Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1.
Mutations of the AGXT gene encoding the alanine:glyoxylate aminotransferase liver enzyme (AGT) cause primary hyperoxaluria type 1 (PH1). Here we report a molecular modeling study of selected missense AGXT mutations: the common Gly170Arg and the recently described Gly47Arg and Ser81Leu variants, predicted to be pathogenic using standard criteria. Taking advantage of the refined 3D structure of AGT, we computed the dimerization energy of the wild-type and mutated proteins. Molecular modeling predicted that Gly47Arg affects dimerization with a similar effect to that shown previously for Gly170Arg through classical biochemical approaches. In contrast, no effect on dimerization was predicted for Ser81Leu. Therefore, this probably demonstrates pathogenic properties via a different mechanism, similar to that described for the adjacent Gly82Glu mutation that affects pyridoxine binding. This study shows that the molecular modeling approach can contribute to evaluating the pathogenicity of some missense variants that affect dimerization. However, in silico studies--aimed to assess the relationship between structural change and biological effects--require the integrated use of more than 1 tool.


Magnetic resonance imaging of cardiac and pericardial disease.
To date, most application of cardiovascular MRI relate to the evaluation of major vessels rather than the heart itself. However, MRI plays a major role in the evaluation of specific types of cardiovascular pathology, namely intracardiac and paracardiac masses, pericardial disease, and congenital heart disease. Because the visualization of cardiovascular anatomy with MR is non-invasive and permits three-dimensional analysis, it is clear that MRI will have a growing and significant impact over the next years. We will review some of the technical aspects of cardiac MRI and will describe the current and potential clinical and investigative applications of this new methodology.


A system for systems is required for quality health systems.
Improving quality of health-care requires a systematic approach at many different levels within a health system. The levels range from the interactions between individual patient-health provider to the international stage. The provision of care within and between each level needs to be systematically organised if the quality of our health-care is to improve. There is a need to develop a systematic approach to the multiple systems within health care. An organisational structure similar to the Cochrane Collaboration may provide the mechanism to better coordinate all our efforts to improve health-care quality.


Antibiotics for upper respiratory tract infections in ambulatory practice in the United States, 1997-1999: does physician specialty matter?
The dangers of overuse of antibiotics for upper respiratory infections (URIs) has been widely recognized, but the rate of change in prescribing patterns in recent years is unknown. Data on the use of antibiotics for URIs was extracted from the 1997 to 1999 National Ambulatory Medical Care Survey (a national multistage probability sample survey of patients' office visits to office-based physicians). Adult patients (>/=18 years) with a primary diagnosis of URI (bronchitis, common colds, and other acute upper respiratory infections) were included. The decision to prescribe antibiotics was modeled as a function of patient, physician, and practice characteristics using logistic regression. The rate of antibiotic prescription for URIs decreased from 52.1% in 1997 to 41.5% in 1999. In a multivariate logistic regression model, treatment by general internal medicine physicians [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.18 to 0.76] was associated with lower prescription rates. Of patients visiting general internal medicine physicians for URIs, 36.2% received antibiotics compared with 42.9% of those seeing a general/family medicine physician. Patients treated by their primary care physicians had a higher risk of receiving antibiotics (OR, 1.70; 95% CI, 1.08 to 2.68). Despite a downward trend in antibiotic prescribing over the years, overprescription of antibiotics for upper respiratory infections persists. General internal medicine physicians are less likely than general/family physicians to prescribe antibiotics, but this gap seems to be narrowing. Specific interventions must be designed to address these disparities.


A small asparagine-rich protein required for S-allele-specific pollen rejection in Nicotiana.
Although S-locus RNases (S-RNases) determine the specificity of pollen rejection in self-incompatible (SI) solanaceous plants, they alone are not sufficient to cause S-allele-specific pollen rejection. To identify non-S-RNase sequences that are required for pollen rejection, a Nicotiana alata cDNA library was screened by differential hybridization. One clone, designated HT, hybridized strongly to RNA from N. alata styles but not to RNA from Nicotiana plumbaginifolia, a species known to lack one or more factors necessary for S-allele-specific pollen rejection. Sequence analysis revealed a 101-residue ORF including a putative secretion signal and an asparagine-rich domain near the C terminus. RNA blot analysis showed that the HT-transcript accumulates in the stigma and style before anthesis. The timing of HT-expression lags slightly behind S(C10)-RNase in SI N. alata S(C10)S(C10) and is well correlated with the onset of S-allele-specific pollen rejection in the style. An antisense-HT construct was prepared to test for a role in pollen rejection. Transformed (N. plumbaginifolia x SI N. alata S(C10)S(C10)) hybrids with reduced levels of HT-protein continued to express S(C10)-RNase but failed to reject S(C10)-pollen. Control hybrids expressing both S(C10)-RNase and HT-protein showed a normal S-allele-specific pollen rejection response. We conclude that HT-protein is directly implicated in pollen rejection.


Localization and photodynamic efficacy of two cationic porphyrins varying in charge distributions.
Two meso-tetraphenylporphyrin derivatives bearing adjacent: 5,10-di[4-(N-trimethylaminophenyl)-15,20-diphenylporphyrin (DADP-a) or opposite: 5,15-di[4-(N-trimethylaminophenyl)-10,20-diphenylporphyrin (DADP-o) cationic-N-(CH3)3+ groups on two of the para-phenyl positions were examined with regard to photodynamic properties as a function of charge distribution. The two adjacent positive charges in the DADP-a structure result in a molecular distortion (asymmetry), likely from electrostatic repulsion. This could be responsible for the unusual interaction of this compound with some solvents and detergent micelles. In contrast, DADP-o is a much more symmetric molecule. In a cellular environment, fluorescence spectra of the two agents were essentially identical. Subcellular localization played a major role in photodynamic efficacy. DADP-a localized in mitochondria, and irradiation of photosensitized cells (640-650 nm) resulted in a rapid loss of the mitochondrial membrane potential (delta(psi)m), usually a prelude to apoptotic cell death. In contrast, DADP-o localized in lysosomes, and extensive lysosomal photodamage was observed after irradiation. Both steady-state accumulation levels and absorbance spectra favored DADP-o, but the light dose required for a 90% cell kill was two-fold greater for DADP-o than for DADP-a, at a constant extracellular sensitizer concentration. These data indicate that, on a photons/cell basis, DADP-a was five-fold more efficacious. Fluorescence emission spectra in different solvents and detergents demonstrated a tendency for DADP-a association. We interpret these results to indicate partition of both drugs to membrane loci, with mitochondriabeing the more lethal site for photodamage.


Explicit and implicit motor learning in children with unilateral cerebral palsy.
The current study aimed to investigate the capacity for explicit and implicit learning in children with unilateral cerebral palsy. Children with left and right unilateral cerebral palsy and typically developing children shuffled disks toward a target. A prism-adaptation design was implemented, consisting of pre-exposure, prism exposure, and post-exposure phases. Half of the participants were instructed about the function of the prism glasses, while the other half were not. For each trial, the distance between the target and the shuffled disk was determined. Explicit learning was indicated by the rate of adaptation during the prism exposure phase, whereas implicit learning was indicated by the magnitude of the negative after-effect at the start of the post-exposure phase. Results No significant effects were revealed between typically developing participants and participants with unilateral cerebral palsy. Comparison of participants with left and right unilateral cerebral palsy demonstrated that participants with right unilateral cerebral palsy had a significantly lower rate of adaptation than participants with left unilateral cerebral palsy, but only when no instructions were provided. The magnitude of the negative after-effects did not differ significantly between participants with right and left unilateral cerebral palsy. The capacity for explicit motor learning is reduced among individuals with right unilateral cerebral palsy when accumulation of declarative knowledge is unguided (i.e., discovery learning). In contrast, the capacity for implicit learning appears to remain intact among individuals with left as well as right unilateral cerebral palsy. Implications for rehabilitation Implicit motor learning interventions are recommended for individuals with cerebral palsy, particularly for individuals with right unilateral cerebral palsy Explicit motor learning interventions for individual with cerebral palsy - if used - best consist of singular verbal instruction.


Radiotherapy for Locally Advanced Pancreatic Adenocarcinoma-A Critical Review of Randomised Trials.
Pancreatic cancer is rising as one of the leading causes of cancer-related death worldwide. Patients often present with advanced disease, limiting curative treatment options and therefore making management of the disease difficult. Systemic chemotherapy has been an established part of the standard treatment in patients with both locally advanced and metastatic pancreatic cancer. In contrast, the use of radiotherapy has no clear defined role in the treatment of these patients. With the evolving imaging and radiation techniques, radiation could become a plausible intervention. In this review, we give an overview over the available data regarding radiotherapy, chemoradiation, and stereotactic body radiation therapy. We performed a systematic search of Embase and the PubMed database, focusing on studies involving locally advanced pancreatic cancer (or non-resectable pancreatic cancer) and radiotherapy without any limitation for the time of publication. We included randomised controlled trials involving patients with locally advanced pancreatic cancer, including radiotherapy, chemoradiation, or stereotactic body radiation therapy. The included articles represented mainly small patient groups and had a high heterogeneity regarding radiation delivery and modality. This review presents conflicting results concerning the addition of radiation and modality in the treatment regimen. Further research is needed to improve outcomes and define the role of radiation therapy in pancreatic cancer.


