The sensitization of mice with a wild-type and cold-adapted variant of influenza A virus. II. Secondary cytotoxic T cell responses.
Reductions in virus titres and the generation of enhanced cytotoxic T cell (Tc) activity in the lungs of mice primed either with a wild-type, parental (H2N2) influenza virus, A/AA/6/60, or a cold-adapted variant A/AA/6/60-ca and challenged 6 weeks later with a H1N1 A/WSN virus showed that both H2N2 viruses could sensitize the mice. A comparison of graded sensitizing doses of each virus showed that inocula of 10(6) tissue culture infective doses (TCID50) of the ca-variant or 10(3) TCID50 of the wild-type virus gave similar results. The spleens and lungs of normal mice were found to contain similar levels (circa 1/10(5) cells) of precursor Tc cells and the level in the lung did not increase 2 days after intranasal (i.n.) inoculation of A/WSN virus. Two and 6 weeks after priming mice with 10(5) TCID50 of either virus, the lungs contained about a 20-fold increase in the precursor Tc cell frequency. In contrast, sensitization with a sub-lethal dose of a mouse-adapted A/WSN virus caused a 100-fold or greater increase. Sensitization of mice with the parental but not the ca-variant virus caused an increase in frequency of precursor Tc cells in the spleens of the sensitized mice and this might reflect the very low level of replication of the ca-variant virus in the mouse lung.


Task meaningfulness and degree of cognitive impairment: do they affect self-generated learning in persons with multiple sclerosis?
Self-generated learning has been shown to improve memory performance in persons with multiple sclerosis (MS), although little is known about the variables that influence its efficacy. This study examined whether task meaningfulness and degree of cognitive impairment influence the effectiveness of self-generation in improving learning and memory in MS. A mixed design with both a within- and between-subject factors was employed. The setting was a nonprofit rehabilitation research institution. Participants included 35 persons with MS with moderate to severe learning and memory impairments (SEVERE-MS), and 35 persons with little to no impairment (MILD-MS). Participants in both groups learned two types of tasks (functional everyday tasks and laboratory tasks), each in two learning conditions (Provided and Generated). Participants were required to recall the information immediately, 30 minutes, and 1 week following initial learning. Significantly more words were recalled from the generated condition relative to the provided condition. Additionally, self-generation was more effective in recall on the functional tasks compared to the laboratory tasks, consistent for both memory impaired and non-impaired participants. Self-generation may be influenced by variables such as task meaningfulness during learning and memory. In addition, type of task (functional versus laboratory) has a significant effect on memory. Implications for cognitive rehabilitation in MS are discussed.


The role of goal adjustment in symptoms of depression, anxiety and fatigue in cancer patients receiving psychosocial care: a longitudinal study.
This study examined whether cancer patients reported increases in their goal adjustment capacities while receiving psychosocial care and whether these increases were related to changes in symptoms of depression, anxiety and fatigue. Goal adjustment was conceptualised as two independent capacities: goal disengagement (i.e. disengage from unattainable goals) and goal reengagement (i.e. reengage into new goals). This naturalistic, longitudinal study focused on 241 cancer patients receiving psychosocial care at one of the seven psycho-oncology institutions in the Netherlands. Data was collected before the start of psychosocial care (T1) and nine months thereafter (T2). Hierarchical regression analysis was used to examine the research questions. Goal adjustment, symptoms of depression, anxiety and fatigue. At group level, patients reported small increases in goal disengagement (d = .22) but no significant change in goal reengagement (d = .09). At an individual level, 34% of cancer patients reported an increase in goal disengagement and 30% reported an increase in goal reengagement. Increases in goal reengagement were significantly associated with decreases in both depressive and anxiety symptoms, but not to changes in fatigue. Findings indicate that particularly improvements in goal reengagement are beneficial for cancer patients' psychological functioning.


Significance of the presence of microscopic vascular invasion after complete resection of Stage I-II pT1-T2N0 non-small cell lung cancer and its relation with T-Size categories: did the 2009 7th edition of the TNM staging system miss something?
The aim of this study was to assess the significance of microscopic vascular invasion (MVI) in a population of resected patients with early-stage non-small cell lung cancer (NSCLC), along with an analysis of the effect of the combination of MVI and tumor size for the T-size categories T1a-T2b according to the 2009 7th edition of the tumor, node, metastasis (TNM) classification. From January 1993 to August 2008, 746 patients with pT1-T2N0 NSCLC received resection at our institution. MVI was ascertained using histopathological and immunohistochemical techniques. MVI was observed in 257 patients (34%). Prevalence was higher in adenocarcinoma (ADK) than in squamous cell carcinoma (p = 0.002). A significant correlation was found between MVI and ADK (p = 0.03), increased tumor dimension (p = 0.05), and the presence of tumor-infiltrating lymphocytes (p = 0.02). The presence of MVI was associated with a reduced 5-year survival overall (p = 0.003) and in ADK (p = 0.0002). In a multivariate survival analysis, MVI was an indicator of poor survival overall (p = 0.003) and in ADK (p = 0.0005). In each T category (T1a-T2b) of the 2009 TNM staging system, survival of MVI+ patients was significantly lower than the corresponding MVI- patients; T1a and T1b MVI+ patients had a survival similar to MVI- T2 patients. The finding of MVI in pT1-T2N0 NSCLC is frequent. MVI correlates with adenocarcinoma histotype, increased tumor dimensions, and tumor-infiltrating lymphocytes. The presence of MVI is an independent negative prognostic factor. In our experience, MVI was a stronger prognostic indicator than T size in T1a-T2b categories according to the 2009 TNM staging system.


Mate choice decisions of stickleback females predictably modified by MHC peptide ligands.
Sexual selection has been proposed as one mechanism to explain the maintenance of high allelic diversity in MHC genes that control the extent of resistance against pathogens and parasites in natural populations. MHC-based sexual selection is known to involve olfactory mechanisms in fish, mice, and humans. During mate choice, females of the three-spined stickleback (Gasterosteus aculeatus) use an odor-based selection strategy to achieve an optimal level of MHC diversity in their offspring, equipping them with optimal resistance toward pathogens and parasites. The molecular mechanism of odor-based mate-selection strategies is unknown. Because peptide ligands for MHC class I molecules function as individuality signals in mice, we hypothesized that female sticklebacks might assess the degree of MHC diversity of potential partners by means of the structural diversity of the corresponding peptide ligands in perceived odor signals. We show that structurally diverse MHC ligands interact with natural odors of male sticklebacks to predictably modify MHC-related mate choice. For a mating pair with suboptimal numbers of MHC alleles, peptides increase the attractiveness of male water, whereas for a mating pair with superoptimal numbers, attractiveness is decreased. Our results suggest that female sticklebacks use evolutionarily conserved structural features of MHC peptide ligands to evaluate MHC diversity of their prospective mating partners.


The Role of Oscillatory Phase in Determining the Temporal Organization of Perception: Evidence from Sensory Entrainment.
Recent behavioral, neuroimaging, and neurophysiological studies have renewed the idea that the information processing within different temporal windows is linked to the phase and/or frequency of the ongoing oscillations, predominantly in the theta/alpha band (∼4-7 and 8-12 Hz, respectively). However, being correlational in nature, this evidence might reflect a nonfunctional byproduct rather than having a causal role. A more direct link can be shown with methods that manipulate oscillatory activity. Here, we used audiovisual entrainment at different frequencies in the prestimulus period of a temporal integration/segregation task. We hypothesized that entrainment would align ongoing oscillations and drive them toward the stimulation frequency. To reveal behavioral oscillations in temporal perception after the entrainment, we sampled the segregation/integration performance densely in time. In Experiment 1, two groups of human participants (both males and females) received stimulation either at the lower or the upper boundary of the alpha band (∼8.5 vs 11.5 Hz). For both entrainment frequencies, we found a phase alignment of the perceptual oscillation across subjects, but with two different power spectra that peaked near the entrainment frequency. These results were confirmed when perceptual oscillations were characterized in the time domain with sinusoidal fittings. In Experiment 2, we replicated the findings in a within-subject design, extending the results for frequencies in the theta (∼6.5 Hz), but not in the beta (∼15 Hz), range. Overall, these findings show that temporal segregation can be modified by sensory entrainment, providing evidence for a critical role of ongoing oscillations in the temporal organization of perception.SIGNIFICANCE STATEMENT The continuous flow of sensory input is not processed in an analog fashion, but rather is grouped by the perceptual system over time. Recent studies pinpointed the phase and/or frequency of the neural oscillations in the theta/alpha band (∼4-12 Hz) as possible mechanisms underlying temporal windows in perception. Here, we combined two innovative methodologies to provide more direct support for this evidence. We used sensory entrainment to align neural oscillations to different frequencies and then characterized the resultant perceptual oscillation with a temporal dense sampling of the integration/segregation performance. Our results provide the first evidence that the frequency of temporal segregation can be modified by sensory entrainment, supporting a critical role of ongoing oscillations in the integration/segregation of information over time.


