[Incidental prostatic adenocarcinoma in the ere of the PSA].
Prostate adenocarcinoma is occasionally and incidentally found in the prostate gland after enucleation through adenomectomy or transurethral resection (incidentaloma). We contribute 17 cases (3.38%) of incidentaloma found among 503 patients who underwent adenomectomy vs. TUR due to prostate obstructive-irritative symptomatology of likely benign etiology. The diagnostic methods, pathological findings, treatment and evolution in our series versus other recent ones are explained.


Policy and Strategic Responses to Food and Nutrition Security in Ethiopia.
Food and nutrition insecurity continues to be one of the persistent challenges in Ethiopia. The country has been responding to the challenges in various ways to foster sustainable development. The objective of the study is to assess national food and nutrition security policy and strategic responses. A qualitative review of policies, strategies, programs, guidelines, and a government commitment, document was conducted. Interviews with experts from food and nutrition-implementing governmental and nongovernmental organizations were also employed. Thematic analysis with description was used. The results of the study revealed that global initiatives stimulated Ethiopia to progressively take various strategic directions to address the ongoing food and nutrition challenges. In addition to various policy directions, the country has been implementing nutrition-specific and nutrition-sensitive programs under the multisectoral approach. The concepts and practices of food and nutrition security shifted from simply balancing the demand and supply of food to a broader and more inclusive food system approach with the involvement of multiple actors. However, more has been said than done. The policy, strategic objectives, and initiatives have not been adequately translated into practices. Actions toward ensuring food and nutrition security, on the other hand, are constrained by institutional, environmental, technological, and emerging priorities like an outbreak of a pandemic and political instability. The study concluded that available policy and strategic intents have sufficiently addressed food and nutrition challenges in documents and need to be fully translated into practices.


Homografts in congenital heart disease: current applications and future directions.
The first clinical use of homograft tissue in cardiovascular surgery was in 1948, when Gross used cadaveric arterial grafts to construct systemic to pulmonary artery shunts in patients with tetralogy of Fallot, and to repair coarctation of the aorta. Eighteen years later, a valved homograft was used for the first time in the treatment of congenital heart disease for reconstruction of the right ventricular outflow tract in a child with pulmonary atresia. Since these pioneering advances, valve and vascular homografts have become central to the management of congenital anomalies of the heart and great vessels. The primary use for homografts in congenital heart surgery today is establishment of a valved connection between the right ventricle and pulmonary arteries in children with tetralogy of Fallot with pulmonary atresia or other complicating factors, truncus arteriosus, transposition complexes, and double-outlet right ventricle, and in patients undergoing the Ross procedure. Homograft reconstruction of the left ventricular outflow tract has also been performed for many years in children with aortic insufficiency or recurrent aortic stenosis, but early homograft degeneration in young children has been a significant problem. Many surgeons are turning away from homografts in the systemic circulation in favor of the pulmonary autograft. Homograft is also widely used as a vascular patch material. In the present report, we discuss the various uses of homografts in congenital heart surgery, the benefits and drawbacks of homografts in young patients, and some of the future possibilities for homograft development and application in patients with congenital heart disease.


Relationship between school dropout and teen pregnancy among rural South African young women.
Sexual activity may be less likely to occur during periods of school enrolment because of the structured and supervised environment provided, the education obtained and the safer peer networks encountered while enrolled. We examined whether school enrolment was associated with teen pregnancy in South Africa. Using longitudinal demographic surveillance data from the rural Agincourt sub-district, we reconstructed the school enrolment status from 2000 through 2011 for 15 457 young women aged 12-18 years and linked them to the estimated conception date for each pregnancy during this time. We examined the effect of time-varying school enrolment on teen pregnancy using a Cox proportional hazard model, adjusting for: age; calendar year; household socioeconomic status; household size; and gender, educational attainment and employment of household head. A secondary analysis compared the incidence of pregnancy among school enrolees by calendar time: school term vs school holiday. School enrolment was associated with lower teen pregnancy rates [adjusted hazard ratio (95% confidence interval): 0.57 (0.50, 0.65)].This association was robust to potential misclassification of school enrolment. For those enrolled in school, pregnancy occurred less commonly during school term than during school holidays [incidence rate ratio (95% confidence interval): 0.90 (0.78, 1.04)]. Young women who drop out of school may be at higher risk for teen pregnancy and could likely benefit from receipt of accessible and high quality sexual health services. Preventive interventions designed to keep young women in school or addressing the underlying causes of dropout may also help reduce the incidence of teen pregnancy.


Reproducible Tissue Homogenization and Protein Extraction for Quantitative Proteomics Using MicroPestle-Assisted Pressure-Cycling Technology.
The reproducible and efficient extraction of proteins from biopsy samples for quantitative analysis is a critical step in biomarker and translational research. Recently, we described a method consisting of pressure-cycling technology (PCT) and sequential windowed acquisition of all theoretical fragment ions-mass spectrometry (SWATH-MS) for the rapid quantification of thousands of proteins from biopsy-size tissue samples. As an improvement of the method, we have incorporated the PCT-MicroPestle into the PCT-SWATH workflow. The PCT-MicroPestle is a novel, miniaturized, disposable mechanical tissue homogenizer that fits directly into the microTube sample container. We optimized the pressure-cycling conditions for tissue lysis with the PCT-MicroPestle and benchmarked the performance of the system against the conventional PCT-MicroCap method using mouse liver, heart, brain, and human kidney tissues as test samples. The data indicate that the digestion of the PCT-MicroPestle-extracted proteins yielded 20-40% more MS-ready peptide mass from all tissues tested with a comparable reproducibility when compared to the conventional PCT method. Subsequent SWATH-MS analysis identified a higher number of biologically informative proteins from a given sample. In conclusion, we have developed a new device that can be seamlessly integrated into the PCT-SWATH workflow, leading to increased sample throughput and improved reproducibility at both the protein extraction and proteomic analysis levels when applied to the quantitative proteomic analysis of biopsy-level samples.


Molecular Dynamics Simulations of Wild Type and Mutants of SAPAP in Complexed with Shank3.
Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95⁻associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the βN extension presents high flexibility in all systems, especially for M5P. The high flexibility of βN extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with βN1' remain. In M5P system, although the interactions with βN1' are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the βN1' extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors.


Lymphangioleiomyomatosis: a metastatic lung disease.
Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease. The cellular constituents of LAM are very diverse, including mesenchymal, epithelial, endothelial, and immune cells. LAM is characterized by dysregulation of many cell signaling pathways, distinct populations of LAM cells, and a rich microenvironment, in which the immune system appears to play an important role. This review delineates the heterogeneity of LAM and focuses on the metastatic features of LAM, the deregulated signaling mechanisms and the tumor microenvironment. Understanding the tumor-host interaction in LAM may provide insights into the development of new therapeutic strategies, which could be combinatorial or superlative to Sirolimus, the current U.S. Food and Drug Administration-approved treatment.


The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.
The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-gamma/interleukin (IL)-4 and transforming growth factor (TGF)-beta activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L(+) CD4(+) T cells exacerbated colitis in reconstituted SCID mice, T-bet-deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet-deficient CD62L(-) CD4(+) T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-beta signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-gamma/IL-4 and TGF-beta responses and the development of chronic intestinal inflammation in T cell-mediated colitis. Furthermore, TGF-beta was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-beta and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell-mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.


Low concentrations of methamphetamine can suppress inflammation in trophoblast JEG-3 cell line induced by nicotine.
Nicotine at high concentrations induces apoptosis in trophoblastic cells through induction of cell cytotoxicity and Reactive Oxygen Species (ROS). Methamphetamine in low dose has pharmaceutical properties. It seems that this components in low dose can protect the trophoblastic cells from nicotine-induced cell death. Trophoblastic (JEG-3) cells grown in DMEM culture medium. MTT assay test detected the cell viability and Lactate Dehydrogenase test measured the cells cytotoxicity. Griess reaction was used for NO production analysis. Cell migration traced by wounding technique. Human Cytokine Array Focused 13-plex was also used for analysis of IL-1α, IL-1β, IL-6, INFγ, and TNFα pre-inflammatory cytokines. Methamphetamine, in very low dose (pM), increased the cell viability and NO production, and decreased cell cytotoxicity, IL-1α, IL-1β, IL-6, INFγ, and TNFα pre-inflammatory cytokines of JEG-3 cell which were exposed to high dose of nicotine, respectively. Cell migration was enhanced by low dose of methamphetamine in JEG-3 cells. Methamphetamine in very low dose suppressed the JEG-3 cell death induced by high dose of nicotine (Fig. 5, Ref. 48) Keywords: methamphetamine, nicotine, cell death, NO.


Phospholipase D and the SNARE Sso1p are necessary for vesicle fusion during sporulation in yeast.
Spore formation in Saccharomyces cerevisiae requires the de novo formation of prospore membranes. The coalescence of secretory vesicles into a membrane sheet occurs on the cytoplasmic surface of the spindle pole body. Spo14p, the major yeast phospholipase D, is necessary for prospore membrane formation; however, the specific function of Spo14p in this process has not been elucidated. We report that loss of Spo14p blocks vesicle fusion, leading to the accumulation of prospore membrane precursor vesicles docked on the spindle pole body. A similar phenotype was seen when the t-SNARE Sso1p, or the partially redundant t-SNAREs Sec9p and Spo20p were mutated. Although phosphatidic acid, the product of phospholipase D action, was necessary to recruit Spo20p to the precursor vesicles, independent targeting of Spo20p to the membrane was not sufficient to promote fusion in the absence of SPO14. These results demonstrate a role for phospholipase D in vesicle fusion and suggest that phospholipase D-generated phosphatidic acid plays multiple roles in the fusion process.


