Personal Values as a Mediator of Relations Between Perceived Parental Support and Control and Youth Substance Use.
Tobacco and marijuana smoking are very popular in adolescence and there is a high rate of comorbidity between them, even in young adulthood. Parental support and control may hinder involvement in the use of these substances by promoting conventional values among adolescents. The present study investigates the relations between family functioning (parental support and control) and psychoactive substance use (tobacco and marijuana smoking) and determines whether these relationships are mediated by personal values (in terms of disapproval of deviance and beliefs about the importance of school, health and religion). 175 Italian late adolescents (17 to 20 years old) participated in this two-wave longitudinal study. Data were collected at school through an anonymous questionnaire. Greater parental control and support were directly associated with lower adolescent tobacco and marijuana use; adolescent acceptance of conventional values mediated the association between parenting and adolescent marijuana use. Findings emphasize the influence of family relationships throughout adolescence. The transmission of conventional values to adolescents may be a critical mechanism through which parenting protects adolescents from substance use, especially marijuana use.


Antigen-independent regulation of cytoplasmic calcium in B cells with a 12-kDa B-cell growth factor and anti-CD19.
Increases in cytoplasmic free calcium ([Ca2+]i) can be induced in resting B cells either by a low molecular weight (12-kDa) B-cell growth factor (LMW-BCGF) or by crosslinking the B-cell antigen CD19 with monoclonal antibody (mAb). LMW-BCGF causes a slow [Ca2+]i increase in peripheral blood and tonsillar B cells but has no effect on [Ca2+]i in resting T cells. B-cell [Ca2+]i responses mediated by anti-surface immunoglobulin (sIg) or anti-CD19 are potentiated by LMW-BCGF, but anti-sIg and anti-CD19 do not show additive [Ca2+]i responses. LMW-BCGF- and anti-CD19-induced [Ca2+]i signals are similar to the sIgM or sIgD-mediated signals in that they are inhibited by prior treatment with phorbol 12-myristate 13-acetate. However, LMW-BCGF- and CD19-mediated signals do not depend on the expression of sIg, since they were also observed on sIg-B-cell precursor acute lymphoblastic leukemia (ALL) cells. Both anti-CD19 and LMW-BCGF stimulated in vitro colony formation by ALL cells and showed additive effects when used together. [Ca2+]i responses to LMW-BCGF or CD19 cross-linking were also evident on certain pre-B-cell and lymphoma B-cell lines.


The role of endothelin-1 and endothelin receptor antagonists in allergic rhinitis inflammation: ovalbumin-induced rat model.
Desloratadine is a biologically active metabolite of loratadine which is indicated for the treatment of allergic rhinitis. Bosentan is a dual endothelin receptor antagonist used to treatment of pulmonary artery hypertension (PAH). In this study, we aimed to determine the role of endothelins in allergic rhinitis (AR) and the effects of endothelin receptor antagonists in AR rat models through comparison with desloratadine. In total, 20 adult Sprague-Dawley rats were used in this study. An ovalbumin-induced allergic rhinitis model was formed in three study groups except for the control group. Bosentan (100 mg/kg/day) was given to the bosentan-treated group for 7 days and desloratadine (10 mg/kg/day) was administered to the antihistaminic-treated group for 7 days. Nasal symptom scorings and histopathological examinations of the nasal tissues were carried out. Serum IgE levels and ET-1 and TNF-alpha mRNA expression levels were analysed. Between group comparisons for nasal symptoms, histopathological analysis, and molecular analyses were performed with a one-way ANOVA and Duncans multiple comparison tests. Significance was accepted at p smaller than 0.05. Bosentan inhibited nasal symptom more significantly than desloratadine. The IgE level, ET-1 and TNF-alpha mRNA expression levels statistically increased in the allergic rhinitis group when compared to other groups. Conversely, the bosentan-treatment group showed a significant recovery from the same parameters. The deterioration in histopathological parameters reached the highest levels in the allergic rhinitis group. The histopathological findings were close to those of the control group in the bosentan and antihistaminic-treated group. ET-1 is one of the mediators that impact AR development and ET-1 antagonists can be useful for symptom control and for decreasing allergic inflammation in AR patients.


Hyperhomocysteinemia in preeclampsia is associated to higher risk pressure profiles.
Homocysteine levels have been determined with Chromatography on HPLC column, between the 20th and the 24th week of pregnancy, in women with analogous characteristics (a) normotensive, (b) with pregnancy-induced hypertension (PIH), low (LR), medium (MR), high risk (HR). The group they belonged to was confirmed after natural or caesarean delivery. All the patients were submitted to 24 hour blood pressure monitoring for the evaluation of further pressure risk parameters: mean arterial pressure (MAP), non dippers, percentages of pressure peaks. Homocysteine levels in normotensive pregnant women (5.8 +/- 1.7 microM) were low. Significant high levels of homocysteine were present proportionally to the risk degree of PIH. Higher levels of homocysteine statistically significant were present in non dippers of all groups (MR p < 0.05; HR p < 0.01). A direct correlation between plasmatic homocisteine levels and pressure profiles was found out in non dippers (r = 0.56, r = 0.55, r = 0.50 respectively) and in dippers (r = 0.7, r = 0.75, r = 0.60 respectively), and also between levels of homocysteine, MAP value, and pathological percentages of systolic and diastolic nocturnal peaks. In pregnant women presenting preeclampsia afterwards, high levels of homocysteine were not different from mean values present in high risk PIH pregnant women (13.3 +/- 1.9 vs. 16.4 +/- 1.7 microM). High levels of homocysteine early determined in the second trimester of PIH pregnancies seem to be associated to a pregnancy higher risk, coexisting with dangerous pressure profiles. High levels confirm a pregnant woman to belong to a higher or lower risk degree of vascular damage, but in the same group context high levels of homocisteine do not allow to identify those pregnant women who will develop eclampsia.


Evaluating mortality and disease severity in congenital diaphragmatic hernia using the McGoon and pulmonary artery indices.
Lung hypoplasia is associated with mortality in congenital diaphragmatic hernia (CDH). However, the association between lung hypoplasia and disease severity is unclear. Early prediction of disease severity would provide parents with more precise information about the anticipated course of treatment, minimize treatment disruption, and maximize the efficient management of patients with CDH. We aimed at identifying the relationship between McGoon index (MGI) and pulmonary artery index (PAI) scores and disease severity among infants with CDH. We retrospectively reviewed the medical records of 19 high-risk patients with CDH born between January 2006 and December 2007. McGoon index and PAI scores were determined on admission. We evaluated statistically the relationship between these scores and variables representing severity as follows: number of vasodilators, use of inhaled nitric oxide (iNO), closed method of diaphragm, duration of intubation, duration of hospitalization, and use of home oxygen therapy. Statistical significance was P < .05. Overall median MGI and PAI scores were 1.40 and 108, respectively; scores for nonsurvivors were significantly (P < .05 and P < .01, respectively) lower than those for survivors. Among survivors, PAI scores were significantly (P < .05) lower in infants requiring iNO than in infants not requiring iNO and patch repair. The PAI scores were significantly correlated with the number of vasodilators (r = -0.789; P < .01) and duration of intubation (r = -0.610; P < .05). McGoon index (cutoff value, 1.31) and PAI (cutoff value, 90) are reliable indices for predicting mortality in CDH. Pulmonary artery index appears to be more useful than MGI for predicting disease severity among survivors.


Proteogenomic Analysis and Discovery of Immune Antigens in Mycobacterium vaccae.
Tuberculosis (TB) is one of the leading causes of death worldwide, especially in developing countries. Neonatal BCG vaccination occurs in various regions, but the level of protection varies in different populations. Recently, Mycobacterium vaccae is found to be an immunomodulating therapeutic agent that could confer a significant level of protection against TB. It is the only vaccine in a phase III trial from WHO to assess its efficacy and safety in preventing TB disease in people with latent TB infection. However, the mechanism of immunotherapy of M. vaccae remains poorly understood. In this study, the full genome of M. vaccae was obtained by next-generation sequencing technology, and a proteogenomic approach was successfully applied to further perform genome annotation using high resolution and high accuracy MS data. A total of 3,387 proteins (22,508 unique peptides) were identified, and 581 proteins annotated as hypothetical proteins in the genome database were confirmed. Furthermore, 38 novel protein products not annotated at the genome level were detected and validated. Additionally, the translational start sites of 445 proteins were confirmed, and 98 proteins were validated through extension of their translational start sites based on N terminus-derived peptides. The physicochemical characteristics of the identified proteins were determined. Thirty-five immunogenic proteins of M. vaccae were identified by immunoproteomic analysis, and 20 of them were selected to be expressed and validated by Western blot for immunoreactivity to serum from patients infected with M. tuberculosis The results revealed that eight of them showed strong specific reactive signals on the immunoblots. Furthermore, cellular immune response was further examined and one protein displayed a higher cellular immune level in pulmonary TB patients. Twelve identified immunogenic proteins have orthologous in H37Rv and BCG. This is the first study to obtain the full genome and annotation of M. vaccae using a proteogenomic approach, and some immunogenic proteins that were validated by immunoproteomic analysis could contribute to the understanding of the mechanism of M. vaccae immunotherapy.


High GDF-8 in follicular fluid is associated with a low pregnancy rate in IVF patients with PCOS.
Polycystic ovary syndrome (PCOS) is the most common cause of female infertility. Growth differentiation factor-8 (GDF-8) is expressed in the ovary and can be detected in human follicular fluid which provides an important microenvironment for maintaining physiological functions of the ovarian follicle. To date, the relationship between GDF-8 levels in follicular fluid and the risk of PCOS is completely unknown. In the present study, we show that during the process of the controlled ovarian hyperstimulation (COH), serum GDF-8 levels are higher on the day of gonadotropin administration and 14 days after embryo transfer in in vitro fertilization (IVF) patients with PCOS than they are in IVF patients without PCOS. Importantly, GDF-8 levels in follicular fluid at oocyte retrieval are also higher in PCOS patients than in non-PCOS patients. Treatment of primary human granulosa-lutein (hGL) cells with GDF-8 downregulates StAR protein expression and the inhibition is more pronounced in hGL cells from PCOS patients than it is in cells from non-PCOS patients. Importantly, high GDF-8 levels and low progesterone (P4) levels were associated with poor pregnancy outcomes in PCOS patients. Our results provide the first evidence that aberrant expression of GDF-8 in the follicular fluid of PCOS patients results in abnormal P4 expression, which leads to poor pregnancy outcomes.