Well-defined nanostructured surface-imprinted polymers for highly selective magnetic separation of fluoroquinolones in human urine.
The construction of molecularly imprinted polymers on magnetic nanoparticles gives access to smart materials with dual functions of target recognition and magnetic separation. In this study, the superparamagnetic surface-molecularly imprinted nanoparticles were prepared via surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization using ofloxacin (OFX) as template for the separation of fluoroquinolones (FQs). Benefiting from the living/controlled nature of RAFT reaction, distinct core-shell structure was successfully constructed. The highly uniform nanoscale MIP layer was homogeneously grafted on the surface of RAFT agent TTCA modified Fe3O4@SiO2 nanoparticles, which favors the fast mass transfer and rapid binding kinetics. The target binding assays demonstrate the desirable adsorption capacity and imprinting efficiency of Fe3O4@MIP. High selectivity of Fe3O4@MIP toward FQs (ofloxacin, pefloxacin, enrofloxacin, norfloxacin, and gatifloxacin) was exhibited by competitive binding assay. The Fe3O4@MIP nanoparticles were successfully applied for the direct enrichment of five FQs from human urine. The spiked human urine samples were determined and the recoveries ranging from 83.1 to 103.1% were obtained with RSD of 0.8-8.2% (n = 3). This work provides a versatile approach for the fabrication of well-defined MIP on nanomaterials for the analysis of complicated biosystems.


Speciation in a biodiversity hotspot: Phylogenetic relationships, species delimitation, and divergence times of Patagonian ground frogs from the Eupsophus roseus group (Alsodidae).
The alsodid ground frogs of the Eupsophus genus are divided into two groups, the roseus (2n = 30) and vertebralis (2n = 28), which are distributed throughout the temperate Nothofagus forests of South America. Currently, the roseus group is composed by four species, while the vertebralis group consists of two. Phylogenetic relationships and species delimitation within each group are controversial. In fact, previous analyses considered that the roseus group was composed of between four to nine species. In this work, we evaluated phylogenetic relationships, diversification times, and species delimitation within the roseus group using a multi-locus dataset. For this purpose, mitochondrial (D-loop, Cyt b, and COI) and nuclear (POMC and CRYBA1) partial sequences from 164 individuals were amplified, representing all species. Maximum Likelihood (ML) and Bayesian approaches were used to reconstruct phylogenetic relationships. Species tree was estimated using BEAST and singular value decomposition scores for species quartets (SVDquartets). Species limits were evaluated with six coalescent approaches. Diversification times were estimated using mitochondrial and nuclear rates with LogNormal relaxed clock in BEAST. Nine well-supported monophyletic lineages were recovered in Bayesian, ML, and SVDquartets, including eight named species and a lineage composed by specimens from the Villarrica population (Bootstrap:>70, PP:> 0.99). Single-locus species delimitation analyses overestimated the species number in E. migueli, E. calcaratus, and E. roseus lineages, while multi-locus analyses recovered as species the nine lineages observed in phylogenetic analyses (Ctax = 0.69). It is hypothesized that Eupsophus diversification occurred during Mid-Pleistocene (0.42-0.14 Mya), with most species having originated after the Last Southern Patagonian Glaciation (0.18 Mya). Our results revitalize the hypothesis that the E. roseus group is composed of eight species and support the Villarrica lineage as a new putative species.


Strain engineering for the solution of efficiency droop in InGaN/GaN light-emitting diodes.
We present a method of increasing light output power and suppressing efficiency droop in vertical-structure InGaN/GaN MQW LEDs without modifying their epitaxial layers. These improvements are achieved by reducing the quantum-confined Stark effect (QCSE) by reducing piezoelectric polarization that results from compressive stress in the GaN epilayer. This compressive stress is relaxed due to the external stress induced by an electro-plated Ni metal substrate. In simulations, the severe band bending in the InGaN quantum well is reduced and subsequently internal quantum efficiency increases as the piezoelectric polarization is reduced.


Treatment comparisons for a partially categorical outcome applied to a biomarker with assay limit.
The plasma level of HIV-RNA has been shown to be a strong prognostic biomarker for clinical progression and death in HIV infected patients and is widely used as the primary outcome in clinical trials to evaluate antiretroviral treatments. Currently approved assays to measure HIV-RNA levels have a lower limit of reliable quantification (LoQ). Current regulatory guidelines recommend using the proportion of patients achieving HIV-RNA levels below the assay limit at a certain time point (e.g. 24 or 48 weeks) as the primary endpoint for regulatory approval. However, a substantial decrease in HIV-RNA that does not go below the LoQ still is considered clinically beneficial for patients with advanced diseases who have failed many other therapies and are unlikely to maximally suppress the virus and achieve HIV-RNA levels below the LoQ. An experimental treatment may not be distinguishable from a control solely in terms of the proportions of patients whose HIV-RNA levels fall below the LoQ. The sensitivity of the comparison between the experimental treatment and the control could be increased by considering as well the difference between the treatments with respect to the HIV-RNA reductions of patients not achieving HIV-RNA levels below the LoQ. In this paper, we introduce a best-rank analysis which assigns the best rank to patients who achieve the HIV-RNA levels below the LoQ and applies the Mann-Whitney-Wilcoxon rank test to compare the two treatment groups. The Mann-Whitney-Wilcoxon statistic is shown to be a weighted sum of two statistics: one to compare the proportions of patients achieving the HIV-RNA levels below the LoQ and one to compare the viral reductions in patients with HIV-RNA levels above the LoQ. The corresponding statistical null and alternative hypotheses and the clinical interpretations of this best-rank test procedure are also discussed. An example is used to illustrate this approach and a simulation study is used to compare this approach with other methods.


Vegetarian dietary practices and endurance performance.
Confounding influences of varying fat, protein, and carbohydrate (CHO) levels, training habits, and lifestyle patterns make the interpretation of specific influences of the diet on endurance performance unclear. In general, exhaustion during prolonged, hard endurance exercise is tied to low muscle glycogen stores. Athletes in heavy training are urged to consume 70% of calories as CHO to maximize body CHO stores. A deemphasis in animal products with an emphasis in high-CHO plant foods would facilitate athletes in conforming to nutritional recommendations. Some female athletes may increase their risk of iron deficiency and/or amenorrhea if a restrictive vegetarian diet is adopted. In general, the high-CHO nature of the vegetarian diet can help the endurance athlete in heavy training maximize body glycogen stores and thus the ability to perform. The balanced vegetarian diet provides the athlete with added reduction in coronary risk factors while meeting all known nutritional needs.


Spontaneous atherosclerosis in pigeons. A model system for studying metabolic parameters associated with atherogenesis.
The interpretation of metabolic studies related to early changes in spontaneous atherosclerosis has been hampered by the focal nature of the disease and by the lack of a well-defined model system of the disease process. Gross, histologic and ultrastructural observations of lesion development at the celiac bifurcation of the aorta in atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer pigeons are compared and discussed in terms of hemodynamics, muscular aggregation and altered metabolism of smooth muscle cells. Detailed knowledge of the morphologic sequence of events in lesion localization makes the celiac bifurcation in White Carneau and Show Racer pigeons a useful model for genetic comparisons of arterial wall metabolism and for investigating metabolic alterations occurring with atherogenesis.


Using an Ecosystem Approach to complement protection schemes based on organism-level endpoints.
Radiation protection goals for ecological resources are focussed on ecological structures and functions at population-, community-, and ecosystem-levels. The current approach to radiation safety for non-human biota relies on organism-level endpoints, and as such is not aligned with the stated overarching protection goals of international agencies. Exposure to stressors can trigger non-linear changes in ecosystem structure and function that cannot be predicted from effects on individual organisms. From the ecological sciences, we know that important interactive dynamics related to such emergent properties determine the flows of goods and services in ecological systems that human societies rely upon. A previous Task Group of the IUR (International Union of Radioecology) has presented the rationale for adding an Ecosystem Approach to the suite of tools available to manage radiation safety. In this paper, we summarize the arguments for an Ecosystem Approach and identify next steps and challenges ahead pertaining to developing and implementing a practical Ecosystem Approach to complement organism-level endpoints currently used in radiation safety.


Ethanol extract of Pueraria lobata improve acute myocardial infarction in rats via regulating gut microbiota and bile acid metabolism.
Acute myocardial infarction (AMI) is a multifactorial disease with high mortality rate worldwide. Ethanol extract of Pueraria lobata (EEPL) has been widely used in treating cardiovascular diseases in China. This study aimed to explore the underlying therapeutic mechanism of EEPL in AMI rats. We first evaluated the anti-AMI efficacy of EEPL through immunohistochemistry staining and biochemical indexes. Then, UPLC-MS/MS, 16S rDNA, and shotgun metagenomic sequencing were used to analyze the alterations in bile acid metabolism and intestinal flora. Finally, the influence of EEPL on ilem bile acid metabolism, related enzymes expression, and transporter proteins expression in rats were verified by mass spectrometry image and ELISA. The results showed that EEPL can reduce cardiac impairment in AMI rats. Besides, EEPL effectively increased bile acid levels and regulated gut microbiota disturbance in AMI rats via increasing CYP7A1 expression and restoring intestinal microbiota diversity, separately. Moreover, it can increase bile acids reabsorption and fecal excretion through inhibiting FXR-FGF15 signaling pathway and increasing OST-α expression, which associated with Lachnoclostridium. Our findings demonstrated that EEPL alleviated AMI partially by remediating intestinal dysbiosis and promoting bile acid biosynthesis, which provided new targets for AMI treatment.


Involvement of nitric oxide in regulation of the medullary respiratory rhythm in neonatal rats.
The NADPH-diaphorase (as a neuronal NO-synthase) reactivity in the medullary structures of the respiratory rhythm (RR) generator and the role of NO in the regulation of respiratory activity in the phrenic nerve of artificially superfused semi-isolated medulla-spinal cord preparations were investigated in newborn rats. NADPH-diaphorase positive neurons were found in all nuclei of both dorsal and ventral respiratory groups of neurons. The maximal density of stained cells was present within the rostral part of the ventrolateral medulla (VLM), in the region of the lateral paragigantocellular reticular nucleus. It was found that endogenous NO mediates the mechanism of tonic inhibitory control of the RR frequency located in the rostral VLM under normal and hypoxic conditions, and appears to be involved in generation of the basic RR by the more caudal structures of VLM. It was shown that NO biosynthesis mediates the effect of NMDA receptors activation on the RR.