Basal activation of protein kinase C in rat alveolar macrophages: implications for arachidonate metabolism.
Alveolar macrophages (AM) exhibit numerous functional differences from other mononuclear phagocyte populations, even though they are derived from a common circulating monocytic precursor. Yet no differences in fundamental signaling mechanisms uniquely expressed by AM have been elucidated to date. Protein kinase C (PKC) is one signal transduction mechanism thought to have an important role in regulating macrophage function and about which little information exists for AM. This study was undertaken to assess the state of activation of PKC in cultured resident rat AM compared with resident rat peritoneal macrophages (PM) and the means by which active PKC regulates arachidonic acid (AA) metabolism in the two cell types. As assessed by a histone phosphorylation assay, resting AM, in contrast to PM, exhibited constitutive activation of PKC as evidenced by localization of a majority of PKC activity to the membrane fraction. Ionophore A23187-stimulated release and metabolism of AA were attenuated by depletion of or inhibition of cellular PKC activity in AM but not in PM. In contrast, A23187-stimulated AA metabolism was augmented by activation of PKC to a greater extent in PM than in AM. Results from both cell types indicated that the 5-lipoxygenase pathway was particularly upregulated by PKC activation. We conclude that activation of PKC occurs uniquely during macrophage residence in the alveolar space and that this property as well as the downregulation of PKC which results have profound consequences for the regulation of at least one important macrophage function, the synthesis of bioactive eicosanoids.


[Use of noninvasive mechanical ventilation to avoid intubation during acute respiratory insufficiency].
To determine the value of noninvasive mechanical ventilation in patients with acute respiratory insufficiency. Descriptive. Noninvasive mechanical ventilation was considered in all patients with acute respiratory insufficiency in the intensive care unit of the Rijnstate Hospital, Arnhem, the Netherlands, between 1 June 1998 and 31 January 1999. Indication for mechanical ventilation was: respiratory frequency > or = 28/min, and PaCO2 > 6.0 kPa, pH < 7.35, and/or PaO2 < 8.0 kPa. Patients were intubated immediately in case of systolic blood pressure < 90 mmHg, cardiac or respiratory arrest, coma or a severely diminished consciousness. The other patients received noninvasive mechanical ventilation by nasal or full face mask (pressure support: 10-20 cmH2O; positive end expiratory pressure (PEEP): 0-5 cmH2O). Patients were intubated if the respiratory frequency or the level of consciousness or a blood gas value deteriorated. Of the 97 patients who needed ventilation support, 67 were immediately intubated. Noninvasive mechanical ventilation was administered in the other 30 (31%) patients, 22 men and 8 women with a mean age of 67 years (SD: 15). Causes for acute respiratory failure were: chronic obstructive pulmonary disease (COPD) (n = 12); pneumonia (n = 6); heart failure (n = 4); and other (n = 8). Median characteristics at baseline in the noninvasive mechanical ventilation group: acute physiology and chronic health evaluation (APACHE) II score: 17 (range: 1-25); respiratory frequency: 30/min (28-59); pH: 7.33 (6.99-7.54); PaCO2: 9.3 kPa (3.2-18.7); PaO2: 7.4 kPa (4.2-13.4); SaO2: 85% (63-95). Intubation was avoided in 9/30 (30%) of all patients and in 7/12 (58%) of the patients with COPD. Intubation was needed in 21/30 patients (70%): in 8/30 (27%) immediately because of clinical deterioration within 2 hours and in 13/30 (43%) after a mean period of stabilisation of 6 hours (2-16). Noninvasive mechanical ventilation prevented intubation in over half of the selected patients presenting with acute respiratory failure due to an exacerbation of COPD. The method appears to be less successful in acute respiratory failure due to other causes.


Vibroarthrography-based Knee Lesions Location via Multi-Label Embedding Learning.
Vibration arthrography (VAG) signals are widely utilized for knee pathology recognition due to their non-invasive and radiation-free nature. While most studies focus on determining knee health status, few have examined using VAG signals to locate knee lesions, which would greatly aid physicians in diagnosis and patient monitoring. To address this, we propose using Multi-Label classification (MLC) to efficiently locate different types of lesions within a single input. However, current MLC methods are not suitable for knee lesion location due to two major issues: 1) the positive-negative imbalance of pathological labels in knee pathology recognition is not considered, leading to poor performance, and 2) sparse label correlations between different lesions cannot be effectively extracted. Our solution is a label autoencoder incorporating a pre-trained model (PTM-LAE). To mitigate the positive-negative disequilibrium, we propose a pre-trained feature mapping model utilizing focal loss to dynamically adjust sample weights and focus on difficult-to-classify samples. To better explore the correlations between sparse labels, we introduce a Factorization-Machine-based neural network (DeepFM) that combines higher-order and lower-order correlations between different lesions. Experiments on our collected VAG data demonstrate that our model outperforms state-of-the-art methods.


Therapeutic Inertia: Still a Long Way to Go That Cannot Be Postponed.
In the context of type 2 diabetes, the definition of therapeutic inertia should include the failure not only to intensify therapy, but also to deintensify treatment when appropriate and should be distinguished from appropriate inaction in cases justified by particular circumstances. Therapy should be intensified when glycemic control deteriorates to prevent long periods of hyperglycemia, which increase the risk of complications. Strategic plans to overcome therapeutic inertia must include actions focused on patients, prescribers, health systems, and payers. Therapeutic inertia affects the management of glycemia, hypertension, and lipid disorders, all of which increase the risk for cardiovascular diseases. Thus, multifactorial interventions that act on additional therapeutic goals beyond glycemia are needed.


Effect of the Prognostic Nutrition Index on Long-Term Outcomes in Unprotected Left Main Coronary Artery Revascularization.
Objective The prognostic nutritional index (PNI) is a practical, applicable, prognostic scoring system. However, its clinical significance in unprotected left main coronary artery (ULMCA) patients undergoing percutaneous coronary intervention (PCI) has not yet been clarified. This study aimed to examine the relationship between malnutrition as assessed by PNI and major adverse cardiac events (MACE) in ULMCA patients undergoing PCI.Material and methods 185 patients who were hospitalized in our clinic underwent coronary angiography, had a critical LMCA lesion, and underwent angiography-guided PCI were included. The study population was divided into tertiles based on the PNI values. A high PNI (n=142) was defined as a value in the third tertile (≥ 34.0), and a low PNI (n=43) was defined as a value in the lower 2 tertiles (< 34.0). The primary endpoint was MACE.Results MACE and mortality rates in the low PNI group were significantly higher compared to the high PNI group (51 % vs. 30 %, p=0.009; 44 % vs. 20 %, p=0.002, respectively). High PNI (HR:1.902; 95 % CI:1.112-3.254; p=0.019), previous stroke (HR:3.025; 95 % CI:1.038-8.810; p=0.042) and SYNTAX score (HR:1.028; 95 % CI:1.004-1.057, p=0.023) were independent predictors of MACE in the multivariable cox regression analyzes.Conclusions In patients undergoing ULMCA PCI, nutritional status can be considered an indicator of MACE rates by evaluating the PNI score. This index can be used for risk classification.


Assessing the Impact of Cyclosporin A on Lentiviral Transduction and Preservation of Human Hematopoietic Stem Cells in Clinically Relevant Ex Vivo Gene Therapy Settings.
Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to lentiviral vector (LV) transduction without compromising their biological properties remains critical for broad-range implementation of gene therapy as a treatment option for several inherited diseases. This study demonstrates that the use of one-hit ex vivo LV transduction protocols based on either cyclosporin A (CsA) or rapamycin enable as efficient gene transfer as the current two-hit clinical standard into bone marrow-derived CD34+ cells while better preserving their engraftment capacity in vivo. CsA was additive with another enhancer of transduction, prostaglandin E2, suggesting that tailored enhancer combinations may be applied to overcome multiple blocks to transduction simultaneously in HSPC. Interestingly, besides enhancing LV transduction, CsA also significantly reduced HSPC proliferation, preserving the quiescent G0 fraction and the more primitive multipotent progenitors, thereby yielding the highest engraftment levels in vivo. Importantly, no alterations in the vector integration profiles could be detected between CsA and control transduced HSPC. Overall, the present findings contribute to the development of more efficient and sustainable LV gene therapy protocols, underscoring the benefits of scaling down required vector doses, as well as shortening the HSPC ex vivo culture time.


Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung.
Children are uniquely susceptible to ozone because airway and lung growth continue for an extensive period after birth. Early-life exposure of the rhesus monkey to repeated ozone cycles results in region-specific disrupted airway/lung growth, but the mediators and mechanisms are poorly understood. Substance P (SP), neurokinin-1 receptor (NK-1R); and nuclear receptor Nur77 (NR4A1) are signaling pathway components involved in ozone-induced cell death. We hypothesize that acute ozone (AO) exposure during postnatal airway development disrupts SP/NK-1R/Nur77 pathway expression and that these changes correlate with increased ozone-induced cell death. Our objectives were to 1) spatially define the normal development of the SP/NK-1R/Nur77 pathway in conducting airways; 2) compare how postnatal age modulates responses to AO exposure; and 3) determine how concomitant, episodic ozone exposure modifies age-specific acute responses. Male infant rhesus monkeys were assigned at age 1 mo to two age groups, 2 or 6 mo, and then to one of three exposure subgroups: filtered air (FA), FA+AO (AO: 8 h/day × 2 days), or episodic biweekly ozone exposure cycles (EAO: 8 h/day × 5 days/14-day cycle+AO). O3 = 0.5 ppm. We found that 1) ozone increases SP/NK-1R/Nur77 pathway expression in conducting airways, 2) an ozone exposure cycle (5 days/cycle) delivered early at age 2 mo resulted in an airway that was hypersensitive to AO exposure at the end of 2 mo, and 3) continued episodic exposure (11 cycles) resulted in an airway that was hyposensitive to AO exposure at 6 mo. These observations collectively associate with greater overall inflammation and epithelial cell death, particularly in early postnatal (2 mo), distal airways.


Disease liability prediction from large scale genotyping data using classifiers with a reject option.
Genome-wide association studies (GWA) try to identify the genetic polymorphisms associated with variation in phenotypes. However, the most significant genetic variants may have a small predictive power to forecast the future development of common diseases. We study the prediction of the risk of developing a disease given genome-wide genotypic data using classifiers with a reject option, which only make a prediction when they are sufficiently certain, but in doubtful situations may reject making a classification. To test the reliability of our proposal, we used the Wellcome Trust Case Control Consortium (WTCCC) data set, comprising 14,000 cases of seven common human diseases and 3,000 shared controls.


A stereological study on organelle distribution in human oocytes at prophase I.
The ultrastructural analysis of human oocytes at different maturation stages has only been descriptive. The aim of this study was to use a stereological approach to quantify the distribution of organelles in oocytes at prophase I (GV). Seven immature GV oocytes were processed for transmission electron microscopy and a classical manual stereological technique based on point-counting with an adequate stereological grid was used. The Kruskal-Wallis test and Mann-Whitney U-test with Bonferroni correction were used to compare the means of the relative volumes occupied by organelles in oocyte regions: cortex (C), subcortex (SC) and inner cytoplasm (IC). Here we first describe in GV oocytes very large vesicles of the smooth endoplasmic reticulum (SER), vesicles containing zona pellucida-like materials and coated vesicles. The most abundant organelles were the very large vesicles of the SER (6.9%), mitochondria (6.3%) and other SER vesicles (6.1%). Significant differences in organelle distribution were observed between ooplasm regions: cortical vesicles (C: 1.3% versus SC: 0.1%, IC: 0.1%, P = 0.001) and medium-sized vesicles containing zona pellucida-like materials (C: 0.2% versus SC: 0.02%, IC: 0%, P = 0.004) were mostly observed at the oocyte cortex, whereas mitochondria (C: 3.6% versus SC: 6.0%, IC: 7.2%, P = 0.005) were preferentially located in the subcortex and inner cytoplasm, and SER very large vesicles (IC: 10.1% versus C: 0.9%, SC: 1.67%, P = 0.001) in the oocyte inner cytoplasm. Further quantitative studies are needed in immature metaphase-I and mature metaphase-II oocytes, as well as analysis of correlations between ultrastructural and molecular data, to better understand human oocyte in vitro maturation.


Analysis of Arabidopsis floral transcriptome: detection of new florally expressed genes and expansion of Brassicaceae-specific gene families.
The flower is essential for sexual reproduction of flowering plants and has been extensively studied. However, it is still not clear how many genes are expressed in the flower. Here, we performed RNA-seq analysis as a highly sensitive approach to investigate the Arabidopsis floral transcriptome at three developmental stages. We provide evidence that at least 23, 961 genes are active in the Arabidopsis flower, including 8512 genes that have not been reported as florally expressed previously. We compared gene expression at different stages and found that many genes encoding transcription factors are preferentially expressed in early flower development. Other genes with expression at distinct developmental stages included DUF577 in meiotic cells and DUF220, DUF1216, and Oleosin in stage 12 flowers. DUF1216 and DUF577 are Brassicaceae specific, and together with other families experienced expansion within the Brassicaceae lineage, suggesting novel/greater roles in Brassicaceae floral development than other plants. The large dataset from this study can serve as a resource for expression analysis of genes involved in flower development in Arabidopsis and for comparison with other species. Together, this work provides clues regarding molecular networks underlying flower development.


Management of a child with autism and severe bruxism: a case report.
Autism is a developmental disorder characterized by severe deficits in social interaction and communication. A wide spectrum of medical and behavioral symptoms is exhibited by children with autism, which makes routine dental care very difficult in them. Bruxism or forceful grinding of teeth is one of the sleep problems commonly observed in children with autism. Our patient, a 4-year-old male child with autism, presented with complaints of pain and sensitivity of the teeth. There was history of excessive grinding and clenching of teeth. Limited oral examination revealed severe attrition of all primary teeth. Treatment was planned under general anesthesia because of his poor cognitive abilities. Full-mouth rehabilitation, including placement of stainless steel crowns for all primary molars, was done. Following treatment there was a significant decrease in the grinding habit over the next 2 months. Although the communication and behavioral problems in children with autism pose challenges for the dentist, treatment with proper planning and a lot of patience can definitely make a difference.


Bleeding risk assessment in patients with atrial fibrillation who are taking oral anticoagulants.
Prevention of thromboembolism is the key priority in the management of patients with atrial fibrillation (AF). Clinical decisions on antithrombotic management should be based on the balance between an individual's thromboembolic and hemorrhagic risk. The HAS-BLED score is a simple and user-friendly tool for the assessment of bleeding risk. It is recommended for bleeding risk assessment by the 2010 European Society of Cardiology guidelines for the management of AF, and the latest guidelines of the Canadian Cardiovascular Society for the prevention of stroke and systemic thromboembolism in patients with AF and atrial flutter. A HAS-BLED score ≥ 3 indicates high risk for hemorrhage and suggests that modifiable risk factors affecting bleeding (eg, blood pressure, hepatic/renal function, international normalized ratio, antiplatelet agents, and nonsteroidal anti-inflammatory drugs) be reviewed and corrected. Patients at high risk for stroke (CHA2DS2-VASc score ≥ 2) and hemorrhage (HAS-BLED score ≥ 3) seem to gain significant benefit from oral anticoagulants. As a general rule, oral anticoagulants should be considered for all patients with AF, except those at very low risk for stroke (CHA2DS2-VASc score of 0) and those at extremely high risk for bleeding. The newer oral anticoagulants (eg, dabigatran, rivaroxaban, and apixaban) are promising alternatives to vitamin K antagonists for the prevention of stroke in patients with nonvalvular AF.


Trans-Species Polymorphism in Immune Genes: General Pattern or MHC-Restricted Phenomenon?
Immunity exhibits extraordinarily high levels of variation. Evolution of the immune system in response to host-pathogen interactions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the genetic variability. Many studies have documented that immunologically relevant polymorphism observed today may be tens of millions years old and may predate the emergence of present species. This pattern can be explained by the concept of trans-species polymorphism (TSP) predicting the maintenance and sharing of favourable functionally important alleles of immune-related genes between species due to ongoing balancing selection. Despite the generality of this concept explaining the long-lasting adaptive variation inherited from ancestors, current research in TSP has vastly focused only on major histocompatibility complex (MHC). In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern. Further research should clearly pay more attention to the investigation of TSP in innate immune genes and especially pattern recognition receptors which are promising candidates for this type of evolution. More effort should also be made to distinguish TSP from convergent evolution and adaptive introgression. Identification of balanced TSP variants may represent an accurate approach in evolutionary medicine to recognise disease-resistance alleles.


Perceived barriers to leisure-time physical activity in adults: an ecological perspective.
Perceived barriers are modifiable correlates of participation in physical activity. Associations of specific perceived barriers with participation in and level of walking for recreation, and other leisure-time physical activity (LTPA) were examined. Personal, social, and environmental factors associated with these perceived barriers were then examined. From 2003 to 2004, 2 surveys collected data on recreational walking and other LTPA, perceived barriers to participation, and personal, social, and environmental attributes, from 2194 Australian adults. Zero-inflated negative binomial regression models examined associations of perceived barriers with walking and other LTPA. Generalized linear models identified the correlates of these perceived barriers. The perceived barriers of lack of motivation and time were associated with level of LTPA, while lack of motivation, poor health, and lack of facilities were associated with the odds of nonparticipation in LTPA. Personal, social, and environmental factors independently contributed to variations in perceived barriers. Level and likelihood of participation in LTPA are associated with different perceived barriers. Perceived barriers are a function of both nonmodifiable personal factors and potentially modifiable personal, social, and environmental factors. These findings suggest that the provision of relevant environmental opportunities and social support may effectively reduce perceived barriers to LTPA.


Initiation of Conceptus Elongation Coincides with an Endometrium Basic Fibroblast Growth Factor (FGF2) Protein Increase in Heifers.
Fibroblast growth factors (FGF) play an important role during embryo development. To date, the role of FGF and the respective receptors (FGFR) during the preimplantation phase in cattle are not fully characterized. We examined FGF1, FGF2, FGFR1, FGFR2, and FGFR3 in cyclic and early pregnant heifers at Days 12, 15, and 18 after insemination (Day 0). Endometrial FGF1 mRNA transcript abundance in heifers varied significantly with respect to the day after insemination, the pregnancy status, and their interaction. The expression was higher in nonpregnant than in pregnant heifers at Day 18. The conceptus transcripts abundance of FGFR2 and FGFR3 were significantly lower at Day 15 than 18. In the endometrium, FGF1 protein abundance significantly decreased from Day 12 onwards and FGF2 protein abundance showed a minor, but a significant increase at Day 15 in comparison to Days 12 and 18. We concluded that the decrease in FGF1 mRNA expression in pregnant heifers at Day 18 points towards a potential contribution of FGF1 in the preimplantation process. Additionally, successful embryo elongation might require a spatiotemporal FGF2 protein increase in the endometrium.