Update in ARDS management: recent randomized controlled trials that changed our practice.
In the last 7 years, 14 randomized controlled trials in patients with acute respiratory distress syndrome (ARDS) have shown that: Mechanical ventilation with a tidal volume of 6 mL/kg of predicted body weight is better than mechanical ventilation with a tidal volume of 12 mL/kg of predicted body weight. Prone positioning improves oxygenation but poses safety concerns. A high level of positive end-expiratory pressure does not improve survival. High-frequency oscillatory ventilation is in theory the ideal "lung-protective" method, but its benefits have not been proven. No drug therapy has been shown to improve survival in patients with ARDS. Exogenous surfactant may improve oxygenation but has no significant effect on the death rate or length of use of mechanical ventilation. Low-dose inhaled nitric oxide has no substantial impact on the duration of ventilatory support or on the death rate. Partial liquid ventilation may be beneficial in young patients with acute lung injury or ARDS, although further study is needed to confirm this.


Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease.
We recently hypothesized that in the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), the presumably homogeneous patient group characterized by early onset of disease, a female predilection, the presence of antinuclear antibodies (ANA), asymmetric arthritis, and the risk for iridocyclitis is classified into different categories. We sought to investigate whether ANA-positive patients belonging to the ILAR categories of oligoarthritis and rheumatoid factor (RF)-negative polyarthritis share homogeneous features and to compare these features with those of ANA-negative patients with JIA in the same categories. We identified patients who were followed up during a 15-year period. All patients had JIA according to the ILAR criteria, with oligoarticular or polyarticular onset. ANA positivity was defined as 2 or more positive results at a titer of >or=1:160. Demographic and clinical features, including the number of joints involved over time and measures of JIA severity at the last followup visit, were recorded retrospectively. A total of 256 patients were included: 190 were ANA positive (109 had persistent oligoarthritis, 48 had extended oligoarthritis, and 33 had RF-negative polyarthritis), and 66 were ANA negative (35 had RF-negative polyarthritis, and 31 had oligoarthritis). All patients who were positive for ANA were similar in terms of age at disease presentation, female-to-male ratio, and frequency of symmetric arthritis and iridocyclitis. Compared with ANA-positive patients with polyarticular disease, ANA-negative patients with polyarticular arthritis were older at disease presentation and had a lower frequency of iridocyclitis, a higher frequency of symmetric arthritis, a greater cumulative number of joints affected over time, and a different pattern of joint disease, with a greater frequency of shoulder and hip involvement. The strong relationship between the presence of ANA and younger age at disease presentation, asymmetric arthritis, and development of iridocyclitis was confirmed by multivariate regression analysis. Our results support the hypothesis that patients with similar characteristics are currently classified into different JIA categories. The value of ANA positivity as a possible modifier of the current classification system deserves consideration.


Monte Carlo simulation and SAFT modeling study of the solvation thermodynamics of dimethylformamide, dimethylsulfoxide, ethanol and 1-propanol in the ionic liquid trimethylbutylammonium bis(trifluoromethylsulfonyl)imide.
Understanding fundamental solvation phenomena and mixture thermodynamic properties for organic molecules in ionic liquids is essential to the development of ionic liquids in many application areas. In the present work, molecular simulations were used to compute a wide range of properties for the pure ionic liquid trimethylbutylammonium bis(trifluoromethylsulfonyl)imide as well as mixtures of this ionic liquid with ethanol, 1-propanol, dimethylformamide, and dimethylsulfoxide. A new force field for the ionic liquid was developed and validated by computing ionic liquid surface tension and density as a function of temperature. Force fields for ethanol and propanol were taken from the literature, while new force fields were developed for dimethylformamide and dimethylsulfoxide. These force fields were shown to yield vapor-liquid coexistence curves, vapor pressure curves and critical points in excellent agreement with experimental data. Absorption isotherms, enthalpies of mixing and mixture volumes were then computed and shown to agree well with available literature. The simulations help rationalize the observed trends in solubility and enthalpy of mixing in terms of the relative strength of hydrogen bonding between the solutes and the ionic liquid. It was found that the entropy of absorption plays a very important role in the solvation process. The PCIP-SAFT equation of state was able to fit the experimental data (or simulation results when experiments were unavailable) very accurately with only small adjustable binary interaction parameters.


Impaired episodic memory for events encoded during mania in patients with bipolar disorder.
To date, very few studies have focused on autobiographical memory in patients with bipolar disorder. We examined whether mood state at the time of event encoding (i.e., manic, depressed, euthymic) influences subsequent recollection in these patients. We administered the Autobiographical Interview, a method that allowed us to dissociate episodic and semantic aspects of autobiographical memory. We also compared the memory perspective from which patients recollected these events. Patients were selectively impaired in recollecting episodic details of events encoded during mania but not depression or euthymia. No significant differences emerged between patients and controls for recollection of non-episodic details, regardless of mood state. Patients with bipolar disorder were also more likely than matched controls to recall memories from an observer perspective. These preliminary findings indicate a moderating influence of mood state at the time of event encoding on the subsequent recollection of autobiographical events in patients with bipolar disorder.


Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus.
The current study was conducted to test the hypothesis that patterns of failure are correlated with the degree of residual carcinoma after preoperative chemoradiotherapy (CRT) in patients with esophageal carcinoma. The authors analyzed the clinical characteristics of patients with carcinoma of the esophagus who underwent preoperative CRT. The residual carcinoma in the resected specimen was categorized into 3 groups (0%, 1-50%, and > 50%). The initial patterns of failure were analyzed according to these categories. Of the 235 patients who underwent CRT, 69 (29%) achieved a pathologic complete response (pathCR; Group A), 109 patients (46%) achieved a response but it was less than a pathCR (1-50% residual carcinoma; Group B), and 57 (24%) had no response (> 50% residual carcinoma; Group C). The time to locoregional recurrence was significantly longer for Group A compared with Group C (P = 0.05). The rate of distant metastases was significantly lower in Groups A and B compared with Group C (14% in Group A, 29% in Group B, and 33% in Group C; P = 0.03). The distant metastases-free survival was found to be significantly longer in Groups A and B compared with Group C (Group A vs. Group B, P = 0.01; Group A vs. Group C, P < 0.0001; and Group B vs. Group C, P = 0.03). A significantly higher proportion of patients in the responding groups (Groups A and B) had no disease recurrence compared with Group C (81% in Group A, 67% in Group B, and 61% in Group C; P = 0.04). The overall survival and disease-free survival were found to be significantly longer in Groups A and B compared with Group C. Data from the current study demonstrate that the proportion of residual carcinoma after preoperative CRT is significantly correlated with patterns of locoregional and distant failure. Future investigations should focus on reducing the proportion of residual carcinoma and metastatic disease progression in patients with esophageal carcinoma.


Analysis of rainbow scattering by a chiral sphere.
Based on the scattering theory of a chiral sphere, rainbow phenomenon of a chiral sphere is numerically analyzed in this paper. For chiral spheres illuminated by a linearly polarized wave, there are three first-order rainbows, with whose rainbow angles varying with the chirality parameter. The spectrum of each rainbow structure is presented and the ripple frequencies are found associated with the size and refractive indices of the chiral sphere. Only two rainbow structures remain when the chiral sphere is illuminated by a circularly polarized plane wave. Finally, the rainbows of chiral spheres with slight chirality parameters are found appearing alternately in E-plane and H-plane with the variation of the chirality.


Multiple interacting QTLs affect disease challenge survival in common carp (Cyprinus carpio).
With the steady growth of the human population, food security becomes a prime challenge. Aquaculture is the fastest growing sector providing proteins from an animal source, but outbreaks of infectious diseases repeatedly hamper the production and further development of this sector. Breeding of disease-resistant strains is a desired sustainable solution to this problem. Cyprinid herpes virus-3 (CyHV-3) is a dsDNA virus damaging production of common carp, an important food and ornamental fish. Previously, we have demonstrated successful introgression of CyHV-3 resistance from a feral strain to commercial strains. Here, we used genotyping by sequencing to identify two novel quantitative trait loci (QTLs) for disease survival that map to different linkage groups than two other QTLs that we previously identified. Effects of these four QTLs were validated and further studied in 14 families with various levels of disease resistance. CyHV-3 survival was found to be a quantitative trait conditioned by mild additive QTL effects and by intricate dominant allelic and epistatic QTL-QTL interactions. Both rare feral alleles and alleles common to feral and cultured strains contributed to survival. This and other advantages of feral alleles introgression were demonstrated. These QTLs, which affected survival of individuals within families, had no significant effect on variation in cumulative family % survival, suggesting that more between family variation remains to be explored. Unraveling the underlying genetics of survival is important for enhancing the breeding of resistant strains and our knowledge of disease resistance mechanisms.


Methodological Quality Assessment of Budget Impact Analyses for Orphan Drugs: A Systematic Review.
Objectives: This research aims to evaluate the methodological quality of budget impact analyses for orphan drugs and to provide suggestions for future analyses. Methods: Conference abstracts and peer-reviewed literature on budget impact analyses were collected through searches of Pubmed and Embase. ISPOR good practice guidelines were used as a methodological standard for budget impact analyses. Examined parameters encompassed: perspective, target population, data sources, intervention and comparator(s), time horizon, scope of costs, discounting, validation, assumptions and sensitivity analysis. Results: Seventy studies on individual orphan drugs and 21 studies on a combination of orphan drugs analyzing budget impact were identified. Overall, analyses considered a third-party payer perspective, reported periodic budget impacts over a one-to-five-year time horizon, and did not apply discounting. A dynamically fluctuating population and costs beyond drug costs were accounted for in 18.7% and 51.7% of studies, respectively. Input data were retrieved from published literature, clinical trials, registries, claims databases, expert opinions, historical data and market research. Assumptions were mostly made about population size and intervention/comparator(s) market uptake, but these assumptions were rarely justified and their impact was insufficiently explored through sensitivity analyses. Budget impact results were rarely validated. Conclusion: Existing budget impact analyses for orphan drugs are concise, vary greatly and are of substandard methodological quality. To eliminate possible bias in future budget impact analyses, future studies should adhere to national or ISPOR good practice guidelines on budget impact analysis.