Inhibition of fibroblast-induced angiogenic phenotype of cultured endothelial cells by the overexpression of tissue inhibitor of metalloproteinase (TIMP)-3.
In this study, we examined the effect of overexpression of tissue inhibitor of metalloproteinase (TIMP)-3 on the angiogenic phenotype expressed by vascular endothelial cells (ECs). ECs were infected with a recombinant adenovirus carrying the TIMP-3 gene at various multiplicities of infection, and TIMP-3 expression by transfected cells was confirmed by Western blotting and reverse zymography. At transfection doses of 6.25, 12.5, 25, 50 and 100 multiplicity of infection, EC migration was reduced to 66, 45, 25, 17 and 5%, respectively, of that of the control. At the multiplicity of infection of 20, capillary tube length was reduced by 80% compared to that of the control. Thus, expression of TIMP-3 by ECs effectively inhibited EC migration and tube formation. Overexpression of TIMP-3 by ECs may be considered a gene therapy strategy for the treatment of pathological angiogenesis such as cancer and diabetic retinopathy.


Incorporation of frailties into a cure rate regression model and its diagnostics and application to melanoma data.
Cure rate models have been widely studied to analyze time-to-event data with a cured fraction of patients. Our proposal consists of incorporating frailty into a cure rate model, as an alternative to the existing models to describe this type of data, based on the Birnbaum-Saunders distribution. Such a distribution has theoretical arguments to model medical data and has shown empirically to be a good option for their analysis. An advantage of the proposed model is the possibility to jointly consider the heterogeneity among patients by their frailties and the presence of a cured fraction of them. In addition, the number of competing causes is described by the negative binomial distribution, which absorbs several particular cases. We consider likelihood-based methods to estimate the model parameters and to derive influence diagnostics for this model. We assess local influence on the parameter estimates under different perturbation schemes. Deriving diagnostic tools is needed in all statistical modeling, which is another novel aspect of our proposal. Numerical evaluation of the considered model is performed by Monte Carlo simulations and by an illustration with melanoma data, both of which show its good performance and its potential applications. Particularly, the illustration confirms the importance of statistical diagnostics in the modeling.


The expression of annexin-A1 in esophageal squamous cell carcinoma and its association with the biological behavior of the primary human esophageal squamous carcinoma cell line.
This study aimed to observe the differential expression of Annexin-A1 in esophageal squamous cell carcinoma (ESCC) and explored the effect of small interfering ribonucleic acid (RNAi)-Annexin-A1 on the biological behavior of CE81T-0 cells. An immunohistochemical approach was used to detect the expression of Annexin-A1 in 86 pairs of ESCC samples. Quantitative reverse transcription polymerase chain reaction was used to detect the expression of Annexin-A1 in CE81T-0 and CE81T-4 cells, and the expression of Annexin-A1 in CE81T-0 cells was knocked out by RNAi. A methyl-thiazolyl-tetrazolium assay was used to observe the effect of Annexin-A1 on cell proliferation, and flow cytometry was conducted to analyze its effect on cell cycles and apoptosis. A scratch assay and a Transwell chamber were used to detect changes in cell migration and invasion. From the results, compared with the Annexin-A1 expression rate of 59.3% in para-carcinoma tissues, the expression of Annexin-A1 in cancer was reduced to only 32.6% in ESCC cells. Annexin-A1 was strongly expressed in highly differentiated ESCC cells without lymphatic metastasis and highly expressed in the CE81T-0 cell group with low metastasis. Annexin-A1 gene silencing promoted cell proliferation and inhibited apoptosis, blocked cells in the S-phase, and increased cell migration, leading to an increase in the number of invaded cells. Above all, Annexin-A1 could reflect the differentiation degree and lymph node metastasis of ESCC cells to some extent and was involved in the invasion, metastasis, proliferation, and other biological behaviors of ESCC cells, indicating an experimental basis for Annexin-A1 as a molecular marker in the early diagnosis of ESCC and the prediction of cell metastasis, invasion, and differentiation degree.


Aberration fields of off-axis astronomical telescopes induced by rotational misalignments.
Due to the absence of rotational symmetry, off-axis astronomical telescopes with off-set pupil become subject to rotational misalignments. Rotational misalignments of large off-axis mirrors with reference to their geometric center can greatly degrade the imaging quality. This paper presents an in-depth discussion on the net aberration fields of off-axis astronomical telescopes induced by rotational misalignments. Aberration function of off-axis telescopes with rotational misalignments is derived based on the framework of nodal aberration theory. Expressions of several important aberrations are obtained under some approximations. Then the specific field characteristics of these aberrations are presented and explicated. Meanwhile, we demonstrate that rotational misalignments can be converted to a kind of surface decenters; on the other hand, the effects of rotational misalignments have their special features which are different from the effects of general surface decenters. Besides, some other insightful discussions are further presented. This work is also applicable to the rotational misalignments of the off-axis segments of primary mirror in segmented mirror astronomical telescopes.


Paxillin confers resistance to tyrosine kinase inhibitors in EGFR-mutant lung cancers via modulating BIM and Mcl-1 protein stability.
Tyrosine kinase inhibitors (TKIs) have been documented to have substantial clinical benefits to non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutation. TKI resistance occurs in nearly all patients who receive TKI-targeting therapy, resulting in a modest overall survival benefit. Therefore, establishing a biomarker for early prediction and exploring the mechanism of primary TKI resistance is essential for improving the therapeutic efficacy in non-small cell lung cancer patients. In this study, we provide evidence indicating that paxillin (PXN) overexpression may confer TKI resistance in EGFR-mutant lung cancer cells. Mechanistically, PXN-mediated extracellular signal-regulated kinases (ERK) activation is responsible for TKI resistance via decreased Bcl2-interacting mediator of cell death (BIM) and increased Mcl-1 expression due to modulating their protein stabilities by phosphorylation of BIM at serine 69 and Mcl-1 at threonine 163. The mechanistic action in the cell model was further confirmed by the observation of xenograft tumors in nude mice, revealing that the PXN-mediated TKI resistance was conquered by ERK inhibitor (AZD6244) and Bcl-2 family inhibitor (obatoclax), but the TKI resistance overcome by AZD6244 is more effective than that of obatoclax. Therefore, we suggest that PXN expression may be useful in predicting primary TKI resistance, and combining TKI with ERK inhibitors may clinically benefit EGFR-mutant non-small cell lung cancer patients whose tumors exhibit high PXN expression.


[Experimental simulation of the structure of gastrointestinal microbial biocenosis].
Structural analysis of human and rat gastrointestinal microbial communities revealed their general similarity. The structure of microbial biocenosis in ileum parietal mucin appears to be highly sensitive to nutritional factors. Inadequate nutrition leads to destruction of microbial microassociations in parietal mucin, a calcium-deficient diet has similar effect in feces. Fiber-rich diets stimulates build-up of indigenous communities while artificial nutrients and calcium-enriched diets promote formation of mixed indigenous-transient microbial associations. Bacteria themselves prove to be weak modifiers of the observed effects.


Out of balance: consequences of a partial keratin 10 knockout.
Recently we generated keratin 10 knockout mice which provided a valuable model for the dominantly inherited skin disorder epidermolytic hyperkeratosis. Here we investigated the molecular basis for their phenotype. Hetero- and homozygotes expressed a truncated keratin 10 peptide which has been identified directly by microsequencing. Epitope mapping of monoclonal antibodies to keratin 10T enabled us to study its distribution relative to keratin 6, which is highly expressed in keratin 10 knockout mice, by double-immunogold electron microscopy. This revealed that keratin 10T was restricted to complexes with keratin 1 but did not mix with keratin 6. The latter did not form extended filaments with keratins 16/17 but aggregates. Keratins 6/16 were unable to compensate for the lack of normal keratin 1/10 filaments. Remarkably keratin 6 aggregates strictly colocalized with keratohyalin granules. Residual keratin 1/10T clumps were located in the cell periphery and at desmosomes which maintained a normal architecture. Surprisingly keratin 2e, a keratin tailored to sustain mechanical stress, was completely lost in paw sole epidermis of homozygous keratin 10 knockout mice, pointing to keratin 10 as its partner. The selective pairing of keratin 10T and the loss of keratin 2e indicate that in vivo keratins are less promiscuous than in vitro. Skin fragility in keratin 10 knockout mice and in epidermolytic hyperkeratosis is probably the consequence of two complementing mechanisms namely a decrease of normal keratin 1/10 filaments and an increase in keratins 6/16 with a poor filament-forming capacity.


L-theanine and Neumentix mixture improves sleep quality and modulates brain neurotransmitter levels in mice.
L-theanine (L-THE), a natural amino acid found in green tea, has been shown to improve anxiety and sleep. Neumentix proprietary spearmint extract (PSE), which is commonly found in beverage flavoring a pharmaceutical, also has a wide range of health benefits, including cognitive performance improvement. Four experiments tested the effects of L-THE and PSE on sleep: a direct sleeping test, pentobarbital-induced sleeping test, sub-hypnotic pentobarbital-induced sleeping test, and sodium barbital-induced sleeping test. Presence of neurotransmitters in brain tissue was detected by liquid chromatography mass spectroscopy (HP LC-MS) during these studies. Pentobarbital-induced sleeping and sodium barbital-induced sleeping tests examined the potential effect of L-THE/PSE mixture on synergistic sleep, while neurotransmitter levels in the brain were determined by the high performance liquid chromatography/mass spectroscopy (HPLC/MS) method. L-THE and L-THE/PSE mixture showed increased sleep duration and shortened sleep latency when co-administrated with pentobarbital or sodium barbital. The mixture also increased sleeping rate when co-administrated with the pentobarbital at sub-hypnotic dose. Additionally, the L-THE, PSE and L-THE/PSE mixture significantly increased the concentrations of acetylcholine (Ach), γ-aminobutyric acid (GABA), and decreased the concentration of serotonin (5-HT) in the brain. These data demonstrated that L-THE/PSE mixture regulates sleep disorders via the GABA receptor and neurotransmitter systems.


