severity being negative interpretation of semantic ambiguity when reading ambiguous text descriptions. Subsidiary group analyses confirmed that severely depressed individuals interpreted emotionally ambiguous information in a more negative way than did their mildly or moderately depressed counterparts. These findings indicate that the degree of negative interpretive bias is closely related to depression severity and that bias manifests especially strongly at the most severe levels of depression. Our findings may help us to refine cognitive theories of depression and be helpful in guiding therapy.


Stab wounds involving the brachial plexus. A review of operated cases.
Of 64 patients with stab wounds involving the brachial plexus operated on by one surgeon, 18 were followed up in detail, with a view to reviewing operative techniques, results and the lessons to be learned. Primary nerve grafting produced better results than end-to-end repair, even in fresh cases. The recognition of nerve compression by a false aneurysm is important, since in these cases, vascular repair alone may not give recovery and neurolysis may be necessary. The overall results of operation were good; lesions of C5 and C6 roots recovered better than those of more distal roots.


[The effect of inhaled heparin on post-leukotriene bronchoconstriction in children with bronchial asthma].
Heparin besides its anticoagulant properties, possesses anti-inflammatory actions. Inhaled heparin has been shown to reduce early and late phase of asthmatic reaction and suppresses allergen induced rise in bronchial hyperreactivity. The exact mechanism of heparin action in bronchial asthma remains obscure. The mechanism involved in the control of bronchial hyperreactivity by heparin has been studied little and is yet poorly understood. The purpose of the present study was to investigate the effect of inhaled heparin on the airway response to leukotriene D4 Fourteen children with typical history of mild atopic asthma participated in this randomized, double-blind, placebo controlled and cross-over study. At the first visit subjects underwent provocation challenge test with leukotriene D4. Patients came back 14 days later to inhale heparin or placebo followed by provocation test with leukotriene. The third study day was 14 days after the second day and provocation test was performed in the same manner except for that patients who inhaled heparin at the second visit, now were administered placebo and opposite. Ten patients completed the study. One patient was withdrawn from the study because of consent withdrawal and three patients were unable to complete the provocation test because of asthma exacerbation. Single dose of inhaled heparin significantly decreased bronchial hyperreactivity to leukotriene in children with mild asthma (p = 0.005). PC20L after heparin inhalation increased in eight patient and decreased in two. It has been shown that histamine, metacholine, and leukotriene play a role in eosinophil recruitment to the airway. Since histamine, metacholine and leukotriene act through receptor binding to protein G, it is possible that heparin (by displacing eosinophil proteins from receptor-protein G binding) restore binding between receptor and G protein and in such mechanism, decrease bronchial hyperreactivity to leukotriene. In our study heparin was inhaled just before leukotriene provocation test and thus the effect of heparin on eosinophil proteins is less likely possible.


Did the popsicle melt? Preschoolers' performance in an episodic-like memory task.
Episodic memory has been tested in non-human animals using depletion paradigms that assess recollection for the "what", "where" and "when" (i.e., how long ago). This paradigm has not been used with human children, yet doing so would provide another means to explore their episodic memory development. Using a depletion paradigm, preschool-aged children were presented in two trials with a preferred food that was only edible after a short interval and a less-preferred food that was edible after the short and long intervals. Younger (mean = 40 months) and older (mean = 65 months) children tended to choose their preferred food after the short intervals, but did not switch to selecting their less-preferred food after the long intervals. Importantly, their choices did not differ with age. Although older children better remembered "what", "where", and "what is where" than did younger children, neither age group successfully estimated "how long ago" an event occurred. Finally, both age groups spontaneously recalled information about Trial 1. We also analysed the relation between the different measures used in the study but no clear patterns emerged. Results are discussed with respect to the cognitive mechanisms necessary to succeed in depletion paradigms and the measurement of episodic memory more broadly.