A proteomic approach to monitor the dynamic response of the female oviductal epithelial cell surface to male gametes.
Sophisticated strategies to analyze cell surface proteins are indispensable to study fundamental biological processes, such as the response of cells to environmental changes or cell-cell communication. Herein, we describe a refined mass spectrometry-based approach for the specific characterization and quantitation of cell surface proteins expressed in the female reproductive tract. The strategy is based on in situ biotinylation of rabbit oviducts, affinity enrichment of surface exposed biotin tagged proteins and dimethyl labeling of the obtained tryptic peptides followed by LC-MS/MS analysis. This approach proved to be sensitive enough to analyze small sample amounts (<1μg) and allowed further to trace the dynamic composition of the surface proteome of the oviductal epithelium in response to male gametes. The relative protein expression ratios of 175 proteins were quantified. Thirty-one of them were found to be altered over time, namely immediately, 1h and 2h after insemination compared to the time-matched control groups. Functional analysis demonstrated that structural reorganization of the oviductal epithelial cell surface was involved in the early response of the female organ to semen. In summary, this study outlines a workflow that is capable to monitor alterations in the female oviduct that are related to key reproductive processes in vivo. The proper interaction between the female reproductive tract, in particular, the oviduct and the male gametes, is fundamental to fertilization and embryonic development under physiological conditions. Thereby the oviductal epithelial cell surface proteins play an important role. Besides their direct interaction with male gametes, these molecules participate in signal transduction and, thus, are involved in the mandatory cellular response of the oviductal epithelium. In this study we present a refined LC-MS/MS based workflow that is capable to quantitatively analyze the expression of oviductal epithelial cell surface proteins in response to insemination in vivo. A special focus was on the very early interaction between the female organ and the male gametes. At first, this study clearly revealed an immediate response of the surface proteome to semen, which was modulated over time. The described methodology can be applied for studies of further distinct biological events in the oviduct and therefore contribute to a deeper insight into the formation of new life.


Mouse chromosome 7 harbors a quantitative trait locus for isoflurane minimum alveolar concentration.
The minimum alveolar concentration (MAC) of isoflurane is a quantitative trait because it varies continuously in a population. The location on the genome of genes or other genetic elements controlling quantiative traits is called quantitative trait loci (QTLs). In this study we sought to detect a quantitative trait locus underlying isoflurane MAC in mice. To accomplish this, two inbred mouse strains differing in isoflurane MAC, the C57BL/6J and LP/J mouse strains, were bred through two generations to produce genetic recombination. These animals were genotyped for microsatellite markers. We also applied an independent, computational method for identifying QTL-regulating differences in isoflurane MAC. In this approach, the isoflurane MAC was measured in a panel of 19 inbred strains, and computationally searched for genomic intervals where the pattern of genetic variation, based on single nucleotide polymorphisms, correlated with the differences in isoflurane MAC among inbred strains. Both methods of genetic analysis identified a QTL for isoflurane MAC that was located on the proximal part of mouse chromosome 7.


The lessons of life: keynote address to the nutrition and cancer conference.
Some 15 years ago there began to emerge a consensus among epidemiologists that diet might be responsible for 30-60% of cancers in the developed world, in the sense that it should be possible to reduce age-specific incidence rates by this amount by practicable dietary change. Within about 6 years it was also broadly agreed that the principal changes required to bring about this effect were a reduction in the consumption of fat; an increase in the consumption of fruit, green and yellow vegetables, dietary fiber, and some micronutrients; and possibly an improvement in the methods of food preservation. Very small effects, if any, were attributed to food additives and to the pollution of food by trace pesticides, which the public, who accepted much of the consensus advice, have increasingly regarded as important causes of risk. These past conclusions are reviewed in the light of increased knowledge of the etiology of cancer and the trends in its incidence. Contrary to common belief, the trends are broadly encouraging.


Generalized Functional Linear Models with Semiparametric Single-Index Interactions.
We introduce a new class of functional generalized linear models, where the response is a scalar and some of the covariates are functional. We assume that the response depends on multiple covariates, a finite number of latent features in the functional predictor, and interaction between the two. To achieve parsimony, the interaction between the multiple covariates and the functional predictor is modeled semiparametrically with a single-index structure. We propose a two step estimation procedure based on local estimating equations, and investigate two situations: (a) when the basis functions are pre-determined, e.g., Fourier or wavelet basis functions and the functional features of interest are known; and (b) when the basis functions are data driven, such as with functional principal components. Asymptotic properties are developed. Notably, we show that when the functional features are data driven, the parameter estimates have an increased asymptotic variance, due to the estimation error of the basis functions. Our methods are illustrated with a simulation study and applied to an empirical data set, where a previously unknown interaction is detected. Technical proofs of our theoretical results are provided in the online supplemental materials.


The Poynting vector and angular momentum of Airy beams.
We analyze and describe the evolution of the Poynting vector and angular momentum of the Airy beam as it propagates through space. A numerical approach is used to show the Poynting vector follows the tangent line of the direction of propagation. A similar approach is used to show that while the total angular momentum of the Airy beam is zero, the angular momentum of the main intensity peak and the Airy "tail" are non-zero.


Uniform carbon dots@TiO2 nanotube arrays with full spectrum wavelength light activation for efficient dye degradation and overall water splitting.
This work presents a novel approach for preparing photocatalysts based on TiO2 nanotube arrays (TiO2 NTAs) anchored with carbon dots (CDs) by a facile two-step method which includes an electrochemical anodization technique followed by electrochemical deposition. The synthesized high quality graphitic carbon dots can act as sensitizers to extend the spectral range of light absorption towards the full solar spectrum. It is confirmed that TiO2 NTAs anchored with CDs (CDs/TiO2 NTAs) display greatly improved photocatalytic activity and excellent photocatalytic stability. By tuning the light absorption of the TiO2 NTAs, the utilization of light in charge generation and separation is well synergized with the CDs for enhanced photocatalytic pollutant degradation and water splitting, achieving significantly improved rates of photocatalytic degradation and H2 production in the visible and full spectra, respectively.


Pimavanserin Treatment for Parkinson's Disease Psychosis in Clinical Practice.
Parkinson's disease psychosis (PDP) is a common, nonmotor symptom of Parkinson's disease (PD), which may affect up to 60% of patients and is associated with impaired quality of life, increased healthcare costs, and nursing home placement, among other adverse outcomes. Characteristic symptoms of PDP include illusions; visual, auditory, tactile, and olfactory hallucinations; and delusions. PDP symptoms typically progress over its course from being mild, infrequent, and often untroubling to complex, sometimes constant, and potentially highly disturbing. PDP has traditionally been treated with atypical antipsychotics (e.g., clozapine and quetiapine) although these are not approved for this indication and clozapine requires frequent white blood cell count monitoring due to the risk of agranulocytosis. Pimavanserin is a newer atypical antipsychotic with highly selective binding to serotonergic receptors, no evidence for worsening motor symptoms in PD, and no need for white blood cell count monitoring. It is currently the only approved medication indicated for PDP treatment. However, because it was approved relatively recently (2016), clinical experience with pimavanserin is limited. Case Presentations. A wide variety of representative clinical scenarios are presented, each with distinct variables and complications. Issues addressed include distinguishing PDP from similar symptoms caused by other disorders such as dementia, coordinating pimavanserin with other PD medications and with deep brain stimulation, adapting pimavanserin dosing for optimal benefit and tolerability, and recognizing variability of PDP symptoms due to patients' changing life circumstances. These scenarios provide multiple insights regarding PDP management and the role of pimavanserin. Effective treatment of PDP may reduce disturbing symptoms of psychosis, thus improving patient function and quality of life. In addition, effective pharmacotherapy for PDP may also facilitate the use of other medications needed to treat neurological symptoms of PD (e.g., tremor, bradykinesia, and dyskinesia), although they may also have adverse effects that contribute to symptoms of PDP.


Fetal Doppler velocimetry and bronchopulmonary dysplasia risk among growth-restricted preterm infants: an observational study.
To investigate whether fetal growth restriction (FGR) diagnosis, based on pathological prenatal fetal Doppler velocimetry, is associated with bronchopulmonary dysplasia (BPD) independently of being small for gestational age (SGA) per se at birth among very preterm infants. Prospective, observational study. FGR was defined as failing fetal growth in utero and fetal Doppler velocimetry abnormalities. Policlinico Universitario Agostino Gemelli, Roma, Italy. Preterm newborns with gestational age ≤30 weeks and birth weight (BW) ≤1250 g. Bronchopulmonary dysplasia. In the study period, 178 newborns were eligible for the study. Thirty-nine infants (22%) were considered fetal growth-restricted infants. Among the 154 survived babies at 36 weeks postmenstrual age, 12 out of 36 (33%) of the FGR group developed BPD versus 8 out of 118 (7%) of the NO-FGR group (p<0.001). BPD rate was sixfold higher among the SGA-FGR infants compared with the SGA-NO-FGR infants. In a multivariable model, FGR was significantly associated with BPD risk (OR 5.1, CI 1.4 to 18.8, p=0.01), independently from BW z-score that still remains a strong risk factor (OR 0.5, CI 0.3 to 0.9, p=0.01). Among SGA preterm infants, BPD risk dramatically increases when placenta dysfunction is the surrounding cause of low BW. Antenatal fetal Doppler surveillance could be a useful tool for studying placenta wellness and predicting BPD risk among preterm babies. Further research is needed to better understand how FGR affects lung development.


