Towards a predictive systems-level model of the human microbiome: progress, challenges, and opportunities.
The human microbiome represents a vastly complex ecosystem that is tightly linked to our development, physiology, and health. Our increased capacity to generate multiple channels of omic data from this system, brought about by recent advances in high throughput molecular technologies, calls for the development of systems-level methods and models that take into account not only the composition of genes and species in a microbiome but also the interactions between these components. Such models should aim to study the microbiome as a community of species whose metabolisms are tightly intertwined with each other and with that of the host, and should be developed with a view towards an integrated, comprehensive, and predictive modeling framework. Here, we review recent work specifically in metabolic modeling of the human microbiome, highlighting both novel methodologies and pressing challenges. We discuss various modeling approaches that lay the foundation for a full-scale predictive model, focusing on models of interactions between microbial species, metagenome-scale models of community-level metabolism, and models of the interaction between the microbiome and the host. Continued development of such models and of their integration into a multi-scale model of the microbiome will lead to a deeper mechanistic understanding of how variation in the microbiome impacts the host, and will promote the discovery of clinically relevant and ecologically relevant insights from the rich trove of data now available.


The distinction between obstructive uropathy and nephropathy by radioisotope transit times.
Deconvolution analysis of different regions of interest on gamma camera renography enables obstructive lesions causing impairment of nephron function to be distinguished from obstructive lesions which parenchymal function is unimpaired. Quantitation of isotope transit time through the parenchyma is a reliable method of diagnosing upper urinary tract obstruction.


Long-term mortality in patients with chronic obstructive pulmonary disease following extracorporeal membrane oxygenation for cardiac assist after cardiovascular surgery.
Information on predisposing risk factors influencing long-term survival after extracorporeal membrane oxygenation (ECMO) support remains scarce. In critically ill patients chronic obstructive pulmonary disease (COPD) is an independent risk factor for mortality and morbidity. We assessed the influence of COPD on cardiovascular and all-cause mortality in patients undergoing ECMO therapy. We prospectively included 191 patients undergoing veno-arterial ECMO therapy following cardiovascular surgery at a university-affiliated tertiary care center into our registry. The median follow-up time was 51 months (IQR 34-71 months) corresponding to 4,197 overall months of follow-up. A total of 125 patients (65 %) died; 88 % of deaths were due to cardiovascular causes. Long-term survival was decreased in patients with COPD after 1 year (23 % vs. 44 %) and after 6 years (14 % vs. 35 %) compared to patients without COPD. COPD was independently associated with all-cause mortality with a hazard ratio of 4.22 (95 % CI 1.04-17.11, p = 0.04) and cardiovascular mortality with a hazard ratio of 5.87 (95 % CI 1.41-24.47, p = 0.02). We identified COPD as a strong and independent predictor of long-term all-cause mortality and cardiovascular mortality in patients undergoing ECMO therapy following cardiovascular surgery. The current study presents valuable information for a comprehensive decision-making process prior to ECMO implantation and helps to identify high-risk patients that may benefit from intensified treatment of co-morbidities and close check-ups after hospital discharge.


The genomic structure of two protein kinase CK2alpha genes of Xenopus laevis and features of the putative promoter region.
Protein kinase CK2 is an enzyme that is ubiquitous in eukaryotes. This enzyme, composed of catalytic (alpha and alpha') and regulatory (beta) subunits, is responsible for the phosphorylation of a large number of proteins and is implicated in cell division. Genomic clones coding for the CK2alpha subunit of Xenopus laevis have been isolated. Initial restriction enzyme profiles and subsequent PCR analysis and DNA sequencing indicated that these genomic clones correspond to two different genes. The two genes are highly homologous in the regions of the coding sequence (only 3 amino acid differences) but differ considerable in their intron sequences and lengths. Gene 1 corresponds to the cDNA of XlCK2alpha which had been previously isolated and described. The genomic clone for this gene was truncated. Gene 2 contains the entire coding region for CK2alpha subunit as well as a fragment of 6.4 kb of the 5' upstream region. The exon/intron boundaries of both genes obey the GT/AG rule with the exception of intron V where the less common GC/AG is seen. Comparison of the size of ten coding exons and sites where these are interrupted by introns shows strong conservation with respect to the human CK2alpha gene. RT-PCR analysis of mRNAs from X. laevis ovary, oocytes and early embryos using a specific primer for gene 2 demonstrated that this gene is expressed in these tissues and cells. Analysis of transcription start sites using 5'RACE and RNA from stage VI oocytes demonstrated that there are multiple start sites in the XlCK2alpha mRNA. It was also seen that a noncoding exon 1 is present 4 kb upstream of the translation start site and that alternate splicing occurs in gene 2 to give exon 1 of different lengths. Sequencing of the entire upstream genomic region of gene 2 revealed that there are regions of homology to the sequence of exon 1 of the human CK2alpha gene. Other sequences with consensus to transcription factor binding sites that are seen in the promoter region of human CK2alpha are also found in the X. laevis CK2alpha gene 2. These sites include Ets1, E2F, CCAAT and GC rich regions. No canonical TATA motif is observed.


Managing chemotherapy for tuberculosis.
The recent increase in cases of tuberculosis has renewed interest in its management. This paper describes drug treatment and outlines possible side-effects that may influence patient care.


α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease.
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/Treg imbalance remains unknown. Here, we examined the percentage of Th17 cells, the percentage of Tregs and the α-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro. We found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon α-Syn stimulation when naïve CD4+ T cells were cultured under Th17-polarizing conditions. Mechanistically, α-Syn promotes the transcription of RORC, encoding RORγt, in Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. Intriguingly, the increase in Th17 cells, decrease in Tregs and apoptosis of DA were suppressed by a RORγt inhibitor (GSK805) in MPTP-treated mice. Together, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4+ T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.


MEN signaling: daughter bound pole must escape her mother to be fully active.
Budding yeast divide asymmetrically and must therefore align the position of the mitotic spindle with the plane of division. The success of this process is monitored by a checkpoint-signaling mechanism. Two recent papers in Molecular Cell reveal an important new facet of this signal transduction pathway.


Acute myeloid leukemia with isolated del(5q) is associated with IDH1/IDH2 mutations and better prognosis when compared to acute myeloid leukemia with complex karyotype including del(5q).
Myelodysplastic syndrome with isolated del(5q) is a well-recognized entity with a relatively favorable prognosis. Isolated del(5q) in acute myeloid leukemia is rare and acute myeloid leukemia cases with isolated del(5q) are not well characterized. Del(5q) has been shown to be a poor prognostic marker in acute myeloid leukemia based on multivariable analysis in large cohort studies, which contained mostly cases with del(5q) in the context of multiple chromosomal abnormalities. To further characterize acute myeloid leukemia with isolated del(5q), clinicopathologic characterization including mutation analysis was performed. During a 10-year period, we identified 12 cases of acute myeloid leukemia with isolated del(5q), 7 cases of acute myeloid leukemia with del(5q) plus one additional chromosome abnormality not involving chromosome 7, as well as two control groups composed of 124 cases of acute myeloid leukemia with complex karyotype including del(5q), and 40 cases of myelodysplastic syndrome with isolated del(5q). At diagnosis, cases of acute myeloid leukemia with isolated del(5q) had higher platelet counts (p = 0.044), hemoglobin (p = 0.011), and mean corpuscular volume (p = 0.017) compared with cases of acute myeloid leukemia with complex karyotype including del(5q). Acute myeloid leukemia with isolated del(5q) was less likely therapy-related (p = 0.037), more likely to have IDH1/IDH2 mutations (p = 0.009), and less likely to have TP53 mutations (p = 0.005) when compared to acute myeloid leukemia with complex karyotype including del(5q). Acute myeloid leukemia with isolated del(5q) also showed longer overall survival than acute myeloid leukemia with complex karyotype cases including del(5q) (p = 0.004). In summary, acute myeloid leukemia with isolated del(5q) appeared to show some distinct clinicopathologic and genomic features as compared to cases of acute myeloid leukemia with complex karyotype including del(5q).


Cryopreserved homograft valves in the pulmonary position: risk analysis for intermediate-term failure.
The purpose of this study was to examine the durability of cryopreserved homografts used to replace the "pulmonary" valve and to identify factors associated with their late deterioration. We reviewed our entire experience (1985-1997) with 331 survivors in whom cryopreserved homograft valves (pulmonary, n = 304; aortic, n = 27) were used to reconstruct the pulmonary outflow tract. Median age was 14 years (range, 2 days-62 years). Operations included Ross operation (n = 259), tetralogy of Fallot (n = 41), truncus arteriosus (n = 14), Rastelli operation (n = 11), and others (n = 6). Median follow-up was 3.8 years (range, 0.2-11.2 years); late echographic follow-up was complete for 97% of patients. Homograft failure was defined as the need for explantation and valve-related death; homograft dysfunction was defined as a pulmonary insufficiency grade 3/4 or greater and a transvalvular gradient of 40 mm Hg or greater. Homograft failure occurred in 9% (30 of 331 patients; Kaplan-Meier); freedom from failure was 82% +/- 4% at 8 years. Homograft dysfunction occurred in 12% (39 of 331 patients), although freedom from dysfunction was 76% +/- 4% at 8 years. For aortic homografts, this was 56% +/- 11%, compared to 80% +/- 4% for pulmonary homografts (P =.003). For patients aged less than 3 years (n = 38), this was 51% +/- 12%, compared with 87% +/- 4% for older patients (P =.0001). By multivariable analysis, younger age of homograft donors, non-Ross operation, and later year of operation were associated with homograft failure; younger age of homograft donors, later year of operation, and use of an aortic homograft were associated with homograft dysfunction. Homograft valves function satisfactorily in the pulmonary position at mid-term follow-up. The pulmonary homograft valve appears to be more durable than the aortic homograft valve in the pulmonary position.


Interactive graphical isolation of homogeneous data subgroups.
A method is described for compacting homogeneous and separating heterogeneous data subcomponents. Allowance is made for heterogeneity due to a concomitant variable. When used with a large sample size, the major component of bivariate normal data will tend to be compacted to a single point. By applying the algorithm twice, the major component of bivariate lognormal data will tend to be compacted to a single point. These procedures have been implemented as part of an interactive graphical system for convenient use by biomedical researchers.


Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model.
Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R-GFP(+) macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2-like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP(+) cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R(+) population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas.


Effect of homemade compound microbial inoculum on the reduction of terramycin and antibiotic resistance genes in terramycin mycelial dreg aerobic composting and its mechanism.
In order to tackle the issue of terramycin mycelial dreg (TMD) diagnosis and removal of terramycin and antibiotic resistance genes (ARGs), this study adopted aerobic composting (AC) technology and added homemade compound microbial inoculum (HCMI) to promote the AC of TMD and enhance the removal of terramycin and ARGs. The findings demonstrated that terramycin residue could be basically harmless after AC. Moreover, HCMI not only reduced QacB and tetH but also increased the degradation rates of VanRA, VanT, and dfrA24 by 40.81%, 5.65%, and 54.18%, respectively. The HCMI improved the removal rate of ARG subtypes to a certain extent. According to redundancy analysis, during AC, the succession of the microbial community had a stronger influence on the variance of ARG subtype than the environmental conditions. Differences in the abundance of various bacteria due to changes in temperature may be an intrinsic mechanism for the variation of ARG subtypes.


Potent cyclic urea HIV protease inhibitors with 3-aminoindazole P2/P2' groups.
Cyclic ureas containing 3-aminoindazole P2/P2' groups are extremely potent inhibitors of HIV protease. The parent 3-aminoindazole 6 showed a Ki < 0.01 nM but poor translation of enzyme activity to antiviral activity was observed. A series of 3-alkylaminoindazoles revealed that translation improved with increasing lipophilicity. An X-ray crystal structure of 6 bound to HIV protease was obtained.


Characterization of a conserved "threonine clasp" in CAP-Gly domains: role of a functionally critical OH/pi interaction in protein recognition.
XH/pi hydrogen bonds have been predicted to make important contributions to protein structure and function. NMR evidence is presented for an OH/pi interaction between a highly conserved threonine and phenylalanine pair found specifically in CAP-Gly domains associated with mictrotubule plus ends. The functional contribution of this nonclassical hydrogen bond in target peptide recognition is demonstrated via subtle point mutagenesis. The OH/pi interaction is part of a TxFxxxxW motif that comprises a conserved "threonine clasp" that defines function in CAP-Gly domains.


The Downregulation of Prognosis- and Immune Infiltration-Related Gene CYFIP2 Serves as a Novel Target in ccRCC.
Increasing evidence indicated that the aberrant expression of the cytoplasmic FMR1-interacting protein (CYFIP) family might possess critical role and potential functions in cancer. But the role of CYFIP2 in clear cell renal cell carcinoma (ccRCC) is still uncharacteristic. We investigated the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for the expression profile, clinicopathological variables, clinical prognosis information, and promoter methylation levels of CYFIPs in ccRCC. The aberrant CYFIP2 protein expression was validated by the Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to uncover CYFIP2 mRNA levels in 28 pairs of ccRCC cancer tissues. Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard regression were performed to assess CYFIPs' prognosis value. Gene set enrichment analysis (GSEA) was used to determined hallmark functions, gene ontology of CYFIP2. TIMER database was utilized to assess the correlation with immune infiltration in ccRCC. Results showed CYFIP2 was downregulated in ccRCC, relative to paired normal tissues in TCGA-KIRC database and 28 pairs of clinical samples (P < 0.0001). Similarly, a decreased CYFIP2 protein expression was confirmed by ccRCC tissues. The results showed CYFIP2 was negatively regulated by promoter DNA methylation. Survival analysis results showed CYFIP2 could be an independent biomarker for ccRCC and its reduction predicted a poor overall survival (OS) and disease-free survival (DFS). GSEA showed CYFIP2 was involved in metabolic pathways and epithelial-mesenchymal transition (EMT). Immune infiltration analysis revealed that a list of immune markers was significantly correlated with CYFIP2 expression especially with CD4+ cells and CD8+ cells in ccRCC. These results show that CYFIP2 was downregulated in ccRCC patients and predicted an unfavorable prognosis. CYFIP2 might be a potential novel prognostic molecule, and related to immune infiltration, the metabolism, as well as EMT process in ccRCC. CYFIP2 could act as tumor suppressor gene in ccRCC and positive modulation of CYFIP2 might lead to development of a novel strategy for ccRCC treatment.


Decreased GABAergic signaling, fewer parvalbumin-, somatostatin- and calretinin-positive neurons in brain of a rat model of simulated transport stress.
Transport stress (TS) in animals lead to change in blood composition, brain structure, and the endocrine system as well as behavior. γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system (CNS), influences many physiological functions and plays a significant role in coping with stress. This study aimed to explore the effect of stress on behavior, HPA axis, GABA transmitters and the distribution of GABAergic interneurons in the prefrontal cortex (PFC) and striatum of the brain by a rat model of simulated transport stress (STS). Thirty-six male Sprague Dawley rats were randomly divided into a control group (n = 12, no stress), a TS1d group (n = 12, 2 h stress for 1 d) and a TS7d group (n = 12, 2 h stress each day for 7 d). After STS, the rats were subjected to open-field testing (OFT) followed by serologic analysis, colorimetry, Western blot and immunohistochemistry. The total score of the OFT showed the similar profile with serum concentrations of corticosterone (CORT) and norepinephrine (NE), which in the TS7d group were all higher than the TS1d group but lower than the control group. STS also reduced GABA, glutamate decarboxylase 67 (GAD67) and GABA transporter 1 (GAT1) expression in the TS1d and these markers were increased in the TS7d, suggesting that GABA was related to hypothalamic-pituitary-adrenal (HPA) axis activation under stress. The number of parvalbumin (PV)-, somatostatin (SOM)-, and calretinin (CR)- positive cells were decreased with stress increase. Our findings revealed that STS affected the behavior of rats, synthesis and release of GABA by altering the HPA axis.


Mercury concentrations in feathers of marine birds in Arctic Canada.
Mercury (Hg) concentrations are a concern in the Canadian Arctic, because they are relatively high compared to background levels and to similar species farther south, and are increasing in many wildlife species. Among marine birds breeding in the Canadian Arctic, Hg concentrations have been monitored regularly in eggs and intermittently in livers, but feathers have generally not been used as an indicator of Hg exposure or burden. We examined Hg concentrations in six marine bird species in the Canadian Arctic. Ivory gull Pagophila eburnea, feather Hg was exceptionally high, while glaucous gull Larus hyperboreus feather Hg was unexpectedly low, and ratios of feather THg to egg THg varied across species. The proportion of total Hg that was comprised of methyl Hg in ivory gull feathers was lower than in other species, and may be related to photo-demethylation or keratin breakdown in semi-opaque feather tissue.


A randomized trial of intravenous heparin in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex) in acute myocardial infarction: the Duke University Clinical Cardiology Study (DUCCS) 1.
We designed a randomized trial to evaluate the effects of heparin administration in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex [APSAC]) on arterial patency and clinical end points. The role of conjunctive intravenous heparin therapy with APSAC has not been tested despite the recommendations that intravenous heparin should be used. Four hours after APSAC administration, 250 patients with acute myocardial infarction were randomly assigned to receive 325 mg of either aspirin alone or aspirin and a continuous infusion of heparin (15 IU/kg body weight per h). Clinical ischemic events and bleeding complications were monitored. On hospital day 5, coronary arteriography and left ventriculography were performed. The primary end point of the trial (the combined outcome of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery) occurred in 42% of the heparin-treated group versus 43% of the group treated without heparin (p = 0.94). A patent infarct-related artery was present in 80% of the patients treated with heparin and in 73% of those treated without heparin (p = 0.26). Left ventricular function, as measured by ejection fraction, was well preserved in both groups (52% vs. 50.5%, respectively, p = 0.29). The overall bleeding rate was higher in patients with (32%) than without (17.2%) heparin (p = 0.006). Weight-adjusted intravenous heparin therapy after APSAC in acute myocardial infarction does not reduce the combined incidence of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery. Furthermore, withholding intravenous heparin therapy is associated with a 46% reduction in bleeding complications. Our findings do not support the addition of intravenous heparin after APSAC therapy, as currently recommended, and suggest that a strategy of withholding heparin is simpler and safer and does not place the patient at increased risk for ischemic complications after myocardial infarction.


A natural impact-resistant bicontinuous composite nanoparticle coating.
Nature utilizes the available resources to construct lightweight, strong and tough materials under constrained environmental conditions. The impact surface of the fast-striking dactyl club from the mantis shrimp is an example of one such composite material; the shrimp has evolved the capability to localize damage and avoid catastrophic failure from high-speed collisions during its feeding activities. Here we report that the dactyl club of mantis shrimps contains an impact-resistant coating composed of densely packed (about 88 per cent by volume) ~65-nm bicontinuous nanoparticles of hydroxyapatite integrated within an organic matrix. These mesocrystalline hydroxyapatite nanoparticles are assembled from small, highly aligned nanocrystals. Under impacts of high strain rates (around 104 s-1), particles rotate and translate, whereas the nanocrystalline networks fracture at low-angle grain boundaries, form dislocations and undergo amorphization. The interpenetrating organic network provides additional toughening, as well as substantial damping, with a loss coefficient of around 0.02. An unusual combination of stiffness and damping is therefore achieved, outperforming many engineered materials.


Hemothorax caused by spontaneous rupture of hepatocellular carcinoma: a case report and review of the literature.
We report a rare case in which hemothorax occurred in addition to hemoperitoneum due to spontaneous rupture of hepatocellular carcinoma (HCC) originating from the caudate lobe of the liver. The case pertains to a 56-year-old female who was transported to our hospital for impaired consciousness due to hemorrhagic shock. Computed tomography (CT) demonstrated ruptured HCC originating from the caudate lobe and accompanying hemoperitoneum and right hemothorax. Hemostasis was carried out by transcatheter arterial embolization (TAE), and surgery was conducted approximately one month after TAE. In the present case, no lesions as possible sources of bleeding were observed inside the pleural cavity, and, moreover, the diaphragm had no abnormalities in the intraoperative findings, suggesting that blood from the ruptured tumor may have traversed the intact diaphragm to enter the right pleural cavity soon after the HCC rupture. However, to the best of our knowledge, no similar cases of HCC have been reported to date, and this case is thus believed to be very rare. This unusual phenomenon may therefore be strongly associated with the location of the ruptured tumor and the formation of a hematoma inside the omental bursa. We discuss the mechanism causing hemothorax in the present case and also review the previously reported cases of ruptured HCC complicated by hemothorax.