Urinary sodium excretion after gastric bypass surgery.
Gut-kidney signaling is implicated in sodium homeostasis and thus blood pressure regulation. Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity confers a pronounced and long-lasting blood pressure lowering effect in addition to significant weight loss. We set out to establish whether RYGB is associated with an intrinsic change in urinary sodium excretion that may contribute to the reported blood pressure lowering effects of the procedure. University hospital METHODS: Five female patients (age range: 28-50 yr) without metabolic or hypertensive co-morbidities were included in a study involving four 24-hour residential visits: once before surgery and 10 days, 3 months, and 20 months after surgery. Creatinine and sodium were measured in fasting plasma samples and 24-hour urine samples and creatinine clearance, estimated glomerular filtration rate, and indices of urinary sodium excretion were calculated. Fasting and 60-minute postprandial blood samples from each study day were assayed for pro-B-type natriuretic peptide (NT-proBNP). Increases in weight-normalized urinary sodium excretion of up to 2.3-fold in magnitude occurred at 20 months after surgery. Median fractional excretion of sodium at 20 months was double that seen before surgery. Fasting NT-proBNP levels were stable or increased (1.5- to 5-fold). Moreover, a small postprandial increase in NT-proBNP was observed after surgery. Renal fractional excretion of sodium is increased after RYGB. A shift toward increased postoperative basal and meal associated levels of NT-proBNP coincides with increased urinary sodium excretion. The data support a working hypothesis that an enhanced natriuretic gut-kidney signal after RYGB may be of mechanistic importance in the blood pressure lowering effects of this procedure.


Complete Genome Sequence of Kocuria palustris MU14/1.
Presented here is the first completely assembled genome sequence of Kocuria palustris, an actinobacterial species with broad ecological distribution. The single, circular chromosome of K. palustris MU14/1 comprises 2,854,447 bp, has a G+C content of 70.5%, and contains a deduced gene set of 2,521 coding sequences.


Cortical and Subcortical Anatomy of the Orbitofrontal Cortex: A White Matter Microfiberdissection Study and Case Series.
The literature on white matter anatomy underlying the human orbitofrontal cortex (OFC) is scarce in spite of its relevance for glioma surgery. To describe the anatomy of the OFC and of the underlying white matter fiber anatomy, with a particular focus on the surgical structures relevant for a safe and efficient orbitofrontal glioma resection. Based on anatomical and radiological data, the secondary objective was to describe the growth pattern of OFC gliomas. The study was performed on 10 brain specimens prepared according to Klingler's protocol and dissected using the fiber microdissection technique modified according to U.T., under the microscope at high magnification. A detailed stratigraphy of the OFC was performed, from the cortex up to the frontal horn of the lateral ventricle. The interposed neural structures are described together with relevant neighboring topographic areas and nuclei. Combining anatomical and radiological data, it appears that the anatomical boundaries delimiting and guiding the macroscopical growth of OFC gliomas are as follows: the corpus callosum superiorly, the external capsule laterally, the basal forebrain and lentiform nucleus posteriorly, and the gyrus rectus medially. Thus, OFC gliomas seem to grow ventriculopetally, avoiding the laterally located neocortex. The findings in our study supplement available anatomical knowledge of the OFC, providing reliable landmarks for a precise topographical diagnosis of OFC lesions and for perioperative orientation. The relationships between deep anatomic structures and glioma formations described in this study are relevant for surgery in this highly interconnected area.


Modular asymmetric synthesis of 1,2-diols by single-pot allene diboration/hydroboration/cross-coupling.
Chiral allyl vinyl boronates are generated by catalytic enantioselective diboration of prochiral allenes. They may then be reacted, in situ, with a hydroborating reagent to form a novel triboron intermediate. The least hindered and most reactive C-B bond then participates in cross-coupling wherein the coupling is brought about by the same catalyst as that which catalyzed the diboration reaction. The remaining C-B bonds are then oxidized in the reaction workup, thereby allowing for the modular synthesis of chiral diols in a concise single-pot fashion.