Differentiating autoimmune pancreatitis from pancreatic cancer.
Differential diagnosis between autoimmune pancreatitis (AIP) and pancreatic cancer can be very difficult. The main clinical symptoms in patients with autoimmune pancreatitis are jaundice, weight loss, abdominal pain and new onset of diabetes mellitus. Unfortunately, the same symptoms could be observed in patients with pancreatic carcinoma too. Imaging methods as computed tomography (CT) scan, magnetic resonance imaging (MRI) and endosonography (EUS); together with serological examination (IgG4 and Ca 19-9) play the important role in differentiation autoimmune pancreatitis from pancreatic cancer. Extrapancreatic findings are distinctive in patients with autoimmune pancreatitis. In some cases the pancreatic biopsy is indicated, mainly in patients with focal or multifocal form of autoimmune pancreatitis. Response to steroids (decreased pancreatic or extrapancreatic lesion or damage) is distinctive to AIP. In clinical practice, CT scan seems to be the most reasonable tool for examining the patients with obstructive jaundice with or without present pancreatic mass. Stratification the patients with possible AIP versus pancreatic cancer is important. In patients with AIP it may avoid pancreatic resection, as well as incorrect steroid treatment in patients with pancreatic carcinoma.


Introduction While some studies have investigated the cooling properties of warm beverages, no studies have examined thermal well-being in warm environments in relation to beverage temperature. Methods Thirty researchers were randomised in a 1:1 ratio in a double-blinded cross-over study. Participants were randomised to drink 10cl of 10°C and 50°C decaffeinated tea, 15 minutes apart while staying outside in the Turkish summer heat at noon. Well-being was assessed using the American Society of Heating, Refrigeration and Air-conditioning Engineers (ASHRAE) thermal sensation scale, Bedford thermal comfort scale, Brief Mood Introspection Scale (BMIS), and the last two domains of EuroQol 5-domain, 5-point scale: EQ-5D-5L. Results Neither clinically nor statistically significant differences were found in well-being between warm and cold tea. Moods soured significantly as the trial course passed (using BMIS, µ 1.9; P=0.03), but comfort in the heat bettered (using Bedford, µ -0.37; P less-than 0.001). These changes were not considered to be clinically significant. Conclusion We were unable to show any correlation between beverage temperature and comfort in a hot environment. The mood of participants did, however, deteriorate as time passed-a lesson to any future researchers conducting drawn-out experiments just before lunch. Funding none. Trial registration NCT05900960.


Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities.
Loss of lung-fluid homeostasis is the hallmark of acute lung injury (ALI). Association of catenins and actin cytoskeleton with vascular endothelial (VE)-cadherin is generally considered the main mechanism for stabilizing adherens junctions (AJs), thereby preventing disruption of lung vascular barrier function. The present study identifies endothelial focal adhesion kinase (FAK), a nonreceptor tyrosine kinase that canonically regulates focal adhesion turnover, as a novel AJ-stabilizing mechanism. In wild-type mice, induction of ALI by intraperitoneal administration of lipopolysaccharide or cecal ligation and puncture markedly decreased FAK expression in lungs. Using a mouse model in which FAK was conditionally deleted only in endothelial cells (ECs), we show that loss of EC-FAK mimicked key features of ALI (diffuse lung hemorrhage, increased transvascular albumin influx, edema, and neutrophil accumulation in the lung). EC-FAK deletion disrupted AJs due to impairment of the fine balance between the activities of RhoA and Rac1 GTPases. Deletion of EC-FAK facilitated RhoA's interaction with p115-RhoA guanine exchange factor, leading to activation of RhoA. Activated RhoA antagonized Rac1 activity, destabilizing AJs. Inhibition of Rho kinase, a downstream effector of RhoA, reinstated normal endothelial barrier function in FAK-/- ECs and lung vascular integrity in EC-FAK-/- mice. Our findings demonstrate that EC-FAK plays an essential role in maintaining AJs and thereby lung vascular barrier function by establishing the normal balance between RhoA and Rac1 activities.


[Out-of-hospital cardiac arrest: current diagnostic and therapeutical concepts].
Out-of-hospital circulatory arrest represents a challenging situation in emergency medicine even until today. Despite optimal emergency care and clinical treatment pathways, we are faced with a mortality rate above 90 %. It is possible to improve the survival rate to more than 40 % under ideal clinical and preclinical conditions. Thus, more people's life could be saved by standardized SOPs and networks in emergency medicine. About 14.000 preclinical resuscitation cases are reported in Germany per year. The prognosis out-of-hospital circulatory arrest patients is determined by best preclinical treatment including early resuscitation by bystanders. However, ethical considerations for not performing cardiopulmonary resuscitation include comorbidities, advanced age, and prognostic markers of intensive care medicine like lactate level or neuron-specific enolase. Since myocardial infarction is the underlying disease in about 3 quarters of acute circulatory arrest cases, early angiography and coronary revascularization is of upmost importance. In addition, it is essential to provide hemodynamic stabilization for prevention of multiorgan dysfunction syndrome. Neuroprotection by therapeutic hypothermia may further help to improve survival and quality of life. Mechanical circulatory support devices may be considered adjunct to pharmacological measures for hemodynamic stabilization. Due to lack of evidence, these devices are currently under evaluation and prospectively randomized trials. We expect new treatment algorithms for optimal care of these high-risk patients in the near future.


Temporal and Spatial Variations of Bacterial and Faunal Communities Associated with Deep-Sea Wood Falls.
Sinking of large organic food falls i.e. kelp, wood and whale carcasses to the oligotrophic deep-sea floor promotes the establishment of locally highly productive and diverse ecosystems, often with specifically adapted benthic communities. However, the fragmented spatial distribution and small area poses challenges for the dispersal of their microbial and faunal communities. Our study focused on the temporal dynamics and spatial distributions of sunken wood bacterial communities, which were deployed in the vicinity of different cold seeps in the Eastern Mediterranean and the Norwegian deep-seas. By combining fingerprinting of bacterial communities by ARISA and 454 sequencing with in situ and ex situ biogeochemical measurements, we show that sunken wood logs have a locally confined long-term impact (> 3y) on the sediment geochemistry and community structure. We confirm previous hypotheses of different successional stages in wood degradation including a sulphophilic one, attracting chemosynthetic fauna from nearby seep systems. Wood experiments deployed at similar water depths (1100-1700 m), but in hydrographically different oceanic regions harbored different wood-boring bivalves, opportunistic faunal communities, and chemosynthetic species. Similarly, bacterial communities on sunken wood logs were more similar within one geographic region than between different seas. Diverse sulphate-reducing bacteria of the Deltaproteobacteria, the sulphide-oxidizing bacteria Sulfurovum as well as members of the Acidimicrobiia and Bacteroidia dominated the wood falls in the Eastern Mediterranean, while Alphaproteobacteria and Flavobacteriia colonized the Norwegian Sea wood logs. Fauna and bacterial wood-associated communities changed between 1 to 3 years of immersion, with sulphate-reducers and sulphide-oxidizers increasing in proportion, and putative cellulose degraders decreasing with time. Only 6% of all bacterial genera, comprising the core community, were found at any time on the Eastern Mediterranean sunken wooden logs. This study suggests that biogeography and succession play an important role for the composition of bacteria and fauna of wood-associated communities, and that wood can act as stepping-stones for seep biota.


Epitaxial growth and defect repair of heterostructured CuInSexS2-x/CdSeS/CdS quantum dots.
Heterostructured quantum dots (hetero-QDs) have outstanding optical properties and chemical/photostability, which make them promising building blocks for use in various optoelectronic devices. Here, CuInSexS2-x/CdSeS/CdS hetero-QDs were synthesized through a facile two-step method. Their particle size, three-dimensional (3D) shapes and the epitaxial relationship between the CuInSexS2-x/CdSeS core and CdS shell were investigated by high-resolution transmission electron microscopy (HRTEM). Our investigation proves that the as-synthesized hetero-QDs have a regular tetrahedron 3D shape with four {111} crystal facets. The epitaxial relationship between the CuInSexS2-x/CdSeS core and CdS shell is determined to be [110]core//[110]shell, {112}core//{111}shell. In situ HRTEM observations show that the screw dislocation inside the hetero-QDs can be efficiently repaired using e-beam irradiation. These results may help in designing hetero-QDs with high-quality interfaces and identifying the strategies for synthesizing defect-free hetero-QDs.


Visualization and quantification of inhomogeneous and anisotropic magnetic fields by polarized neutron grating interferometry.
The intrinsic magnetic moment of a neutron, combined with its charge neutrality, is a unique property which allows the investigation of magnetic phenomena in matter. Here we present how the utilization of a cold polarized neutron beam in neutron grating interferometry enables the visualization and characterization of magnetic properties on a microscopic scale in macroscopic samples. The measured signal originates from the phase shift induced by the magnetic potential. Our method enables the detection of previously inaccessible magnetic field gradients, in the order of T cm-1, extending the probed range by an order of magnitude. We visualize and quantify the phase shift induced by a well-defined square shaped uniaxial magnetic field and validate our experimental findings with theoretical calculations based on Hall probe measurements of the magnetic field distribution. This allows us to further extend our studies to investigations of inhomogeneous and anisotropic magnetic field distribution.