Indobufen inhibits tissue factor in human monocytes through a thromboxane-mediated mechanism.
To assess whether indobufen, a reversible inhibitor of platelet cyclooxygenase (Cox) activity, affects tissue factor (TF) in human monocytes and to investigate the relationship between Cox-derived products and TF. TF was evaluated in isolated adherent monocytes, both resting and lipopolysaccharide (LPS)-stimulated, in terms of procoagulant activity, protein, and mRNA levels. The expression of TF surface antigen was determined in LPS-stimulated whole blood monocytes by flow cytometry. The levels of the stable thromboxane A2 (TxA2) metabolite, TxB2, and of prostaglandin E2 (PGE2) were measured in monocyte supernatant by immunoenzymatic techniques. Cox-1 and Cox-2 protein level, tyrosine phosphorylation, and mitogen-activated protein kinase (MAP-kinase) activation were determined by Western blot analysis. Indobufen prevents TF expression and activity both in isolated and in whole blood monocytes. Reduction of TxA2 synthesis, coupled with a lack of effect on PGE2 levels and prevention of ERK1/2 phosphorylation are highlighted as the mechanisms through which indobufen negatively affects TF. Data show that indobufen down-regulates TF in monocytes. This novel activity, coupled with the antiplatelet effect of the drug, may add benefit for its use in the management of atherothrombosis.


Recent trends in miRNA therapeutics and the application of plant miRNA for prevention and treatment of human diseases.
Researchers now have a new avenue to investigate when it comes to miRNA-based therapeutics. miRNAs have the potential to be valuable biomarkers for disease detection. Variations in miRNA levels may be able to predict changes in normal physiological processes. At the epigenetic level, miRNA has been identified as a promising candidate for distinguishing and treating various diseases and defects. In recent pharmacology, plants miRNA-based drugs have demonstrated a potential role in drug therapeutics. The purpose of this review paper is to discuss miRNA-based therapeutics, the role of miRNA in pharmacoepigenetics modulations, plant miRNA inter-kingdom regulation, and the therapeutic value and application of plant miRNA for cross-kingdom approaches. Target prediction and complementarity with host genes, as well as cross-kingdom gene interactions with plant miRNAs, are also revealed by bioinformatics research. We also show how plant miRNA can be transmitted from one species to another by crossing kingdom boundaries in this review. Despite several unidentified barriers to plant miRNA cross-transfer, plant miRNA-based gene regulation in trans-kingdom gene regulation may soon be valued as a possible approach in plant-based drug therapeutics. This review summarised the biochemical synthesis of miRNAs, pharmacoepigenetics, drug therapeutics and miRNA transkingdom transfer.


Heterologous expression and purification of a marine alginate lyase in Escherichia coli.
Alginate lyase digestion is an efficient way to degrade alginate into oligosaccharides, which are useful in various areas including chemistry, pharmacy and food industry. Here we determined the sequence of Vibrio sp. QY102 sourced alginate lyase, and set up its heterologous expression in E. coli. We improved its secretion efficiency by replacing the original secretive sequence by E. coli specific signal peptide ompA. We successfully purified the full-length protein in shake flask culture, however, degradation happened during fed batch cultivation. By domain and disorder examination, we found that the protein was completely functional by expressing the C terminal fragment alone. For the final strain we constructed (HMS-ompA-CF), the extracellular enzyme activity reached 375 U/ml in shake flask and 1789 U/ml in fed batch cultivation (5 L bioreactor). And the final protein yield reached 0.58 g/L in fed batch cultivation. We determined that the optimal pH and temperature for the shortened alginate lyase were 7.0 and 39 °C, respectively.


Two synchronous adenocarcinomas of the small bowel in a patient with undiagnosed Crohn's disease of the terminal ileum.
A small but significant excess of deaths for tumors of the digestive system has been described in Crohn's disease. In a study analyzing all cancers of the small intestine within a defined population, Crohn's disease was the major underlying factor for cancer of the small intestine. Areas of the small intestine containing strictures are unusually prone to malignant transformation. We report the rare case of a patient in whom surgery for intestinal occlusion disclosed Crohn's disease of the distal ileum complicated by two adenocarcinomas arising within distinct areas of the inflamed bowel.


An original amino acid formula favours in vitro corneal epithelial wound healing by promoting Fn1, ITGB1, and PGC-1α expression.
Corneal disorders are frequent, involving most diabetic patients; among its manifestations, they include delayed wound healing. Since maintenance of mitochondrial homeostasis is fundamental for the cell, stimulation of mitochondrial biogenesis represents a unique therapeutic tool for preventing and treating disorders with a deficit in energy metabolism. We have recently demonstrated that a branched-chain amino acid (BCAA)-enriched mixture (BCAAem) supported mitochondrial biogenesis in cardiac and skeletal muscle, reduced liver damage caused by alcohol, and prevented the doxorubicin-dependent mitochondrial damage in cardiomyocytes. The present study aimed to investigate a new amino acid mixture, named six amino acids (6AA), to promote corneal epithelial wound healing by regulating mitochondrial biogenesis. A murine epithelium cell line (TKE2) exposed to this mixture showed increased mitochondrial biogenesis markers, fibronectin 1 (Fn1) and integrin beta 1 (ITGB1) involved in extracellular matrix synthesis and cell migration. Most importantly, the 6AA mixture completely restored the wound in scratch assays, confirming the potential of this new formula in eye disorders like keratopathy. Moreover, our results demonstrate for the first time that peroxisome proliferator-receptor γ coactivator 1 α (PGC-1α) is expressed in TKE2 cells, which controls mitochondrial function and corneal repair process. These results could be relevant for the treatment mainly focused on corneal re-epithelialisation.


Antimicrobial activities of sesquiterpene lactones and inositol derivatives from Hymenoxys robusta.
Six compounds from the aerial parts of the Argentinean plant Hymenoxys robusta (Rusby) Parker were isolated and their structures elucidated using extensive spectroscopic analyses. These compounds comprise two inositol derivatives and four 3,4-seco-pseudoguaianolides, including vermeerin. Bioactivity assays of these compounds against bacterial and fungal pathogens showed that only vermeerin possessed antimicrobial activity specific against Staphylococcus aureus, and showed no toxicity when exposed to human-derived macrophages.


2-Isopropylthioxanthone-Catalyzed Divergent Functionalization of Bicyclo[1.1.0]butanes under Visible-Light Irradiation.
1,3-Functionalized cyclobutane structural motifs are ubiquitous in natural products and pharmaceuticals. Photoinduced alkylation of bicyclo[1.1.0]butanes (BCBs) offers a step-economical strategy for accessing 1,3-functionalized cyclobutane motifs. Herein, we disclose a general and mild photocatalytic protocol of bromoallylation and alkylation of BCBs in a metal, additive-free manner by using the same photocatalyst, 2-isopropylthioxanthone, in different catalytic roles. Furthermore, the synthetic utility of these products was illustrated in the synthesis of various valuable and complex cyclobutane derivatives.


HPLC separation of corticosterone metabolites and its use in following corticosterone metabolism and transport in the isolated rat hepatocyte.
Incubating isolated rat hepatocytes with tritium labelled and unlabelled corticosterone at 37 degrees C resulted in the rapid appearance of at least nine corticosterone metabolites. A quick, relatively easy, and quantitative high performance liquid chromatographic (HPLC) method was used to separate these metabolites and follow their rate of appearance both intra- and extracellularly. We found different intra- and extracellular amounts of each metabolite at a particular time and this suggested that some metabolites were more available for transport than others.


High-resolution non-destructive 3D interrogation of dentin using X-ray nanotomography.
Dentin, a calcareous material sandwiched between the pulp and the enamel in the tooth structure contains highly orientated tubules. As a result of enamel erosion, gum recession, physical trauma or caries the dentin tubules can become patent to the oral cavity. It has been demonstrated in vivo that dentinal fluid flows out of the tubule lumen into the oral cavity and it has been postulated that alterations in fluid flow form the basis of dentin hypersensitivity. In order to better understand the mode of action of desensitising occlusion-based agents the ability to interrogate dentin non-destructively is paramount. Destructive analysis of the tooth structure may yield subtle artifacts leading to erroneous conclusions or inhibit the accurate assessment of the relationship between an occluding agent and the internal dentin morphology. This paper describes the use of a novel and accessible, non-invasive, high-focused X-ray computer tomographic technique for analysis of the dentin substructure. Dentin slices, ca. 300microm3 in size, were taken from the coronal section of unerupted human third molars and etched in citric acid to reveal the open tubule structure. Samples were analyzed, in their dry state, using the Skyscan 2011 nanoCT system. Numerous, homogeneously dispersed elliptical features, distinguished by their contrast and hence low-mineral density, were observed. These features are observed to be approximately 2-5microm in diameter at a density equivalent to 10(6)cm(-2). 2D CT re-slices demonstrate that these circular features form highly orientated cylindrical manifestations extending throughout the sample. Ultra-high-resolution X-ray computed tomography has been shown to be a powerful new technique for interrogating the submicron tubular structure of dentin non-destructively.


Intranasal oxytocin decreases fear generalization in males, but does not modulate discrimination threshold.
A previously acquired fear response often spreads to perceptually or conceptually close stimuli or contexts. This process, known as fear generalization, facilitates the avoidance of danger, and dysregulations in this process play an important role in anxiety disorders. Oxytocin (OT) has been shown to modulate fear learning, yet effects on fear generalization remain unknown. We employed a randomized, placebo-controlled, double-blind, between-subject design during which healthy male participants received either intranasal OT or placebo (PLC) following fear acquisition and before fear generalization with concomitant acquisition of skin conductance responses (SCRs). Twenty-four to 72 h before the fear learning and immediately after the fear generalization task, participants additionally complete a discrimination threshold task. Relative to PLC, OT significantly reduced perceived risk and SCRs towards the CS+ and GS1 (the generalization stimulus that is most similar to CS+) during fear generalization, whereas the discrimination threshold was not affected. Together, the results suggest that OT can attenuate fear generalization in the absence of effects on discrimination threshold. This study provides the first evidence for effects of OT on fear generalization in humans and suggests that OT may have therapeutic potential in anxiety disorders characterized by dysregulated fear generalization.