Microbial contamination associated with consumption and the growth in plastic bottled beverage.
Plastic bottles enable the storage of unfinished beverages, and most of microbial contamination has occurred in the unfinished beverage that was left. Therefore, we investigated microorganisms in various beverages contaminated by pouring and drinking directly by mouth from the bottle, and analyzed the growth of microorganisms in the beverages at room temperature. In the pouring test, microbial growth was detected in 60 of 320 samples, and 13 bacterial strains, 49 mold strains, and 8 yeast strains were isolated. Molds including Cladosporium spp., Tramets spp., Bjerkandera spp., and Penicillium spp. accounted for the majority of isolated microorganisms. In the drinking test, microbial growth was detected in 181 of 352 samples, and 225 bacterial strains, 27 mold strains and 77 yeast strains were isolated. Bacteria including Streptococcus spp. such as S. salivarius and Staphylococcus spp. such as S. aureus accounted for the majority of isolated microorganisms. Enterotoxin-producing S. aureus and Bacillus cereus were also isolated. The pH of the beverage influenced the growth of bacteria. The Brix values of the beverage did not correlate with the growth of microorganisms. These results revealed that various microorganisms including foodborne pathogens were able to grow in numerous types of beverages and that the storage of unfinished beverage in inappropriate condition, such as the storage at room temperature led microorganism to grow easily in beverage. Therefore, it is necessary to consume beverages as soon as possible after opening the bottle.


Protection of vascular endothelial cells injured by angiotensin II and hypoxia in vitro by Ginkgo biloba (Ginaton).
The objective of this study was to explore the protective effect and the possible mechanism of Ginkgo biloba extract (Ginaton) on human vascular endothelial cells (VECs) injured by angiotensin II (Ang-II) and hypoxia. The human aortic VECs were divided into different groups to observe the changes in endothelin (ET), calcium concentration ([Ca(2+)]i), and mitochondrial membrane potential (MMP). The results showed that Ginaton had inhibited ET secretion induced by hypoxia and Ang-II (P < .01). the protection offered by Ginaton at mid (10 mg/mL) and low (5 mg/mL) concentrations was obviously better than that offered at high concentration (25 mg/mL). The [Ca(2+)]i increased and MMP decreased significantly in both hypoxia group and Ang-II group (P < .01); however, the changes in [Ca(2+)]i and MMP could be meliorated by Ginaton. This study suggested that Ginaton could effectively protect VECs against injury, and the dose used clinically would rather be low than too high for getting better results.


Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic machinery, resulting in retention of low-density lipoprotein on the cell surface.
The influence of platelets on the cellular metabolism of atherogenic lipoproteins has not been characterized in detail. Therefore, we investigated the effect of platelet factor 4 (PF4), a cationic protein released in high concentration by activated platelets, on the uptake and degradation of low-density lipoprotein (LDL) via the LDL receptor (LDL-R). LDL-R-dependent binding, internalization, and degradation of LDL by cultured cells were inhibited 50%, 80%, and 80%, respectively, on addition of PF4. PF4 bound specifically to the ligand-binding domain of recombinant soluble LDL-R (half-maximal binding 0.5 microg/mL PF4) and partially (approximately 50%) inhibited the binding of LDL. Inhibition of internalization and degradation by PF4 required the presence of cell-associated proteoglycans, primarily those rich in chondroitin sulfate. PF4 variants with impaired heparin binding lacked the capacity to inhibit LDL. PF4, soluble LDL-R, and LDL formed ternary complexes with cell-surface proteoglycans. PF4 induced the retention of LDL/LDL-R complexes on the surface of human fibroblasts in multimolecular clusters unassociated with coated pits, as assessed by immuno-electron microscopy. These studies demonstrate that PF4 inhibits the catabolism of LDL in vitro in part by competing for binding to LDL-R, by promoting interactions with cell-associated chondroitin sulfate proteoglycans, and by disrupting the normal endocytic trafficking of LDL/LDL-R complexes. Retention of LDL on cell surfaces may facilitate proatherogenic modifications and support an expanded role for platelets in the pathogenesis of atherosclerosis.


RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation.
The molecules underlying neuron loss in Parkinson's disease (PD) are essentially unknown, and current therapies focus on diminishing symptoms rather than preventing neuron death. We identified RTP801 as a gene whose transcripts were highly induced in a cellular model of PD in which death of neuronal catecholaminergic PC12 cells was triggered by the PD mimetic 6-OHDA. Here, we find that RTP801 protein is also induced in this and additional cellular and animal PD models. To assess the relevance of these observations to PD, we used immunohistochemistry to compare RTP801 expression in postmortem brains from PD and control patients. For all PD brains examined, expression was highly elevated within neuromelanin-containing neurons of the substantia nigra but not in cerebellar neurons. Evaluation of the potential role of RTP801 induction in our cellular model revealed that RTP801 overexpression is sufficient to promote death but does not further elevate death caused by 6-OHDA. Furthermore, RTP801 induction is requisite for death in our cellular PD models and in 6-OHDA-treated cultured sympathetic neurons in that its knockdown by short hairpin RNAs (shRNAs) is protective. The mechanism by which 6-OHDA and RTP801 induce neuron death appears to involve repression of mammalian target of rapamycin (mTOR) kinase activity, and such death is inhibited by shRNAs targeting TSC2 (tuberous sclerosis complex), a protein with which RTP801 interacts to block mTOR activation. Our findings thus suggest that the elevation of RTP801 we detect in PD substantia nigral neurons may mediate their degeneration and death and that RTP801 and its signaling cascade may be novel potential therapeutic targets for the disease.