Identification of Proteins Associated with the Early Restoration of Insulin Sensitivity After Biliopancreatic Diversion.
Insulin resistance (IR) is a risk factor for type 2 diabetes, diabetic kidney disease, cardiovascular disease and nonalcoholic steatohepatitis. Biliopancreatic diversion (BPD) is the most effective form of bariatric surgery for improving insulin sensitivity. To identify plasma proteins correlating with the early restoration of insulin sensitivity after BPD. Prospective single-center study including 20 insulin-resistant men with morbid obesity scheduled for BPD. Patient characteristics and blood samples were repeatedly collected from baseline up to 4 weeks postsurgery. IR was assessed by homeostatic model assessment for insulin resistance (HOMA-IR), Matsuda Index, and by studying metabolic profiles during meal tolerance tests. Unbiased proteomic analysis was performed to identify plasma proteins altered by BPD. Detailed plasma profiles were made on a selected set of proteins by targeted multiple reaction monitoring mass spectrometry (MRM/MS). Changes in plasma proteome were evaluated in relation to metabolic and inflammatory changes. BPD resulted in improved insulin sensitivity and reduced body weight. Proteomic analysis identified 29 proteins that changed following BPD. Changes in plasma levels of afamin, apolipoprotein A-IV (ApoA4), and apolipoprotein A-II (ApoA2) correlated significantly with changes in IR. Circulating levels of afamin, ApoA4, and ApoA2 were associated with and may contribute to the rapid improvement in insulin sensitivity after BPD.


Expression of Na(+)-K(+)-ATPase in the brown trout, Salmo trutta: in vivo modulation by hormones and seawater.
Expression of the Na(+)-K(+)-ATPase alpha-subunit was investigated in the gill and trunk kidney of Salmo trutta. Groups of freshwater (FW) fish were treated with various hormones [cortisol: 3 x 4.0 micrograms/g; recombinant salmon growth hormone (rsGH): 3 x 0.25 micrograms/g; salmon prolactin (sPRL): 3 x 0.25 micrograms/g; recombinant bovine insulin-like growth factor-I (rbIGF-I): 2 x 0.01 micrograms/g; or 2 x 0.1 micrograms/g] or transferred to 25 parts per thousand seawater (SW) and sampled after 1, 2, 3, and 50 days. Total RNA was analyzed by Northern blotting using Xenopus laevis Na(+)-K(+)-ATPase alpha-subunit cDNA as probe. The probe detected a 3.8-kb transcript. Relative to untreated FW control fish, the abundance of alpha-subunit Na(+)-K(+)-ATPase mRNA in gill tissue increased 1.7-to 2.5-fold after treatment with cortisol, rsGH, and rbIGF-I and after transfer to SW. Na(+)-K(+)-ATPase enzyme activity was also significantly stimulated in these groups, except at 0.01 micrograms/g rbIGF-I. sPRL was without effect. In the kidney, alpha-subunit mRNA level and Na(+)-K(+)-ATPase activity were unaffected by hormone treatment and SW transfer. The results indicate that an increased abundance of alpha-subunit mRNA is part of the molecular mechanism behind the increased gill Na(+)-K(+)-ATPase activity induced by SW transfer, cortisol, GH, and IGF-I.


Predator-hunting success and prey vulnerability: quantifying the spatial scale over which lethal and non-lethal effects of predation occur.
1. The shape of the function linking predator-attack success rate with distance to predator-concealing cover, or prey refuge, will affect population dynamics, distribution patterns and community trophic structure. Theory predicts that predator-attack success should decline exponentially with distance from predator-concealing cover, resulting in a threshold distance value above which there is little change in risk. Animals should then completely avoid areas of otherwise suitable habitat below this threshold, except when starvation risk exceeds predation risk. 2. We measured the shape of the function linking attack success with distance from cover in a system of Eurasian Sparrowhawks Accipiter nisus attacking (n = 445) and killing (n = 71) Redshanks Tringa totanus. We then determined if there was a threshold value and whether redshanks avoided areas below this threshold. 3. Sparrowhawk success rate with distance to predator-concealing cover declined exponentially with a threshold value of approximately 30 m. Redshanks used habitat above the threshold according to profitability and only fed below it, on average, in cold weather when starvation risk can be imminently high. Above about 5 degrees C, 26% of available habitat was avoided. 4. Our data support the hypothesis that predators create discrete areas with respect to cover that are avoided by prey. Large areas of suitable habitat may be unused, except in times of high starvation risk, when such areas may provide a foraging reserve, with large implications for population distribution and dynamics. 5. Our results are generated from a system in which predators attack their prey from concealing cover. But in the theoretically identical reverse scenario where the prey animal's distance from protective cover determines predation risk, such non-lethal effects will be equally important, especially in heavily fragmented landscapes.


Authenticity, ambivalence and recognition in caring at the end of life and beyond.
Informal caring at the end of life is often a fraught experience that extends well beyond the death of the person receiving care. However, analyses of informal carers' experiences are frequently demarcated relative to death, for example in relation to anticipatory grief (pre-death) or grief in bereavement (post-death). In contrast to this tendency to epistemologically split pre- and post-death experiences, we analyse informal caring across two separate qualitative interviews with 15 informal carers in one metropolitan city in Australia-one before and one after the death of the person for whom they cared. In doing so, we focus on accounts of care across dying and bereavement including: the evolving ambivalence of carers' social relations at the end of life and beyond; dying and death as a challenge to the ideal of authenticity; and, the potential for misrecognition and social estrangement in caring relations at the end of life. We draw on social theory addressing the themes of ambivalence, authenticity and recognition to enhance our understanding of caring as a social practice that occurs across dying and bereavement, rather than as structured primarily by the context of one or the other.


Cholesterol strongly affects the organization of lipid monolayers studied as models of the milk fat globule membrane: Condensing effect and change in the lipid domain morphology.
The biological membrane that surrounds the milk fat globules exhibits phase separation of polar lipids that is poorly known. The objective of this study was to investigate the role played by cholesterol in the organization of monolayers prepared as models of the milk fat globule membrane (MFGM). Differential scanning calorimetry and X-ray diffraction experiments allowed characterization of the gel to liquid crystalline phase transition temperature of lipids, Tm ~35°C, in vesicles prepared with a MFGM lipid extract. For temperature below Tm, atomic force microscopy revealed phase separation of lipids at 30 mN·m(-1) in Langmuir-Blodgett monolayers of the MFGM lipid extract. The high Tm lipids form liquid condensed (LC) domains that protrude by about 1.5 nm from the continuous liquid expanded (LE) phase. Cholesterol was added to the MFGM extract up to 30% of polar lipids (cholesterol/milk sphingomyelin (MSM) molar ratio of 50/50). Compression isotherms evidenced the condensing effect of the cholesterol onto the MFGM lipid monolayers. Topography of the monolayers showed a decrease in the area of the LC domains and in the height difference H between the LC domains and the continuous LE phase, as the cholesterol content increased in the MFGM lipid monolayers. These results were interpreted in terms of nucleation effects of cholesterol and decrease of the line tension between LC domains and LE phase in the MFGM lipid monolayers. This study revealed the major structural role of cholesterol in the MFGM that could be involved in biological functions of this interface (e.g. mechanisms of milk fat globule digestion).


Social rejection magnifies impulsive behavior among individuals with greater negative urgency: An experimental test of urgency theory.
Impulsivity is a multifaceted trait with substantial implications for human well-being. One facet of impulsivity is negative urgency, the tendency to act impulsively in response to negative affect. Correlational evidence suggests that negative affect magnifies impulsive behavior among individuals with greater negative urgency, yet causal evidence for this core pillar of urgency theory is lacking. To fill this gap in the literature, participants (N = 363) were randomly assigned to experience social rejection (a situation shown to induce negative affect) or acceptance. Participants then reported their subjective negative affect, completed a behavioral measure of impulsivity, and reported their negative urgency. Among individuals with relatively high and average negative urgency, social rejection increased their impulsive behavior through greater experiences of negative affect. These indirect effects were not observed among individuals relatively low in negative urgency. These findings suggest that negative urgency exists at the nexus of urgent dispositions and situations that elicit negative affect, which offers novel support for urgency theory. (PsycINFO Database Record


Diradicals acting through diamagnetic phenylene vinylene bridges: Raman spectroscopy as a probe to characterize spin delocalization.
We present a complete Raman spectroscopic study in two structurally well-defined diradical species of different lengths incorporating oligo p-phenylene vinylene bridges between two polychlorinated triphenylmethyl radical units, a disposition that allows sizeable conjugation between the two radicals through and with the bridge. The spectroscopic data are interpreted and supported by quantum chemical calculations. We focus the attention on the Raman frequency changes, interpretable in terms of: (i) bridge length (conjugation length); (ii) bridge conformational structure; and (iii) electronic coupling between the terminal radical units with the bridge and through the bridge, which could delineate through-bond spin polarization, or spin delocalization. These items are addressed by using the "oligomer approach" in conjunction with pressure and temperature dependent Raman spectroscopic data. In summary, we have attempted to translate the well-known strategy to study the electron (charge) structure of π-conjugated molecules by Raman spectroscopy to the case of electron (spin) interactions via the spin delocalization mechanism.