Locomotor adjustments for circumvention of an obstacle in the travel path.
Independent living requires the navigation of a surrounding environment which is often cluttered with obstacles. When walking around an obstacle in the travel path, safe clearance requires some degree of body-segment reorientation. While body-segmental coordination strategies have been well studied for steering tasks that require moving the body in a new walking direction, it has never been established just what coordination strategies are used in different walking tasks. To address this issue, the current study was designed to investigate the timing of body segment coordination strategies and whole-body anticipatory locomotor adjustments employed when circumventing an obstacle placed in the travel path. Six healthy adults were asked to walk at their natural pace during unobstructed walking, as well as during avoidance to the right or left of a cylindrical obstacle (OBS) located in the travel path. Data analyzed were center of mass (COM) clearance from the OBS, forward velocity, step length and width, yaw angles of the head and trunk, roll angle of the trunk, and medial-lateral COM displacement. Onset of change in these variables from unobstructed walking was calculated as the time from OBS crossing. Avoidance involved two equally used strategies: lead limb close to or away from the OBS during the crossing step. Medial-lateral COM deviations were controlled by changes in step width without changes in trunk roll. There were no differences in the onset times of body segment reorientation for path deviation. These results are in contrast to previous studies on change in travel direction where the head segment initiates the body reorientation. Contrary to a steering task, circumventing an obstacle requires a different coordination for a transient change in COM trajectory with the underlying travel-direction maintained.


Anatomical distribution of 3He apparent diffusion coefficients in severe chronic obstructive pulmonary disease.
To evaluate the anatomical distribution of apparent diffusion coefficients (ADC) using hyperpolarized helium-3 (3He) MRI in chronic obstructive pulmonary disease (COPD). Hyperpolarized 3He MRI was performed in eight healthy and seven COPD subjects under breathhold conditions in the supine position to determine ADC values from diffusion-weighted images and evaluate anterior-posterior (AP) and superior-inferior (SI) differences. ADC differences between anterior and posterior slices, DeltaAP, was 0.06 +/-0.01 cm2/second for healthy volunteers and 0.04 +/-0.02 cm2/second for COPD subjects and was significant for each subject (P < 0.01). The AP ADC gradient was -3.98 x 10(-3) +/-0.59 cm2/second/cm for healthy volunteers and -2.04 x 10(-3) +/-0.89 cm2/second/cm for COPD subjects. The difference in ADC between superior and inferior regions of interest (ROIs), DeltaSI, was 0.02 +/-0.02 cm2/second for healthy volunteers and 0.10 +/-0.09 cm2/second for COPD subjects, which was significant for each subject (P < 0.05). The SI ADC gradient was -0.63 x 10(-3) +/-2.23 cm2/second/cm for healthy volunteers and -6.61 x 10(-3) +/-6.68 cm2/second/cm for COPD subjects. DeltaAP, AP-gradient, and SI-gradient were significantly different between healthy volunteers and COPD subjects (P < 0.05). In all subjects, ADC anatomical differences were significant and mean ADC was dependent on anatomic location and disease status.


Epithelial deposition of gold in the cornea in patients receiving systemic therapy.
Epithelial gold deposits were demonstrated biomicroscopically in 13 of 15 patients receiving gold therapy for rheumatoid arthritis. Only one of six further patients who had received gold therapy in the past showed such deposits. Deposits appeared with a cumulative dose of sodium thiomalate exceeding 100 mg. The earliest appearance was after seven months of therapy and deposits were visible in one subject as long as nine months after therapy had stopped. The density of deposit does not appear to increase over the whole of the dose range, possibly as a result of the effect of epithelial turnover. No symptoms attributable to the deposit were encountered in any patient.


Mediastinal lymph node dissection affects survival in patients with stage I non-small cell lung cancer.
The therapeutic value of mediastinal lymph node dissection (LND) for early-stage non-small cell lung cancer (NSCLC) remains controversial. We conducted a retrospective study to investigate the impact of mediastinal LND on survival in patients with stage I NSCLC. Clinical data of patients with stage I NSCLC who were treated with surgical resection during a period of ten years were reviewed. The patients were categorized into lobectomy (or pneumonectomy) combined with mediastinal LND or lymph node sampling (LNS) according to the record of their operative procedures. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for multivariate analysis. Of the 319 patients who were included in the study, 139 patients received mediastinal LND, while 180 underwent LNS. There was a significant difference in overall survival (OS) between the group with LND and the group with LNS (5-year survival rate: 76.4 % vs. 65.9 %, P = 0.015 by log rank test). Multivariate analysis showed that lymph node dissection (RR = 0.548, 95 %CI: 0.350 - 0.858, P = 0.009), together with the stage, significantly influenced overall survival. Lobectomy combined with mediastinal LND can improve survival in patients with stage I NSCLC. It should be performed in all patients with clinical stage I NSCLC.


Wording of American Urological Association Guideline Recommendations Does Not Signal the Strength of Recommendation.
To systematically analyze the wording of American Urological Association (AUA) clinical practice guidelines' recommendations. We systematically identified all AUA guideline documents that used the current AUA framework and extracted the individual recommendations, their statement type, and their corresponding evidence level (if applicable), and analyzed the recommendation wording separating out the modal verbs (eg, should, may, or must) as well as the main verbs (eg, recommend, treat, perform). We performed descriptive statistics using SPSS Version 27. We included 18 documents with 754 distinct recommendations; the median number of recommendations per guideline was 36 (interquartile range: 29; 48.5). Expert opinion was the most used statement type (193; 25.6%), followed by clinical principle (156; 20.7%). Four-hundred-four recommendations were either strong, moderate, or conditional: 135 (17.9%), 187 (24.8%) and 83 (11.0%), respectively. Most recommendation statements (701; 93.0%) used modal verbs to express a level of obligation. Overall, "should" was the most employed modal verb used (73.9%), followed by "may" (17.6%) and "must" (1.5%). Both "may" and "should" were used in conjunction with all five statement types, whereas "must" was limited to strong recommendations and clinical principles. The wording of AUA recommendation statements does not signal the strength of recommendation and the intended level of obligation, which may represent a barrier to guideline implementation. More consistent wording of recommendations by strength may improve guideline understanding, uptake, and adherence.


Effect of water quality on mercury toxicity to Photobacterium phosphoreum: Model development and its application in natural waters.
Mercury (Hg) compounds are widely distributed toxic environmental and industrial pollutants and they may bring danger to growth and development of aquatic organisms. The distribution of Hg species in the 3 percent NaCl solution was calculated using the chemical equilibrium model Visual MINTEQ, which demonstrated that Hg was mainly complexed by chlorides in the pH range 5.0-9.0 and the proportions of HgCl4(2-), HgCl3(-) and HgCl2(aq) reached to 95 percent of total Hg. Then the effects of cations (Ca(2+), Mg(2+), K(+) and H(+)), anions (HCO3(-), NO3(-), SO4(2-) and HPO4(2-)) and complexing agents (ethylene diamine tetraacetic acid (EDTA) and dissolved organic matter (DOM)) on Hg toxicity to Photobacterium phosphoreum were evaluated in standardized 15min acute toxicity tests. The significant increase of 6.3-fold in EC50 data with increasing pH was observed over the tested pH range of 5.0-8.0, which suggested the possible competition between hydroxyl and the negatively charged chloro-complex. By contrast, it was found that major cations (Ca(2+), Mg(2+) and K(+)) have little effect on Hg toxicity to P. phosphoreum. An interesting finding was that the addition of HPO4(2-) significantly increased Hg toxicity, which may imply that the addition of phosphate increased the soluble Hg-chloro complex species. Additions of complexing agents (EDTA and DOM) into the exposure water increased Hg bioavailability via complexation of Hg. Finally, a model which incorporated the effect of pH, HPO4(2-), HCO3(-), SO4(2-) and DOM on Hg toxicity was developed to predict acute Hg toxicity for P. phosphoreum, which may be a useful tool in setting realistic water quality criteria for different types of water.


Comparison of risk factors of cardiovascular diseases in male and female nurses.
Cardiovascular disease is one of the most important causes of mortality in the world; identifying and correcting the modifiable risk factors reduce the prevalence of coronary artery disorders. Nurses, with regard to their employment conditions, can be prone to cardiovascular disease. The aim of this study was to compare the risk factors of cardiovascular diseases in male and female nurses. In this descriptive cross-sectional study, 263 nurses from Jahrom University of Medical Sciences hospitals were enrolled in the study by convenience sampling. The data collection tool was self-report Framingham Risk Score and has two parts: first part: personal data, history of disease, history, cigarette, stress and fat disorder, alcohol consumption, diet, exercise, and average hours and second part: height, weight, body mass index (BMI), waist-to-stature ratio (WSR), waist-to-hip ratio (WHR), blood pressure, triglyceride (TG), cholesterol, and fasting blood sugar. The benchmark for blood pressure was the JNC-7 guide. The Adult Treatment Panel III was the guideline. Independent t-test, Chi-square, and Mann-Whitney tests were used for data analysis. None of the staff reported smoking or alcohol history. Data were analyzed using descriptive and inferential statistics. There was no statistically significant difference between the mean of fasting blood glucose, systolic and diastolic blood pressure, TG and cholesterol, Framingham percentage, religious practices, green tea and black tea, fish, vegetables, and fast food. The data were analyzed with independent t-test, Chi-square, and Mann-Whitney tests. There was no statistically significant difference between the mean of fasting blood glucose, systolic and diastolic blood pressure, TG and cholesterol, Framingham Percentage, religious practices, green tea and black tea, fish, vegetables, and fast food and sports and walking of men and women were not observed. However, there was a statistically significant difference between women and men in indicators such as eating breakfast, family history, fruit consumption, high-density lipoprotein, BMI, WSR, and WHR. The results of the study showed that men are at higher risk for cardiovascular diseases and complications than women.