Dynamic contrast-enhanced MRI assessment of hyperemic fractional microvascular blood plasma volume in peripheral arterial disease: initial findings.
The aim of the current study was to describe a method that assesses the hyperemic microvascular blood plasma volume of the calf musculature. The reversibly albumin binding contrast agent gadofosveset was used in dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) to assess the microvascular status in patients with peripheral arterial disease (PAD) and healthy controls. In addition, the reproducibility of this method in healthy controls was determined. Ten PAD patients with intermittent claudication and 10 healthy control subjects were included. Patients underwent contrast-enhanced MR angiography of the peripheral arteries, followed by one DCE MRI examination of the musculature of the calf. Healthy control subjects were examined twice on different days to determine normative values and the interreader and interscan reproducibility of the technique. The MRI protocol comprised dynamic imaging of contrast agent wash-in under reactive hyperemia conditions of the calf musculature. Using pharmacokinetic modeling the hyperemic fractional microvascular blood plasma volume (V(p), unit: %) of the anterior tibial, gastrocnemius and soleus muscles was calculated. V(p) was significantly lower for all muscle groups in PAD patients (4.3±1.6%, 5.0±3.3% and 6.1±3.6% for anterior tibial, gastrocnemius and soleus muscles, respectively) compared to healthy control subjects (9.1±2.0%, 8.9±1.9% and 9.3±2.1%). Differences in V(p) between muscle groups were not significant. The coefficient of variation of V(p) varied from 10-14% and 11-16% at interscan and interreader level, respectively. Using DCE MRI after contrast-enhanced MR angiography with gadofosveset enables reproducible assessment of hyperemic fractional microvascular blood plasma volume of the calf musculature. V(p) was lower in PAD patients than in healthy controls, which reflects a promising functional (hemodynamic) biomarker for the microvascular impairment of macrovascular lesions.


Carboplatin-induced gene expression changes in vitro are prognostic of survival in epithelial ovarian cancer.
We performed a time-course microarray experiment to define the transcriptional response to carboplatin in vitro, and to correlate this with clinical outcome in epithelial ovarian cancer (EOC). RNA was isolated from carboplatin and control-treated 36M2 ovarian cancer cells at several time points, followed by oligonucleotide microarray hybridization. Carboplatin induced changes in gene expression were assessed at the single gene as well as at the pathway level. Clinical validation was performed in publicly available microarray datasets using disease free and overall survival endpoints. Time-course and pathway analyses identified 317 genes and 40 pathways (designated time-course and pathway signatures) deregulated following carboplatin exposure. Both types of signatures were validated in two separate platinum-treated ovarian and NSCLC cell lines using published microarray data. Expression of time-course and pathway signature genes distinguished between patients with unfavorable and favorable survival in two independent ovarian cancer datasets. Among the pathways most highly induced by carboplatin in vitro, the NRF2, NF-kB, and cytokine and inflammatory response pathways were also found to be upregulated prior to chemotherapy exposure in poor prognosis tumors. Dynamic assessment of gene expression following carboplatin exposure in vitro can identify both genes and pathways that are correlated with clinical outcome. The functional relevance of this observation for better understanding the mechanisms of drug resistance in EOC will require further evaluation.