Influence of anesthesia on bladder hyperactivity induced by middle cerebral artery occlusion in the rat.
The effect of anesthesia or an N-methyl-D-aspartate (NMDA) glutamatergic antagonist (MK-801) on bladder hyperactivity induced by unilateral middle cerebral artery (MCA) occlusion was examined in female rats. Before infarction, control bladder contractions were monitored in two groups of rats: 1) awake and 2) urethan anesthetized. The awake rats were then anesthetized with halothane, and MCA occlusion was performed in both groups. After recovery from halothane, bladder capacity in awake rats was significantly reduced (60.8 +/- 1.3%) 0.5-4.5 h after MCA occlusion but not changed in urethan-anesthetized rats. MK-801 (0.1 mg/kg i.v.) administered before MCA occlusion blocked the reduction in bladder capacity in awake rats 1.5-4.5 h after MCA occlusion. Bladder capacity was not changed by sham operation in either the awake or urethan-anesthetized rats. Urethan administered after recovery from halothane anesthesia increased bladder capacity in MCA-occluded awake rats but not in sham-operated awake rats. Infarct areas in halothane, urethan-anesthetized, or MK-801-treated rats were not significantly different. These results indicate that cerebral infarction induces bladder hyperactivity in awake rats and that urethan or MK-801 inhibits the development of this hyperactivity, most likely by blocking glutamatergic transmission in the brain.


Bile salt regulation of fatty acid absorption and esterification in rat everted jejunal sacs in vitro and into thoracic duct lymph in vivo.
This study was performed to investigate whether the malabsorption of fat in the blind loop syndrome is due to the presence of free bile acids or to a deficiency of conjugated bile salts produced by bacterial degradation of normal bile salts, as well as to learn something of the mechanisms by which bile salts might regulate fat absorption. In the everted gut sac of the rat in vitro, conjugated bile salts were necessary for maximal rates of fatty acid esterification to triglycerides, whereas free bile acids inhibited this process even in the presence of physiologically normal or higher concentrations of conjugated bile salts. In contrast, in the living animal the addition of similar or higher concentrations of free bile acids to infusions of fatty acids in taurocholate micellar solutions produced no reduction in the amount of fatty acid absorbed into lymph or the amount of fatty acid esterified into lymph triglyceride. Both in vitro and in the living animal, reduction in the conjugated bile salt concentration reduced both the rate of fatty acid uptake by the intestine and the esterification into triglycerides. It is concluded that the steatorrhea of the blind loop syndrome or other conditions in which upper intestinal stasis allows bacterial proliferation is not due to presence of increased gut luminal concentrations of free bile acids, but rather is a consequence of lowered concentrations of conjugated bile salts.


Temporal trends in physical activity in England: the Health Survey for England 1991 to 2004.
Physical activity is an established risk factor for chronic disease but very little is known about its temporal trends in England. Such information is crucial for planning public health interventions. We explored temporal trends in occupational activity, walking, domestic activity, and sports using Health Survey for England data in 95,342 adults aged 16 and over. Data were collected annually in 1991-4, 1997-9, and 2003-04. Multivariate logistic regression and multiple linear regression models assessed trends in physical activity for dichotomous and continuous outcomes, respectively. Analyses were adjusted for age and social class. Physical activity levels at work declined over time but there was a consistent and significant upward trend in regular sports participation among all age groups. Changes in questions in 1997 and 1999 confounded trends in walking and heavy domestic activity and total physical activity. Between 1999 and 2004 (when physical activity questions remained unchanged), there were significant increases in average time spent in all activity types and the percentage of adults meeting the current physical activity recommendations. These short-term increases were more marked among adults aged 35 to 64. The common perception that overall physical activity levels are declining may be over-simplistic as despite the decreases in occupational physical activity, there is a clear upward trend in sports participation. Changes in the measuring methodology over time preclude the presentation of a clear picture of the total temporal trends in physical activity in England.


Mooren's ulcer.
Mooren's ulcer is a rapidly progressive, painful, ulcerative keratitis which initially affects the peripheral cornea and may spread circumferentially and then centrally. Mooren's ulcer can only be diagnosed in the absence of an infectious or systemic cause and must be differentiated from other corneal abnormalities, such as Terrien's degeneration. Although the etiology remains unknown, recent research has proposed an underlying immune process and a possible association with the hepatitis C virus. The response to medical and surgical intervention is typically poor, and the visual outcome can be devastating. Three patients presented to our clinic with inferior peripheral corneal defects characteristic of Mooren's ulceration. The first patient, a 67-year-old white male, presented with an area of progressive peripheral thinning of the left inferior cornea 1 week after a preoperative skin cleanser was inadvertently splashed in both eyes. This occurred during a surgical procedure to remove a basal cell carcinoma. The second patient, a 56-year-old white male, was treated for a recurrent left inferior corneal ulcer with impending risk of perforation. The third patient was a 68-year-old white male referred for a painful left inferior peripheral ulcer, which rapidly progressed into a bilateral corneal melt disorder. All patients were diagnosed with Mooren's ulcerative keratitis after they underwent extensive medical and laboratory testing to rule out an infectious or systemic cause of their corneal melt. The first patient was treated with oral steroids, as well as doxycycline, to control his acne rosacea. The second patient responded to aggressive treatment with topical steroid therapy. This patient also tested positive for hepatitis C. The third patient rapidly developed a perforated left cornea and was treated with a penetrating keratoplasty after a patch graft had failed. Mooren's ulcer is an idiopathic, painful, progressive ulceration of the peripheral cornea. These ulcers usually respond poorly to conventional therapy, as there is limited knowledge of the pathophysiology of the disease. Evidence of an autoimmune component advocates the use of steroids and immunosuppressive agents. With further research and understanding of Mooren's ulcer, better treatment options may be available in the future.


Xylella fastidiosa Isolates from Both subsp. multiplex and fastidiosa Cause Disease on Southern Highbush Blueberry (Vaccinium sp.) Under Greenhouse Conditions.
Xylella fastidiosa is a xylem-limited gram-negative plant pathogen that affects numerous crop species, including grape, citrus, peach, pecan, and almond. Recently, X. fastidiosa has also been found to be the cause of bacterial leaf scorch on blueberry in the southeastern United States. Thus far, all X. fastidiosa isolates obtained from infected blueberry have been classified as X. fastidiosa subsp. multiplex; however, X. fastidiosa subsp. fastidiosa isolates are also present in the southeastern United States and commonly cause Pierce's disease of grapevines. In this study, seven southeastern U.S. isolates of X. fastidiosa, including three X. fastidiosa subsp. fastidiosa isolates from grape, one X. fastidiosa subsp. fastidiosa isolate from elderberry, and three X. fastidiosa subsp. multiplex isolates from blueberry, were used to infect the southern highbush blueberry 'Rebel'. Following inoculation, all isolates colonized blueberry, and isolates from both X. fastidiosa subsp. multiplex and X. fastidiosa subsp. fastidiosa caused symptoms, including characteristic stem yellowing and leaf scorch symptoms as well as dieback of the stem tips. Two X. fastidiosa subsp. multiplex isolates from blueberry caused more severe symptoms than the other isolates examined, and infection with these two isolates also had a significant impact on host mineral nutrient content in sap and leaves. These findings have potential implications for understanding X. fastidiosa host adaptation and expansion and the development of emerging diseases caused by this bacterium.


Subacromial injection of autologous platelet-rich plasma versus corticosteroid for the treatment of symptomatic partial rotator cuff tears.
Rotator cuff tears are one of the most common causes of chronic shoulder pain and disability. They significantly affect the quality of life. Reduced pain and improved function are the goals of conventional therapy, which includes relative rest, pain therapy, physical therapy, corticosteroid injections and surgical intervention. Tendons have a relative avascular nature; hence, their regenerative potential is limited. There is some clinical evidence that the application of autologous platelets may help to revascularize the area of injury in rotator cuff pathologies. This prospective randomized controlled study was done to evaluate the results of subacromial injection of platelet-rich plasma (PRP) versus corticosteroid injection therapy in 40 patients with symptomatic partial rotator cuff tears. All patients were assessed before injection, 6 weeks, 3 and 6 months after injection, using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), the Constant-Murley Score (CMS), the Simple Shoulder Test (SST) and a Visual Analog Scale (VAS) for pain. An MRI was performed before and 6 months after the injection for all the included patients and was graded on 0-5 scale. Both injection groups showed statistically significantly better clinical outcomes over time compared with those before injection. There was a statistically significant difference between RPP group and corticosteroid group 12 weeks after injection, regarding VAS, ASES, CMS and SST in favor of the RPP group. MRI showed an overall slight nonsignificant improvement in grades of tendinopathy/tear in both groups, however, without statistically significant differences between the two groups. PRP injections showed earlier better results as compared to corticosteroid injections, although statistically significant better results after 6 months could not be found. Therefore, subacromial RPP injection could be considered as a good alternative to corticosteroid injection, especially in patients with a contraindication to corticosteroid administration. II.


Differentiable Design Galleries: A Differentiable Approach to Explore the Design Space of Transfer Functions.
The transfer function is crucial for direct volume rendering (DVR) to create an informative visual representation of volumetric data. However, manually adjusting the transfer function to achieve the desired DVR result can be time-consuming and unintuitive. In this paper, we propose Differentiable Design Galleries, an image-based transfer function design approach to help users explore the design space of transfer functions by taking advantage of the recent advances in deep learning and differentiable rendering. Specifically, we leverage neural rendering to learn a latent design space, which is a continuous manifold representing various types of implicit transfer functions. We further provide a set of interactive tools to support intuitive query, navigation, and modification to obtain the target design, which is represented as a neural-rendered design exemplar. The explicit transfer function can be reconstructed from the target design with a differentiable direct volume renderer. Experimental results on real volumetric data demonstrate the effectiveness of our method.