Risk factors affecting postoperative pulmonary function in congenital diaphragmatic hernia.
It is well known that congenital diaphragmatic hernia (CDH) in infants impacts pulmonary function rehabilitation after surgery. However, the risk factors of postoperative pulmonary function are still unclear. In this research, we analyzed the potential risk factors of postoperative pulmonary function in CDH patients in order to improve the clinical management of CDH patients. Thirty-three cases CDH infants followed were enrolled from November 2016 to September 2018. Clinical data were reviewed. Tidal breathing pulmonary function testing was performed after surgery. Correlation between pulmonary function and clinical characteristics was evaluated using multivariate analysis of variance. Pulmonary dysfunction was detected in 87.9% patients (29 of 33). The defect size was found to be significantly larger in patients with obstructed and mixed ventilatory disorders (P = 0.001). Diagnosis of gestational age (GA) was also significantly earlier compared to restrictive ventilatory disorders (P = 0.001). Larger defect size, and earlier prenatal diagnosis of GA were detected in severe obstructive ventilatory disorders (P = 0.007, P = 0.001, retrospectively). Most patients had various degrees of pulmonary dysfunction after surgery. Patients with larger defect size and earlier diagnosis time might be vulnerable to severe obstructive and mixed ventilatory disorders.


P53 modulates the effect of loss of DNA mismatch repair on the sensitivity of human colon cancer cells to the cytotoxic and mutagenic effects of cisplatin.
This study examined how the DNA mismatch repair (MMR) system and p53 interact to maintain genomic integrity in the presence of the mutagenic stress induced by cisplatin (DDP). Sensitivity to the cytotoxic and mutagenic effect of DDP was assessed using a panel of sublines of the MMR-deficient HCT116 colon carcinoma cells in which MMR function had been restored by transfer of a copy of MLH1 on chromosome 3 or in which p53 function had been disabled by expression of HPV-16 E6. Loss of p53 function by expression of E6 in MMR-proficient HCT116+ ch3 cells conferred only 1.1-2.0-fold resistance to a panel of commonly used chemotherapeutic agents, whereas disruption of p53 in MMR-deficient HCT116 cells resulted in substantial levels of resistance to some agents (paclitaxel, 1.9-fold; gemcitabine, 2.7-fold; 6-thioguanine, 3.3-fold; and etoposide, 4.4-fold) but sensitization to other agents (topotecan, 2.5-fold; and DDP, 3.3-fold). Loss of MMR or p53 alone had only a minor effect on sensitivity to the mutagenic effect of DDP as measured by the appearance of variants resistant to 6-thioguanine, etoposide, topotecan, gemcitabine, and paclitaxel in the population 10 days later (1.0-2.4-fold), whereas loss of both p53 and MMR had a more profound effect (1.7-6.5-fold). Loss of both p53 and MMR increased the basal frequency insertion/deletion mutations detected by a shuttle vector-based assay to a greater extent than loss of either alone. In association with DDP-induced injury, loss of p53 or MMR alone resulted in 1.2- and 1.7-fold more mutations, whereas loss of both resulted in a 5.1-fold increase in mutant frequency. Examination of the impact of loss of p53 and/or MMR on the DDP-induced cell cycle checkpoint activation, p53 induction, ability of the cell to tolerate adducts in its DNA, and the rate of disappearance of platinum from genomic DNA indicated the effects of the loss of p53 and/or MMR on all of these parameters, suggesting a multifactorial etiology for the changes in sensitivity to the cytotoxic and mutagenic effects of DDP. These results indicate that p53 and MMR can cooperate to control sensitivity to the cytotoxic effect of DDP and to limit its mutagenic potential in the colon cancer cells.


The Burden of Rhinitis and the Impact of Medication Management within the Community Pharmacy Setting.
The burden of rhinitis is high. It is unknown to what extent this burden is related to inappropriate medication use. This study aimed to identify the way in which people with rhinitis medicate their condition and to evaluate the appropriateness of this medication management. Pharmacy customers who visited Sydney metropolitan community pharmacies and purchased medication for nasal symptoms were the sampling frame for this study. To determine the condition for which the participants were seeking medication and the appropriateness of their medication selection, the following data were collected with a researcher-administered questionnaire: participant's demographics, symptoms, medication selected. An expert panel of clinical researcher pharmacists and specialist respiratory physician evaluated the appropriateness of medication selection based on the Allergic Rhinitis and its Impact on Asthma international guidelines. Two hundred and ninety-six participants were recruited from 8 pharmacies; 63.2% had a doctor's diagnosis for the symptoms for which they were selecting treatment. Seventy percent of participants self-selected their medications. Seventy-one percent of the participants were identified as having rhinitis. Overall, 16.5% of participants who had rhinitis selected optimal medications. Sixteen percent of participants with allergic rhinitis reported wheezing (6.3% selected optimal medications). The majority of the participants with rhinitis selected suboptimal medications from community pharmacy highlighting the significant burden of rhinitis in community pharmacy and the contribution of medication management. Pharmacists need to take a proactive and evidence-based role in the management of rhinitis supported by clinical pathways when need to be articulated and promoted in all rhinitis guidelines.


Molecular cloning, characterization and function of a germinal center kinase MST4 gene from Litopenaeus vannamei in response to Vibrio alginolyticus challenge in TLR-TRAF6 signaling pathway.
The serine/threonine protein kinase MST4 plays multiple roles in the regulation of signaling pathways that govern cellular processes including mitosis, migration, homeostasis, polarity, proliferation, differentiation and apoptosis. Here we report the identification and characterization of the full-length sequence of LvMST4 from the shrimp L. vannamei, and investigations into its role in the shrimp's immune response to infection by the pathogenic bacterium Vibrio alginolyticus. Subcellular localization assays demonstrated the enzyme's presence in the shrimp's cytoplasm, and tissue-specific expression analysis revealed that it is expressed ubiquitously but at different levels in different tissues. Infection with V. alginolyticus increased LvMST4 expression and induced a rapid response via the TLR-TRAF6 signaling pathway, causing a decline in the total hemocyte count (THC) and an increase in respiratory burst (RB) activity. In non-infected shrimp, RNAi silencing of LvMST4 with dsRNA had no significant effect on THC but seemed to activate the TRAF6-MKK6-p38 pathway and reduced RB activity. In shrimp challenged with V. alginolyticus, LvMST4 silencing reduced bacterial clearance and increased the initial upregulation of LvTRAF6 while reducing the expression of LvMKK6 and Lvp38. LvMST4 silencing also slightly reduced the THC but caused pronounced increases in RB activity and cumulative mortality. These findings suggest that LvMST4 contributes to antimicrobial responses via the TLR-TRAF6 signal pathway, and helps maintain immunological homeostasis in L. vannamei.