HLA molecule--cytoskeleton associations induced by cross-linking with specific antibodies.
Sera of patients with antibodies against HLA-typed panel, control human sera, anti-beta 2-microglobulin monoclonal antibody recognizing HLA class I molecules, anti-HLA class II monoclonal antibodies and control antibodies were used in indirect immunofluorescence study of living human peripheral blood lymphocytes and their cytoskeletons. Lymphocytes immobilized on concanavalin A-precoated glass slides enabling extraction procedures and repeated washings were found useful for such a study. If the lymphocytes were treated with human polyclonal anti-HLA antibodies only, or with two antibodies (i.e. with a specific monoclonal anti-HLA antibody and an anti-mouse Ig polyclonal antibody labelled with fluorescein isothiocyanate (FITC), the cross-linking of the surface molecules caused their resistance to the detergent effect. Murine monoclonal anti-HLA antibodies alone, bound to the cell surface molecules, formed immune complexes easily extracted with Triton solution. In such cases, the second anti-mouse Ig antibody labelled with FITC did not visualize specific molecules in the remaining matrix. No significant changes in the microtubules of cells treated with anti-HLA antibodies were observed.


Sample size in orthodontic randomized controlled trials: are numbers justified?
Sample size calculations are advocated by the Consolidated Standards of Reporting Trials (CONSORT) group to justify sample sizes in randomized controlled trials (RCTs). This study aimed to analyse the reporting of sample size calculations in trials published as RCTs in orthodontic speciality journals. The performance of sample size calculations was assessed and calculations verified where possible. Related aspects, including number of authors; parallel, split-mouth, or other design; single- or multi-centre study; region of publication; type of data analysis (intention-to-treat or per-protocol basis); and number of participants recruited and lost to follow-up, were considered. Of 139 RCTs identified, complete sample size calculations were reported in 41 studies (29.5 per cent). Parallel designs were typically adopted (n = 113; 81 per cent), with 80 per cent (n = 111) involving two arms and 16 per cent having three arms. Data analysis was conducted on an intention-to-treat (ITT) basis in a small minority of studies (n = 18; 13 per cent). According to the calculations presented, overall, a median of 46 participants were required to demonstrate sufficient power to highlight meaningful differences (typically at a power of 80 per cent). The median number of participants recruited was 60, with a median of 4 participants being lost to follow-up. Our finding indicates good agreement between projected numbers required and those verified (median discrepancy: 5.3 per cent), although only a minority of trials (29.5 per cent) could be examined. Although sample size calculations are often reported in trials published as RCTs in orthodontic speciality journals, presentation is suboptimal and in need of significant improvement.


Validating the measurement of upper limb sensorimotor behavior utilizing a tablet in neurologically intact controls and individuals with chronic stroke.
Intact sensorimotor function of the upper extremity is essential for successfully performing activities of daily living. After a stroke, upper limb function is often compromised and requires rehabilitation. To develop appropriate rehabilitation interventions, sensitive and objective assessments are required. Current clinical measures often lack precision and technological devices (e.g. robotics) that are objective and sensitive to small changes in sensorimotor function are often unsuitable and impractical for performing home-based assessments. Here we developed a portable, tablet-based application capable of quantifying upper limb sensorimotor function after stroke. Our goal was to validate the developed application and accompanying data analysis against previously validated robotic measures of upper limb function in stroke. Twenty individuals with stroke, twenty age-matched older controls, and twenty younger controls completed an eight-target Visually Guided Reaching (VGR) task using a Kinarm Robotic Exoskeleton and a Samsung Galaxy Tablet. Participants completed eighty trials of the VGR task on each device, where each trial consisted of making a reaching movement to one of eight pseudorandomly appearing targets. We calculated several outcome parameters capturing various aspects of sensorimotor behavior (e.g., Reaction Time, Initial Direction Error, Max Speed, and Movement Time) from each reaching movement, and our analyses compared metric consistency between devices. We used the previously validated Kinarm Standard Analysis (KSA) and a custom in-house analysis to calculate each outcome parameter. We observed strong correlations between the KSA and our custom analysis for all outcome parameters within each participant group, indicating our custom analysis accurately replicates the KSA. Minimal differences were observed for between-device comparisons (tablet vs. robot) in our outcome parameters. Additionally, we observed similar correlations for each device when comparing the Fugl-Meyer Assessment (FMA) scores of individuals with stroke to tablet-derived metrics, demonstrating that the tablet can capture clinically-based elements of upper limb impairment. Tablet devices can accurately assess upper limb sensorimotor function in neurologically intact individuals and individuals with stroke. Our findings validate the use of tablets as a cost-effective and efficient assessment tool for upper-limb function after stroke.