Mutation of the Erwinia amylovora argD gene causes arginine auxotrophy, nonpathogenicity in apples, and reduced virulence in pears.
Fire blight is caused by Erwinia amylovora and is the most destructive bacterial disease of apples and pears worldwide. In this study, we found that E. amylovora argD(1000)::Tn5, an argD Tn5 transposon mutant that has the Tn5 transposon inserted after nucleotide 999 in the argD gene-coding region, was an arginine auxotroph that did not cause fire blight in apple and had reduced virulence in immature pear fruits. The E. amylovora argD gene encodes a predicted N-acetylornithine aminotransferase enzyme, which is involved in the production of the amino acid arginine. A plasmid-borne copy of the wild-type argD gene complemented both the nonpathogenic and the arginine auxotrophic phenotypes of the argD(1000)::Tn5 mutant. However, even when mixed with virulent E. amylovora cells and inoculated onto immature apple fruit, the argD(1000)::Tn5 mutant still failed to grow, while the virulent strain grew and caused disease. Furthermore, the pCR2.1-argD complementation plasmid was stably maintained in the argD(1000)::Tn5 mutant growing in host tissues without any antibiotic selection. Therefore, the pCR2.1-argD complementation plasmid could be useful for the expression of genes, markers, and reporters in E. amylovora growing in planta, without concern about losing the plasmid over time. The ArgD protein cannot be considered an E. amylovora virulence factor because the argD(1000)::Tn5 mutant was auxotrophic and had a primary metabolism defect. Nevertheless, these results are informative about the parasitic nature of the fire blight disease interaction, since they indicate that E. amylovora cannot obtain sufficient arginine from apple and pear fruit tissues or from apple vegetative tissues, either at the beginning of the infection process or after the infection has progressed to an advanced state.


Blood pressure variability activates cardiac mineralocorticoid receptor and induces cardiac remodeling in hypertensive rats.
Hypertensive patients with large blood pressure variability (BPV) have aggravated target organ damage. Because the aldosterone/mineralocorticoid receptor (MR) system is a possible mechanism of hypertensive organ damage, we investigated in spontaneously hypertensive rats (SHRs) whether a specific MR blocker, eplerenone, would prevent BPV-induced aggravation of hypertensive cardiac remodeling. A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHRs. SAD increased BPV without changing mean BP. SAD induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac hypertrophy, resulting in LV systolic dysfunction. Immunohistostaining revealed SAD-induced translocation of MRs into the nuclei (ie, MR activation) of the intramyocardial arterial medial cells and cardiac myocytes. SAD increased phosphorylation of p21-activated kinase1 (PAK1), a regulator of MR nuclear translocation. Chronic administration of a subdepressor dose of eplerenone prevented MR translocation, macrophage infiltration, myocardial fibrosis, cardiac hypertrophy, and LV dysfunction, while not affecting BPV. Circulating levels of aldosterone and cortisol were not changed by SAD. Eplerenone inhibited the aggravation of cardiac inflammation and hypertensive cardiac remodeling, and thereby prevented progression of LV dysfunction in SHRs with large BPV. This suggests that the PAK1-MR pathway plays a role in cardiac inflammation and remodeling induced by large BPV superimposed on hypertension, independent of circulating aldosterone.


Moving from the Trial to the Real World: Improving Medication Adherence Using Insights of Implementation Science.
Medication nonadherence is a serious public health concern. Although there are promising interventions that improve medication adherence, most interventions are developed and tested in tightly controlled research environments that are dissimilar from the real-world settings where the majority of patients receive health care. Implementation science methods have the potential to facilitate and accelerate the translation shift from the trial world to the real world. We demonstrate their potential by reviewing published, high-quality medication adherence studies that could potentially be translated into clinical practice yet lack essential implementation science building blocks. We further illustrate this point by describing an adherence study that demonstrates how implementation science creates a junction between research and real-world settings. This article is a call to action for researchers, clinicians, policy makers, pharmaceutical companies, and others involved in the delivery of care to adopt the implementation science paradigm in the scale-up of adherence (research) programs.


Predicting Autistic Traits Using Eye Movement during Visual Perspective Taking and Facial Emotion Identification.
Autistic traits are broad in severity and difficult to measure quantitatively. Quantitative measurement would be helpful in determining the effectiveness of training and therapy for autistic traits. The development of eye-tracking technology has made it easier to understand autistic traits. Previous works showed that autistic traits can be predicted from eye movements in the facial emotion identification task. It may be possible to measure autistic traits more accurately than the only prediction from facial emotion identification ability. In this study, we used a visual perspective taking task. The results showed that the Social Responsiveness Scale-2 score, which is associated with autistic traits, was predicted at 0.414 in Spearman's correlation coefficient by using eye movements obtained from the two tasks.


Cimetidine-induced thrombocytopenia.
This report described a case of cimetidine-induced thrombocytopenia documented by accidental rechallenge. With the increasing use of cimetidine, especially in patients with complicated problems that predispose to gastrointestinal blood loss, it is important to recognize thrombocytopenia as one of the possible side effects of cimetidine therapy and to monitor platelet studies frequently.


[Efferent neurons of the auditory center in the midbrain of the frog Rana ridibunda].
Individual cells which produce projections from the torus semicircularis in the frog have been visualized after injection of horseradish peroxidase (HRP) to various thalamic and isthmal areas. Labeled toral cells were observed if HRP had been injected to the posterodorsal areas of the thalamus or to the isthmal areas where lateral lemniscus fibers and cells of the premature lateral lemniscal nucleus are situated. Medium and large size cells in the rostrolateral torus semicircularis were mainly labeled. Thalamic injections of the HRP produced more labeled cells in the lateral part of the magnocellular nucleus, whereas isthmal injections produced labeled cells mainly in the lateral part of the laminar nucleus. A few HRP containing cells were observed in the principal nucleus of the torus. Specificity of the neuronal organisation of the auditory pathway in amphibians is discussed.


[Utility-based evaluation of the quality of life of patient's with gastric cancer who receive chemotherapy--comparison of patients' quality of life between oral TS-1 and conventional injectable combination therapy].
We tried to clarify the applicability of "utility" for the evaluation of patient's QOL with gastric cancer after chemotherapy and attempted to compare differences in QOL after treatment with the oral antitumor agent TS-1 or with a conventional injectable combination. Three items, moving activity, pain, and gastrointestinal symptoms, were employed as indicators of patient QOL, and then the assessment of utility was compared based on the expected outcomes that 9 pharmacists working on a ward, 9 nurses working on a neurosurgery ward, and 9 nurses working on a gastrointestinal surgery ward estimated directly using the three methods of standard gamble, time trade-off, and rating scale according to predictive scenarios based on each scenario. The QOL of patients who received the two different types of chemotherapy were also compared as the average utilities from the direct estimation depending on patient conditions as used for chart review. Furthermore, the average utilities were compared with the utility of the mapping method, which can be estimated by applying a utility-converting table defined in the EQ-5D survey. The average utility from each practitioner using the direct estimation revealed that the assessed utility from nurses working on a neurosurgery ward was higher than those of the pharmacists. The average utility obtained using the standard gamble method was higher than those using the rating scale and time trade-off methods. The average utility in the TS-1 therapy group was 0.84-0.94, and that in the conventional injectable therapy group was 0.52-0.79 (p<0.05). The result suggests that utility is applicable for estimation of gastric cancer patient QOL after chemotherapy, and that TS-1 therapy is superior to the traditional injectable combination therapy.


Host ecotype generates evolutionary and epidemiological divergence across a pathogen metapopulation.
The extent and speed at which pathogens adapt to host resistance varies considerably. This presents a challenge for predicting when--and where--pathogen evolution may occur. While gene flow and spatially heterogeneous environments are recognized to be critical for the evolutionary potential of pathogen populations, we lack an understanding of how the two jointly shape coevolutionary trajectories between hosts and pathogens. The rust pathogen Melampsora lini infects two ecotypes of its host plant Linum marginale that occur in close proximity yet in distinct populations and habitats. In this study, we found that within-population epidemics were different between the two habitats. We then tested for pathogen local adaptation at host population and ecotype level in a reciprocal inoculation study. Even after controlling for the effect of spatial structure on infection outcome, we found strong evidence of pathogen adaptation at the host ecotype level. Moreover, sequence analysis of two pathogen infectivity loci revealed strong genetic differentiation by host ecotype but not by distance. Hence, environmental variation can be a key determinant of pathogen population genetic structure and coevolutionary dynamics and can generate strong asymmetry in infection risks through space.


Electrostatic control and chloride regulation of the fast gating of ClC-0 chloride channels.
The opening and closing of chloride (Cl-) channels in the ClC family are thought to tightly couple to ion permeation through the channel pore. In the prototype channel of the family, the ClC-0 channel from the Torpedo electric organ, the opening-closing of the pore in the millisecond time range known as "fast gating" is regulated by both external and internal Cl- ions. Although the external Cl- effect on the fast-gate opening has been extensively studied at a quantitative level, the internal Cl- regulation remains to be characterized. In this study, we examine the internal Cl- effects and the electrostatic controls of the fast-gating mechanism. While having little effect on the opening rate, raising [Cl-]i reduces the closing rate (or increases the open time) of the fast gate, with an apparent affinity of >1 M, a value very different from the one observed in the external Cl- regulation on the opening rate. Mutating charged residues in the pore also changes the fast-gating properties-the effects are more prominent on the closing rate than on the opening rate, a phenomenon similar to the effect of [Cl-]i on the fast gating. Thus, the alteration of fast-gate closing by charge mutations may come from a combination of two effects: a direct electrostatic interaction between the manipulated charge and the negatively charged glutamate gate and a repulsive force on the gate mediated by the permeant ion. Likewise, the regulations of internal Cl- on the fast gating may also be due to the competition of Cl- with the glutamate gate as well as the overall more negative potential brought to the pore by the binding of Cl-. In contrast, the opening rate of the fast gate is only minimally affected by manipulations of [Cl-]i and charges in the inner pore region. The very different nature of external and internal Cl- regulations on the fast gating thus may suggest that the opening and the closing of the fast gate are not microscopically reversible processes, but form a nonequilibrium cycle in the ClC-0 fast-gating mechanism.