Effect of fixation tasks on multifocal visual evoked potentials.
This study investigated the effects of cognitive influence on the multifocal visual evoked potential (mVEP) at different levels of eccentricity. Three different foveal fixation conditions were utilized involving varying levels of task complexity. A more complex visual fixation task has been known to suppress peripheral signals in subjective testing. Twenty normal subjects had monocular mVEPs recorded using the AccuMap objective perimeter. This allowed simultaneous stimulation of 58 segments of the visual field to an eccentricity of 24 degrees. The mVEP was recorded using three different fixation conditions in random order. During task 1 the subject passively viewed the central fixation area. For task 2 alternating numbers were displayed within the fixation area; the subject on viewing the number '3' in the central fixation area indicated recognition by pressing a button. Throughout task 3, numbers were displayed as in task 2. The subject had the cognitive task of summating all the numbers. Analysis revealed that the increased attention and concentration demanded by tasks 2 and 3 in comparison with task 1 resulted in significantly enhanced central amplitudes of 9.41% (Mann-Whitney P = 0.0002) and 13.45% (P = 0.0002), respectively. These amplitudes became reduced in the periphery and approached those of task 1, resulting in no significant difference between the three tasks. Latencies demonstrated no significant difference between each task nor at any eccentricity (P > 0.05). As the complexity of each task increased the amount of alpha rhythm was significantly reduced. Our findings indicate that task 1 required a minimal demand of cognition and was associated with the greatest amount of alpha rhythm. It was also the most difficult to perform because of loss of interest. The other two tasks required a greater demand of higher order cognitive skills resulting in significantly enhanced amplitudes centrally and the attenuation of alpha rhythm. Therefore, amplitudes are increased around the area of attention.


Second-generation bone cement-injectable cannulated pedicle screws for osteoporosis: biomechanical and finite element analyses.
Biomechanical and finite element analyses were performed to investigate the efficacy of second-generation bone cement-injectable cannulated pedicle screws (CICPS) in osteoporosis. This study used the biomechanical test module of polyurethane to simulate osteoporotic cancellous bone. Polymethylmethacrylate (PMMA) bone cement was used to anchor the pedicle screws in the module. The specimens were divided into two groups for the mechanical tests: the experimental group (second-generation CICPS) and control group (first-generation CICPS). Safety was evaluated using maximum shear force, static bending, and dynamic bending tests. Biomechanical stability evaluations included the maximum axial pullout force and rotary torque tests. X-ray imaging and computed tomography were used to evaluate the distribution of bone cement 24 h after PMMA injection, and stress distribution at the screw fracture and screw-cement-bone interface was assessed using finite element analysis. Mechanical testing revealed that the experimental group (349.8 ± 28.6 N) had a higher maximum axial pullout force than the control group (277.3 ± 8.6 N; P < 0.05). The bending moments of the experimental group (128.5 ± 9.08 N) were comparable to those of the control group (113.4 ± 20.9 N; P > 0.05). The screw-in and spin-out torques of the experimental group were higher than those of the control group (spin-in, 0.793 ± 0.015 vs. 0.577 ± 0.062 N, P < 0.01; spin-out, 0.764 ± 0.027 vs. 0.612 ± 0.049 N, P < 0.01). Bone cement was mainly distributed at the front three-fifths of the screw in both groups, but the distribution was more uniform in the experimental group than in the control group. After pullout, the bone cement was closely connected to the screw, without loosening or fragmentation. In the finite element analysis, stress on the second-generation CICPS was concentrated at the proximal screw outlet, whereas stress on the first-generation CICPS was concentrated at the screw neck, and the screw-bone cement-bone interface stress of the experimental group was smaller than that of the control group. These findings suggest that second-generation CICPS have higher safety and stability than first-generation CICPS and may be a superior choice for the treatment of osteoporosis.


Development and evaluation of an off-the-slide genotyping technique for identifying Giardia cysts and Cryptosporidium oocysts directly from US EPA Method 1623 slides.
This study developed and systematically evaluated performance and limit of detection of an off-the-slide genotyping procedure for both Cryptosporidium oocysts and Giardia cysts. Slide standards containing flow-sorted (oo)cysts were used to evaluate the off-the-slide genotyping procedure by microscopy and PCR. Results show approximately 20% of cysts and oocysts are lost during staining. Although transfer efficiency from the slide to the PCR tube could not be determined by microscopy, it was observed that the transfer process aided in the physical lysis of the (oo)cysts likely releasing DNA. PCR detection rates for a single event on a slide were 44% for Giardia and 27% for Cryptosporidium, and a minimum of five cysts and 20 oocysts are required to achieve a 90% PCR detection rate. A Poisson distribution analysis estimated the relative PCR target densities and limits of detection, it showed that 18 Cryptosporidium and five Giardia replicates are required for a 95% probability of detecting a single (oo)cyst on a slide. This study successfully developed and evaluated recovery rates and limits of detection of an off-the-slide genotyping procedure for both Cryptosporidium and Giardia (oo)cysts from the same slide. This off-the-slide genotyping technique is a simple and low cost tool that expands the applications of US EPA Method 1623 results by identifying the genotypes and assemblages of the enumerated Cryptosporidium and Giardia. This additional information will be useful for microbial risk assessment models and watershed management decisions.


Effects of dietary fish oil on serum lipids and blood coagulation in peritoneal dialysis patients.
The effects of a daily fish oil supplement rich in eicosapentaenoic acid were studied in 11 stable continuous ambulatory peritoneal dialysis (CAPD) patients. Serum lipids, platelet aggregation studies, and template bleeding times were determined before and after 4 weeks of fish oil treatment. The lipid studies were repeated approximately 20 weeks after stopping fish oil supplement. At the end of the treatment period, serum triglycerides (mean +/- SEM) decreased from 297 +/- 42 to 211 +/- 29 mg/dL (P less than .01), high density lipoprotein (HDL) cholesterol fell from 45 +/- 3 to 41 +/- 3 mg/dL (P less than .05), and low density lipoprotein (LDL) cholesterol increased from 172 +/- 16 to 208 +/- 19 mg/dL (P less than .05). After discontinuing the fish oil supplement, the triglycerides increased to 278 +/- 39 mg/dL, which was no different than the value before fish oil treatment. No significant changes occurred in template bleeding time (TBT), platelet count, hematocrit, or platelet aggregation response. Clinically important uremic bleeding was not apparent. We conclude that in CAPD patients a fish oil supplement favorably effects hypertriglyceridemia and can be ingested without promoting uremic bleeding. The likely beneficial impact on atherogenesis resulting from the lowering of the triglycerides may, however, be counteracted by concomitant changes in HDL- and LDL-cholesterol.


Correction to: Malachite Green and Crystal Violet Decolorization by Ganoderma lucidum and Pleurotus ostreatus Supernatant and by rGlLCC1 and rPOXA 1B Concentrates: Molecular Docking Analysis.
The original version of this article unfortunately contained a mistake. The replacement image of Fig. 4 provided by the first corresponding author, Aura M. Pedroza-Rodríguez, is incorrect and that the originally submitted Fig. 4 should have been retained. The original article has been corrected.


Results of microsurgical management of ruptured intracranial aneurysms.
The authors report the results of microsurgical management of 209 cases of ruptured intracranial aneurysms. The outcome of the surgery is discussed from the point of view of operative timing, preoperative grade, age and the effect of vasospasm. The operative results at the time of discharge were as follows: 137 excellent cases, 18 good, 31 fair, 8 poor and 15 deaths. The overall mortality rate was 7% and those patients designated as excellent and good who returned to work fully accounted for 74%. The result was achieved even though 65% of the patients were operated on within 2 weeks after the onset, and 44% of the patients were categorized as grade III, IV and V in Hunt's classification. In the morbidity and mortality, over half of the patients categorized as fair, poor and death were complicated by vasospasm, and the result was attributed mainly to the vasospasm. Therefore, we strongly believe that radical surgery is recommended to prevent rebleeding in the waiting period, there should be a greater understanding of "vasospasm" in order to improve overall morbidity and mortality.


Labial salivary gland biopsy for diagnosis of amyloid polyneuropathy.
Biopsies of peroneal nerve and labial salivary gland (LSG) were performed in 32 patients with polyneuropathy of unknown origin. Amyloid deposits were detected in 7 LSG (transthyretin=5; amyloid, light chain derived=2) and 6 nerve biopsies. Familial amyloid and light chain amyloid polyneuropathies were subsequently confirmed by relevant tests. We propose that LSG biopsy, a minimally invasive test that may document both sicca syndrome and amyloidosis, should be systematically performed in the investigation of patients with axonal polyneuropathies.


3D navigation of endoscopic rhizotomy at the lumbar spine.
We present a detailed description of the surgical technique and the preliminary results of an endoscopic denervation for patients with chronic low back pain (CLBP) originating from the facet joints (FJ). Endoscopic denervation of the medial branches of the dorsal rami supplying the FJ has recently been appraised as providing excellent intraoperative visualization and long term pain relief for these patients. Conventional endoscopic rhizotomy has been expanded to include a the precise localization of 3D navigation. A surgical description and the results of our first four patients treated with 3D navigated endoscopic rhizotomy (3DNER) are presented. Four patients with a mean age of 59years and a follow-up time of 2months were included. All patients reported pain reduction in the immediate postoperative period, while three patients (75%) had long lasting relief. The patient without persisting relief had previously sustained a lumbar disc prolapse and only achieved minor pain relief with preoperative FJ infiltration, compared to the significant relief that was seen in the other patients. In contrast to conventional rhizotomy, 3DNER enables the surgeon to ablate more precisely and extensively, which is especially useful if scar tissue is present from previous injuries or surgeries. When successful, this technique may provide long lasting pain relief, especially if the preoperative FJ infiltrations are followed by a substantial pain reduction.