Correlation of the cranial base angle and its components with other dental/skeletal variables and treatment time.
Many authors have studied the correlation of cranial base flexure and the degree of mandibular prognathism and classification of malocclusion. This indicates that the cranial base flexure may or may not have an effect on the degree of mandibular prognathism and classification of malocclusion. This study evaluates the correlation of the pretreatment cranial base angle and its component parts to other dental and skeletal cephalometric variables as well as treatment time. The sample consisted of 99 Angle Class II and Class I malocclusions treated in the mixed dentition with cervical headgear and incisor bite plane. Thirty of the patients required full appliance treatment. Treatment duration averaged 4.3 years (SD, 1.5 years). Only the starting cephalograms were used to acquire linear, proportional, and angular cranial base dimensions using Ba-S-N (total cranial base), Ba-S/FH (posterior cranial base), and SN/FH (anterior cranial base). Pearson product moment correlation coefficients were computed and used to assess the association of the following skeletal and dental variables: N-Pg/FH, MP/FH, Y-axis/FH, U1/L1, L1/MP, A-NPg mm, A-Perp, B-Perp, and treatment time with the cranial base measurements. Significance was determined only when the confidence level was P < .05. Although there was no significant correlation of BaSN or SN/FH with NPg, the angular BaS/FH, linear BaS mm, and proportional length of BaS %BaN were all statistically negatively correlated to the facial angle. This indicates that the posterior cranial base leg is the controlling factor in relating the cranial base to mandibular prognathism.


Neuroscience in China. Introduction.
The edition of a special issue entitled "Neuroscience in China" provides a unique opportunity to introduce neuroscience research undertakings in China today. Among the biological sciences at large, neuroscience is one of the most advanced fields in China. To take two examples, more than 70% of the articles published in the Chinese Journal of Physiology were in the category of neuroscience; among the members of the Chinese Academy of Sciences (CAS), scientists in the field of neuroscience outnumber scientists in other disciplines of basic medical sciences. This assay tries to analyze the historical and contemporary background underlying the current status.


New Jersey's union-centered healthy schools work.
Healthy schools work is taking place on the state level throughout the United States. Perhaps more than in other states, New Jersey healthy schools work has been union-centered. The New Jersey Education Association (NJEA) collaborated with the New Jersey Work Environment Council (WEC) to produce educational materials and training sessions, provide technical assistance to local education associations, and pursue policy objectives. Pressure from members, personal connections among individuals with experience in health and safety coalitions, progressive union leadership, financial commitment, and a change in focus from regulatory compliance to member organizing contributed to the genesis and success of the work. Others doing healthy schools work may discover new possibilities from the New Jersey experience.


Smoking affects the oral glucose tolerance test profile and the relationship between glucose and HbA1c in gestational diabetes mellitus.
Current smokers in the general population have a lower 2 h plasma glucose after an oral glucose tolerance test (OGTT) and a higher HbA1c than non-smokers, but the relationships between OGTT/HbA1c and smoking status have not been addressed in pregnancy. We analysed glycaemic measurements in women with gestational diabetes mellitus in relation to smoking status. We performed a review of the prospectively collected database of the diabetes and pregnancy clinic. We included women with gestational diabetes mellitus and a singleton pregnancy who delivered between 1986 and 2006. Bivariate and multivariate analyses were used to evaluate patient characteristics in relation to smoking status. A total of 2361 women met the inclusion criteria: 556 (23.5%) were active smokers, 266 (11.3%) quit during pregnancy and 1539 (65.2%) were non-smokers. Most baseline characteristics were similar across groups. Diagnostic OGTT was performed at a gestational age of [median (25th, 75(th) centiles)] 29 weeks (26, 33). Women who smoked at the beginning of pregnancy had a higher 1-h plasma glucose than non-smokers [11.8 (11, 12.7), 11.6 (11, 12.6) and 11.5 (10.8, 12.5) mmol/l, for active smokers, those who quit during pregnancy and non-smokers, respectively, P < 0.001] and a lower 3-h plasma glucose [7.3 (5.9, 8.4), 7.6 (6.4, 8.7) and 8.0 (6.8, 9.0) mmol/l, respectively, P < 0.001]. HbA1c was higher in women who smoked at the beginning of pregnancy. Multiple regression analysis confirmed the independent association of smoking status with HbA1c and OGTT plasma glucose. In women with gestational diabetes mellitus who smoke at the beginning of pregnancy, the shape of the OGTT is consistent with accelerated glucose absorption, and HbA1c is higher than expected for glycaemic values.