Tag SNPs detect association of the CYP1B1 gene with primary open angle glaucoma.
The cytochrome p450 family 1 subfamily B (CYP1B1) gene is a well known cause of autosomal recessive primary congenital glaucoma. It has also been postulated as a modifier of disease severity in primary open angle glaucoma (POAG), particularly in juvenile onset families. However, the role of common variation in the gene in relation to POAG has not been thoroughly explored. Seven tag single nucleotide polymorphisms (SNPs), including two coding variants (L432V and N543S), were genotyped in 860 POAG cases and 898 examined normal controls. Each SNP and haplotype was assessed for association with disease. In addition, a subset of 396 severe cases and 452 elderly controls were analyzed separately. There was no association of any individual SNP in the full data set. Two SNPs (rs162562 and rs10916) were nominally associated under a dominant model in the severe cases (p<0.05). A common haplotype (AGCAGCC) was also found to be nominally associated in both the full data set (p=0.048, OR [95%CI]=0.83 [0.69-0.90]) and more significantly in the severe cases (p=0.004, OR [95%CI]=0.68 [0.52-0.89]) which survives correction for multiple testing. Although no major effect of common variation at the CYP1B1 locus on POAG was found, there could be an effect of SNPs tagged by rs162562 and represented on the AGCAGCC haplotype.


First detection and genome sequencing of SARS-CoV-2 in an infected cat in France.
After its first description in Wuhan (China), SARS-CoV-2 the agent of coronavirus disease 2019 (COVID-19) rapidly spread worldwide. Previous studies suggested that pets could be susceptible to SARS-CoV-2. Here, we investigated the putative infection by SARS-CoV-2 in 22 cats and 11 dogs from owners previously infected or suspected of being infected by SARS-CoV-2. For each animal, rectal, nasopharyngeal swabs and serum were taken. Swabs were submitted to RT-qPCR assays targeting 2 genes of SARS-CoV-2. All dogs were tested SARS-CoV-2 negative. One cat was tested positive by RT-qPCR on rectal swab. Nasopharyngeal swabs from this animal were tested negative. This cat showed mild respiratory and digestive signs. Serological analysis confirms the presence of antibodies against the SARS-CoV-2 in both serum samples taken 10 days apart. Genome sequence analysis revealed that the cat SARS-CoV-2 belongs to the phylogenetic clade A2a like most of the French human SARS-CoV-2. This study reports for the first time the natural infection of a cat in France (near Paris) probably through their owners. There is currently no evidence that cats can spread COVID-19 and owners should not abandon their pets or compromise their welfare.


Ruptured renal artery aneurysm during pregnancy.
A 38-year-old woman (gravida 4, para 1) underwent arteriography at 19 weeks' gestation after two exploratory laparotomies had failed to identify a source of retroperitoneal and intra-abdominal hemorrhage. The arteriogram demonstrated a large right renal artery aneurysm (RAA) and a very small left RAA. Emergency repair of the aneurysm was attempted but was impossible, so a right nephrectomy was performed. The fetus had died prior to arteriography and a cesarean section was performed concomitantly. The postoperative course was unremarkable. RAAs are rare and usually asymptomatic, but pregnancy is associated with a higher risk of rupture. Prior to 1970, reported rupture occurred most often on the left side, during the third trimester, and was associated with a 92% maternal mortality and a 100% fetal mortality rate. Since 1970, published reports have not shown a left-sided predominance, and survival after this catastrophic event has greatly improved, even though preoperative diagnosis is still rare. The possibility of a ruptured RAA should be considered in pregnant women with evidence of retroperitoneal hemorrhage. Arterial repair should be attempted but has not been feasible in most cases. This case was unusual because it occurred during the second trimester of pregnancy. Recent cases and technical considerations regarding repair are discussed.


A single-step purification of bothropstoxin-1.
Bothrops venoms are complex mixtures of components with a wide range of biological activities. Among these substances, myotoxins have been investigated by several groups. Bothropstoxin-1 (Bthtx-1) is a phospholipase A2-like basic myotoxin from Bothrops jararacussu. The purification of this component involves two chromatographic steps. Although providing a pure material, the association of these two steps is time consuming and a single-step method using high performance chromatography media would be useful. In the present study, we describe a single-step purification method for Bthtx-1. Bothrops jararacussu venom was dissolved in 1 ml buffer. After centrifugation, the supernatant was injected into a Resource-S cation exchange column connected to an FPLC system and eluted with a linear salt gradient. The complete procedure took 20 min, representing a considerable time gain when compared to a previously described method (Homsi-Brandenburgo MI et al. (1988) Toxicon, 26: 615-627). Bthtx-1 purity and identity, assessed by SDS-PAGE and N-terminal sequencing, resulted in a single band with a molecular mass of about 14 kDa and the expected sequence of the first 5 residues, S-L-F-E-L. Although the amount of protein purified after each run is lower than in the previously described method, we believe that this method may be useful for small-scale purifications.


Quantitative Recovery of Viable Lactobacillus paracasei CNCM I-1572 (L. casei DG®) After Gastrointestinal Passage in Healthy Adults.
Probiotics are live microorganisms, and viability after transit through the gastrointestinal tract (GIT) is considered an inherent property of the health benefits of probiotics. The aim of the present study was to quantify the viable and total loads of Lactobacillus paracasei DG cells after passage through the GIT following the consumption of the probiotic product Enterolactis (L. casei DG®; L. paracasei CNCM I-1572; L. paracasei DG) from drinkable vials by healthy adults. We developed a novel method for discriminating and enumerating culturable L. paracasei DG cells based on the unique sticky, filamentous phenotype of this strain on MRS agar containing vancomycin and kanamycin. The identity of DG was also confirmed with strain-specific primers by colony PCR. This method was used for a recovery study of the DG strain to quantify viable cells in the fecal samples of 20 volunteers during a 1-week probiotic consumption period and a 1-week follow-up. We isolated L. paracasei DG from at least one fecal sample from all the volunteers. The highest concentration of viable DG cells [ranging from 3.6 to 6.7 log10 colony-forming unit (CFU) per gram of feces] in the feces was observed between 4 and 8 days from the beginning of Enterolactis intake and for up to 5 days after cessation of intake. As expected, the total DG count determined by real-time quantitative PCR (qPCR) was mostly higher than the viable DG cells recovered. Viable count experiments, carried out by combining ad hoc culture-based discriminative conditions and strain-specific molecular biological protocols, unambiguously demonstrated that L. paracasei DG can survive gastrointestinal transit in healthy adults when ingested as Enterolactis in drinkable vials containing no less than one billion CFU at the end of shelf life.


Pyrrolizidine Alkaloids-Pros and Cons for Pharmaceutical and Medical Applications.
Heterocyclic organic compounds named pyrrolizidine alkaloids (PAs) belong to a group of alkaloids and are synthesized by either plants or microorganisms. Therefore, they are naturally occurring secondary metabolites. They are found in species applied in the pharmaceutical and food industries, thus a thorough knowledge of their pharmacological properties and toxicology to humans is of great importance for their further safe employment. This review is original because it synthesizes knowledge of plant and microbial PAs, which is unusual in the scientific literature. We have focused on the Boraginaceae family, which is unique due to the exceptional richness and diversity of its PAs in plant species. We have also presented the microbial sources of PAs, both from fungi and bacteria. The structure and metabolism of PAs have been discussed. Our main aim was to summarize the effects of PAs on humans, including both negative, toxic ones, mainly concerning hepatotoxicity and carcinogenicity, as well as potentially positive ones for pharmacological and medical applications. We have collected the results of studies on the anticancer activity of PAs from plant and microbial sources (mainly Streptomyces strains) and on the antimicrobial activity of PAs on different strains of microorganisms (bacteria and fungi). Finally, we have suggested potential applications and future perspectives.


Biomechanical investigation of a novel hybrid dorsal double plating for distal radius fractures by integrating topology optimization and finite element analysis.
Currently available dorsal locking plates for the treatment of distal radius fractures are far less then volar locking plates, and there is limited evidence about biomechanical strength of dorsal plates. The aim of this study is to develop a novel hybrid dorsal double plating, which enhance biomechanical strength in the articular fixation region and achieve the minimally invasive surgical technique requirement of distal radius fracture treatment by combining weighted topology optimization and finite element (FE) analysis METHODS: A dorsal template bone plate design (based on dorsal double plating (DDP)) was constructed to perform weighted topology optimization and FE analysis under six fracture models with 50%, 30%, and 20% weighting of the joint subjected to axial, bending, and torsion moments, respectively. A novel hybrid dorsal double plating (HDDP) was generated using the union of six single dorsal plates to subtract the intersection of the original template dorsal model. A 100 N axial load with 1 Nm bending and torsion moments were applied at the end of the distal radius onto six fracture FE models to investigate the biomechanical differences between the DDP and HDDP approaches. Results of weighted topology optimization showed that the profile of the HDDP presented a "Y" shape. Simulation results showed that the bone plate stress values for the distal radius fractures fixed with HDDP was much smaller than those with DDP regardless of the type of bone fractures and load conditions. The maximum bone stress value of the DDP approach was much higher than that of HDDP when the distal radius was a complete sagittal articular fracture and partial articular fracture involving lunate fossa. The corresponding maximum bone stress values for different loads might be higher than the ultimate strength of bone (150 MPa) and induced the risk of future bone fractures. It is concluded that the novel HDDP demonstrated better resistance to functional loads, provided sufficient screw fixation at the articular surface, and can be placed on the dorsal site of the distal radius through the standard dorsal approach to minimize invasive surgeries and eliminate tendon irritations.


Development and characterization of clinically relevant tumor models from patients with renal cell carcinoma.
Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo. To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy. In vivo and in vitro animal experiments. Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC. RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC. We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy.