Changes in islet glucan-1,4-alpha-glucosidase activity modulate sulphonylurea-induced but not cholinergic insulin secretion.
We have previously presented indirect in vivo evidence for the involvement of islet acid glucan-1,4-alpha-glucosidase (acid amyloglucosidase), a lysosomal glucose-producing enzyme, in certain insulin secretory processes. In the present in vitro and in vivo investigation, we studied whether differential changes in islet acid amyloglucosidase activity would be related to the insulin secretory response induced by two mechanistically different secretagogues, the sulphonylurea derivative, glibenclamide and the acetylcholine receptor agonist, carbachol. It was observed that the selective alpha-glucosidehydrolase inhibitors emiglitate and acarbose markedly reduced glibenclamide-induced insulin release from isolated islets. Insulin release stimulated by carbachol or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate), was not inhibited. Basal insulin secretion was unaffected by emiglitate and acarbose. Further, pretreatment of mice with emiglitate resulted in a marked reduction of the in vivo insulin response to glibenclamide. Moreover, in vivo pretreatment with purified fungal amyloglucosidase ('enzyme replacement'), a procedure known to increase islet amyloglucosidase activity, greatly enhanced the insulin response to i.v. glibenclamide. This insulin release was accompanied by a marked depression of the blood glucose levels. In contrast, enzyme pretreatment did not influence the insulin response or the blood glucose levels after carbachol. The data strongly suggest that islet acid amyloglucosidase is involved in the insulin secretory processes induced by glibenclamide but not in those involving stimulation of muscarinic receptors or direct activation of protein kinase C. The results also indicate separate or at least partially separate pathways for insulin release induced by glibenclamide and cholinergic stimulation.


The middle colic vein: an alternative source of portal inflow in orthotopic liver transplantation complicated by portal vein thrombosis.
Portal vein thrombosis (PVT) was previously considered a contraindication to orthotopic liver transplantation (OLT) since adequate portal blood supply is mandatory for graft function and patient survival. Improvements in surgical technique, however, have meant that this problem now can be circumvented in most instances. Nevertheless portal vein thrombosis remains an obstacle in OLT and is associated with increased incidence of primary non-function and long-term liver failure. A 55-yr-old patient underwent OLT for secondary biliary cirrhosis associated with hepatitis C infection and complicated by long standing PVT. Involvement of the portal, mesenteric, and splenic veins prevented standard portal venous reconstruction. Portal inflow was accomplished by a side-to-end anastomosis between the middle colic vein and the donor portal vein. Hepatic reperfusion and subsequent liver function were excellent. Portal blood flow, as measured by color-enhanced Doppler ultrasound, was normal following surgery until discharge. The post-operative course was complicated by abdominal wound dehiscence and recurrent cytomegalovirus (CMV) infection. The patient was discharged in good clinical condition, with excellent liver function and patent portal vein 89 d after OLT. The middle colic vein is a novel, not previously described, source of portal venous inflow for OLT complicated by extensive splanchnic venous inflow thrombosis.


A systematic review of the validity, reliability, and feasibility of measurement tools used to assess the physical activity and sedentary behaviour of pre-school aged children.
Physical activity (PA) and sedentary behaviour (SB) of pre-school aged children are associated with important health and developmental outcomes. Accurate measurement of these behaviours in young children is critical for research and practice in this area. The aim of this review was to examine the validity, reliability, and feasibility of measurement tools used to assess PA and SB of pre-school aged children.Searches of electronic databases, and manual searching, were conducted to identify articles that examined the measurement properties (validity, reliability or feasibility) of measurement tools used to examine PA and/or SB of pre-school aged children (3-7 years old). Following screening, data were extracted and risk of bias assessment completed on all included articles.A total of 69 articles, describing 75 individual studies were included. Studies assessed measurement tools for PA (n = 27), SB (n = 5), and both PA and SB (n = 43). Outcome measures of PA and SB differed between studies (e.g. moderate to vigorous activity, step count, posture allocation). Most studies examined the measurement properties of one measurement tool only (n = 65). Measurement tools examined included: calorimetry, direct observation, combined heart rate and accelerometry, heart rate monitors, accelerometers, pedometers, and proxy report (parent, carer or teacher reported) measures (questionnaires or diaries). Studies most frequently assessed the validity (criterion and convergent) (n = 65), face and content validity (n = 2), test-retest reliability (n = 10) and intra-instrument reliability (n = 1) of the measurement tools. Feasibility data was abstracted from 41 studies.Multiple measurement tools used to measure PA and SB in pre-school aged children showed some degree of validity, reliability and feasibility, but often for different purposes. Accelerometers, including the Actigraph (in particular GT3X versions), Actical, ActivPAL and Fitbit (Flex and Zip), and proxy reported measurement tools used in combination may be useful for a range of outcome measures, to measure intensity alongside contextual information.


Abstinence-contingent wage supplements for adults experiencing homelessness and alcohol use disorder: A randomized clinical trial.
This study evaluated the effectiveness of abstinence-contingent wage supplements in promoting alcohol abstinence and employment in adults experiencing homelessness and alcohol use disorder. A randomized clinical trial was conducted from 2019 to 2022. After a 1-month Induction period, 119 participants were randomly assigned to a Usual Care Control group (n = 57) or an Abstinence-Contingent Wage Supplement group (n = 62). Usual Care participants were offered counseling and referrals to employment and treatment programs. Abstinence-Contingent Wage Supplement participants could earn stipends for working with an employment specialist and wage supplements for working in a community job but had to maintain abstinence from alcohol as determined by transdermal alcohol concentration monitoring devices to maximize pay. Abstinence-Contingent Wage Supplement participants reported significantly higher rates of alcohol abstinence than Usual Care participants during the 6-month intervention (82.8% vs. 60.2% of months, OR = 3.4, 95% CI 1.8 to 6.3, p < .001). Abstinence-Contingent Wage Supplement participants were also significantly more likely to obtain employment (51.3% vs. 31.6% of months, OR = 2.6, 95% CI 1.5 to 4.4, p < .001) and live out of poverty (38.2% vs. 16.7% of months, OR = 3.7, 95% CI 2.0 to 7.1, p < .001) than Usual Care participants. These findings suggest that Abstinence-Contingent Wage Supplements can promote alcohol abstinence and employment in adults experiencing homelessness and alcohol use disorder. ClinicalTrials.gov Identifier: NCT03519009.


Liquid chromatography-tandem mass spectrometric assay with a novel method of quantitation for the simultaneous determination of bulaquine and its metabolite, primaquine, in monkey plasma.
A sensitive and selective liquid chromatography-tandem mass spectrometry method (LC-MS-MS) for the simultaneous estimation of bulaquine and primaquine has been developed and validated in monkey plasma. The mobile phase consisted of acetonitrile/ammonium acetate buffer (20 mM, pH 6) (50:50 v/v) at a flow-rate of 1 ml/min. The chromatographic separations were achieved on two spheri cyano columns (5 microm, 30 x 4.6 mm I.D.) connected in series. The quantitation was carried out using a Micromass LC-MS-MS with an electrospray source in the multiple reaction monitoring (MRM) mode. The analytes were quantified from the summed total ion value of their two most intense molecular transitions. This is another novel method leading to increased sensitivity and precision. A simple liquid-liquid extraction with 2 x 1.0 ml n-hexane/ethyl acetate/dimethyloctyl amine (90:10:0.05, v/v) was utilized. The method was validated in terms of recovery, linearity, accuracy and precision (within- and between-assay variation). The recoveries from spiked control samples were >or=90 and 50% for bulaquine and primaquine, respectively. Linearity in plasma was observed over a dynamic range of 1.56-400 and 3.91-1000 ng/ml for bulaquine and primaquine, respectively.


Improving Quality and Access to Radiation Therapy-An IAEA Perspective.
The International Atomic Energy Agency (IAEA) has been involved in radiation therapy since soon after its creation in 1957. In response to the demands of Member States, the IAEA׳s activities relating to radiation therapy have focused on supporting low- and middle-income countries to set up radiation therapy facilities, expand the scope of treatments, or gradually transition to new technologies. In addition, the IAEA has been very active in providing internationally harmonized guidelines on clinical, dosimetry, medical physics, and safety aspects of radiation therapy. IAEA clinical research has provided evidence for treatment improvement as well as highly effective resource-sparing interventions. In the process, training of researchers occurs through this program. To provide this support, the IAEA works with its Member States and multiple partners worldwide through several mechanisms. In this article, we review the main activities conducted by the IAEA in support to radiation therapy. IAEA support has been crucial for achieving tangible results in many low- and middle-income countries. However, long-term sustainability of projects can present a challenge, especially when considering health budget constraints and the brain drain of skilled professionals. The need for support remains, with more than 90% of patients in low-income countries lacking access to radiotherapy. Thus, the IAEA is expected to continue its support and strengthen quality radiation therapy treatment of patients with cancer.


Anti-alpha-fodrin antibodies do not add much to the diagnosis of Sjögren's syndrome.
The presence of anti-alpha-fodrin autoantibodies has been reported to be a highly specific and sensitive test for the diagnosis of Sjögren's syndrome (SjS). We looked (in Nijmegen) for anti-alpha-fodrin, anti-Ro60, and anti-La autoantibodies in a cohort of 51 patients with rheumatic diseases (primary SjS [21], secondary SjS 6, rheumatoid arthritis [RA] 12, systemic lupus erythematosus [SLE] 6, and scleroderma 6) and in 28 healthy subjects, using ELISA, immunoblotting, and immunoprecipitation. The same samples were analyzed with an alternative anti-alpha-fodrin ELISA in Hanover. The Nijmegen ELISA of the sera from primary SjS showed sensitivities of 43% and 48% for IgA- and IgG-type anti-alpha-fodrin antibodies, respectively. The Hanover ELISA showed sensitivities of 38% and 10% for IgA- and IgG-type anti-alpha-fodrin antibodies, respectively. The ELISAs for alpha-fodrin showed six (Nijmegen) and four (Hanover) anti-alpha-fodrin-positive RA sera. IgA and IgG anti-fodrin antibodies were also present in four patients with secondary SjS. The sensitivities of Ro60 and La-antibodies in the Nijmegen ELISA were 67% and 62%, respectively. Unlike anti-alpha-fodrin antibodies, all anti-Ro60 and anti-La positive sera could be confirmed by immunoblotting or RNA immunoprecipitation. Thus, anti-Ro and anti-La autoantibodies were more sensitive than anti-alpha-fodrin autoantibodies in ELISA and were more frequently confirmed by other techniques. Anti-La antibodies appear to be more disease-specific than anti-alpha-fodrin antibodies, which are also found in RA sera. Therefore, the measurement of anti-alpha-fodrin autoantibodies does not add much to the diagnosis of Sjögren's syndrome.