The lumbar erector spinae plane block: a cadaveric study.
The aim of this cadaveric study was to investigate the erector spinae plane block (ESPB) in lumbar region and to elucidate the possible mechanisms of action of these injections in lumbar radicular pain by means of detecting expected dye dispersion to the neural structures. Ultrasound-guided lumbar ESPB was performed in three formaldehyde-embalmed human cadavers. For this purpose, a 10 mL of methylene blue was injected into the fascial space between the L4 transverse process and the erector spinae muscles. T hen, the cadavers were dissected, the cephalocaudal and lateral spread of the dye was examined, and the involvement of the dorsal rami, dorsal root ganglia and ventral rami were analyzed. The distribution into the epidural space was also evaluated. The involvement of the dorsal rami was found to extend up to the T12 level and down to the L5 spinal nerves. Although dye dispersion was detected on the dorsal root ganglion in all specimens, it was found to be limited to one or two levels, unlike the dorsal rami. In half of the specimens, distribution to the ventral ramus and posterior epidural space was observed.


[Calcium hypothesis of Alzheimer disease].
Alzheimer's disease is the most common neurodegenerative disorder characterized by progressive memory and cognitive abilities loss. The etiology of Alzheimer's disease is poorly understood. In this regard, there is no effective treatment for the disease. Various hypotheses to explain the nature of the pathology of Alzheimer's disease led to the development of appropriate therapeutics. Despite of decades of research and clinical trials available therapeutics, at best, can only slow down the progression of the disease, but cannot cure it. This review dedicated to the one of modern hypotheses of Alzheimer's disease pathogenesis implied the impairment of calcium homeostasis as a key event for the development of neurodegenerative processes.


Perforin expression in peripheral blood lymphocytes in rejecting and tolerant kidney transplant recipients.
Perforin (P) is a cytolytic molecule expressed in the granules of cytolytic T cells and natural killer cells. Although cytotoxic cells have been implicated in graft rejection, no prospective clinical study has been published that examines the dynamics of perforin expressing cells in peripheral blood lymphocytes of transplanted patients. The cytofluorimetric assay developed in our laboratory previously for the simultaneous detection of intracellular perforin together with cell surface molecules was used for posttransplantation monitoring of patients, for the assessment of the efficiency of immunosuppressive treatment, and for the prediction of acute kidney transplant rejection and the stability of tolerance to long lived kidney transplants. Immunosuppression for the purpose of allotransplantation causes a decline in the number of perforin-expressing cells in peripheral blood. In contrast, in patients with clinical signs of acute rejection, the total number of perforin-expressing lymphocytes was increased in comparison with nonrejecting patients. Analyzing perforin-expressing subsets, rejection crises were accompanied by a relative decrease of perforin expression in the CD4+ subpopulation while increasing in the CD8+ subset. In the CD56+ and CD16+ NK subpopulations changes in perforin expression were mixed. In nonrejecting patients the ratio of perforin expression in CD4+ cells was high compared with CD8+ cells. Intensive therapy of acute rejection episodes with high doses of corticosteroids (methylprednisolonet [Solumedrol] bolus) strongly and significantly decreased the percentage of both, the subpopulations of perforin-positive T cells and the subpopulation of CD56+P+ NK cells. The lowest level of perforin expression, including low frequencies of perforin among CD8+ and CD4+ cells, was found in the group of patients tolerating transplanted kidneys for several years. These changes in perforin protein expression in peripheral blood can be used to discriminate between immunosuppressed patients who are immunologically quiescent and those who undergo transplant rejection. Our results confirm the hypothesis that cytotoxicity mediated by perforin may be an important effector mechanism in the rejection of allografted kidneys.


Being Young and Getting Cancer: Development of a Questionnaire Reflecting the Needs and Experiences of Adolescents and Young Adults with Cancer.
Cancer is the leading cause of nonaccidental deaths among adolescents and young adults (AYAs). In Denmark, there are substantial gaps in knowledge concerning how AYAs with cancer perceive their diagnostic and therapeutic trajectory and report health-related outcomes. The aim of this study is to describe the development of a questionnaire targeting AYAs with cancer aiming to evaluate treatment and survivorship from the perspective of the patients. Identification of themes and development of items included in the questionnaire were based on a synthesis of literature and qualitative interviews with AYAs in an iterative process involving both a professional advisory panel and a youth panel. During the development process, items were validated through cognitive interviews. The final questionnaire contained 151 closed- and open-ended items divided into 6 sections regarding: (1) "Time before treatment," (2) "Being told about your illness," (3) "Being a young patient," (4) "Your treatment," (5) "Receiving help living with and after Cancer," and (6) "How are you feeling today?." One hundred one items were specifically developed for this study, while 50 were standardized validated indexes. The questionnaire combined different types of items such as needs, preferences, experiences, and patient-reported outcomes. This is one of few developed questionnaires aiming to evaluate the perspective of AYAs with cancer through their whole cancer trajectory. Results from the questionnaire survey are intended for quality improvements and research in AYA cancer care. The study highlights the importance of an extensive patient involvement in all steps of a questionnaire development process.


AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity.
Developing T cells encounter peripheral self-antigens in the thymus in order to delete autoreactive clones. It is now known that the autoimmune regulator protein (AIRE), which is expressed in thymic medullary epithelial cells, plays a key role in regulating the thymic transcription of these peripheral tissue-specific antigens. Mutations in the AIRE gene are associated with a severe multiorgan autoimmune syndrome (APECED), and autoimmune reactivities are manifest in AIRE-deficient mice. Functional AIRE protein is expressed as distinct nuclear puncta, although no structural basis existed to explain their relevance to disease. In addressing the cell biologic basis for APECED, we made the unexpected discovery that an AIRE mutation hot spot lies in a caspase recruitment domain. Combined homology modeling and in vitro data now show how APECED mutations influence the activity of this transcriptional regulator. We also provide novel in vivo evidence for AIRE's association with a global transcription cofactor, which may underlie AIRE's focal, genome-wide, alteration of the transcriptome.


A novel feature selection algorithm for identifying hub genes in lung cancer.
Lung cancer, a life-threatening disease primarily affecting lung tissue, remains a significant contributor to mortality in both developed and developing nations. Accurate biomarker identification is imperative for effective cancer diagnosis and therapeutic strategies. This study introduces the Voting-Based Enhanced Binary Ebola Optimization Search Algorithm (VBEOSA), an innovative ensemble-based approach combining binary optimization and the Ebola optimization search algorithm. VBEOSA harnesses the collective power of the state-of-the-art classification models through soft voting. Moreover, our research applies VBEOSA to an extensive lung cancer gene expression dataset obtained from TCGA, following essential preprocessing steps including outlier detection and removal, data normalization, and filtration. VBEOSA aids in feature selection, leading to the discovery of key hub genes closely associated with lung cancer, validated through comprehensive protein-protein interaction analysis. Notably, our investigation reveals ten significant hub genes-ADRB2, ACTB, ARRB2, GNGT2, ADRB1, ACTG1, ACACA, ATP5A1, ADCY9, and ADRA1B-each demonstrating substantial involvement in the domain of lung cancer. Furthermore, our pathway analysis sheds light on the prominence of strategic pathways such as salivary secretion and the calcium signaling pathway, providing invaluable insights into the intricate molecular mechanisms underpinning lung cancer. We also utilize the weighted gene co-expression network analysis (WGCNA) method to identify gene modules exhibiting strong correlations with clinical attributes associated with lung cancer. Our findings underscore the efficacy of VBEOSA in feature selection and offer profound insights into the multifaceted molecular landscape of lung cancer. Finally, we are confident that this research has the potential to improve diagnostic capabilities and further enrich our understanding of the disease, thus setting the stage for future advancements in the clinical management of lung cancer. The VBEOSA source codes is publicly available at https://github.com/TEHNAN/VBEOSA-A-Novel-Feature-Selection-Algorithm-for-Identifying-hub-Genes-in-Lung-Cancer .


Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases.
The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in orthotopic models of human primary and secondary brain tumors. Autoradiography and pharmacokinetic analyses were performed on rats and mice to determine passage across the blood-brain barrier and organ distribution of sagopilone. Mice bearing intracerebral human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma, or patient-derived non-small-cell lung cancer [NSCLC]) were treated with sagopilone 5-10 mg/kg, paclitaxel 8-12.5 mg/kg (or temozolomide, 100 mg/kg) or control (vehicle only). Tumor volume was measured to assess antitumor activity. Sagopilone crossed the blood-brain barrier in both rat and mouse models, leading to therapeutically relevant concentrations in the brain with a long half-life. Sagopilone exhibited significant antitumor activity in both the U373 and U87 models of human glioblastoma, while paclitaxel showed a limited effect in the U373 model. Sagopilone significantly inhibited the growth of tumors from CNS metastasis models (MDA-MB-435 melanoma and patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has free access to the brain. Sagopilone demonstrated significant antitumor activity in orthotopic models of both glioblastoma and CNS metastases compared with paclitaxel or temozolomide, underlining the value of further research evaluating sagopilone in the treatment of brain tumors. Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma.


Molecular mobility of nematic E7 confined to molecular sieves with a low filling degree.
The nematic liquid crystalline mixture E7 was confined with similar filling degrees to molecular sieves with constant composition but different pore diameters (from 2.8 to 6.8 nm). Fourier transform infrared analysis proved that the E7 molecules interact via the cyanogroup with the pore walls of the molecular sieves. The molecular dynamics of the system was investigated by broadband dielectric spectroscopy (10(-2)-10(9) Hz) covering a wide temperature range of approximately 200 K from temperatures well above the isotropic-nematic transition down to the glass transition of bulk E7. A variety of relaxation processes is observed including two modes that are located close to the bulk behavior in its temperature dependence. For all confined samples, two relaxation processes, at frequencies lower than the processes observed for the bulk, were detected. At lower temperatures, their relaxation rates have different temperature dependencies whereas at higher temperatures, they seem to collapse into one chart. The temperature dependence of the slowest process (S-process) obeys the Vogel-Fulcher-Tammann law indicating a glassy dynamics of the E7 molecules anchored to the pore surface. The pore size dependence of both the Vogel temperature and fragility revealed a steplike transition around 4 nm pore size, which indicates a transition from a strong to a fragile behavior. The process with a relaxation rate in between the bulklike and the S-process (I-process) shows no dependence on the pore size. The agreement of the I-process with the behavior of a 5CB surface layer adsorbed on nonporous silica leads to the assignment of E7 molecules anchored at the outer surface of the microcrystals of the molecular sieves.


Stabilization of transmittance fluctuations caused by beam wandering in continuous-variable quantum communication over free-space atmospheric channels.
Transmittance fluctuations in turbulent atmospheric channels result in quadrature excess noise which limits applicability of continuous-variable quantum communication. Such fluctuations are commonly caused by beam wandering around the receiving aperture. We study the possibility to stabilize the fluctuations by expanding the beam, and test this channel stabilization in regard of continuous-variable entanglement sharing and quantum key distribution. We perform transmittance measurements of a real free-space atmospheric channel for different beam widths and show that the beam expansion reduces the fluctuations of the channel transmittance by the cost of an increased overall loss. We also theoretically study the possibility to share an entangled state or to establish secure quantum key distribution over the turbulent atmospheric channels with varying beam widths. We show the positive effect of channel stabilization by beam expansion on continuous-variable quantum communication as well as the necessity to optimize the method in order to maximize the secret key rate or the amount of shared entanglement. Being autonomous and not requiring adaptive control of the source and detectors based on characterization of beam wandering, the method of beam expansion can be also combined with other methods aiming at stabilizing the fluctuating free-space atmospheric channels.


Water quality guidance for protection of freshwater mussels (Unionidae) from ammonia exposure.
Ammonia toxicity data for freshwater mussels (Unionidae), a significantly imperiled taxa, were used to derive estimates of concentrations that would not likely be harmful in acute and chronic exposures and to assess the protectiveness of current U.S. Environmental Protection Agency (U.S. EPA) water quality criteria to this family of organisms. Thirty acute (24-96-h) median lethal concentrations (LC50s), covering 10 species in eight unionid genera, were used to calculate genus mean acute values (GMAVs) ranging from 2.56 to 8.97 mg/L total ammonia as N at pH 8. Freshwater mussels are at the sensitive end of the range when added to the GMAVs from the database used to derive the U.S. EPA criteria maximum concentration (CMC). We derived two estimates of acute exposure water quality guidance for the protection of freshwater mussels (CMC(FM)) by a recalculation of the CMC after adding freshwater mussel GMAVs to the U.S. EPA data set. The CMC(FM)s of 1.75 and 2.50 mg/L total ammonia as N at pH 8 average 60% less than the U.S. EPA CMC of 5.62 mg/L total ammonia as N at pH 8 for application when salmonids are present. These values average about 75% less than the CMC for application when salmonids are absent. No chronic ammonia exposure data existed for unionids. Thus, we applied a range of estimated acute:chronic ratios to the acute toxicity data set, expanded with the freshwater mussel GMAVs. to estimate continuous ammonia concentrations that may be protective of freshwater mussels. These estimates ranged from 0.3 to 1.0 mg/L total ammonia as N at pH 8, about 20 to 75% less than the U.S. EPA criteria continuous concentration (CCC) of 1.24 mg/L total ammonia as N at pH 8 and 25 degrees C. The current numeric criteria for ammonia may not be protective of mussels, more than half of whose nearly 300 species are in decline in North America. While the CMC(FM) and CCC(FM) are not equivalent to revised U.S. EPA criteria, they are offered as interim guidance for the protection of freshwater mussels.


Recognition of RNA by the p53 tumor suppressor protein in the yeast three-hybrid system.
The p53 tumor suppressor protein is a homotetrameric transcription factor whose gene is mutated in nearly half of all human cancers. In an unrelated screen of RNA/protein interactions using the yeast three-hybrid system, we inadvertently detected p53 interactions with several different RNAs. A literature review revealed previous reports of both sequence-specific and -non-specific interactions between p53 and RNA. Using yeast three-hybrid selections to identify preferred RNA partners for p53, we failed to identify primary RNA sequences or obvious secondary structures required for p53 binding. The cationic p53 C-terminus was shown to be required for RNA binding in yeast. We show that while p53 strongly discriminates between certain RNAs in the yeast three-hybrid assay, the same RNAs are bound equally by p53 in vitro. We further show that the p53 RNA-binding preferences in yeast are mirrored almost exactly by a recombinant tetrameric form of the HIV-1 nucleocapsid (NC) protein thought to be a sequence-nonspecific RNA-binding protein. However, the possibility of specific RNA binding by p53 could not be ruled out because p53 and HIV-1 NC displayed certain differences in RNA-binding preference. We conclude that (1) p53 binds RNA in vivo, (2) RNA binding by p53 is largely sequence-nonspecific in the yeast nucleus, (3) some structure-specific RNA binding by p53 cannot be ruled out, and (4) caution is required when interpreting results of RNA screens in the yeast three-hybrid system because sequence-dependent differences in RNA folding and display can masquerade as sequence-dependent differences in protein recognition.


Synthesis, biological activity, and conformational analysis of CD-ring modified trans-decalin 1 alpha,25-dihydroxyvitamin D analogs.
A novel series of analogs of 1,25-dihydroxyvitamin D3, the hormonally active metabolite of vitamin D3, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study.