Assessing the rider's seat and horse's behavior: difficulties and perspectives.
A correct seat and position are the basis for a good performance in horseback riding. This study aimed to measure deviations from the correct seat, test a seat improvement program (dismounted exercises), and investigate whether horse behavior was affected by the rider's seat. Five experienced trainers defined 16 seat deviations and scored the occurrence in 20 riders in a dressage test. Half the riders then carried out an individual training program; after 9 weeks, riders were again scored. The study took no video or heart-rate recordings of horses and riders. Panel members did not agree on the deviations in the rider's seat; the study detected no differences-with the exception of improvement of backward-tilted pelvis-between the groups. Horse behavior, classified as "evasive," increased; horse heart rate decreased in the experimental group. Heart rates of riders in both groups decreased. Seven of 9 riders in the experimental group had the impression that the exercises improved their riding performance. There is a clear need to develop a robust system that allows trainers to objectively evaluate the rider's seat.


A virulent and pathogenic infectious clone of Senecavirus A.
Senecavirus A (SVA) is a picornavirus that circulates in swine populations worldwide causing vesicular disease (VD) in affected animals. Here we developed a reverse genetics system for SVA based on the well-characterized wild-type SVA strain SD15-26 (wt SVA SD15-26). The full-length cDNA genome of SVA was cloned into a plasmid under a T7 RNA polymerase promoter. Following in vitro transcription, the genomic viral RNA was transfected into BHK-21 cells and rescue of infectious virus (rSVA SD15-26) was shown by inoculation of highly susceptible H1299 cells. In vitro characterization of the rSVA SD15-26 showed similar replication properties and protein expression levels as the wt SVA SD15-26. A pathogenesis study was conducted in 15-week-old finishing pigs to evaluate the pathogenicity and infection dynamics of the rSVA SD15-26 virus in comparison to the wt SVA SD15-26. Animals from both rSVA- and wt SVA SD15-26-inoculated groups presented characteristic SVA clinical signs (lethargy and lameness) followed by the development of vesicular lesions on the snout and/or feet. The clinical outcome of infection, including disease onset, severity and duration was similar in rSVA- and the wt SVA SD15-26-inoculated animals. All animals inoculated with rSVA or with wt SVA SD15-26 presented a short-term viremia, and animals from both groups shed similar amounts of virus in oral and nasal secretion, and faeces. Our data demonstrates that the rSVA SD5-26 clone is fully virulent and pathogenic in pigs, presenting comparable pathogenesis and infection dynamics to the wt SVA SD15-26 strain. The infectious clone generated here is a useful platform to study virulence determinants of SVA, and to dissect other aspects of SVA infection biology, pathogenesis and persistence.


Childhood acid maltase deficiency. A clinical, biochemical, and morphologic study of three patients.
Three children, including two siblings and a patient with sporadic glycogenosis type II (childhood form of acid maltase deficiency [AMD] ), were studied clinically, biochemically, and morphologically. In addition to a delay in developmental milestones and mild generalized muscle weakness, nasal vocalization and an electromyographic finding of abnormal insertion voltage, followed by pseudomyotonic discharge, were assumed to be characteristic diagnostic findings for the childhood form of AMD. Since the neutral maltase activity was highest in the muscle biopsy specimen from the patient with the least severe weakness, the enzyme may play a role in reducing muscle involvement. Selective type 2A fiber atrophy and type 2B fiber deficiency in the affected muscles were the common histochemical findings in this particular form of AMD.


Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts.
The human immunodeficiency virus (HIV-1) promoter directs the synthesis of two classes of RNA molecules, short transcripts and full-length transcripts. The synthesis of short transcripts depends on a bipartite DNA element, the inducer of short transcripts (IST), located in large part downstream of the HIV-1 start site of transcription. IST does not require any viral product for function and is thought to direct the assembly of transcription complexes that are incapable of efficient elongation. Nothing is known, however, about the biochemical mechanisms that mediate IST function. Here, we report the identification and purification of a factor that binds specifically to the IST. This factor, FBI-1, recognizes a large bipartite binding site that coincides with the bipartite IST element. It is constituted at least in part by an 86-kDa polypeptide that can be specifically cross-linked to IST. FBI-1 also binds to promoter and attenuation regions of a number of cellular and viral transcription units that are regulated by a transcription elongation block. This observation, together with the observation that the binding of FBI-1 to IST mutants correlates with the ability of these mutants to direct IST function, suggests that FBI-1 may be involved in the establishment of abortive transcription complexes.


Endothelin-1 selectively contracts portal vein through both ETA and ETB receptors in isolated rabbit liver.
We determined the constrictive effects of endothelin (ET)-1 on the hepatic vascular resistance distribution and the receptor subtype responsible for the effect in isolated rabbit livers perfused via the portal vein with 5% albumin-Krebs solution. The sinusoidal pressure was estimated using the double vascular occlusion pressure. The basal portal venous resistance comprised 59% of the total portal-hepatic venous resistance. In response to a bolus injection of ET-1 (0.05-5 micrograms), which led to a final concentration of 0.1-10 nM in the recirculating perfusate, the portal venous resistance increased in a dose-dependent manner, whereas the hepatic venous resistance did not change significantly at any concentration. This hepatic vasoconstriction was associated with liver weight loss. The selective portal venous constriction induced by ET-1 was confirmed in livers perfused retrogradely from the hepatic vein to the portal vein. The ET-1-induced hepatic vasoconstriction was significantly attenuated by the selective ETA receptor antagonist BQ-123 (1 microM). The ETB receptor antagonist BQ-788 (1 microM) also attenuated the constriction at ET-1 concentrations less than 10 nM. The combination of BQ-123 and BQ-788 tended to inhibit the hepatic vasoconstriction more effectively than BQ-123 alone. These results suggest that ET-1 selectively constricts the portal vein via both ETA and ETB receptors, with predominance of ETA receptor in isolated albumin-Krebs-perfused rabbit livers.


Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms.
To evaluate the prolonged release (PR) of the long-acting somatostatin analog lanreotide in patients with gastrointestinal neuroendocrine tumors and its effect on hormone-related symptomatology, tumor markers, tumor size, tolerability, and quality of life (QOL). Eligible patients had the following substantial daily symptoms: for patients with carcinoid tumors, three or more stools and/or 1.5 or more flushing episodes; for patients with gastrinoma, greater than 50% elevated basic acid output; and for patients with vasoactive intestinal peptide-secreting tumors (VIPomas), four or more stools and/or a stool volume of >/= 800 mL, a measurable tumor, and an elevated biochemical tumor marker (>/= two times the upper limit of the normal reference range). Lanreotide PR was administered intramuscularly every 14 days at 30 mg for 6 months. We measured efficacy by studying symptoms, tumor markers, tumor size, and QOL. Side effects were scored according to the National Cancer Institute's toxicity grading system and ultrasound examination of the gallbladder. Fifty-five patients were included in the study (48 patients with carcinoid tumors, six patients with gastrinoma, and one patient with VIPoma). Symptomatic improvement (> 50% reduction) occurred in 38% of the assessable patients with carcinoid tumors, in 67% of the gastrinoma patients, and in the VIPoma patient. Tumor markers normalized in two of 45 assessable patients, 19 patients exhibited a reduction (> 50%), 19 patients exhibited no change, and tumor markers rose by more than 50% in five patients. Tumor size was reduced in two of 31 assessable patients and remained stable in 25 patients; four patients experienced progression. QOL assessments after 1 month showed improvements in emotional and cognitive function, and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones. Lanreotide PR is a well-tolerated somatostatin analog with significant clinical, biochemical, and antitumor effects that bring about a significant improvement in QOL for patients with neuroendocrine tumors.


Reemergence of the language network during recovery from severe traumatic brain injury: A pilot functional MRI study.
We hypothesized that, in patients with acute severe traumatic brain injury (TBI) who recover basic language function, speech-evoked blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) responses within the canonical language network increase over the first 6 months post-injury. We conducted a prospective, longitudinal fMRI pilot study of adults with acute severe TBI admitted to the intensive care unit. We also enrolled age- and sex-matched healthy subjects. We evaluated BOLD signal in bilateral superior temporal gyrus (STG) and inferior frontal gyrus (IFG) regions of interest acutely and approximately 6 months post-injury. Given evidence that regions outside the canonical language network contribute to language processing, we also performed exploratory whole-brain analyses. Of the 16 patients enrolled, eight returned for follow-up fMRI, all of whom recovered basic language function. We observed speech-evoked longitudinal BOLD increases in the left STG, but not in the right STG, right IFG, or left IFG. Whole-brain analysis revealed increases in the right supramarginal and middle temporal gyri but no differences between patients and healthy subjects (n = 16). This pilot study suggests that, in patients with severe TBI who recover llanguage function, speech-evoked responses in bihemispheric language-processing cortex reemerge by 6 months post-injury.


The Correlation of Magee EquationsTM and Oncotype DX® Recurrence Score From Core Needle Biopsy Tissues in Predicting Response to Neoadjuvant Chemotherapy in ER+ and HER2- Breast Cancer.
Oncotype DX® recurrence score (RS) can be predicted from Magee EquationsTM (MS) postoperatively. The aim of this study is to investigate correlation of MS with RS from pretreatment core needle biopsy (CNB) tissues, and their clinical usefulness in prediction of response to neoadjuvant chemotherapy (NCT) in estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer (BC). Pretreatment CNB tissue samples from 60 patients with ER+/HER2- invasive BC were analyzed for MS and RS correlation. MS and RS were categorized as follows: low (<18), intermediate (18-30), and high (≥ 31). Percentage Tumor size Reduction (%TR) was used to assess tumor response to NCT, and substantial %TR was defined as at least 50% reduction (≥50%TR). Correlation between MS and RS, and predictive factors for the ≥50%TR achievement were assessed. MS and RS represented a strong correlation (Spearman's correlation; r=0.58, p<0.0001) as a continuous variable. As a categorical variable, the concordance between MS and RS was 43.3%, and it increased to 80% (r=0.61, p=0.003) with the exclusion of the intermediate risk categories. Although, there was pathologic complete response (pCR), MS showed the highest predictive power for the ≥50% TR achievement, none of the factors were statistically significant (p≥0.07). Our study demonstrated that there was a strong correlation between MS and RS from pretreatment biopsy tissue samples in ER+ and HER2- invasive BC.