Performing Drug Safety Research During Pregnancy and Lactation: Biomedical HIV Prevention Research as a Template.
Evidence-based guidance regarding use of nearly all pharmaceuticals by pregnant and lactating women is limited. Models for performing research may assist in filling these knowledge gaps. Internationally, reproductive age women are at high risk of human immunodeficiency virus (HIV) acquisition. Susceptibility to HIV infection may be increased during pregnancy, and risk of maternal-child transmission is increased with incident HIV infection during pregnancy and lactation. A multidisciplinary meeting of experts was convened at the United States National Institutes of Health to consider paradigms for drug research in pregnancy and lactation applicable to HIV prevention. This report summarizes the meeting proceedings and describes a framework for research on candidate HIV prevention agent use during pregnancy and lactation that may also have broader applications to other pharmaceutical products.


Prognostic significance of nucleolar organizer regions in adenoid cystic carcinomas of the head and neck.
To determine the prognostic use of nucleolar organizing region (AgNOR) counts and clinical and histopathological features in adenoid cystic carcinoma. Argyrophilic staining was applied to ordinary formalin-fixed, paraffin-embedded specimens and evaluated to obtain the mean number of AgNORs and the percentage of nuclei with more than 1 (pAgNOR > 1), more than 2, more than 3, and more than 4 AgNORs. Using the log rank test, the mean AgNOR count showed no correlation with the disease-free period. All pAgNOR parameters exceeding the respective overall mean had poorer prognosis when compared with those below the mean (P = .02). The pAgNOR > 1 appeared as the best discriminator, singling out all treatment failures (P < or = .001). This parameter also showed a high degree of intraobserver and interobserver reproducibility. Stage of the disease, violated resection margins, and presence of the histopathological solid subtype were markers of an unfavorable prognosis. Multivariate analysis by the Cox model showed that pAgNOR > 1 (P < or = .001) and tumor stage (P = .03) were the only statistically significant parameters. Estimation of pAgNOR > 1 is easy, quick, and highly reproducible. It may become a useful prognostic parameter in adenoid cystic carcinoma, but larger studies should be performed to confirm the reliability of this method.


Safety concerns surrounding AAV and CRISPR therapies in neuromuscular treatment.
Gene therapies, notably those leveraging CRISPR and adeno-associated virus vectors (AAVs), have risen to the forefront of potential treatments for neuromuscular disorders. The recent demise of a Duchenne muscular dystrophy (DMD) patient following a trial utilizing CRISPR transactivation with AAV has cast a spotlight on the potential risks associated with these approaches.1.


[Study of the immunological activity of blood in various rickettsial and viral infections].
The content of various types of antibodies were studied in the blood serum of laboratory animals in experimental tick-borne rickettsiosis of Northern Asia. This was done by a simultaneous staging of indirect hemagglutination, indirect hemolysis, compliment fixation under cold conditions, and agglutination with Proteus antigen OX19 tests. Immune horse sera to the influenza virus were also studied with the aid of several serological tests. The data obtained pointed to the significant differences in the properties of individual types of antibodies. Immunological activity of the sera under study depended on the correlation in them of various types of antibodies at various periods of the infectious process in combination with the influence upon the immunogenesis of the individual and species immunological reactivity.


Molecular and Metabolic Imaging of Hepatic Neuroendocrine Tumors Following Radioembolization with 90Y-microspheres.
Liver is the predominant site of metastatization for neuroendocrine tumors (NETs). Up to 75% of patients affected by intestinal NETs present liver metastases at diagnosis. For hepatic NET, surgery represents the most effective approach but is often unfeasible due to the massive involvement of multifocal disease. In such cases, chemotherapy, peptide receptor radionuclide therapy and loco-regional treatments may represent alternative therapeutic options. In particular, radioembolization with 90Y-microspheres has been introduced as a novel technique for treating hepatic malignant lesions, combining the principles of embolization and radiation therapy. In order to evaluate the response to 90Y-radioembolization, standard radiologic criteria have been demonstrated to present several limitations. 18Fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) is routinely used for monitoring the response to therapy in oncology. Nevertheless, NETs often present low glycolytic activity thus the conventional 18FDG PET may not be adequate for these tumors. For many years, somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide has been used for diagnosis and staging of NETs. More recently, three 68Ga-DOTA-compounds have been developed and introduced for the imaging of NETs with PET technology. The aim of the present paper was to review the existing literature concerning the application of different metabolic and molecular probes for the imaging evaluation of hepatic NETs following 90Y-RE.


(R)-3-(8'-Hydroxyfarnesyl)-indole and other chemical constituents from the flowers of Anomianthus dulcis and their antimalarial and cytotoxic activities.
A new farnesylindole, (R)-3-(8'-hydroxyfarnesyl)-indole (1), as a scalemic mixture (33% ee) along with nine known compounds (2-10), including one farnesylindole, three flavanones, three flavone derivatives and two chalcone derivatives were isolated from the methanolic crude extract of the flowers from Anomianthus dulcis. All compounds were purified by appropriate chromatographic techniques and their structures elucidated by spectroscopic methods. Compounds 1, 2 and 8 showed moderate antiplasmodial activities against TM4/8.Two and K1CB1 strains of which compound 2 displayed the best activity with IC50 values of 27.9 ± 2.57 and 21.4 ± 1.68 µM, respectively. In addition, compound 1 also presented modest cytotoxicity against a KB cell line with an IC50 value of 22.3 ± 0.39 µM. None of these compounds showed cytotoxicity against Vero cells.


The effect of hepatitis C virologic clearance on cardiovascular disease biomarkers in human immunodeficiency virus/hepatitis C virus coinfection.
Successful hepatitis C virus (HCV) treatment may reduce cardiovascular disease (CVD) risk and improve levels of CVD biomarkers produced outside the liver (nonhepatic biomarkers). Stored serum or plasma from before and 24 weeks after end of HCV treatment (EOT) from human immunodeficiency virus (HIV)/HCV-coinfected subjects who received up to 72 weeks of peginterferon/ribavirin, 27 with and 27 without sustained virologic response (SVR) matched by race, ethnicity and sex, were tested for nonhepatic (soluble intercellular adhesion molecule-1 [sICAM-1], soluble P-selectin [sP-selectin], interleukin [IL]-6, d-dimer, and lipoprotein-associated phospholipase A2 [Lp-PLA2]) and hepatic (cholesterol and high-sensitivity C-reactive protein) CVD and macrophage activation markers (soluble CD163 [sCD163] and soluble CD14). Changes in biomarkers and their association with SVR were examined by t tests or Wilcoxon tests and regression models. Of the 54 subjects, 30 were white, 24 were black, and 44 were male. Pretreatment levels of nonhepatic biomarkers were high: sICAM-1 overall median, 439.2 ng/mL (interquartile range [IQR], 365.6-592.8]; sP-selectin, 146.7 ng/mL (IQR, 94.1-209.9), and IL-6, 2.32 pg/mL (IQR, 1.61-3.49). Thirty-seven of 52 (71%) subjects had Lp-PLA2 >235 ng/mL. Sustained virologic response was associated with decrease in sICAM-1 (P = .033) and sCD163 (P = .042); this result was attenuated after controlling for changes in the alanine aminotransferase level. At 24 weeks after EOT, 17 (63%) SVRs had Lp-PLA2 >235 ng/mL vs 25 (93%) non-SVRs (P = .021). Hepatitis C virus clearance may reduce hepatic and, subsequently, systemic inflammation and CVD risk in HIV/HCV coinfection.


General principles of external beam radiation therapy for skeletal metastases.
Radiation therapy plays a major role in the treatment of patients with bone metastases. The primary goals of treatment include pain relief and relief of neurologic symptoms, if present. Approximately 70% of patients will achieve pain relief with palliative external beam radiotherapy. Improvement in the severity of pain may occur within as few as 48 to 72 hours of initiation of therapy, but in some patients significant relief of pain may not occur for 4 weeks after completion of therapy. Treatment schemes ranging from 800 cGy in a single treatment to 3000 cGy in 10 treatments have not been shown to result in major differences in outcome. Treatment decisions must be individualized based on factors such as the patient's performance status, life expectancy, location of the lesion, and size of area to be treated. External beam radiotherapy is recommended after surgical treatment of pathologic fractures or impending fractures to decrease the need for a second surgical procedure and improve the patient's functional outcome. External beam radiotherapy continues to be an important component of the palliative treatment of bone metastases. Its integration with newer therapeutic modalities such as vertebroplasty and radiofrequency ablation currently is being studied.


Potential citric acid exposure and toxicity to Hawaiian hoary bats (Lasiurus cinereus semotus) associated with Eleutherodactylus frog control.
We examined potential exposure of Hawaiian hoary bats (Lasiurus cinereus semotus) to citric acid, a minimum risk pesticide registered for control of invasive Eleutherodactylus frog populations. Hoary bats are nocturnal insectivores that roost solitarily in foliage, federally listed as endangered, and are endemic to Hawaii. Oral ingestion during grooming of contaminated fur appears to be the principal route by which these bats might be exposed to citric acid. We made assessments of oral toxicity, citric acid consumption, retention of material on fur, and grooming using big brown bats (Eptesicus fuscus) as a surrogate species. We evaluated both ground application and aerial application of 16 % solutions of citric acid during frog control operations. Absorbent bat effigies exposed to ground and aerial operational spray applications retained means of 1.54 and 0.02 g, respectively, of dry citric acid, although retention by the effigies was much higher than bat carcasses drenched in citric acid solutions. A high dose delivered orally (2,811 mg/kg) was toxic to the big brown bats and emesis occurred in 1 bat dosed as low as the 759 mg/kg level. No effect was observed with the lower doses examined (≤ 542 mg/kg). Bats sprayed with 5 ml of 16 % (w/w) citric acid solution showed no evidence of intoxication. In field situations, it is unlikely that bats would be sprayed directly or ingest much citric acid retained by fur. Based on our observations, we believe Hawaiian hoary bats to be at very low risk from harmful exposure to a toxic dose of citric acid during frog control operations.