Context-dependent associations of the ACE I/D polymorphism with blood pressure.
The objective of the present study was to assess whether the influences of gender, age, or measures of body size on blood pressure are homogeneous among genotypes of the insertion/deletion (I/D) polymorphism of the gene that codes for angiotensin-converting enzyme (ACE). We studied a sample of 1875 non-Hispanic white individuals (988 female and 887 male subjects) between 5 and 90 years of age from the general population of Rochester, Minn. When statistical interactions between effects associated with the I/D polymorphism and age, height, and weight were not considered, there was no evidence of a significant relationship between variation in blood pressure level or diagnostic category (hypertension versus normotension) and variation in ACE genotype in either gender. However, in females 5 to 29.9 years of age, the linear regression relationships of systolic blood pressure level with age and weight and of diastolic blood pressure level with age were significantly heterogeneous among ACE genotypes. For these concomitant traits, the rank order of expected blood pressure levels associated with each genotype reversed from low values of the concomitant, in which blood pressure was lower for I/D heterozygotes than for II or DD homozygous, to high levels of the concomitant, in which blood pressure was higher for I/D heterozygotes than for II or DD homozygotes. In male subjects 50 to 90 years of age, the logistic regression relationship of the probability of having hypertension with height was also heterogeneous among ACE genotypes; it was statistically significant in II homozygotes but not statistically significant in either I/D heterozygotes or DD homozygotes. Findings of this study are consistent with the conclusion that the influence of variation in the ACE gene on interindividual variation in blood pressure is dependent on contexts that are indexed by gender, age, and measures of body size.


Identification of Essential Residues for Ciprofloxacin Resistance of Ciprofloxacin-Modifying Enzyme (CrpP) of pUM505.
The ciprofloxacin-resistance crpP gene, encoded by the pUM505 plasmid, isolated from a P. aeruginosa clinical isolate, confers an enzymatic mechanism of antibiotic phosphorylation, which is ATP-dependent, that decreases ciprofloxacin susceptibility. Homologous crpP genes are distributed across extended spectrum beta-lactamase (ESBL)-producing isolates obtained from Mexican hospitals and which confer decreased susceptibility to CIP. The analysis of sequences of the CrpP of proteins showed that the residues Gly7, Thr8, Asp9, Lys33 and Gly34 (located at the N-terminal region) and Cys40 (located at the C-terminal region) are conserved in all proteins, suggesting that these residues could be essential for CrpP function. The aim of this study was to investigate the amino acids essential to ciprofloxacin resistance, which is conferred by the CrpP protein of pUM505 plasmid. Mutations in the codons encoding Gly7, Asp9, Lys33 and Cys40 of CrpP protein from pUM505 were generated by PCR fusion. The results showed that all mutations generated in CrpP proteins increased ciprofloxacin susceptibility in Escherichia coli. In addition, the CrpP modified proteins were purified and their enzymatic activity on ciprofloxacin was assayed, showing that these modified proteins do not exert catalytic activity on ciprofloxacin. Moreover, by infrared assays it was determined that the modified proteins were are not able to modify the ciprofloxacin molecule. Our findings are the first report that indicate that the amino acids, namely Gly7, Asp9, Lys33 and Cys40, which are conserved in the CrpP proteins, possess an essential role for the enzymatic mechanism that confers ciprofloxacin resistance.


The experience of discharge for patients with an acquired brain injury from the inpatient to the community setting: A qualitative review.
Discharge planning for patients with an acquired brain injury (ABI) is considered best practice for assisting the patient and caregiver to successfully transition from hospital to home and is complex because of the long-term care and support needs of the patient. This review aimed to describe and synthesize the perspectives of patients with ABI and their family/caregivers on the transition from hospital to home to better understand opportunities to optimize the process. Electronic medical databases (n = 5) and grey literature published between January-May 2015 were searched to identify qualitative studies on the experience of transition from the hospital to home setting following ABI. Relevant studies were appraised and narratively synthesized. Nine eligible studies that met the inclusion criteria were identified. Two major themes were identified-Engagement and Support. Three underlying sub-themes-poor communication, limited participation and disorganized arrangements for support services-were identified as key contributors to an unsatisfactory experience for patients and their family/caregivers. The transition for patients with an ABI and their family/caregivers was characterized as fragmented and unsatisfactory for supporting a successful return home. This review highlights the importance of tailored education and involvement of the patient and their family/caregiver to increase readiness for returning home and reduce unplanned re-admissions.


Closely Related Vibrio alginolyticus Strains Encode an Identical Repertoire of Caudovirales-Like Regions and Filamentous Phages.
Many filamentous vibriophages encode virulence genes that lead to the emergence of pathogenic bacteria. Most genomes of filamentous vibriophages characterized up until today were isolated from human pathogens. Despite genome-based predictions that environmental Vibrios also contain filamentous phages that contribute to bacterial virulence, empirical evidence is scarce. This study aimed to characterize the bacteriophages of a marine pathogen, Vibrio alginolyticus (Kiel-alginolyticus ecotype) and to determine their role in bacterial virulence. To do so, we sequenced the phage-containing supernatant of eight different V. alginolyticus strains, characterized the phages therein and performed infection experiments on juvenile pipefish to assess their contribution to bacterial virulence. We were able to identify two actively replicating filamentous phages. Unique to this study was that all eight bacteria of the Kiel-alginolyticus ecotype have identical bacteriophages, supporting our previously established theory of a clonal expansion of the Kiel-alginolyticus ecotype. We further found that in one of the two filamentous phages, two phage-morphogenesis proteins (Zot and Ace) share high sequence similarity with putative toxins encoded on the Vibrio cholerae phage CTXΦ. The coverage of this filamentous phage correlated positively with virulence (measured in controlled infection experiments on the eukaryotic host), suggesting that this phage contributes to bacterial virulence.


Cognitive function in breast cancer patients receiving adjuvant chemotherapy.
Breast cancer patients receiving chemotherapy have complained of difficulties in their ability to remember, think, and concentrate. This study assessed whether there are differences in cognitive function between breast cancer patients treated with standard-dose adjuvant chemotherapy compared with healthy controls. The High Sensitivity Cognitive Screen and the Profile of Mood States (POMS) were used to assess cognitive function and mood in a group of 107 women. The women consisted of 31 breast cancer patients receiving adjuvant chemotherapy (group A), 40 breast cancer patients who had completed adjuvant chemotherapy a median of 2 years earlier (group B), and 36 healthy controls (group C). Univariate analysis showed statistically significant differences (P =.009) in overall cognitive function scores between groups A and C, with poorer function in patients receiving adjuvant chemotherapy. These differences remained significant (P =.046) when controlling for age, education level, and menopausal status. More patients had moderate or severe cognitive impairment in groups A and B than in controls (P </=.002). There were no significant differences in POMS scores between the groups, suggesting that the differences seen in cognitive scores were unlikely to be because of mood disturbance. Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls. These differences did not seem to be caused by significant differences in mood disturbance between the two groups. If confirmed, these results have substantial implications for informed consent, counseling, and psychosocial support of patients receiving adjuvant chemotherapy for breast cancer.


Governance and Sustainability of an Open Source Electronic Health Record: An Interpretive Case Study of OpenDolphin in Japan.
Electronic Health Records (EHRs) are at the heart of reforms aiming for improving the efficiency and quality of citizens healthcare services. Although there is still some skepticism, open source (OS) EHR is a growing phenomenon in health informatics. Given the widespread adoption of OS software (OSS) in several domains, including operating systems, and enterprise systems, the repeated shortfalls faced by healthcare organizations with dominant proprietary EHRs create an opportunity for other alternatives, such as OSS to demonstrate their abilities in addressing these well-documented problems, including inflexibility, high costs, and low interoperability. However, scholars have expressed extensive concerns about the sustainability of OS EHR. Recognizing that OSS project sustainability relies on their governance arrangements, this case study reports on the evolution of the governance and sustainability of a Japanese OS EHR project and provides rich insights to other open source EHR initiative stakeholders, including physicians, developers, researchers, and policymakers.