Titanium interlayer-mediated hydroxyapatite-coated polyetheretherketone cage in transforaminal lumbar interbody fusion surgery.
The variance in clinical responses to polyetheretherketone (PEEK) cages with titanium (Ti) and hydroxyapatite (HA) coatings (PEEK-Ti-HA cages) is still not clear. In this study, we aimed to evaluate the radiographic and clinical outcomes of patients undergoing TLIF using PEEK-Ti-HA cages with a particular focus on fusion rate. A prospective and nonrandomized study was conducted to compare the outcomes of PEEK-Ti-HA cages (group A, n = 32) and uncoated PEEK cages (group B, n = 32). The follow up time was at least 2 years. The radiographic assessments included the regional lordosis (RL), disc height (DH), and fusion rate. The clinical indexes included the Japanese Orthopedic Association (JOA) scores and visual analog scale (VAS) scores (back and leg). No significant differences were found in the pre- and postoperative RL and DH between Group A and Group B. And RL and DH, even if there were any variance initially, were restored not long after surgery in both groups. Though Group A had a significantly higher fusion rate than group B at 3 months post-surgery (93.7% vs. 75.0%), the fusion rates for the two groups reached the same level (100%) when it comes to the final follow-up. Additionally, differences of VAS and JOA scores for the two groups in general approximate. PEEK-Ti-HA cages, in contrast with uncoated PEEK cages, produced a better fusion rate at 3 months after single-level TLIF. The fusion rates of both groups could get 100% at the final follow-up. PEEK-Ti-HA cages could achieve similar RL, DH, JOA scores and VAS scores in comparison with uncoated PEEK cages post-surgery.


Graded contusion model of the mouse spinal cord using a pneumatic impact device.
This study examined the effects of varying magnitudes of controlled spinal cord impact to the mouse spinal cord on neurological and histopathological variables to obtain a mouse model of spinal cord injury (SCI). A laminectomy of the T10 vertebra was performed on anesthetized C57BL/6 mice. A pneumatic pressure-driven impact was performed on the spinal cord through the dura mater. Experimental groups were subdivided according to the energy of impact (0.25-mm-deep deformations): Group 1 (n = 5), impact velocity at 1 m/s; Group 2 (n = 5), impact velocity at 2 m/s; and Group 3 (n = 5), impact velocity at 3 m/s. Functional deficits over time were evaluated up to 28 days after SCI by testing hindlimb reflex and coordinated motor function. The extent of the lesions was analyzed histopathologically and quantified by a morphometric measurement. Mice of all groups exhibited profound functional deficits immediately after injury and subsequent gradual symptomatic recovery. The degrees of recovery were precisely correlated with the magnitudes of impact. The extent of resultant cord lesions was highly reproducible among animals, with little variance: means +/- standard deviation, 0.86 +/- 0.06/100 mm3 in Group 1; 2.4 +/- 0.28/100 mm3 in Group 2; and 11.0 +/- 1.0/100 mm3 in Group 3. Our results indicate that this model provides constant functional and histopathological lesions according to impact energy. This new mouse model of SCI opens a new avenue for studies investigating roles and/or effects of specific genes in the recovery process of SCI.


Histopathology of liver and kidneys of wild living Mallards Anas platyrhynchos and Coots Fulica atra with considerable concentrations of lead and cadmium.
Concentrations of cadmium and lead were measured in liver and kidneys of Mallard (n=60) and Coot (n=50). Free living birds were collected by hunters in years 2006-2008 in the area of fishponds near Zator in southern Poland. Age group was determined according to the appearance of the plumage (Mallards) and iris color (Coot). Concentrations of metals were measured with ET-AA spectrometer. Among all birds specimens with negligible (n=5) and high concentrations (Mallards n=18 and Coots n=17) of cadmium and lead were chosen for further analysis. Histopathological alterations were observed, ranging from circulatory disturbances, retrogressive changes, inflammations to leukocytic infiltration in liver and kidney. They dominated among birds with the highest concentrations of metals. The control group of birds was characterized by a very small number of mentioned lesions. Probably the higher cadmium and lead concentrations in tissues are co-factors in the development of lesions.


The 2010 Haiti earthquake response.
This article presents an overview of the mental health response to the 2010 Haiti earthquake. Discussion includes consideration of complexities that relate to emergency response, mental health and psychosocial response in disasters, long-term planning of systems of care, and the development of safe, effective, and culturally sound mental health services in the Haitian context. This information will be of value to mental health professionals and policy specialists interested in mental health in Haiti, and in the delivery of mental health services in particularly resource-limited contexts in the setting of disasters.


5-Hydroxytryptamine 1A receptors inhibit cold-induced sympathetically mediated cutaneous vasoconstriction in rabbits.
5-HT1A receptor agonists lower body temperature. We have investigated whether activation of 5-HT1A receptors inhibits cutaneous sympathetic discharge so that dilatation of the cutaneous vascular bed lowers body temperature by increasing heat transfer to the environment. We measured ear pinna blood flow in conscious rabbits (with chronically implanted Doppler ultrasound flow probes), and postganglionic sympathetic vasomotor nerve activity in anaesthetized rabbits. Recordings from conscious rabbits were made in a cage at 26 degrees C and the rabbit was then transferred to a cage at 10 degrees C. The ear pinna Doppler signal fell from 56 +/- 4 cm s-1 in the 26 degrees C cage to 4 +/- 1 cm s-1 (P < 0.0001, n = 24) after 30 min in the 10 degrees C cage, and body temperature increased from 38.8 +/- 0.2 to 39.0 +/- 0.2 degrees C (P < 0.01, n = 24). The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg kg-1 I.V.) reversed the cold-induced fall in ear pinna blood flow (Doppler signal increased from 5 +/- 1 to 55 +/- 8 cm s-1, P < 0.001, n = 7) within 5 min when administered 30 min after transfer to the 10 degrees C cage, and prevented the fall in ear pinna blood flow when administered before the rabbit was transferred to the 10 degrees C cage. Body temperature decreased after administration of 8-OH-DPAT. These changes were abolished by the specific 5-HT1A antagonist WAY-100635 (0.1 mg kg-1 I.V.). In anaesthetized rabbits, 8-OH-DPAT (0.1 mg kg-1 I.V.) reduced resting postganglionic cutaneous sympathetic vasomotor discharge, and prevented the increase normally elicited by cooling the trunk. Our experiments constitute the first demonstration that activation of 5-HT1A receptors powerfully inhibits cold-induced increases in cutaneous sympathetic vasomotor discharge, thereby dilating the cutaneous vascular bed and increasing transfer of heat to the environment.


Endocrinological evaluation of dawn phenomenon in patients with diabetes and comparison of insulin glargine U-100 biosimilar (Insulin Glargine BS Injection "Lilly") and glargine U-300 (Lantus XR): a randomized controlled study.
We investigated the pathophysiology of the dawn phenomenon by examining the effects of changes in blood glucose levels from late night to early morning on various hormones in a group taking glargine BS and a group taking Lantus XR, with the goal of achieving better glycemic control. Patients with types 1 and 2 diabetes scheduled for inpatient education were divided into BS and XR groups. Blood glucose levels were tracked from 0:00 to 7:00, while blood samples were extracted at 3:00 and 7:00 to measure glucose levels and hormones related to the dawn phenomenon. Overall, we analyzed blood sample and intermittently scanned Continuous Glucose Monitoring data of 43 and 40 patients, respectively. From 0:00 to 7:00, the mean blood glucose was significantly lower in the BS group, although the fluctuation was similar (p < 0.0001). The BS group also exhibited significantly higher ∆ACTH (p = 0.0215) and ∆ cortisol (p = 0.0430) than the XR group. In the BS group, ∆Glu exhibited a significant negative correlation with ∆ACTH and ∆cortisol (p = 0.0491). Similar findings were not observed in the XR group. These results suggest that XR may be a better choice for long-acting insulin since it is less likely to induce cortisol secretion. Further, analysis of the dawn phenomenon and non-dawn phenomenon groups showed the mean CPR levels at 3:00 and 7:00 were significantly higher in the latter (p = 0.0135). This supports the conventional belief that appropriate basal insulin replacement therapy is a beneficial treatment for the dawn phenomenon.


Mucilaginibacter Phenanthrenivorans sp. nov., a Novel Phenanthrene Degradation Bacterium Isolated from Wetland Soil.
BJC16-A38T, a Gram-negative, aerobic and non-motile rod-shaped strain was isolated from a permafrost wetland soil sample. BJC16-A38T was oxidase- and catalase-positive, and produced pale yellow colonies on modified R2A agar plates. The 16S rRNA gene sequence of BJC16-A38T shared the highest sequence similarity with those of Mucilaginibacter xinganensis BJC16-A31T (97.44%), Mucilaginibacter gotjawali SA3-7T (96.79%) and Mucilaginibacter frigoritolerans FT22T (96.14%). Phylogenetic analysis revealed that BJC16-A38T formed a separate lineage together with strain M. xinganensis BJC16-A31T in the genus Mucilaginibacter. BJC16-A38T contained menaquinone-7 (MK-7) as the predominant isoprenoid quinine. Major fatty acids in cells were iso-C15:0, summed feature 3 (16:1ω7c/16:1ω6c) and iso-C17:03-OH. BJC16-A38T contained phosphatidylethanolamine, two unknown polar lipids, six unidentified phospholipids and an unidentified aminolipid. The Genome of BJC16-A38T was sequenced using the Genome Analyzer IIx sequence platform and 38 contigs were produced in total with an average G + C percentage of 44.00%. The average nucleotide identity (ANI) of BJC16-A38T with respect to those of M. xinganensis BJC16-A31T, M. gotjawali SA3-7T and M. frigoritolerans FT22T were 79.60%, 77.24% and 77.58%, respectively. Digital DNA-DNA hybridization (DDH) values between BJC16-A38T and the tree reference strains were 21.30%, 19.60% and 19.70%, respectively. BJC16-A38T exhibited phenanthrene biodegradation activity that can degrade 88.02% phenanthrene in the MM medium after 7 days cultivation. Phenotypic, chemotaxonomic, phylogenetic and genomic characteristics concluded that strain BJC16-A38T represents a novel species of the genus Mucilaginibacter. Hence, the name Mucilaginibacter phenanthrenivorans sp. nov. is proposed. The type strain is BJC16-A38T (= CGMCC 1.12693T = NBRC 110383T).