What works best, a cemented or cementless primary total hip arthroplasty?: minimum 17-year followup of a randomized controlled trial.
Total hip arthroplasty (THA) has been associated with high survival rates, but debate remains concerning the best fixation mode of THA. We conducted a randomized controlled trial (RCT) with 250 patients with a mean age of 64 years between October 1987 and January 1992 to compare the results of cementless and cemented fixation. Patients were evaluated for revision of either of the components. One hundred twenty-seven patients had died (51%) and 12 (4.8%) were lost to followup. The minimum 17-year followup data (mean, 20 years; range, 17-21 years) for 52 patients of the cementless group and 41 patients of the cemented group were available for evaluation. Kaplan-Meier survivorship analysis at 20 years revealed lower survival rates of cemented compared with cementless THA. The cementless tapered stem was associated with a survivorship of 99%. Age younger than 65 years and male gender were predictors of revision surgery. The efficacy of future RCTs can be enhanced by randomizing patients in specific patient cohorts stratified to age and gender in multicenter RCTs. Including only younger patients might improve the efficacy of a future RCT with smaller sample sizes being required. A minimum 10-year followup should be anticipated, but this can be expected to be longer if the difference in level of quality between the compared implants is smaller. Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum.
The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors' Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.


A PUBLIC HEALTH PERSPECTIVE ON THE IMPORTANCE OF PLASMA PHENYLALANINE AND TYROSINE DETERMINATION IN RELATION TO NEWBORN SCREENING AND MONITORING OF TREATMENT IN PHENYLKETONURIA.
Newborn screening of phenylketonuria (PKU) is performed in many countries, including Romania, in addition to screening for congenital hypothyroidism. Patients affected by PKU require frequent measurements of phenylalanine (Phe) level in blood plasma. Such a determination is important not only in early diagnostic, but also in monitoring the treatment of PKU to maintain phenylalaninemia within limits that will not affect the brain. A simple, highly sensitive, accurate and rather inexpensive procedure for the simultaneous determination of Phe and Tyr plasma concentrations was previously described in this journal. The new procedure may be applied in many clinical laboratories, including those with no previous experience in diagnosis of inherited amino acid metabolic disorders. In this way the major public health problems linked to PKU not being detected in the first weeks of life (including the burden of institutionalized children with preventable mental retardation) may be avoided.


[Cyanoacrylate adhesives for the synthesis of soft tissue].
Tissue adhesives have been used for the synthesis of wound due to their painless application and quick and easy handling. The purpose of this study was to analyze and compare the compatibility of the adhesives ethylcyanoacrylate (Super Bonder) and butyl-cyanoacrylate (Histoacryl), and to compare the reparation of incisions in the dorsum of rats with suture and the respective adhesives. Fifteen rats were used. Two surgical pockets were created in their dorsum. A polyethylene tube (10mm x 1mm) was implanted in each one. Each tube was filled with the adhesives Super Bonder(left side) and Histoacryl (right side). The incisions on the left side were closed with Super Bonder, and the incisions on the right side, with Histoacryl. A median incision between the two other incisions was made and closed with braided silk suture. The animals were killed after, 7, 35 and 120 days. The adhesives used in the present study did not promote inflammatory reaction when used for the synthesis of incisions. However, when implanted subcutaneously, they caused an inflammatory reaction within 120 days. Reaction is more severe with Histoacryl. Super Bonder and Histoacryl can be used effectively in the healing of incised tissues; they aid in the suture of incisions. However, these adhesives can be used for the synthesis of wounds, lacerations or cutaneous incisions.


Variations of physician group profiling indicators for asthma care.
To determine how much of the variation in physician group profiling for asthma care can be attributed to physician groups and how reliable those profiling indicators are. Cross-sectional study. Variations attributable to physician groups are presented using the intraclass correlation coefficient (ICC). The reliability of profiling results was determined using the ICC and sample size of the physician group. Between July 1998 and February 1999, patients with asthma from 20 California physician groups were randomly selected to be surveyed; 2515 patients responded. Quality indicators for physician group profiling were (1) National Asthma Education and Prevention Program guideline-based processes of care, including accessibility of asthma care, self-management knowledge about asthma care, use of inhaled bronchodilators, and use of inhaled corticosteroids, and (2) patient outcomes, including satisfaction with asthma care, improvement in health status, and emergency department visits and hospitalizations attributable to asthma. The variations attributable to physician group were small (< 10%) for process and outcome indicators. For process indicators, self-management knowledge had the highest ICC (9.83%), and use of inhaled bronchodilators had the lowest ICC (3.08%). For outcome indicators, satisfaction with asthma care had the highest ICC (9.53%), and hospitalization had the lowest ICC (1.35%). Despite low ICCs, a large sample size per physician group (n = 126) yielded acceptable reliability (> or = 0.80) for most profiling results. The selected indicators for profiling asthma care at the physician group level were generally reliable. Sampling a sufficient number of cases is key to achieving useful results from profiling.


Creating a path for indigenous student success in baccalaureate nursing education.
To enhance recruitment and retention of indigenous peoples in nursing education, the University of Manitoba launched a cohort initiative in 2007. In this article, we describe the background, implementation, and evaluation of the initiative. Indigenous epistemology was integrated into the curriculum and pedagogy of prerequisite and beginning nursing courses. A cohort approach encourages peer support, which boosts individual and group strengths and academic success. Courses provide students with information about traditional indigenous knowledge, "Western" science, and how the history of colonialism continues to impact indigenous peoples in North America. Using the same instructors and advisors, in concert with tutoring, manageable course loads, and a culturally supportive environment, forges a path for success in indigenous students pursuing a baccalaureate nursing education. Key elements in the initiative may be adopted by nurse administrators and educators globally to inform the development of undergraduate nursing programs for indigenous peoples.


Protein-tyrosine-phosphatase CD45 is phosphorylated transiently on tyrosine upon activation of Jurkat T cells.
The leukocyte common antigen (CD45) is an abundant lymphocyte surface antigen that has been reported to be involved in signaling through the T-cell antigen receptor. CD45 is a transmembrane protein-tyrosine-phosphatase. An internal segment comprises two domains each of which is homologous to other protein-tyrosine-phosphatases; the extracellular segment has the hallmarks of a ligand-binding motif. Since tyrosine phosphorylation is an early signal resulting from stimulation of the T-cell antigen receptor and CD45 is required for proper activation through the receptor, we explored whether CD45 might be regulated by tyrosine phosphorylation. Treatment of a T-cell leukemia line (Jurkat) with either phytohemagglutinin or anti-CD3 antibodies induced phosphorylation of tyrosine residues in CD45; treatment with phorbol 12-myristate 13-acetate did not. Phosphorylation of CD45 was transient, disappearing within 40 min after phytohemagglutinin treatment. The requirement for stringent conditions of phosphatase inhibition suggests that CD45 is capable of autodephosphorylation in vivo. These observations support recent reports indicating CD45 is involved in an early step in the T-cell activation cascade. They also suggest that phosphorylation/dephosphorylation of tyrosine residues in CD45 should be explored further as a possible regulatory mechanism.


Effect of mg and ethylenediaminetetraacetate on the in vitro activity of coumermycin a(1) and novobiocin against gram-negative bacteria.
The effect of Mg(2+) and ethylenediaminetetraacetic acid (EDTA) on the in vitro activity of coumermycin A(1) and novobiocin was determined against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis grown in Trypticase Soy Broth or defined synthetic medium. In the presence of EDTA, the activity of coumermycin A(1) was significantly enhanced (8- to 40-fold) against all four organisms in the synthetic medium lacking Mg(2+); novobiocin activity was increased to a lesser extent (4- to 16-fold) against three strains and remained unchanged against P. mirabilis. Addition of 200 mug of Mg(2+) per ml to the synthetic medium containing EDTA completely reversed the enhancement of activity of both antibiotics by EDTA only against P. aeruginosa. The addition of Mg(2+) to the synthetic medium appreciably inhibited the activity of novobiocin (sixfold) but not coumermycin A(1) against E. coli, and had little or no effect on the activity of either antibiotic against the remaining organisms. K. pneumoniae showed the greatest susceptibility to both antibiotics, and addition of EDTA enhanced this activity from 4-fold to 20-fold in all of the media tested. Subinhibitory concentrations of both antibiotics induced filament formation by all four organisms in all media. In addition, lysis of K. pneumoniae cells was observed.


Insulin secretion, glycosylated haemoglobin and islet cell antibodies in cystic fibrosis children and adolescents with different degrees of glucose tolerance.
In comparison with 12 weight-matched controls, 39 children and adolescents with cystic fibrosis (CF) showed higher fasting glycaemic levels and both delayed and enhanced blood glucose responses to OGTT. Glycaemic response was normal in 30/39 patients (76.9%), impaired in other 7 cases (18%) and diabetic in the remnant two (5.1%). Fasting insulin levels and total insulin output during OGTT did not differ in patients and controls, but insulin peak in CF group was delayed and sustained. In the whole CF series mean HbA1c was higher than in controls but no difference was found between patients with normal and those with impaired glucose tolerance. Islet cell antibodies were absent in the entire CF group. In conclusion, our results confirm the raised prevalence in CF of glucose tolerance abnormalities, which do not seem to depend on auto-immune factor involvement. Delayed insulin response to OGTT can be considered a very early expression of beta cell impairment in the course of CF. In our experience HbA1c assay did not constitute a sensitive and specific screening test for detection of the C patients with glucose intolerance.