Plasma cytokine levels predict mortality in patients with acute renal failure.
Critically ill patients with acute renal failure (ARF) experience a high mortality rate. Animal and human studies suggest that proinflammatory cytokines lead to the development of a systemic inflammatory response syndrome (SIRS), which is temporally followed by a counter anti-inflammatory response syndrome (CARS). This process has not been specifically described in critically ill patients with ARF. The Program to Improve Care in Acute Renal Disease (PICARD) is a prospective, multicenter cohort study designed to examine the natural history, practice patterns, and outcomes of treatment in critically ill patients with ARF. In a subset of 98 patients with ARF, we measured plasma proinflammatory cytokines [interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha)], the acute-phase reactant C-reactive protein (CRP), and the anti-inflammatory cytokine IL-10 at study enrollment and over the course of illness. When compared with healthy subjects and end-stage renal disease patients on maintenance hemodialysis, patients with ARF had significantly higher plasma levels of all measured cytokines. Additionally, the proinflammatory cytokines IL-6 and IL-8 were significantly higher in nonsurvivors versus survivors [median 234.7 (interdecile range 64.8 to 1775.9) pg/mL vs. 113.5 (46.1 to 419.3) pg/mL, P= 0.02 for IL-6; 35.5 (14.1 to 237.9) pg/mL vs. 21.2 (8.5 to 87.1) pg/mL, P= 0.03 for IL-8]. The anti-inflammatory cytokine IL-10 was also significantly higher in nonsurvivors [3.1 (0.5 to 41.9) pg/mL vs. 2.4 (0.5 to 16.9) pg/mL, P= 0.04]. For each natural log unit increase in the levels of IL-6, IL-8, and IL-10, the odds of death increased by 65%, 54%, and 34%, respectively, corresponding to increases in relative risk of approximately 30%, 25%, and 15%. The presence or absence of SIRS or sepsis was not a major determinant of plasma cytokine concentration in this group of patients. There is evidence of ongoing SIRS with concomitant CARS in critically ill patients with ARF, with higher levels of plasma IL-6, IL-8, and IL-10 in patients with ARF who die during hospitalization. Strategies to modulate inflammation must take into account the complex cytokine biology in patients with established ARF.


[Myasthenia gravis with the electrographic response of a myasthenic syndrome. Report of a case].
It is reported a case of a 61 years-old man with progressive asthenia, disfagia, disphonia and diplopia, of variable intensity during the day, who had a very good response to anticolinesterasic drugs and corticosteroids. The repetitive stimulation tests at low frequency, resulted in large increment (maximum 275%) of the basal voltage after exercise. At high frequency he also had a large increment. Radiological and laboratory investigation three times in a seven-year period was normal, without evidence of any neoplasia. Muscle biopsy showed a type II muscle fiber atrophy. The repetitive stimulation tests repeated three times, was typical of myasthenia gravis in one occasion and in the other two, typical of myasthenic syndrome (increment of 418%). A discussion about other cases with similar findings is made after a review of the literature.


Quantitation of 7-ethylguanine in leukocyte DNA from smokers and nonsmokers by liquid chromatography-nanoelectrospray-high resolution tandem mass spectrometry.
There is considerable evidence for the exposure of humans to an unknown ethylating agent, and some studies indicate that cigarette smoking may be one source of this exposure. Therefore, we have developed a liquid chromatography-nanoelectrospray-high resolution tandem mass spectrometry-selected reaction monitoring (LC-NSI-HRMS/MS-SRM) method for the analysis of 7-ethyl-Gua in human leukocyte DNA, a readily available source of DNA. [(15)N(5)]7-Ethyl-Gua was used as the internal standard. Leukocyte DNA was isolated and treated by thermal neutral hydrolysis. The hydrolysate was partially purified by solid-phase extraction. The fraction containing 7-ethyl-Gua was analyzed by LC-NSI-HRMS/MS-SRM using the transition m/z 180 [M + H](+)→ m/z 152.05669 [Gua + H](+) for 7-ethyl-Gua and m/z 185 → m/z 157.04187 for the internal standard. The detection limit was approximately 10 amol on column, while the limit of quantitation was about 8 fmol/μmol Gua starting with 180 μg DNA (corresponding to 36 μg DNA on-column). Leukocyte DNA samples from 30 smokers and 30 nonsmokers were analyzed. Clear peaks for 7-ethyl-Gua and the internal standard were observed in most of the samples. The mean (±SD) level of 7-ethyl-Gua measured in leukocyte DNA from smokers was 49.6 ± 43.3 (range 14.6-181) fmol/μmol Gua, while that from nonsmokers was 41.3 ± 34.9 (range 9.64-157) fmol/μmol Gua. Although a significant difference between smokers and nonsmokers was not observed, the method described here is unique in the use of high resolution mass spectrometry and establishes for the first time the presence of 7-ethyl-Gua in human leukocyte DNA.


Mrs Isabella Elder, LL.D., pioneer and philanthropist.
Mrs Isabella Elder contributed much during her lifetime to further the education of women of all ages and of all levels of attainment. She gifted North Park House to Queen Margaret College in Glasgow as a home in 1884. With her encouragement a medical school for women in Glasgow was opened in Queen Margaret College in 1890. The standard was high and when women were admitted to the Universities in 1892, the first Queen Margaret medical students were able to graduate in 1894. She pioneered a system of teaching home economics in Govan, assisted the development of a district nursing service and built the Elder Cottage Hospital.


Efficacy and safety of biological agents in the treatment of patients with Takayasu arteritis: a systematic review and meta-analysis.
We aimed to systematically review biological agents' efficacy and safety in patients with Takayasu arteritis (TAK). A systematic literature search of 7 electronic databases, including MEDLINE (via PubMed), EMBASE, Elsevier ScienceDirect, EBSCO, Springer Link, Web of Science, and Cochrane Library on the efficacy of biological agents on patients with TAK was conducted. Only studies published in English and with a sample size >5 patients with TAK were included. Two reviewers independently selected studies, extracted data and assessed its methodological quality. Random effects meta-analyses of various effect measures were performed. According to the title and abstract, 961 studies were identified and screened. Subsequently, 31 studies from 29 observational studies and 2 randomized-controlled trials (RCTs), which included a total of 517 patients with TAK that met the inclusion and exclusion criteria, were selected. Observational studies showed a high risk of bias. Pooled remission rates of biological agents were 66% (95% CI: 58%-73%; I2=59%), and the remission rates of anti-tumor necrosis factor (TNF) agents and tocilizumab (TCZ) were similar: 65% (95% CI: 56%-73%; I2=49%) and 70% (95% CI: 55%-86%; I2=69%), respectively. Pooled relapse rates were 23% (95% CI: 15%-31%; I2=66%). The relapse rate was 28% (95% CI: 16%-40%; I2=68%) for anti-TNF agents and 17% (95% CI: 7%-26%; I2=49%) for TCZ. The remission rate of TCZ was slightly higher (p>0.05), but the relapse rate was statistically significantly lower than that of anti-TNF agents (p=0.017). Furthermore, biological agents significantly decreased the doses of glucocorticoid (GC) and levels of acute phase inflammation markers (ESR, CRP) while the proportion of patients with new angiographic lesions or progression of previously noted lesions were 11% (95% CI: 4%-18%; I2=59%). RCTs with a small sample size showed abatacept was ineffective, and TCZ was underpowered to detect a difference in time to relapse compared to placebo. The most common adverse event of biological agents was infection (6%, 95%CI: 2%-10%). No deaths were reported. Although the beneficial effects of biological agents are encouraging in enhancing disease remission, reducing the levels of acute phase inflammation markers and decreasing the treatment doses of GC in patients with TAK, there is still a risk of relapse. More refined studies with larger cohorts are necessary before drawing a definitive opinion.


The representation of self reported affect in body posture and body posture simulation.
It is taken for granted that the non-verbal information we acquire from a person's body posture and position affects our perception of others. However, to date human postures have never been described on an empirical level. This study is the first approach to tackle the unexplored topic of human postures. We combined two approaches: traditional behavior observation and modern anthropometric analysis. Photographs of 100 participants were taken, their body postures were transferred to a three dimensional virtual environment and the occurring body angles were measured. The participants were asked to fill in a questionnaire about their current affective state. A principal component analysis with the items of the affect questionnaire (Positive Negative Affect Scales, PANAS) revealed five main factors: aversion, openness, irritation, happiness, and self-confidence. The body angles were then regressed on these factors and the respective postures were reconstructed within a virtual environment. 50 different subjects rated the reconstructed postures from the positive and negative end of the regression. We found the ratings to be valid and accurate in respect to the five factors.