Time from first detectable PSA following radical prostatectomy to biochemical recurrence: A competing risk analysis.
In this study, we estimated the time from first detectable prostate-specific antigen (PSA) following radical prostatectomy (RP) to commonly used definitions of biochemical recurrence (BCR). We also identified the predictors of time to BCR. We identified subjects who underwent a RP and had an undetectable PSA after surgery followed by at least 1 detectable PSA between 2000 and 2011. The primary outcome was time to BCR (PSA ≥0.2 and successive PSA ≥0.2) and prediction of the rate of PSA rise. Outcomes were calculated using a competing risk analysis, with univariable and multivariable Fine and Grey models. We employed a mixed effect model to test clinical predictors that are associated with the rate of PSA rise. The cohort included 376 patients. The median follow-up from surgery was 60.5 months (interquartile range [IQR] 40.8-91.5) and from detectable PSA was 18 months (IQR 11-32). Only 45.74% (n = 172) had PSA values ≥0.2 ng/mL, while 15.16% (n = 57) reached the PSA level of ≥0.4 ng/mL and rising. On multivariable analysis, the values of the first detectable PSA and pathologic Gleason grade 8 or higher were consistently independent predictors of time to BCR. In the mixed effect model rate, the PSA rise was associated with time from surgery to first detectable PSA, Gleason score, and prostate volume. The main limitation of this study is the large proportion of patients that received treatment without reaching BCR. It is plausible that shorter estimated median times would occur at a centre that does not use salvage therapy at such an early state. The time from first detectable PSA to BCR may be lengthy. Our analyses of the predictors of the rate of PSA rise can help determine a personalized approach for patients with a detectable PSA after surgery.


SAXS studies of RNA: structures, dynamics, and interactions with partners.
Small-angle X-ray scattering, SAXS, is a powerful and easily employed experimental technique that provides solution structures of macromolecules. The size and shape parameters derived from SAXS provide global structural information about these molecules in solution and essentially complement data acquired by other biophysical methods. As applied to protein systems, SAXS is a relatively mature technology: sophisticated tools exist to acquire and analyze data, and to create structural models that include dynamically flexible ensembles. Given the expanding appreciation of RNA's biological roles, there is a need to develop comparable tools to characterize solution structures of RNA, including its interactions with important biological partners. We review the progress toward achieving this goal, focusing on experimental and computational innovations. The use of multiphase modeling, absolute calibration and contrast variation methods, among others, provides new and often unique ways of visualizing this important biological molecule and its essential partners: ions, other RNAs, or proteins. WIREs RNA 2016, 7:512-526. doi: 10.1002/wrna.1349 For further resources related to this article, please visit the WIREs website.


[Transport of D-xylose in isolated frog sartorius muscle in the presence of actinomycin D].
The action of actinomycin D on the basal and insulin stimulated D-xylose uptake has been studied on isolated frog sartorius muscles. Actinomycin D at concentrations of 10 mg/ml or 100 mg/ml exerts no effect on the basal transport of sugar and causes no alteration in the response to insulin. The distribution coefficient of actinomycin D in muscle tissue is equal 0,9--1. It is supposed that the inhibition of RNA synthesis by antibiotics does not influence sugar transport.


Bronchial asthma is associated with increased risk of chronic kidney disease.
Bronchial asthma influences some chronic diseases such as coronary heart disease, diabetes mellitus, and hypertension, but the impact of asthma on vital diseases such as chronic kidney disease is not yet verified. This study aims to clarify the association between bronchial asthma and the risk of developing chronic kidney disease. The National Health Research Institute provided a database of one million random subjects for the study. A random sample of 141 064 patients aged ≥18 years without a history of kidney disease was obtained from the database. Among them, there were 35 086 with bronchial asthma and 105 258 without asthma matched for sex and age for a ration of 1:3. After adjusting for confounding risk factors, a Cox proportional hazards model was used to compare the risk of developing chronic kidney disease during a three-year follow-up period. Of the subjects with asthma, 2 196 (6.26%) developed chronic kidney disease compared to 4 120 (3.91%) of the control subjects. Cox proportional hazards regression analysis revealed that subjects with asthma were more likely to develop chronic kidney disease (hazard ratio [HR]: 1.56; 95% CI: 1.48-1.64; p < 0.001). After adjusting for sex, age, monthly income, urbanization level, geographic region, diabetes mellitus, hypertension, hyperlipidemia, and steroid use, the HR for asthma patients was 1.40 (95% CI: 1.33-1.48; p = 0.040). There was decreased HRs in steroid use (HR: 0.56; 95% CI: 0.62-0.61; p < 0.001) in the development of chronic kidney disease. Expectorants, bronchodilators, anti-muscarinic agents, airway smooth muscle relaxants, and leukotriene receptor antagonists may also be beneficial in attenuating the risk of chronic kidney disease. Patients with bronchial asthma may have increased risk of developing chronic kidney disease. The use of steroids or non-steroidal drugs in the treatment of asthma may attenuate this risk.


Prevalence of subjective poor health symptoms associated with exposure to electromagnetic fields among university students.
The number of people complaining about different symptoms that may be associated with exposure to electromagnetic fields (EMF) has increased rapidly during past years. Students use both mobile phones and video display terminals frequently. The purpose of this study was to investigate the association of mobile phone use and EMF health hazards. Basic demographic data and self-reported symptoms were sought using a questionnaire administered to all apparently healthy students at Rafsanjan University of Medical Sciences (RUMS) and Vali-e-Asr University (VAU). Questions about some major confounding factors such as age, gender, amount of video display terminal work were also included. Exact Fischer Test was used for data analysis. Among self-reported symptoms, headache (53.5%), fatigue (35.6%), difficulties in concentration (32.5%), vertigo/dizziness (30.4%), attention disorders (28.8%), nervousness (28.1%), palpitation (14.7%), low back pain (14.3%), myalgia (12.4%), and tinnitus (9.9%) were the main self-reported symptoms. No significant differences in the prevalence of these symptoms were found between CRT users and those who did not use CRTs. A significant association was found between cordless phone use and difficulties in concentration (P < .05) or attention disorders (P < .05). However, after correction of the gender role, these differences were not significant. No association was found between mobile phone use and the above-mentioned symptoms. No significantly higher prevalence of self-reported symptoms was found in individuals who had used mobile phones, video display terminals or cordless phones more frequently than others. Mass-media's lack of interest in the possible hazards of exposure to EMF in developing countries can explain the difference observed between the results of this study and those of other researchers in some developed countries who have shown an association between EMF exposure and the prevalence of self-reported subjective symptoms. This finding can confirm the results obtained in provocative studies which indicated the role of psychological factors in electromagnetic hypersensitivity. More research is needed to clarify whether daily environmental EMF may cause health problems.


Optimized Planar Microwave Antenna for Nitrogen Vacancy Center Based Sensing Applications.
Individual nitrogen vacancy (NV) color centers in diamond are versatile, spin-based quantum sensors. Coherently controlling the spin of NV centers using microwaves in a typical frequency range between 2.5 and 3.5 GHz is necessary for sensing applications. In this work, we present a stripline-based, planar, Ω-shaped microwave antenna that enables one to reliably manipulate NV spins. We found an optimal antenna design using finite integral simulations. We fabricated our antennas on low-cost, transparent glass substrate. We created highly uniform microwave fields in areas of roughly 400 × 400 μm2 while realizing high Rabi frequencies of up to 10 MHz in an ensemble of NV centers.


Monocyte chemotaxis: stimulation by specific exosite region in thrombin.
Human alpha-thrombin is a potent chemoattractant for human monocytes, with optimum activity occurring at about 10 nanomoles per liter. A variety of thrombins that were chemically modified to alter procoagulant or esterolytic functions showed a similar optimum activity, but complexes of prothrombin or alpha-thrombin with either antithrombin III or hirudin did not. These findings indicate that the regions in thrombin responsible for monocyte chemotaxis are proximate to those involved in certain protein recognition interactions of alpha-thrombin (for example, hirudin binding) but are distinct from the catalytic site and from certain exosites required for clotting.


mRNA expression profiles in circulating tumor cells of metastatic colorectal cancer patients.
The molecular characterization of circulating tumor cells (CTCs) is a promising tool for the repeated and non-invasive evaluation of predictive and prognostic factors. Challenges associated with CTC characterization using the only FDA approved method for CTC enumeration, the CellSearch technique, include the presence of an excess of leukocytes in CTC-enriched blood fractions. Here we aimed to identify colorectal tumor-specific gene expression levels in the blood of patients with and without detectable CTCs according to CellSearch criteria. Blood of 30 healthy donors (HDs) and 142 metastatic colorectal cancer (mCRC) patients was subjected to CellSearch CTC enumeration and isolation. In all samples, 95 mRNAs were measured by reverse transcriptase quantitative PCR (RT-qPCR). HD blood samples and patient samples with three or more CTCs were compared to identify CTC-specific mRNAs. Patient samples without detectable CTCs were separately analyzed. Thirty-four CTC-specific mRNAs were higher expressed in patients with ≥3 CTCs compared with HDs (Mann-Whitney U-test P < 0.05). Among patients without detectable CTCs, a HD-unlike subgroup was identified which could be distinguished from HDs by the expression of epithelial genes such as KRT19, KRT20 and AGR2. Also, in an independent patient set, a similar HD-unlike group could be identified among the patients without detectable CTCs according to the CellSearch system. Extensive molecular characterization of colorectal CTCs is feasible and a subgroup of patients without detectable CTCs according to CellSearch criteria bears circulating tumor load, which may have clinical consequences. This CTC-specific gene panel for mCRC patients may enable the exploration of CTC characterization as a novel means to further individualize cancer treatment.


In vitro evaluation of antibacterial, anticollagenase, and antioxidant activities of hop components (Humulus lupulus) addressing acne vulgaris.
Seven naturally derived components from hop plant (Humulus lupulus L.) extracts were tested for evaluation of biological activities affecting acne vulgaris. Five strains, Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, Kocuria rhizophila and, Staphylococcus pyogenes, were selected as the main acne-causing bacteria. Hop extracts xanthohumol and the lupulones showed strong inhibitory activities against all of the strains. Although hydrogenated derivatives did not show the same level of activity, naturally occurring xanthohumol, humulones, and lupulones all showed moderate to strong anticollagenase inhibitory activities. Antioxidant capacity was also evaluated with seven different methods based on different reactive oxygen species. Xanthohumol showed the highest activity in total oxygen radical absorbance capacity as well as singlet oxygen absorbance capacity.