Does neoadjuvant chemotherapy have therapeutic benefit for node-positive upper tract urothelial carcinoma? Results of a multi-center cohort study.
The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.


Comparison of pectoral Nerve (PECS1) block with combined PECS1 and transversus thoracis muscle (TTM) block in patients undergoing cardiac implantable electronic device insertion - A pilot study.
Pectoral nerve (PECS1) block has been used for patients undergoing cardiac implantable electronic device (CIED) insertions, however, PECS1 block alone may lead to inadequate analgesia during tunneling and pocket creation because of the highly innervated chest wall. Transversus thoracis muscle plane (TTM) block targeting the anterior branches of T2-T6 intercostal nerves can be effectively used in combination with PECS1 for patients undergoing CIED insertion. The present study hypothesized that combined PECS1 and TTM blocks would provide effective analgesia for patients undergoing CIED insertion compared to PECS1 block alone. Thirty adult patients between the age group of 18-85 years undergoing CIED insertion were enrolled in the study. A prospective, randomized, comparative, pilot study was conducted. A total of 30 patients were enrolled, who were randomized to either Group P: PECS1 block (n = 15) or Group PT: PECS1 and TTM blocks (n = 15). The intraoperative requirement of midazolam and local anesthetic and level of sedation by Ramsay sedation score were noted. The pain was assessed by visual analog scale (VAS) at rest and during a cough or deep breathing at 0 h, 3 h, 6 h, 12 h, and 24 h after the procedure. VAS scores at rest were significantly lower in group PT at 0, 3, 6, and 12 h postprocedure, and during cough at 0, 6, and 12 h after the procedure (P < 0.05). At 24 h, VAS scores were comparable between both groups. Intraoperative midazolam consumption was higher in group P compared to group PT (P= 0.002). Fourteen patients in group P received local anesthetic supplementation in comparison to only one patient in group PT (P = 0.0001). Thirteen patients in group P received the first rescue analgesia in comparison to three patients in group PT (P = 0.0003). Combined PECS1 and TTM blocks provide superior analgesia, reduced net consumption of local anesthetic, sedative agents, and rescue analgesics compared to PECS1 block alone in patients undergoing CIED insertion.


Intracellular reactions in single human granulocytes upon phorbol myristate acetate activation using confocal Raman microspectroscopy.
We have obtained new evidence for the occurrence of intracellular NADPH-oxidase activity in neutrophilic and eosinophilic granulocytes upon stimulation with phorbol myristate acetate (PMA). PMA activation leads to a partial translocation of cytochrome b(558) from the membranes of the specific granules to the plasma membrane. It was suggested that NADPH-oxidase activity only takes place in the plasma membrane, leading to an extracellular release of oxygen metabolites because cellular self-destruction can be avoided in this way. The effects of PMA activation were indirectly studied in recent experiments employing scavengers of extracellular superoxide anion and hydrogen peroxide, and support for intracellular NADPH-oxidase activity was obtained. In this paper we use Raman microspectroscopy as a direct method to study intracellular molecular reactions that result from cellular triggering by PMA. The molecular specificity of this microscopic method enables us to show that intracellular reduction of both myeloperoxidase (MPO) and cytochrome b(558) occurs in neutrophilic granulocytes. Control measurements with cytochrome b(558)-deficient neutrophilic granulocytes did not show a reduction of intracellular MPO. This is direct support for the occurrence of intracellular NADPH-oxidase activity in organelles that must be in close contact with the azurophilic granules that contain MPO. Furthermore, a comparison was made with chemical reactions occurring in eosinophilic granulocytes after activation with PMA. Moreover, in these cells an intracellular reduction of eosinophil peroxidase was observed.


Pulmonary cryptococcosis in nonimmunocompromised patients.
Cryptococcus neoformans can cause serious systemic infections requiring systemic antifungal therapy in immunocompromised hosts. However, isolated pulmonary cryptococcosis in nonimmunocompromised hosts has been reported to resolve spontaneously without treatment. s: To determine the role of antifungal therapy in the management of isolated pulmonary cryptococcosis in nonimmunocompromised hosts. Retrospective study. Tertiary care, referral medical center Thirty-six nonimmunocompromised subjects with isolated pulmonary cryptococcosis who received diagnoses at the Mayo Clinic (Rochester, MN) from 1976 to 2001. None. Of 42 nonimmunocompromised subjects with cryptococcal infections, 36 (86%) had isolated pulmonary cryptococcosis. The mean (+/- SD) age of these 36 patients was 61 +/- 15 years (range, 14 to 88 years), and the groups included 17 men (47%) and 19 women (53%). Twenty-four patients (67%) were symptomatic, and 12 patients (33%) were asymptomatic. The most common presenting symptoms were cough, dyspnea, and fever. Cultures of sputum and bronchial washings most commonly yielded the diagnosis. Cerebrospinal fluid examination was performed in 11 patients (31%) and was negative in all of them. Follow-up information was available on 25 patients (69%) with a median duration of 19 months (range, 1 to 330 months). Twenty-three of these patients (92%) had resolution of their disease (no treatment, 8 patients; surgical resection only, 6 patients; and antifungal therapy, 9 patients). The condition of the two remaining patients had improved. There was no documented treatment failure, relapse, dissemination, or death in any of these 25 patients. Our findings suggest that an initial period of observation without the administration of antifungal therapy is a reasonable option for nonimmunocompromised subjects with pulmonary cryptococcosis in the absence of systemic symptoms or evidence of dissemination, as well as after surgical resection for focal cryptococcal pneumonia.


Trends in maternal prepregnancy body mass index (BMI) and its association with birth and maternal outcomes in California, 2007-2016: A retrospective cohort study.
To determine recent trends in maternal prepregnancy body mass index (BMI) and to quantify its association with birth and maternal outcomes. A population-based retrospective cohort study included resident women with singleton births in the California Birth Statistical Master Files (BSMF) database from 2007 to 2016. There were 4,621,082 women included out of 5,054,968 women registered in the database. 433,886 (8.6%) women were excluded due to invalid or missing information for BMI. Exposures were underweight (BMI < 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥ 30 kg/m2) at the onset of pregnancy. Obesity was subcategorized into class I (30.0-34.9 kg/m2), class II (35.0-39.9 kg/m2), and class III (≥ 40 kg/m2), while adverse outcomes examined were low birth weight (LBW), very low birth weight (VLBW), macrosomic births, preterm birth (PTB), very preterm birth (VPTB), small-for-gestational-age birth (SGA), large-for-gestational-age birth (LGA), and cesarean delivery (CD). Descriptive analysis, simple linear regression, and multivariate logistic regression were performed, and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for associations were estimated. Over the ten-year study period, the prevalence of underweight and normal weight women at time of birth declined by 10.6% and 9.7%, respectively, while the prevalence of overweight and obese increased by 4.3% and 22.9%, respectively. VLBW increased significantly with increasing BMI, by 24% in overweight women and by 76% in women with class III obesity from 2007 to 2016. Women with class III obesity also had a significant increase in macrosomic birth (170%) and were more likely to deliver PTB (33%), VPTB (66%), LGA (231%), and CD (208%) than women with a normal BMI. However, obese women were less likely to have SGA infants; underweight women were 51% more likely to have SGA infants than women with a normal BMI. In California from 2007 to 2016, there was a declining trend in women with prepregnancy normal weight, and a rising trend in overweight and obese women, particularly obesity class III. Both extremes of prepregnancy BMI were associated with an increased incidence of adverse neonatal outcomes; however, the worse outcomes were prominent in those women classified as obese.


Bactericidal action of dapsone against Mycobacterium leprae in mice.
Dapsone (4,4'-diaminodiphenylsulfone), incorporated into the mouse chow in a concentration of 0.1 g/100 g of diet, was administered for 1 week to mice in which Mycobacterium leprae had multiplied to the level of 10(6) organisms/footpad. M. leprae were harvested from these and also from control mice, diluted serially, and inoculated into additional mice. The organisms recovered from untreated mice multiplied in passage with a mean doubling time of 12.2 days, and 35% or more of the inoculated organisms were viable, i.e., capable of infecting mice. Growth curves of M. leprae recovered from dapsone-treated animals lagged behind those of organisms from control animals by an average of 78 days, equivalent to 98.8% killing. Foot-by-foot harvests showed that only 0.2% of the M. leprae recovered from treated mice were viable, suggesting that treatment of mice with dapsone had been accompanied by killing of 99.4% of the viable M. leprae.


Evidence for the presence of several lipases n cow's milk.
Skim milks containing sodium chloride (0.75m) were centrifuged at 80000g for 2hr. and portions of the supernatants were submitted to gel filtration on columns of Sephadex G-200. Enzymes in the effluent fractions were assayed titrimetrically for their hydrolytic activities towards tributyrin, triolein and milk-fat emulsions, and triacetin solution. Summation of the measurements gave ratios of activities towards the various substrates similar to those of the original skim milks. Although only partial separation was obtained, five enzymes appeared to be present. They showed some differences in substrate specificity, but all appeared to be lipases in that they hydrolysed the emulsified substrates more rapidly than the dissolved triacetin.