Implementing an outreaching, preference-led stepped care intervention programme to reduce late life depressive symptoms: results of a mixed-methods study.
Depressive symptoms are highly prevalent in old age, but they remain mostly untreated. Several clinical trials have shown promising results in preventing or reducing depressive symptoms. However, it is not clear how robust these effects are in the real world of day-to-day care. Therefore, we have implemented the 'Lust for Life' programme, which significantly reduced depressive symptoms in community-dwelling older adults in the first three months after implementation. This mixed-methods study was conducted alongside the trial to develop a contextualised understanding of factors affecting the implementation. A total of 263 persons of 65 years and older with depressive symptoms were recruited from 18 general practices and home care organizations in the Netherlands. We used qualitative data (in-depth interviews and focus group discussions with participants with depressive symptoms and healthcare professionals) as well as quantitative data (longitudinal data on the severity of depressive symptoms) to explore hindering and facilitating factors to the implementation of the 'Lust for Life' programme. The uptake of the routine screening was poor and imposed significant burdens on participants and healthcare professionals, and drop-out rates were high. Participants' perceived mental problems and need for care played a key role in their decision to participate in the programme and to step up to consequent interventions. Older people preferred interventions that focused on interpersonal contact. The programme was only effective when delivered by mental healthcare nurses, compared to home care nurses with limited experience in providing mental healthcare. The intervention programme was effective in reducing depressive symptoms, and valuable lessons can be learned from this implementation trial. Given the low uptake and high investment, we advise against routine screening for depressive symptoms in general healthcare. Further, agreement between the participant and healthcare professional on perceived need for care and intervention is vital. Rather than providing a stepped care intervention programme, we showed that offering only one single preference-led intervention is effective. Lastly, since the provision of the interventions seems to ask for specific skills and experiences, it might require mental healthcare nurses to offer the programme. Dutch trial register NTR2241.


Spatiotemporal variation of endogenous cell-generated stresses within 3D multicellular spheroids.
Multicellular spheroids serve as an excellent platform to study tissue behavior and tumor growth in a controlled, three-dimensional (3D) environment. While molecular and cellular studies have long used this platform to study cell behavior in 3D, only recently have studies using multicellular spheroids shown an important role for the mechanics of the microenvironment in a wide range of cellular processes, including during tumor progression. Despite the well-established relevance of mechanical cues to cell behavior and the numerous studies on mechanics using 2D cell culture systems, the spatial and temporal variations in endogenous cellular forces within growing multicellular aggregates remain unknown. Using cell-sized oil droplets with controlled physicochemical properties as force transducers in mesenchymal cell aggregates, we show that the magnitude of cell-generated stresses varies only weakly with spatial location within the spherical aggregate, but it increases considerably over time during aggregate compaction and growth. Moreover, our results indicate that the temporal increase in cellular stresses is due to increasing cell pulling forces transmitted via integrin-mediated cell adhesion, consistent with the need for larger intercellular pulling forces to compact cell aggregates.


Mental health service utilization by African Americans and Whites: the Baltimore Epidemiologic Catchment Area Follow-Up.
To compare mental health service utilization and its associated factors between African Americans and whites in the 1980s and 1990s. Household-based longitudinal study with baseline interviews in 1981 and follow-up interviews from 1993 to 1996. The Baltimore Epidemiologic Catchment Area (ECA) Follow-Up. Subjects included 1,662 adults (590 African Americans and 1,072 whites). Use of mental health services, defined as talking to any health professional about emotional or nervous problems or alcohol or drug-related problems within the 6 months preceding each interview. In 1981, crude rates of mental health service use in general medical (GM) settings and specialty mental health settings were similar for African Americans and whites (11.7%). However, after adjustment for predisposing, need, and enabling factors, individuals receiving mental health services were less likely to be African American. Mental health service use increased by 6.5% over follow-up, and African Americans were no longer less likely to report receiving any mental health services in the 1990s. African Americans were more likely than whites to report discussing mental health problems in GM settings without having seen a mental health specialist. They were less likely than whites to report use of specialty mental health services, but this finding was not statistically significant, possibly because of low rates of specialty mental health use by both race groups. Psychiatric distress was the strongest predictor of mental health service use. Attitudes positively associated with use of mental health services were more prevalent among African Americans than whites. Mental health service use increased in the past decade, with the greatest increase among African Americans in GM settings. Although it is possible that the racial disparity in use of specialty mental health services remains, the GM setting may offer a safety net for some mental health concerns of African Americans.


An end-to-end assessment on the accuracy of adaptive radiotherapy in an MR-linac.
To develop and demonstrate an end-to-end assessment procedure for adaptive radiotherapy (ART) within an MR-guided system. A 3D printed pelvic phantom was designed and constructed for use in this study. The phantom was put through the complete radiotherapy treatment chain, with planned internal changes made to model prostate translations and shape changes, allowing an investigation into three ART techniques commonly used. Absolute dosimetry measurements were made within the phantom using both gafchromic film and alanine. Comparisons between treatment planning system (TPS) calculations and measured dose values were made using the gamma evaluation with criteria of 3 mm/3% and 2 mm/2%. Gamma analysis evaluations for each type of treatment plan adaptation investigated showed a very high agreement with pass rates for each experiment ranging from 98.10% to 99.70% and 92.60% to 97.55%, for criteria of 3%/3 mm and 2%/2 mm respectively. These pass rates were consistent for both shape and position changes. Alanine measurements further supported the results, showing an average difference of 1.98% from the TPS. The end-to-end assessment procedure provided demanding challenges for treatment plan adaptations to demonstrate the capabilities and achieved high consistency in all findings.


Lausannevirus, a giant amoebal virus encoding histone doublets.
Large viruses infecting algae or amoebae belong to the NucleoCytoplasmic Large DNA Viruses (NCLDV) and present genotypic and phenotypic characteristics that have raised major interest among microbiologists. Here, we describe a new large virus discovered in Acanthamoeba castellanii co-culture of an environmental sample. The virus, referred to as Lausannevirus, has a very limited host range, infecting Acanthamoeba spp. but being unable to infect other amoebae and mammalian cell lines tested. Within A. castellanii, this icosahedral virus of about 200 nm exhibits a development cycle similar to Mimivirus, with an eclipse phase 2 h post infection and a logarithmic growth leading to amoebal lysis in less than 24 h. The 346 kb Lausannevirus genome presents similarities with the recently described Marseillevirus, sharing 89% of genes, and thus belongs to the same family as confirmed by core gene phylogeny. Interestingly, Lausannevirus and Marseillevirus genomes both encode three proteins with predicted histone folds, including two histone doublets, that present similarities to eukaryotic and archaeal histones. The discovery of Lausannevirus and the analysis of its genome provide some insight in the evolution of these large amoebae-infecting viruses.


Complement Activation in 22q11.2 Deletion Syndrome.
The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.


Interaction between potyvirus helper component-proteinase and capsid protein in infected plants.
Monoclonal antibodies were raised against helper component-proteinase (HcPro) purified from plants infected with the potyvirus Lettuce mosaic virus (LMV). These antibodies were used in a two-site triple antibody sandwich ELISA assay together with polyclonal antibodies directed against purified virions. An interaction between HcPro and the viral coat protein (CP) was demonstrated in extracts of LMV-infected leaves, as well as for two other potyviruses, Plum pox virus and Potato virus Y. The CP-HcPro interaction was not abolished in LMV derivatives with an HcPro GFP N-terminal fusion, or with a deletion from the CP of the amino acids involved in aphid transmission. Electron microscopy indicated that HcPro probably does not interact with the CP in the form of assembled virions or virus-like particles. Together, these results suggest that the interaction detected between CP and HcPro might be involved in a process of the potyvirus cycle different from aphid transmission.