Knowledge of the Tuskegee study and its impact on the willingness to participate in medical research studies.
The under-representation of racial/ethnic minorities among medical research participants has recently resulted in mandates for their inclusion by the National Institutes of Health (NIH). Therefore, there is a need to determine how history, attitudes, cultural beliefs, social issues, and investigator behavior affect minority enrollment in medical research studies. From January 1998 to March 1999, 179 African-American and white residents of the Detroit Primary Metropolitan Statistical Area (PMSA) participated in a mail and telephone survey designed to examine impediments to African-American participation in medical research studies. Chi-square tests were performed to assess differences between the study groups using the Survey Data Analysis Program (SUDAAN). Eighty-one percent of African Americans and 28% of whites had knowledge of the Tuskegee Study (p = <0.001). Knowledge of the Tuskegee Study resulted in less trust of researchers for 51% of African-Americans and 17% of whites (p = 0.02). Forty-six percent of African-Americans and 34% of whites indicated that their knowledge of the study would affect future research participation decisions (p = 0.25). Of these, 49% of African-Americans and 17% of whites would not be willing to participate in future medical research studies (p = 0.05). This study confirms the need for medical researchers to confront the issue of the Tuskegee Study and its continuing impact on African-Americans' trust of medical research studies.


[Depolymerization of actin microfilaments in the I--Z--I brushes of transverse striated muscles by using DNAse I].
To release Z-discs of skeletal muscles myofibrils from actin microfilaments, I--Z--I-brushes (complexes of Z-discs and thin filaments) were treated with DNAse I-both in suspension and on electron microscopical grids. It was shown that such a treatment resulted in depolymerization of actin filaments. The preparations obtained were heterogeneous and contained I--Z--I-brushes with shorter actin filaments and single Z-discs. The structure of Z-discs released from actin filament remained intact. Therefore these preparations may be used in studies on regulation of actin microfilaments assembly.


Heritable variation in expression of multiple tumor associated epitopes on a high molecular weight mucin-like antigen.
Monoclonal antibodies with specificity for mucin-like antigens have shown great promise for the diagnosis and therapy of human cancer. Heterogeneity in the expression of mucin-like antigens by tumor and normal cells has been noted in several previous studies. An understanding of the nature of this heterogeneity has important implications for the diagnostic and therapeutic usefulness of antibodies to mucin-like antigens. We have studied the mechanism of variability in expression of epitopes on a mucin-like antigen defined by monoclonal antibodies W1, W5, and W9 in the lung carcinoma cell line, Calu-1. Using the fluorescence activated cell sorter and clonal analysis, we have demonstrated that intercellular variability in mucin antigen expression by Calu-1 cells can be explained in part by heritable variation in the tumor cell population. Clonal cell lines were isolated which differ greatly in levels of epitopes for all three mucin directed antibodies. Levels of all three epitopes showed significant variation between different clonal lines but in general were coordinately regulated. Differences in epitope expression between two lines studied in detail could be attributed to a dramatic difference in expression of a high molecular weight mucin-like glycoprotein. In immunoblotting experiments the binding of all three antibodies to this glycoprotein was affected by sodium periodate and/or neuraminidase treatment, suggesting that the antibodies recognize carbohydrate epitopes. Thus, heterogeneity in expression of mucin-like glycoprotein antigens can result from heritable variations which affect expression of multiple carbohydrate epitopes.


[Postinflammatory strictures of the urethral canal in women].
The paper is concerned with one of the important problems of current urology--inflammation-induced strictures of the female urethra, covers questions of its etiology, pathogenesis, clinical patterns, diagnosis and treatment. It is emphasized that the strictures take the form of paraurethral fibrosis and should be managed individually. Clinicomorphological parallels are outlined. Indications to conservative and surgical treatment are specified.


Multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population.
The capacity of perineural invasion by carcinoma in prostate needle biopsy tissue to independently predict pathologic stage in radical prostatectomy tissues remains uncertain. We sought to determine, in a prostate specific antigen-based screening population, the ability of needle biopsy histologic grade, tumor extent, and perineural invasion to independently predict pathologic stage and margin status in the whole prostate gland. Perineural invasion, Gleason grade, percentage Gleason pattern 4/5 carcinoma, and multiple measures of needle biopsy tumor extent, including number of positive cores, percentage of positive cores, total percentage of carcinoma, greatest percentage of carcinoma in a single core, and total carcinoma length in millimeters, were captured for 215 men from a prostate specific antigen-based screening program diagnosed with prostate cancer in a median of six procured needle biopsy cores. Pathologic stage and surgical margin status were evaluated in corresponding completely embedded radical prostatectomy specimens. A logistic regression model was used to relate the endpoints of extraprostatic extension by carcinoma and/or positive margins to needle biopsy tissue findings. In univariate analyses, total percentage of carcinoma (p = 0.003), greatest percentage of carcinoma in a single core (p = 0.004), total tumor length in millimeters (p = 0.009), and fraction of positive cores (p = 0.02) were all significantly associated with extraprostatic (pT3) carcinoma, whereas all five measures of carcinoma extent in needle biopsy tissue were related to positive margins. Correlation coefficient determinations showed that all five measures of needle biopsy carcinoma extent were highly interrelated. In multivariate analyses, total percentage of carcinoma was significantly related to pathologic T stage (p = 0.003) and positive margins (p = 0.0002). In a multivariate model with the radical prostatectomy whole gland endpoint of either pT3 disease or positive margins, fraction of positive cores (p = 0.00001) was the only variable with significant predictive value. Perineural invasion by carcinoma in needle biopsy tissue was detected in 11% of cases. Neither presence nor absence of perineural carcinoma nor number nor percentage of positive nerves related to pathologic stage in univariate or multivariate analyses. Amount of carcinoma in prostate needle biopsy tissue, using multiple measurements but not perineural invasion, is a significant histologic attribute predictive of pathologic stage and margin status for men with prostate specific antigen screening detected prostatic carcinoma. Reporting of several measures of carcinoma extent in needle biopsy tissue is recommended.


Interventions for convergence insufficiency: a network meta-analysis.
Convergence insufficiency is a common binocular vision disorder in which the eyes have a strong tendency to drift outward (exophoria) with difficulty turning the eyes inward when reading or doing close work. To assess the comparative effectiveness and relative ranking of non-surgical interventions for convergence insufficiency through a systematic review and network meta-analysis (NMA). We searched CENTRAL, MEDLINE, Embase, PubMed and three trials registers up to 20 September 2019. We included randomized controlled trials (RCTs) examining any form of non-surgical intervention versus placebo, no treatment, sham treatment, or other non-surgical interventions. Participants were children and adults with symptomatic convergence insufficiency. We followed standard Cochrane methodology. We performed NMAs separately for children and adults. We included 12 trials (six in children and six in adults) with a total of 1289 participants. Trials evaluated seven interventions: 1) office-based vergence/accommodative therapy with home reinforcement; 2) home-based pencil/target push-ups; 3) home-based computer vergence/accommodative therapy; 4) office-based vergence/accommodative therapy alone; 5) placebo vergence/accommodative therapy or other placebo intervention; 6) prism reading glasses; and 7) placebo reading glasses. Six RCTs in the pediatric population randomized 968 participants. Of these, the Convergence Insufficiency Treatment Trial (CITT) Investigator Group completed four RCTs with 737 participants. All four CITT RCTs were rated at low risk of bias. Diagnostic criteria and outcome measures were identical or similar among these trials. The four CITT RCTs contributed data to the pediatric NMA, incorporating interventions 1, 2, 3 and 5. When treatment success was defined by a composite outcome requiring both clinical measures of convergence to be normal, and also show a pre-specified magnitude of improvement, we found high-certainty evidence that office-based vergence/accommodative therapy with home reinforcement increases the chance of a successful outcome, compared with home-based computer vergence/accommodative therapy (risk ratio (RR) 1.96, 95% confidence interval (CI) 1.32 to 2.94), home-based pencil/target push-ups (RR 2.86, 95% CI 1.82 to 4.35); and placebo (RR 3.04, 95% CI 2.32 to 3.98). However, there may be no evidence of any treatment difference between home-based computer vergence/accommodative therapy and home-based pencil/target push-ups (RR 1.44, 95% CI 0.93 to 2.24; low-certainty evidence), or between either of the two home-based therapies and placebo therapy, for the outcome of treatment success. When treatment success was defined as the composite convergence and symptom success outcome, we found moderate-certainty evidence that participants who received office-based vergence/accommodative therapy with home reinforcement were 5.12 (95% CI 2.01 to 13.07) times more likely to achieve treatment success than those who received placebo therapy. We found low-certainty evidence that participants who received office-based vergence/accommodative therapy with home reinforcement might be 4.41 (95% CI 1.26 to 15.38) times more likely to achieve treatment success than those who received home-based pencil push-ups, and 4.65 (95% CI 1.23 to 17.54) times more likely than those who received home-based computer vergence/accommodative therapy. There was no evidence of any treatment difference between home-based pencil push-ups and home-based computer vergence/accommodative therapy, or between either of the two home-based therapies and placebo therapy. One RCT evaluated the effectiveness of base-in prism reading glasses in children. When base-in prism reading glasses were compared with placebo reading glasses, investigators found no evidence of a difference in the three outcome measures of near point convergence (NPC), positive fusional vergence (PFV), or symptom scores measured by the Convergence Insufficiency Symptom Survey (CISS). Six RCTs in the adult population randomized 321 participants. We rated only one RCT at low risk of bias. Because not all studies of adults included composite success data, we could not conduct NMAs for treatment success. We thus were limited to comparing the mean difference (MD) between interventions for improving NPC, PFV, and CISS scores individually using data from three RCTs (107 participants; interventions 1, 2, 4 and 5). Compared with placebo treatment, office-based vergence accommodative therapy was relatively more effective in improving PFV (MD 16.73, 95% CI 6.96 to 26.60), but there was no evidence of a difference for NPC or the CISS score. There was no evidence of difference for any other comparisons for any outcomes. One trial evaluated base-in prism glasses prescribed for near-work activities and found that the prism glasses group had fewer symptoms compared with the placebo glasses group at three months (MD -8.9, 95% CI -11.6 to -6.3). The trial found no evidence of a difference with this intervention in NPC or PFV. No adverse effects related to study treatments were reported for any of the included studies. Excellent adherence was reported for office-based vergence/accommodative therapy (96.6% or higher) in two trials. Reported adherence with home-based therapy was less consistent, with one study reporting decreasing adherence over time (weeks 7 to 12) and lower completion rates with home-based pencil/target push-ups. Current research suggests that office-based vergence/accommodative therapy with home reinforcement is more effective than home-based pencil/target push-ups or home-based computer vergence/accommodative therapy for children. In adults, evidence of the effectiveness of various non-surgical interventions is less clear.