In situ synthesis of silver nanoparticle decorated vertical nanowalls in a microfluidic device for ultrasensitive in-channel SERS sensing.
A microfluidic device with integrated novel silver nanoparticle (Ag NPs) decorated nanowall structures was fabricated via in situ electrodeposition of Cu-core/C-sheath nanowalls, followed by a facile in-channel silver galvanic replacement reaction method at room temperature. The integrated microfluidic devices with Ag NPs decorated nanowalls, serving as a highly active Raman substrate, were then applied for in-channel surface-enhanced Raman scattering (SERS) sensing using crystal violet as the model compound. The results show that the presence of a PDMS microfluidic channel does not significantly affect the Raman signal and crystal violet as low as 50 pM is prominently detected. The calculated apparent enhancement factor is 1.1 × 10(9), which allows for the ultra-sensitive detection of analytes in microfluidic devices. The superior enhancement of the in-channel Raman signal and excellent analyte sensitivity can be attributed to the synergistic effect of several distinct traits of the Ag NPs decorated nanowalls - a large available surface for analyte adsorption, a large number of nanocavities surrounded by nanowalls laterally confining the surface plasmons, and numerous "hot spots" resulting from close-contacted Ag NPs and/or the proximate edges of Ag decorated nanowalls. Because preparation of the active SERS substrate and subsequent finger-print SERS detection is completed within a microfluidic device, the developed method opens a new venue to integrate active SERS substrate within microfluidic channels and provides an excellent microfluidic SERS sensor platform for ultrasensitive and selective chemical and biological sensing.


Implementation of synthetic fast-ion loss detector and imaging heavy ion beam probe diagnostics in the 3D hybrid kinetic-MHD code MEGA.
A synthetic fast-ion loss (FIL) detector and an imaging Heavy Ion Beam Probe (i-HIBP) have been implemented in the 3D hybrid kinetic-magnetohydrodynamic code MEGA. First synthetic measurements from these two diagnostics have been obtained for neutral beam injection-driven Alfvén Eigenmode (AE) simulated with MEGA. The synthetic FILs show a strong correlation with the AE amplitude. This correlation is observed in the phase-space, represented in coordinates (Pϕ, E), being toroidal canonical momentum and energy, respectively. FILs and the energy exchange diagrams of the confined population are connected with lines of constant E', a linear combination of E and Pϕ. First i-HIBP synthetic signals also have been computed for the simulated AE, showing displacements in the strike line of the order of ∼1 mm, above the expected resolution in the i-HIBP scintillator of ∼100 μm.


Fall from height: a case report.
The manuscript reports the case of a 16-year-old boy who fell from a height of 15 meters while having a cellphone conversation. Surprisingly, only minor injuries were reported. Prognostic factors related to falls from height are still debated; the present case is a further contribution to the discussion.


Current and future drug therapies for claudication.
The primary objectives of claudication treatment are to reduce cardiovascular mortality and improve walking ability. Patients with claudication have 60% mortality over 10 years, with most deaths due to myocardial infarction and stroke. Aggressive risk-factor modification is required in all these patients, particularly smoking cessation, lipid modification, and treatment of hypertension, diabetes and elevated homocysteine levels. Aspirin, ticlopidine and clopidogrel are all effective in reducing the risk of myocardial infarction, stroke and vascular death, and thus antiplatelet therapy should be considered in all claudicants. Patients with disabling claudication should be considered for therapies that relieve claudication pain and improve exercise performance, the most effective being exercise training and smoking cessation. Pentoxifylline, the only approved claudication drug in the United States, has modest efficacy in improving treadmill exercise performance. Other drugs shown to be of some benefit in patients with claudication include propionyl-L-carnitine, cilostazol and possibly prostaglandin derivatives. Several antiplatelet agents and angiogenic growth factors are also being evaluated for the treatment of claudication.