Effect of ETH615, an inhibitor of leukotriene synthesis and IL-8 gene expression, on murine dermatoses.
ETH615 (4-[2-quinolylmethoxy]-N-[3-fluorobenzyl]-phenylaminometh yl-4-benzoic acid) is a potent inhibitor of leukotriene biosynthesis in A23187-stimulated leukocytes, and of IL-8 gene expression in LPS-stimulated PBMC. It shows anti-inflammatory activity in a canine model of dermal inflammation. A topical formulation is present in phase II clinical trials. In the present study the effect of ETH615 on oxazolone-induced acute inflammation and phorbol ester-induced chronic inflammation in the mouse ear was investigated. Betamethasone (0.04 mg/ear) and ETH615 (1-1.5 mg/ear) significantly inhibited both the oedema formation and the PMN infiltration. The cream and ointment formulations of ETH615 developed for clinical studies were equally active. ETH615 is thus an anti-inflammatory agent in these murine models of dermatosis.


Influence of bed rest on the pharmacokinetics of phenazone.
The pharmacokinetics of a single dose of phenazone was studied in six objects while ambulant and during bed rest for 3 days. Elimination of the drug was followed for 12 h after oral and intravenous administration. The elimination rate constant and total body clearance were significantly increased during bed rest as compared to the ambulant period, but the differences were small. The apparent volume of distribution decreased significantly. No consistent change due to bed rest was found in the rate of absorption or bioavailability of the oral dose.


Diabetes impairs periosteal progenitor regenerative potential.
Diabetics are at increased risk for fracture, and experience severely impaired skeletal healing characterized by delayed union or nonunion of the bone. The periosteum harbors osteochondral progenitors that can differentiate into chondrocytes and osteoblasts, and this connective tissue layer is required for efficient fracture healing. While bone marrow-derived stromal cells have been studied extensively in the context of diabetic skeletal repair and osteogenesis, the effect of diabetes on the periosteum and its ability to contribute to bone regeneration has not yet been explicitly evaluated. Within this study, we utilized an established murine model of type I diabetes to evaluate periosteal cell differentiation capacity, proliferation, and availability under the effect of a diabetic environment. Periosteal cells from diabetic mice were deficient in osteogenic differentiation ability in vitro, and diabetic mice had reduced periosteal populations of mesenchymal progenitors with a corresponding reduction in proliferation capacity following injury. Additionally, fracture callus mineralization and mature osteoblast activity during periosteum-mediated healing was impaired in diabetic mice compared to controls. We propose that the effect of diabetes on periosteal progenitors and their ability to aid in skeletal repair directly impairs fracture healing.


Radiation therapy: Regulatory framework and constraints.
The purpose of this article is to describe the regulatory framework of the radiotherapy practice in France.


Parental inflammatory bowel disease and risk of asthma in offspring: a nationwide cohort study in denmark.
Common genetic and environmental risk factors may explain the concurrent increase in the incidence of both inflammatory bowel disease (IBD) and asthma. We examined whether IBD in a parent is associated with an increased asthma risk in offspring. This was a registry-based cohort study of all children born alive in Denmark in 1979-2009, followed through 2010. IBD and asthma were identified using hospital diagnoses; antiasthma medication was also used to identify asthma. We computed risk of asthma and estimated adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CIs) using Cox proportional-hazards regression. We evaluated asthma risk according to maternal and paternal IBD, Crohn's disease (CD), and ulcerative colitis (UC). Children without parental IBD were the comparison cohort for all comparisons. We identified 1,845,281 children, of whom 14,952 (0.8%) had a parent with IBD. The 10-year risk of asthma was 6.9% among offspring of parents with CD, 5.6% among offspring of parents with UC, and 5.0% among offspring of parents without IBD. The aIRR for asthma associated with parental IBD was 0.98 (95% CI: 0.91-1.04). The aIRR was 1.09 (95% CI: 0.98-1.22) for parental CD and 0.92 (95% CI: 0.84-1.00) for parental UC. Results were similar regardless of parent of origin or inclusion of antiasthma medication to define asthma. Our data do not provide evidence for an increased risk of asthma in offspring with a parental history of IBD.


[Factors Influencing Access to Follow-Up Rehabilitation].
Identification of patient-related influencing factors on access to follow-up rehabilitation METHODS: Partially standardized, written survey of patients between the ages of 18 and 65 in 3 acute hospitals in Hanover, who were assigned to one of the following six defined indication groups on the basis of their diagnosis: (1) surgically treated bone fractures, (2) knee and hip endoprosthesis, (3) malignant disease from visceral surgery, (4) heart disease without surgical intervention, (5) heart disease with surgical intervention, and (6) stroke. In addition to personal information (such as age and gender) personal rehabilitation goals, rehabilitation motivation, disease processing, functioning, state of health, the knowledge of right to request and suffrage and the personal desire to start a follow-up rehabilitation were raised. Of the 1,227 patients surveyed, 42.5% received follow-up rehabilitation. The percentages between the groups of diagnoses varied widely and were lowest after conservatively treated heart disease (3.2%) and highest after knee and hip joint replacement (98.1%). Including cases with a follow-up rehabilitation relevant diagnosis (n=1,000), the proportion of persons with rehabilitation increased to 51.7% (p<0.001). Reasons for an untreated follow-up rehabilitation were in rare cases the rejection by the payer (0.7%), the rejection by the patient (1.6%) or the lack of rehabilitation ability (3.3%). However in most cases the application remained without further differentiation (28.5%). The most important factor influencing follow-up rehabilitation access were diagnosis. Compared to knee- and hip endoprosthesis, the patients from other relevant diagnosis groups had a much lower chance to start a follow-up rehabilitation (OR from 0,01 up to 0,07; p<0,001). The desire of the patient showed the second most and significant influence to get follow-up rehabilitation (OR=8.18; p<0.001). The diagnosis was identified as the most important criterion for follow-up rehabilitation access. No measurable factors of functioning seem to have a big influence. Therefore, the individual doctor's decision to submit an application is of particular importance. Especially because of the low level of medical knowledge on the indication catalog of the German pension insurance, the medical treatment based on professional experience as well as the lack of further education possibilities (Gottschling-Lang, 2016), it can be assumed that the follow-up rehabilitation is less standardized and systematic. In order to ensure a need-based patient care, assessment procedures should be established and the training and continuing education of physicians should be supplemented with the topic of follow-up rehabilitation.


Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor.
Biologic aggressiveness of head and neck carcinoma is reflected in its capability to metastasize to regional lymph nodes and its propensity to recur after treatment. The authors report on 244 patients treated at the Department of Otolaryngology-Head and Neck Surgery of the Free University Hospital, Amsterdam, The Netherlands, with excision of primary tumor with incontinuity neck dissection with or without postoperative radiation therapy between January 1973 and July 1986. All patients had surgical margins free of tumor. The overall recurrence rate was 12.3%. Stages T3-4 and the presence of more than three positive nodes on histopathologic examination were associated with a 16.2% and 26.2% incidence in recurrence at the primary site, respectively. No prognostic influence arose from primary tumor localization, three or fewer positive nodes, extranodal spread, and postoperative radiation therapy. Patients with T3-4 disease and those with more than three positive lymph nodes may benefit from novel adjuvant treatment modalities.


Sleep disorders: causes, effects, and solutions.
Until recently, sleep has been a mystery even to scientists. Research has defined sleep function and the effects of sleep deprivation. Sleep disorders are interrelated with medical and psychiatric illnesses. This article presents insomnia, jet lag, and shift work sleep disorders and reviews issues related to women's health and sleep. Pharmacologic and behavioral treatments for sleep conditions are explored.


A quantitative assay of cortisol in human plasma by high performance liquid chromatography using a selective chemically bonded stationary phase.
The extraction and subsequent liquid chromatographic analysis of human plasma samples for cortisol is described. Extraction and chromatography are optimized, resulting in a recovery for cortisol of 96% and a detection limit of 1 microgram cortisol in 100 ml plasma. The application of two chemically modified silicas has been evaluated. The specificity of the method was tested by field desorption - mass spectrometry experiments.


Developmentally informed pharmacotherapy for child and adolescent depressive disorders.
This article reviews evidence-based pharmacotherapy for children and adolescents with depression. Several randomized controlled trials (RCTs) support the use of fluoxetine for the treatment of childhood and adolescent depression as well as escitalopram in the treatment of adolescent depression. To date, one RCT has demonstrated the effectiveness of sertraline or citalopram for the treatment of major depressive disorder in youth. Only a small number of RCTs for depression have included children, and none of these trials were adequately powered to detect differences in the efficacy of medication between children and adolescents.


Acute alcohol intoxication: significance of the amylase level.
To evaluate the effects of acute alcohol intoxication on serum amylase and isoamylase levels, 58 clinically intoxicated patients with blood alcohol levels greater than 100 mg/dL were studied. Comparisons were made to normal control and a sober chronic alcoholic group. Admitting serum isoamylase levels were determined by cellulose acetate membrane electrophoresis and serum amylase levels measured by the Amylochrome technique. The average blood alcohol level in the intoxicated group was 301 +/- 99 mg/dL. Thirty of the 58 patients had hyperamylasemia (greater than 207 IU). Twenty-five of these 30 patients had hyperamylasemia from nonpancreatic sources (increased salivary isoamylase). Two of the 30 patients had pancreatic hyperamylasemia and three patients had elevated levels of both isoamylases. Neither of the patients with pancreatic hyperamylasemia had clinical evidence of acute pancreatitis. Although nine of the 58 patients had abdominal pain and clinical symptoms suggestive of acute pancreatitis, none of these patients had elevated pancreatic isoamylase. The finding of hyperamylasemia in acutely intoxicated patients is common. This is most frequently due to a rise in the salivary (nonpancreatic) isoamylase. The reliability of the total serum amylase as an indication of pancreatic disease in the intoxicated patient is questioned.


Chronic lymphocytic leukemia--well-differentiated lymphocytic lymphoma with monoclonal IgA:IgA production by circulating lymphocytes.
A patient is described in whom morphologic features of well-differentiated lymphocytic lymphoma (WDL) or chronic lymphocytic leukemia (CLL) and immunologic features of multiple myeloma were present. Studies of isolated peripheral blood lymphocytes demonstrated de novo synthesis of IgA K, the same paraprotein that was identified in the serum. Predominant IgA synthesis by peripheral lymphocytes has not been previously shown in either WDL or CLL.