OPC-28326, a selective peripheral vasodilator with angiogenic activity, mitigates postinfarction cardiac remodeling.
Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with α2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice (n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction.


Mps1p regulates meiotic spindle pole body duplication in addition to having novel roles during sporulation.
Sporulation in yeast requires that a modified form of chromosome segregation be coupled to the development of a specialized cell type, a process akin to gametogenesis. Mps1p is a dual-specificity protein kinase essential for spindle pole body (SPB) duplication and required for the spindle assembly checkpoint in mitotically dividing cells. Four conditional mutant alleles of MPS1 disrupt sporulation, producing two distinct phenotypic classes. Class I alleles of mps1 prevent SPB duplication at the restrictive temperature without affecting premeiotic DNA synthesis and recombination. Class II MPS1 alleles progress through both meiotic divisions in 30-50% of the population, but the asci are incapable of forming mature spores. Although mutations in many other genes block spore wall formation, the cells produce viable haploid progeny, whereas mps1 class II spores are unable to germinate. We have used fluorescently marked chromosomes to demonstrate that mps1 mutant cells have a dramatically increased frequency of chromosome missegregation, suggesting that loss of viability is due to a defect in spindle function. Overall, our cytological data suggest that MPS1 is required for meiotic SPB duplication, chromosome segregation, and spore wall formation.


Plasma AXIN1 expression exhibit negative correlations with inflammatory biomarkers and is associated with gastrointestinal symptoms in endometriosis.
The cytoplasmic protein AXIN1 is involved in the Wnt signalling pathway and its expression is increased in patients with endometriosis compared with healthy controls. The aim of the present cross-sectional study was to further assess the levels of AXIN1 and other inflammatory biomarkers in patients with endometriosis. Patients with laparoscopy-verified endometriosis were recruited (n=172) and completed a questionnaire regarding socioeconomic factors, lifestyle habits and medical history. Plasma AXIN1 and high-sensitivity C-reactive protein (hs-CRP) levels were analysed by ELISA. The levels of calprotectin were determined in the faeces, and the haemoglobin concentration and number of erythrocytes, leukocytes and platelets were determined in the blood in a subgroup of 64 patients during clinical routine procedures. F-calprotectin expression was detected in 18 women (28.1%), who had more severe constipation and more frequently experienced incomplete evacuation when defecating, and 5 women (7.8%) exhibited elevated levels. P-AXIN1 levels were higher in patients who received hormonal treatment, and correlated inversely with faecal-calprotectin levels (P=0.003), B-haemoglobin levels (P=0.030) and the numbers of B-erythrocytes (P=0.033) and B-platelets (P=0.017), but were not correlated with hs-CRP levels (P=0.818). Higher levels of AXIN1 were associated with the duration of the gastrointestinal symptoms and with diarrhoea, constipation, vomiting and nausea and the intestinal symptoms' effect on quality of life, and tended to be associated with the duration of endometriosis. Hs-CRP expression was not associated with the clinical characteristics or symptoms of endometriosis, but higher levels were associated with obesity (P=0.002) and hormonal treatment (P=0.011). In conclusion, P-AXIN1 expression was negatively correlated with certain inflammatory biomarkers and was positively associated with gastrointestinal symptoms. P-AXIN1 levels were increased in patients who received hormonal treatment, highlighting the importance of obtaining native samples for future studies regarding its role in the development and presentation of endometriosis. However, hs-CRP and other studied biomarkers seemed to be of no value for the assessment and diagnosis of endometriosis.


Examination of IgA1-protease activity in Bordetella.
A total of 43 strains of bacterial genus Bordetella was studied as to the possible extracellular enzyme production responsible for Al-immunoglobulin cleavage. This was observed to be cleaved by 9 of 21 controlled strains of B. pertussis, one of 15 strains of B. parapertussis, and one of 7 strains of B. bronchiseptica. No cleavage of G and M human immunoglobulin classes by protease positive strains of B. pertussis was evaluated. The immunochemical method altogether with polyacrylamide gel electrophoresis (PGE) with sodium dodecyl sulphate (SDS) were used to assess the IgA1 cleavage products bordetella and several compounds belonging to the heavy chain fragments were revealed. The obtained data allowed us to make a presumption that the cleavage sites of peptide chain for bordetella and meningococcal proteases were different ones.


The mobility experience and neighborhood attachment.
In this study, I consider variables associated with an individual's most recent move into his or her current residence as predictors of neighborhood attachment. Using the 1978-1979 Seattle Community Attachment Survey, I find that elements of the mobility experience such as an individual's past history of migration, the motivations for moving, the amount of time involved in the move, and the distance traveled during the move have an effect on short- and long-term neighborhood attachment patterns independent of residential stability and investment predictors. The findings imply that psychosocial factors such as familiarity with the environment, increased premove exposure to the new environment, and perceived control during instances of transition have some impact on individuals' postmove attitudes and behaviors, and suggest that researchers should look beyond traditional "types of people" explanations of urban neighborhood attachment.


Essential oil of tarragon (Artemisia dracunculus) antibacterial activity on Staphylococcus aureus and Escherichia coli in culture media and Iranian white cheese.
In this study, the antibacterial effect of essential oil of tarragon (Artemisia dracunculus) on Staphylococcus aureus and Escherichia coli was evaluated in culture media and Iranian white cheese. The tarragon essential oil (EO) obtained by the steam distillation method and its antibacterial activity was evaluated in 96-well microtiter plates containing brain heart infusion broth. The enumeration of S. aureus and E. coli in cheese samples were carried out on the following media: Baired parker agar for S.aureus, incubated at 37°C for 24 h; and MacConkey sorbitol agar for E. coli, incubated at 37°C for 24 h. Iranian white cheese was produced from fresh and whole pasteurized cow milk (2.5%). Bacteria (10(3) cfu/mL) were inoculated to different batches. Cheese was treated with different concentrations of EO (15 and 1500 µg/mL) and separated into four parts in an equal manner. The sensory evaluation was done by a panel of four judges. According to the results obtained, minimum inhibitory concentrations (MIC) for E. coli and S. aureus were 2500 and 1250 µg/mL, respectively. Also, minimum bactericidal concentration (MBC) for the mentioned microorganisms were 5000 and 2500 µg/mL, respectively. All the EO concentrations for each bacteria result in reducing bacterial count of cheese samples compared to control (P<0.05). Also, with increasing concentration of EO in cheese samples, the bacterial count was reduced further (P<0.05). Based on our findings, tarragon essential oil has antibacterial effect on two important pathogen bacteria (S. aureus and E. coli) and can be applied as a preservative in foods such as cheese.


Delivery of health care for children: report of an experiment.
This paper summarizes an experiment evaluating the effectiveness of primary pediatric care delivered to a sample of low-income inner-city families. Primary pediatric care in this study was similar to pediatric group practice. The study findings indicated that the effects of primary care compared with the episodic care received by the control families were appreciable. This included the decreasing of hospitalizations, operations, illness visits, and appointment breaking; increasing of health supervision visits, preventive services, and patient satisfactions; and accomplishing these changes at a lower cost. Patient morbidity was not altered. Medicaid made no difference in the care patterns of the experimental families and apparently benefited only those control families who were white. The controlled clinical trial offers the best opportunity to compare different models of priervices for children.


Ethical Considerations in Microbial Therapeutic Clinical Trials.
As understanding of the human microbiome improves, novel therapeutic targets to improve human health with microbial therapeutics will continue to expand. We outline key considerations of balancing risks and benefits, optimising access, returning key results to research participants, and potential conflicts of interest.


Ethnicity and sex modify the association of serum c-reactive protein with microalbuminuria.
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure. This was a cross-sectional study of 6675 participants who were free from macroalbuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels. The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups). The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.


tRNA Modifications: Impact on Structure and Thermal Adaptation.
Transfer RNAs (tRNAs) are central players in translation, functioning as adapter molecules between the informational level of nucleic acids and the functional level of proteins. They show a highly conserved secondary and tertiary structure and the highest density of post-transcriptional modifications among all RNAs. These modifications concentrate in two hotspots-the anticodon loop and the tRNA core region, where the D- and T-loop interact with each other, stabilizing the overall structure of the molecule. These modifications can cause large rearrangements as well as local fine-tuning in the 3D structure of a tRNA. The highly conserved tRNA shape is crucial for the interaction with a variety of proteins and other RNA molecules, but also needs a certain flexibility for a correct interplay. In this context, it was shown that tRNA modifications are important for temperature adaptation in thermophilic as well as psychrophilic organisms, as they modulate rigidity and flexibility of the transcripts, respectively. Here, we give an overview on the impact of modifications on tRNA structure and their importance in thermal adaptation.