Prognosis of metastatic splenic hilum lymph node in patients with gastric cancer after total gastrectomy and splenectomy.
To clarify the significance of combined resection of the spleen to dissect the No. 10 lymph node (LN). We studied 191 patients who had undergone total gastrectomy with splenectomy, excluding non-curative cases, resection of multiple gastric cancer, and those with remnant stomach cancer. Various clinicopathological factors were evaluated for any independent contributions to No. 10 LN metastasis, using χ(2) test. Significant factors were extracted for further analysis, carried out using a logistic regression method. Furthermore, lymph node metastasis was evaluated for any independent contribution to No. 10 LN metastasis, using the same methods. The cumulative survival rate was calculated using the Kaplan-Meier method. The significance of any difference between the survival curves was determined using the Cox-Mantel test, and any difference was considered significant at the 5% level. From the variables considered to be potentially associated with No. 10 LN metastasis, age, depth, invasion of lymph vessel, N factor, the number of lymph node metastasis, Stage, the number of sites, and location were found to differ significantly between those with metastasis (the Positive Group) and those without (the Negative Group). A logistic regression analysis showed that the localization and Stage were significant parameters for No. 10 LN metastasis. There was no case located on the lesser curvature in the Positive Group. The numbers of No. 2, No. 3, No. 4sa, No. 4sb, No. 4d, No. 7, and No. 11 LN metastasis were each found to differ significantly between the Positive Group and the Negative Group. A logistic regression analysis showed that No. 4sa, No. 4sb, and No. 11 LN metastasis were each a significant parameter for No. 10 LN metastasis. There was no significant difference in survival curves between the Positive Group and the Negative Group. Splenectomy should be performed to dissect No. 10 LN for cases which have No. 4sa, No. 4sb or No. 11 LN metastasis. However, in cases where the tumor is located on the lesser curvature, splenectomy can be omitted.


Topographic mapping of large dissimilarity data sets.
Topographic maps such as the self-organizing map (SOM) or neural gas (NG) constitute powerful data mining techniques that allow simultaneously clustering data and inferring their topological structure, such that additional features, for example, browsing, become available. Both methods have been introduced for vectorial data sets; they require a classical feature encoding of information. Often data are available in the form of pairwise distances only, such as arise from a kernel matrix, a graph, or some general dissimilarity measure. In such cases, NG and SOM cannot be applied directly. In this article, we introduce relational topographic maps as an extension of relational clustering algorithms, which offer prototype-based representations of dissimilarity data, to incorporate neighborhood structure. These methods are equivalent to the standard (vectorial) techniques if a Euclidean embedding exists, while preventing the need to explicitly compute such an embedding. Extending these techniques for the general case of non-Euclidean dissimilarities makes possible an interpretation of relational clustering as clustering in pseudo-Euclidean space. We compare the methods to well-known clustering methods for proximity data based on deterministic annealing and discuss how far convergence can be guaranteed in the general case. Relational clustering is quadratic in the number of data points, which makes the algorithms infeasible for huge data sets. We propose an approximate patch version of relational clustering that runs in linear time. The effectiveness of the methods is demonstrated in a number of examples.


Effect of Borrelia burgdorferi genotype on the sensitivity of C6 and 2-tier testing in North American patients with culture-confirmed Lyme disease.
A potential concern with any serologic test to detect antibodies to Borrelia burgdorferi is whether the epitopes incorporated in the test provide sufficient cross-reactivity to detect infection with all of the pathogenic strains of the species. This is a particular concern for the C6 test, which is based on reactivity to a single peptide. C6 testing and 2-tier testing were performed on acute-phase serum samples obtained from >158 patients with erythema migrans for whom the genotype of the borrelial isolate was defined on the basis of an analysis of the 16S-23S ribosomal DNA spacer region and/or on the genetic variation of the outer surface protein C gene (ospC). The sonicated whole cell-based enzyme-linked immunosorbent assay, the immunoblots used in the 2-tier testing, and the C6 assay all used antigens from B. burgdorferi sensu stricto strain B31. The sensitivity of C6 testing (69.5%) was greater than that of 2-tier testing (38.9%) (P<.001); the difference in sensitivity, however, was statistically significant only for patients infected with 2 of the 3 ribosomal spacer type-defined genotypes. The lower sensitivity of 2-tier testing was attributable to the low sensitivity of the immunoblot tests, rather than the first-tier enzyme-linked immunosorbent assay. There was also a trend for the sensitivity of 2-tier testing to vary according to the ospC genotype for the 14 genotypes represented in the study (P=.07); this relationship was not observed with C6 testing. Lack of sensitivity of the C6 test because of strain diversity seems less likely to be a limitation of this serologic test, compared with 2-tier testing in North American patients with early Lyme disease.


Three-dimensional imaging of orthodontic models: a pilot study.
Computer-based digital orthodontic models have been developed that have the potential to replace dental casts. The aim of this study was to examine the accuracy and reproducibility of measurements made on digital models. Ten sets of orthodontic study models were scanned using the Arius3D Foundation System and three-dimensional (3D) images were produced by computer software. Two examiners individually measured 11 parameters on the conventional casts and the digital models on two occasions. The parameters included mesio-distal crown diameter, intercanine and intermolar width, arch length, overjet, and incisor crown height. The measurement techniques were compared using paired t-tests, the coefficient of reliability, and by calculating mean values and the difference between methods. When comparing measurements made on digital models with those on dental casts, systematic errors were detected for five of the 11 parameters at the 10 per cent level. Random errors were a cause of concern for measurements of three parameters. The most accurate and reproducible measurements were lower intercanine width (mean difference between measurements 0.05 +/- 0.32 mm) and overjet (mean difference 0.07 +/- 0.33 mm). Most parameters on the digital models can be reliably measured, and digital models can potentially eliminate the requirement for the production and storage of dental casts, but this will depend on cost.


Gonadal steroid modulation of naloxone-induced LH secretion in the rat.
The effect of acute administration of the opioid receptor antagonist naloxone hydrochloride (5 mg/kg, s.c.) on plasma LH levels was evaluated in female and male rats 24, 36 and 48 h and 1, 3 and 5 weeks after gonadectomy and in 5-week gonadectomized rats after acute or chronic (2 weeks) administration of oestradiol benzoate (OB, 10 micrograms/rat per day, s.c.), testosterone propionate (TP, 150 micrograms/rat, s.c.) or dihydrotestosterone propionate (DHT, 150 micrograms/rat, s.c.) respectively. Concurrent evaluation of plasma LH after administration of LH releasing hormone (LHRH, 1 microgram/kg, i.p.) was performed in the same experimental groups. In rats of both sexes, a significant rise in plasma LH after naloxone was observed in sham-operated and recently gonadectomized rats (24-48 h); in female rats 36 and 48 h after gonadectomy the rise was higher than in controls. One, 3 and 5 weeks after gonadectomy, naloxone failed to stimulate LH release in both female and male rats. In gonadectomized rats undergoing steroid replacement therapy, OB administered 72 h before testing, TP (16 and 72 h) and DHT (16 h) were the most effective in reinstituting the LH response to naloxone. Chronic administration of gonadal steroids did not restore normal LH responsiveness to naloxone. In most experimental groups, LH responses after naloxone were clearly unrelated to pituitary LH responsiveness to LHRH, which indicates that the opioid antagonist was acting via the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)


A fiberoptic (photodynamic therapy type) device with a photosensitizer and singlet oxygen delivery probe tip for ovarian cancer cell killing.
A portable "fiber optic-based sensitizer delivery" (FOSD) device has been developed and studied. Before there might be success in photodynamic therapy (PDT) and antibacterial ambitions, an understanding of basic factors on device performance was needed. Thus, the device was examined for the localized delivery of sensitizer molecules in ovarian cancer cells and production of high concentrations of singlet oxygen for their eradication in vitro. The device tip releases stored pheophorbide by attack of singlet oxygen from sensitized oxygen gas delivered through the hollow fiber using 669 nm laser light. The performance of the device was enhanced when configured with a fluorosilane tip by virtue of its Teflon-like property compared with a conventional glass tip (greater sensitizer quantities were photoreleased and laterally diffused, and greater amounts of ovarian OVCAR-5 cancer cells were killed). No cell damage was observed at 2.2 N of force applied by the probe tip itself, an amount used for many of the experiments described here.


Effects of endothelin-1 in isolated perfused rat heart.
We examined the effects of the vasoconstrictor peptide endothelin-1 in the isolated heart and defined interactions of endothelin-1 with other hormone systems. Isolated isovolumic rat hearts were perfused with Krebs-Henseleit buffer at constant pressure. First, the effect of a single bolus of endothelin-1 (4-400 pmol) was followed for 90 min. The effect of high dosages (40 and 400 pmol) of endothelin-1 on coronary flow was biphasic, with an early vasodilator and a late vasoconstrictor component that was irreversible. Second, cumulative dose-response curves were obtained for endothelin-1 boluses of 0.04-400 pmol. Coronary flow declined with increasing dosages and was almost abolished at 400 pmol. Neither alpha- nor beta-blocking agents (phentolamine and propranolol) nor the Ca2(+)-channel blocker nifedipine altered the effects of endothelin-1, but prostaglandin synthesis inhibition by indomethacin significantly augmented vasoconstriction by endothelin-1. Angiotensin-converting enzyme (ACE) inhibition by captopril antagonized endothelin-1-dependent vasoconstriction to a small extent at 400 pmol. Coronary constriction due to endothelin-1 could not be reversed by nitroglycerin. We conclude that in isolated rat heart endothelin-1 causes marked and long-lasting coronary constriction. The effect is not influenced by sympathetic and Ca2(+)-channel blockade, is enhanced by prostaglandin synthesis inhibition, and is reduced by ACE inhibition.