Select a suitable treatment strategy for Crohn's disease: step-up or top-down.
Crohn's Disease (CD) is a chronic immune-mediated disorder with progressive and destructive course. Current guidelines on the treatment strategy still recommend a step-up approach with sequential prescription of corticosteroids and immunosuppressives. However, mounting evidences manifested that top-down therapy with early administration of anti-TNF or combination of immunosuppressives can achieve more rapid and higher rate of mucosal healing and has the potential of modifying the natural course of disease. Therefore, who is suitable to accept and when to start anti-TNF therapy have attracted the attention of gastroenterologists. And what benefit/risk can be expected from the two strategies should be carefully taken into account by clinicians. Age stratification, special patients, disease location and extension, genetic and serologic testing are predictors of disease progression and complication and thus guide a personalized treatment approach in CD. A definition of early CD has been proposed to select an algorithm for treatment of moderate-to-severe CD with a suitable strategy. To date mucosal healing has been widely used, the Lémann score, which assesses the extent and severity of bowel damage at a specific time-point and over time, and is a new disability index for patients with CD, will be considered as a new endpoint for future studies of treatment strategies. Besides medicines of the two strategies, surgery, vaccine, Leukocytapheresis and stem cell therapy are all effective therapeutic approaches which lead to another thinking about what should they be putted in the conditional pyramid. However, we are trying to answer these questions.


Morphological characteristics of subaxial cervical pedicles and surrounding critical structures in patients with vertebral artery dominance - an anatomical study based on computed tomographic imaging.
No study has assessed the feasibility and safety of cervical pedicle screw implantation in patients with vertebral artery dominance (VAD), a common vertebral artery (VA) variation which can increase VA injury (VAI) risk. This study was to assess morphological characteristics of the subaxial cervical pedicles and surrounding critical structures, and identify their correlations in patients with VAD. Computed tomography arteriography scans of 152 patients were used for retrospectively measuring parameters including pedicle outer width (POW), the distance from the lateral pedicle border to the closest part of VA (DPVA), diameter of VA (DVA), area of VA (AVA), area of transverse foramen (ATF) and occupational ratio of transverse foramen (TF). Moreover, correlations among some critical parameters were assessed. One hundred eight males and 44 females, with a mean age of 55.9 years were included. POW was smaller on the dominant side than on the non-dominant side, whereas DPVA, DVA, AVA, ATF, and TF were larger on the dominant side than those on the non-dominant side. On both sides, POW < 4 mm and POW + DPVA < 5 mm were observed most frequently at C3 and C4. On both sides, POW was correlated to ATF, and ATF was correlated to DVA and AVA. DPVA was correlated to ATF on the dominant side. Patients with VAD exhibited smaller POW on the dominant side, most frequently at C3 and C4. Dominant VA may indirectly affect POW. TF may be a key determinant of DPVA and POW.


Prevention of Staphylococcus aureus infections: advances in vaccine development.
Staphylococcus aureus is a ubiquitous bacterial species that causes serious disease in a minority of carriers, particularly in hospital settings. S. aureus disease is difficult to treat, and antibiotic-resistant strains have become common. Prevention of S. aureus disease would therefore be the best way to limit the morbidity and mortality caused by this organism, but its virulence is determined by a number of different factors, making design of a widely effective vaccine difficult. Here, various S. aureus virulence factors and attempts to develop vaccines or other protective drugs based on these factors are reviewed. In particular, the results of a Phase III clinical study of a vaccine directed at capsular polysaccharides types 5 and 8 are discussed.


Do patients with panic disorder show a memory bias?
Cognitive models of panic disorder are becoming more and more influential. Therefore, research specifying cognitive processes related to panic disorder is needed. The present study investigated memory bias for panic-related material in patients with panic disorder. Memory bias for panic-related material was investigated experimentally by a memory task requiring classification of panic-related and non-panic-related words. Sixty patients with panic disorder and 60 controls with no diagnosis of a mental disorder participated in the study. As expected, panic patients showed smaller differences in the time needed for classification of panic-related versus non-panic-related material than controls. Patients with panic disorder show a memory bias for panic-related material when conceptual implicit recall is required. In order to clarify whether this bias is involved in the maintenance of the disorder, it seems important to investigate whether the bias is still present after successful therapy.