Cardiocerebral Resuscitation: An Approach to Improving Survival of Patients With Primary Cardiac Arrest.
Out-of-hospital cardiac arrest (OHCA) is a major public health problem. In the United States, OHCA accounts for more premature deaths than any other cause. For over a half-century, the national "Guidelines" for resuscitation have recommended the same initial treatment of primary and secondary cardiac arrests. Using this approach, the overall survival of patients with OHCA, while quite variable, was generally very poor. One reason is that the etiologies of cardiac arrests are not all the same. The vast majority of nontraumatic OHCA in adults are due to a "primary" cardiac arrest, rather than secondary to respiratory arrest. Decades of research and ongoing reviews of the literature led the University of Arizona Sarver Heart Center Resuscitation Research Group to conclude in 2003 that the national guidelines for patients with primary cardiac arrest were not optimal. Therefore, we instituted a new, nonguidelines approach to the therapy of primary cardiac arrest that dramatically improved survival. We called this approach cardiocerebral resuscitation (CCR), as it is the heart and the brain that are the most vulnerable and therefore need to be the focus of resuscitation efforts for these patients. In contrast, cardiopulmonary resuscitation should be reserved for respiratory arrests. Cardiocerebral resuscitation evolved into 3 components: the community, with emphasis for lay individuals to "Check, Call, Compress" and use an automated external defibrillator if available; the Emergency Medical Services, that emphasizes delayed intubation in favor of passive ventilation, urgent and near continuous chest compressions before and immediately after a single indicated shock, and the early administration of epinephrine; and the third component, added in 2007, the designations of hospitals in Arizona that request this designation and agree to receive patients with return of spontaneous circulation following OHCA and to institute state-of-the-art postresuscitation care that includes urgent therapeutic mild hypothermia and cardiac catheterization as a Cardiac Receiving Center. Each component of CCR is critical for optimal survival of patients with primary OHCA. In each city, county, and state where CCR was instituted, the result was a marked increase in survival of the subgroup of patients with OHCA most likely to survive, for example, those with a shockable rhythm. The purpose of this invited article on CCR is to review this alternative approach to resuscitation of patients with primary cardiac arrest and to encourage its adoption worldwide so that more lives can be saved.


Population genomic footprints of selection and associations with climate in natural populations of Arabidopsis halleri from the Alps.
Natural genetic variation is essential for the adaptation of organisms to their local environment and to changing environmental conditions. Here, we examine genomewide patterns of nucleotide variation in natural populations of the outcrossing herb Arabidopsis halleri and associations with climatic variation among populations in the Alps. Using a pooled population sequencing (Pool-Seq) approach, we discovered more than two million SNPs in five natural populations and identified highly differentiated genomic regions and SNPs using FST -based analyses. We tested only the most strongly differentiated SNPs for associations with a nonredundant set of environmental factors using partial Mantel tests to identify topo-climatic factors that may underlie the observed footprints of selection. Possible functions of genes showing signatures of selection were identified by Gene Ontology analysis. We found 175 genes to be highly associated with one or more of the five tested topo-climatic factors. Of these, 23.4% had unknown functions. Genetic variation in four candidate genes was strongly associated with site water balance and solar radiation, and functional annotations were congruent with these environmental factors. Our results provide a genomewide perspective on the distribution of adaptive genetic variation in natural plant populations from a highly diverse and heterogeneous alpine environment.


Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4.
As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P=.00012], 1q42.2-43 [PCAP; LOD score 2.84, P=.0030], and 4q [LOD score 2.80, P=.00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P=.00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample.


BCL6 suppresses RhoA activity to alter macrophage morphology and motility.
BCL6 is a potent transcriptional repressor that plays important roles in germinal center formation, T helper cell differentiation and lymphomagenesis and regulates expression of several chemokine genes in macrophages. In a further investigation of its role in macrophages, we show that BCL6 inactivation in primary bone marrow-derived macrophages leads to decreased polarization, motility and cell spreading accompanied by an increase in peripheral focal complexes, anchored F-actin bundles and cortical F-actin density. These changes were associated with excess RhoA activation. C3 transferase inhibition of RhoA activity reverted the adhesion structure phenotype, which was not affected by Rho kinase inhibitors, suggesting that other downstream effectors of Rho maintain this Bcl6(-/-) phenotype. Excess RhoA activation in BCL6-deficient macrophages is associated with a decrease in the p120RasGAP (RASA1)-mediated translocation of p190RhoGAP (GRLF1) to active RhoA at the plasma membrane and a reduction in cell surface expression of the CSF1R that has been reported to recruit RasGAP to the plasma membrane. Reconstitution of BCL6 expression in Bcl6(-/-) macrophages results in complete reversion of the morphological phenotype and a significant increase in cell surface CSF1R expression whereas overexpression of the CSF1R corrects the polarization and adhesion structure defects. These results demonstrate that BCL6 suppresses RhoA activity, largely through upregulation of surface CSF1R expression, to modulate cytoskeletal and adhesion structures and increase the motility of macrophages.


Morbidity of vaginal hysterectomy for benign tumors as a function of uterine weight.
To evaluate the relationship between uterine weight and morbidity in women undergoing vaginal hysterectomy. A prospective study of vaginal hysterectomy was carried out in women with benign uterine tumors. The only exclusion criteria were a suspected adnexal mass, a very narrow vagina and an immobile uterus. The women were stratified into 3 groups according to uterine weight. The groups were compared as regards indications, operative time, complication rates, analgesia requirements and postoperative recovery. A total of 214 women underwent vaginal hysterectomy: group 1, n = 114, uteri < 180 g; group 2, n = 73, uteri 180-500 g; group 3, n = 27, uteri > 500 g (maximum 1,350 g). The groups differed with respect to mean age (P = .003) and menopausal status (P = .002) but not gravidity, parity, previous pelvic surgery or preoperative hemoglobin levels. Concerning the indications for hysterectomy, only the incidence of pelvic compression differed between the groups (P = .04). There was no difference in the frequency of concomitant surgical procedures (e.g., adnexectomy) between the groups. Morcellation rate was 30% in group 1, 73% in group 2 and 100% in group 3. The overall complication rate was not significantly different between the groups: 20.1%, 15.0% and 22.2%, respectively. The only major complication was an injury to the in-fundibulopelvic ligament in a group 1 patient. Operative time increased significantly with uterine weight (82 +/- 35.4, 91.8 +/- 35.4 and 94.8 +/- 36.5 minutes, respectively; P = .01). There were no significant differences between the groups as regards perioperative hemoglobin loss, analgesia requirements, time to flatus and stool return or length of hospital stay. Vaginal hysterectomy can be performed successfully even in the case of greatly enlarged uteri; nulliparity and a history of pelvic surgery are not absolute contraindications.


Plasmodium falciparum: nitric oxide modulates heme speciation in isolated food vacuoles.
Nitric oxide (NO) and NO-derived reactive nitrogen species (RNS) are present in the food vacuole (FV) of Plasmodium falciparum trophozoites. The product of PFL1555w, a putative cytochrome b(5), localizes in the FV membrane, similar to what was previously observed for the product of PF13_0353, a putative cytochrome b(5) reductase. These two gene products may contribute to NO generation by denitrification chemistry from nitrate and/or nitrite present in the erythrocyte cytosol. The possible coordination of NO to heme species present in the food vacuole was probed by resonance Raman spectroscopy. The spectroscopic data revealed that in situ generated NO interacts with heme inside the intact FVs to form ferrous heme nitrosyl complexes that influence intra-vacuolar heme solubility. The formation of heme nitrosyl complexes within the FV is a previously unrecognized factor that could affect the equilibrium between soluble and crystallized heme within the FV in vivo.


INBORN ENZYMATIC DEFECT AS THE PROBABLE CAUSE OF THE FORMATION OF RENAL STONES CONSISTING OF URIC ACID.
In four persons of one family the existence of an enzymatic defect, presumably consisting of a deficiency of glutaminase in the cells of the renal tubules, is postulated, and is implied by a reduced elimination of ammonia in the urine, by a relatively low urinary pH, and by its increased titratable acidity. The most characteristic clinical symptom is irritation of the distal part of the urinary tract, connected with numerous crystals of uric acid appearing in the urinary sediment. The elimination of uric acid is normal, or even reduced, and the level of uric acid in the blood serum is also within normal limits. After the administration of glutaminic acid elimination of ammonia is further decreased and the quantity of uric acid crystals is increased. Loading with glutaminic acid may also cause an attack of renal pain in the individual suffering from this defect but the administration of ammonium chloride does not cause any increase in ammonia production. It seems probable that the enzymatic defect is connected with the presence of antigen B in the erythrocytes and that it is inherited as a dominant autosomal feature. A suitable diet to make the urine alkaline allows kidneys to function efficiently in individuals suffering from this defect.


Communication: spin-boson model with diagonal and off-diagonal coupling to two independent baths: ground-state phase transition in the deep sub-Ohmic regime.
We investigate a spin-boson model with two boson baths that are coupled to two perpendicular components of the spin by employing the density matrix renormalization group method with an optimized boson basis. It is revealed that in the deep sub-Ohmic regime there exists a novel second-order phase transition between two types of doubly degenerate states, which is reduced to one of the usual types for nonzero tunneling. In addition, it is found that expectation values of the spin components display jumps at the phase boundary in the absence of bias and tunneling.