A proteomic profiling approach to reveal a novel role of Brassica napus drought 22 kD/water-soluble chlorophyll-binding protein in young leaves during nitrogen remobilization induced by stressful conditions.
Despite its water-soluble chlorophyll-binding protein (WSCP) function, the putative trypsin inhibitor (TI) activity of the Brassica napus drought 22 kD (BnD22) protein and its physiological function in young leaves during leaf nitrogen (N) remobilization promoted by stressful conditions remains an enigma. Therefore, our objectives were to determine (1) if BnD22 is related to the 19-kD TI previously detected in B. napus young leaves, and (2) if the levels of BnD22 transcripts, BnD22 protein, and TI activity in young leaves are associated with plant responses to stress conditions (N starvation and methyl jasmonate [MeJA] treatments) that are able to modulate leaf senescence. Compared to control, N starvation delayed initiation of senescence and induced 19-kD TI activity in the young leaves. After 3 d with MeJA, the 19-kD TI activity was 7-fold higher than the control. Using two-dimensional electrophoresis gel, TI activity, and electrospray ionization liquid chromatography tandem mass spectrometry analysis, it was demonstrated that two 19-kD proteins with isoelectric points 5.0 and 5.1 harboring TI activity correspond to BnD22 perfectly. BnD22 gene expression, TI activities, and BnD22 protein presented similar patterns. Using polyclonal anti-WSCP antibodies of Brassica oleracea, six polypeptides separated by two-dimensional electrophoresis were detected in young leaves treated with MeJA. Electrospray ionization liquid chromatography tandem mass spectrometry analysis of six polypeptides confirms their homologies with WSCP. Results suggest that BnD22 possesses dual functions (WSCP and TI) that lead to the protection of younger tissues from adverse conditions by maintaining metabolism (protein integrity and photosynthesis). By sustaining sink growth of stressed plants, BnD22 may contribute to a better utilization of recycling N from sources, a physiological trait that improves N-use efficiency.


Predicting the Speed of Epidemics Spreading in Networks.
Global transport and communication networks enable information, ideas, and infectious diseases to now spread at speeds far beyond what has historically been possible. To effectively monitor, design, or intervene in such epidemic-like processes, there is a need to predict the speed of a particular contagion in a particular network, and to distinguish between nodes that are more likely to become infected sooner or later during an outbreak. Here, we study these quantities using a message-passing approach to derive simple and effective predictions that are validated against epidemic simulations on a variety of real-world networks with good agreement. In addition to individualized predictions for different nodes, we find an overall sudden transition from low density to almost full network saturation as the contagion progresses in time. Our theory is developed and explained in the setting of simple contagions on treelike networks, but we are also able to show how the method extends remarkably well to complex contagions and highly clustered networks.


Daily ultrasound-based image-guided targeting for radiotherapy of upper abdominal malignancies.
Development and implementation of a strategy to use a stereotactic ultrasound (US)-based image-guided targeting device (BAT) to align intensity-modulated radiotherapy (IMRT) target volumes accurately in the upper abdomen. Because the outlines of such targets may be poorly visualized by US, we present a method that uses adjacent vascular guidance structures as surrogates for the target position. We assessed the potential for improvement of daily repositioning and the feasibility of daily application. A total of 62 patients were treated by sequential tomotherapeutic IMRT between October 2000 and June 2003 for cholangiocarcinoma and gallbladder carcinoma (n = 10), hepatocellular carcinoma (n = 10), liver metastases (n = 11), pancreatic carcinoma (n = 20), neuroblastoma (n = 3), and other abdominal and retroperitoneal tumors (n = 8). The target volumes (TVs) and organs at risk were delineated in contrast-enhanced CT data sets. Additionally, vascular guidance structures in close anatomic relation to the TV, or within the TV, were delineated. Throughout the course of IMRT, US BAT images were acquired during daily treatment positioning. In addition to the anatomic structures typically used for US targeting (e.g., the TV and dose-limiting organs at risk), CT contours of guidance structures were superimposed onto the real-time acquired axial and sagittal US images, and target position adjustments, as indicated by the system, were performed accordingly. We report the BAT-derived distribution of shifts in the three principal room axes compared with a skin-mark-based setup, as well as the time required to perform BAT alignment. The capability of the presented method to improve target alignment was assessed in 15 patients by comparing the organ and fiducial position between the respective treatment simulation CT with a control CT study after US targeting in the CT suite. A total of 1,337 BAT alignments were attempted. US images were not useful in 56 setups (4.2%), mainly because of limited visibility due to daily variations in colonic and gastric air. US imaging was facilitated in intrahepatic tumors and asthenic patients. The mean +/- SD shift from the skin mark position was 4.9 +/- 4.35, 6.0 +/- 5.31, and 6.0 +/- 6.7 mm in the x, y, and z direction, respectively. The mean magnitude vector of three-dimensional alignment correction was 11.4 +/- 7.6 mm. The proportion of daily alignments corrected by a magnitude of >10, >15, and >20 mm was 48.9%, 25.1%, and 12.7%, respectively. The magnitude of shifts in the principal directions, as well as the three-dimensional vector of displacement, was statistically significant (test against the zero hypothesis) at p <0.0001. The guidance structures that were the most valuable for identification of the TV position were the branches of the portal vein, hepatic artery, and dilated bile ducts in intrahepatic lesions and the aorta, celiac trunk, superior mesenteric artery, and extrahepatic aspects of the portal vein system in retroperitoneal and extrahepatic lesions. The mean total setup time was 4.6 min. The correlation of BAT targeting with target setup error assessment in the control CT scans in 15 patients revealed setup error reduction in 14 of 15 alignments. The average setup error reduction, assessed as a reduction in the length of setup error three-dimensional magnitude vector, was 54.4% +/- 26.9%, with an observed mean magnitude of residual setup error of 4.6 +/- 3.4 mm. The sole worsening of an initial setup was by a magnitude of <2 mm. US targeting resulted in statistically significant improvements in patient setup (p = 0.03). Daily US-guided BAT targeting for patients with upper abdominal tumors was feasible in the vast majority of attempted setups. This method of US-based image-guided tumor targeting has been successfully implemented in clinical routine. The observed improved daily repositioning accuracy might allow for individualized reduction of safety margins and optional dose escalation. Compared with the established application of the BAT device for prostate radiotherapy, in which the target can be directly visualized, the TV in the present study was predominantly positioned relative to guidance vascular structures in close anatomic relation. We perceived an enormous potential in improved and individualized patient positioning for fractionated radiotherapy and also for stereotactic extracranial radiotherapy and radiosurgery, especially for tumors of the liver and pancreas.


Spiro skeletons: a class of privileged structure for chiral ligand design.
This Focus Review highlights the exciting results obtained in the area of asymmetric catalysis using spirobiindane- or spirobifluorene-based chiral ligands. The spiro, mono, and bidentate ligands have been successfully applied in a wide range of transition-metal-catalyzed asymmetric reactions, including hydrogenations, carbon-carbon and carbon-heteroatom coupling reactions, with superior or comparable enantioselectivities to those obtained by using the related ligands bearing other backbones, thus proving that the spiro skeleton is a type of privileged structure for chiral ligand design. It is expected that the spiro concept for chiral ligand design will stimulate the future efforts to understand the features that account for their broad applicability and to apply this understanding to seek new privileged chiral ligands and catalysts.


[Two-year experience of laparoscopic operations in the Zhitomir regional pediatric hospital].
First experience of laparoscopic operations performance in children in the Zhytomir region was suggested as well as the advantages of laparoscopy, method of "open laparoscopy", variant of assisted laparoscopy and laparotomy under laparoscopic control. The analysis of results of laparoscopic interventions in 205 children, 36--emergent and 169--planned, was conducted.


Reproducibility of bowel ultrasonography in the evaluation of Crohn's disease.
Bowel ultrasonography is increasingly used in the detection and follow-up of patients with Crohn's disease, but a limitation to its further diffusion is the lack of standardisation of ultrasonography parameters. This study aimed to standardise the most common bowel ultrasonography parameters in order to develop an unequivocal imaging interpretation and to assess bowel ultrasonography reproducibility. Twenty patients with Crohn's disease were examined. Six ultrasonographers (mean bowel ultrasonography experience=16 years) performed the study. They chose and discussed a common assessment methodology concerning eight ultrasonography parameters: bowel wall thickness, bowel wall pattern, bowel wall blood flow, enlarged mesenteric lymph nodes, mesenteric hypertrophy, abdominal free fluid, and stenosis or fistulae at four preliminary meetings. The day of the study operators were randomised to two rooms where they independently and in turn performed ultrasonography scans. Interobserver agreement was scored by kappa statistics. Excellent k values were observed for bowel wall thickness (0.72-1). k Values were poor for bowel wall pattern (-0.22-0.85) and good for bowel wall blood flow (0.53-0.89). The presence of lymph nodes was reproducible (0.56-0.90) except in one case (0.25). Concordance on free fluid was excellent (0.85-1), whereas that on mesenteric hypertrophy was generally poor (0.14-0.69). Agreement was excellent for stenosis (0.81-1) whereas that for fistula was fair in room abscesses (0.31-0.48) and very good in room B (0.87-1). Bowel ultrasonography signs used in Crohn's disease can be standardised as most of them showed a fair to good reproducibility. In particular, bowel wall thickness, the most relevant parameter for Crohn's disease detection, showed an excellent reproducibility.


Spuriously elevated plasma calcitonin in a patient with a thyroid nodule not associated with medullary thyroid carcinoma.
An increase in plasma calcitonin concentration is widely regarded as a specific and sensitive indication of underlying medullary thyroid carcinoma (MTC). We present a case in which the association of increased plasma calcitonin concentration and a thyroid nodule was not due to MTC. Subsequent measurement of plasma calcitonin by a variety of methods highlighted the variability that exists in calcitonin measurement and the potential for clinically misleading results. The rationale for investigation and treatment of MTC, including a recommendation to screen all patients with thyroid nodules using plasma calcitonin measurement, is based on the use of specific two-site calcitonin assays which are not universally used in the UK or USA.