Open repair for infrarenal AAA: technical aspects.
The aim of this study was to describe the technique and report our single center experience of abdominal aortic aneurysm (AAA) open surgical repair over the last 17 years. From 1993 to 2010, a total of 4347 open surgical procedures for repair of AAA were performed in our center. The details of 3857 (88.7%) patients undergoing infrarenal AAA open repair were analyzed; mean age at the time of surgery was 71.8 years ranging from 58 to 89 years. Among all repairs, 23.7% (914) were performed in women and 24.3% (937) in octogenarians; 3587 (93.0%) procedures were performed for degenerative aneurysms, 146 (3.8%) for inflammatory aneurysms, 100 (2.6%) for dissecting aneurysms, and 19 (0.5%) for other pattern of disease. In 162 cases (4.2%) surgery was performed for ruptured aneurysm. In most cases (N.=2596; 67.3%) infrarenal AAA open repair was performed by means of aorto-aortic bypass using a tube graft. A total of 1261 patients were treated using a bifurcated graft: 417 (33.1%) aorto-iliac bypasses, 530 (42.0%) aorto-femoral bypasses and 314 (24.9%) aorto-iliac-femoral bypasses were performed. In elective aorto-aortic bypass, mean aortic clamping time was 21.3+6.7 minutes. The average duration of the procedure was 126+84 minutes (range, 42-410 minutes). Mean intraoperative bleeding was 803.4+422.7 mL (range 250-3,100). Overall intraoperative mortality was 0.2%. Intraoperative mesenteric ischemia was observed in 3% of cases, all treated with inferior mesenteric artery reimplantation. The rate of intraoperative lower limbs ischemia was 2.2%. One intraoperative acute type A aortic dissection occurred. The overall 30-day mortality was 0.6%. Permanent renal function impairment occurred in 4.3% of cases. The rate of pulmonary complications was 9.8%. Other complications were myocardial infarction, congestive heart failure, late ischemic colitis, late leg ischemia, wound infection, urinary tract infection, and sepsis. Although endovascular techniques have emerged as a less invasive alternative to open repair, short- and long-term outcomes associated to the surgery of infrarenal AAAs remain satisfactory for a large range of patients.


[Organ cytotoxicity of selected polycyclic aromatic hydrocarbons in mice].
The cytotoxic effects of some PAHs: DMBA, 3-MC and B(a)P on the lymphatic organs, liver and kidney of mice have been investigated. These PAHs in doses of 100 mg/kg were dissolved in 0.5 ml 20% DMSO and were given intraperitoneally in female mice Balb/c. After 7 days, organs weight, cellularity in lymphoid organs and tissue structure of liver and kidney were analyzed. The greatest effect of DMBA was observed on cellularity of spleen. 3-MC and B(a)P caused significant hepatotoxic and nephrotoxic changes. 3-MC induced focal destruction of hepatocytes and sometimes--irregular mitotic figures (c-mitosis). After B(a)P administration in liver cells were mainly observed the changes in distribution of interphase nucleolar organizer region (AgNOR). In kidney--irregular glomeruli and tubuli after 3-MC and B(a)P were noted. The above results may indicate that the cytotoxic effects of PAHs depend on the type of compound administered.


Behavioral and neurochemical components of nicotine sensitization following 15-day pretreatment: studies on contextual conditioning.
The effects of contextual conditioning on the induction of nicotine sensitization of locomotor activity, stereotypy and nucleus accumbens dopamine release were studied using a 15-day pretreatment regimen. Six groups of Sprague-Dawley rats were employed to test for the effects of drug pretreatment, conditioning and novelty. Groups 1-4 were treated with daily nicotine (0.6 mg/kg, s.c.) or saline injections that were either paired with the test chamber or given in the home cage, followed by saline injections in the home cage. Group 5 received saline in the test chamber followed by nicotine in the home cage (unpaired). Group 6 was naive to handling and drug treatment. Pretreated animals were implanted with 2 mm microdialysis probes, via chronic guide cannulae, after completing the 15th day of treatment, and were tested for their response to nicotine (0.6 mg/kg, s.c) or saline on day 16. Naive animals were implanted with microdialysis probes and tested in a similar manner. Nicotine-stimulated locomotor activity was sensitized in the paired, unpaired and homecage pretreatment groups whereas nicotine-stimulated stereotypy was sensitized only in the paired pretreatment group. Nicotine-stimulated nucleus accumbens dopamine release was sensitized in the paired and unpaired pretreatment groups. Saline-stimulated nucleus accumbens dopamine release, but not locomotor activity or stereotypy, was also found in the nicotine-pretreated, paired group. These findings demonstrate the development of sensitization to nicotine-induced locomotor activity, stereotypy and nucleus accumbens dopamine release after a 15-day pretreatment regimen. Each of these responses to nicotine were differentially modulated by contextual conditioning. It is suggested that nicotine-stimulated dopamine release in sensitized animals represents the conditioned component of nicotine sensitization.


Tinnitus and vestibular schwannoma surgery.
The aim of this study was to evaluate the effect of operation on tinnitus in vestibular schwannoma (VS) patients. Altogether, 251 VS patients who underwent surgery during the years 1979 to 1993 at Helsinki University Central Hospital were included in the study. Information on preoperative tinnitus was collected from previously acquired data and postoperative tinnitus was evaluated. Preoperatively, 62.6% of the patients had experienced tinnitus. Of those with preoperative tinnitus, 47.4% also had it postoperatively, but of those 93 patients without preoperative tinnitus, 39.8% had tinnitus postoperatively. Tinnitus is one of the primary symptoms of VS, together with hearing impairment and disequilibrium. The risk of postoperative tinnitus is almost 40%, and with preoperative tinnitus, the risk is 7.6% higher. In the majority tinnitus was not related to the surgery. Only a few patients had severe problems with tinnitus; difficulty understanding speech was the major complaint.


Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza, and other community-acquired pneumonia.
The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by a general lack of relevant disease controls. The scarcity of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in peripheral blood mononuclear cells from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach, we describe shared and diverging transcriptional and phenotypic patterns-including increased levels of type I interferon-stimulated natural killer cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups-and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.


Impact of fatty acid status on growth and neurobehavioural development in humans.
Many studies have been conducted to investigate the effect of n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during the perinatal period on the growth and neurobehavioural development of young children. Most of these intervention trials have involved infants from high-income countries, and a significant proportion have investigated supplementation of infant formulas. Generally, supplementation of infant formula for preterm rather than term infants has demonstrated more consistent, positive effects on aspects of neurobehavioural development, while the growth of both term and preterm infants appears unaffected by LCPUFA supplementation. Maternal n-3 LCPUFA supplementation during pregnancy has consistently resulted in modest increases in birth size, and the most recent study suggests that this is also true from women from low-income environments. The effect of maternal supplementation on global neurobehavioural outcomes for children born at term remains unclear, although n-3 LCPUFA supplementation of women expressing milk for their preterm infants does improve their performance on tests of global neurodevelopment. Further work is required to determine whether dietary n-3 LCPUFA is neuroprotective for children from disadvantaged or low-income backgrounds.


A nigra-subthalamic circuit is involved in acute and chronic pain states.
The basal ganglia modulate somatosensory pain pathways, but it is unclear whether a common circuit exists to mitigate hyperalgesia in pain states induced by peripheral nociceptive stimuli. As a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) may be a candidate for this role. To test this possibility, we optogenetically modulated SNr GABAergic neurons and examined pain thresholds in freely behaving male mice in inflammatory and neuropathic pain states as well as comorbid depression in chronic pain. We observed that stimulation of either SNr GABAergic neurons or their projections to the subthalamic nucleus (STN) significantly alleviated nociceptive responses in all pain states on the contralateral side and comorbid depression in chronic pain, and that this analgesic effect was eliminated when SNr-STN GABAergic projection was blocked. However, SNr modulation did not affect baseline pain thresholds. We also found that SNr-STN GABAergic projection was attenuated in pain states, resulting in disinhibition of STN neurons. Thus, impairment of the SNr-STN GABAergic circuit may be a common pathophysiology for the maintenance of hyperalgesia in both inflammatory and neuropathic pain states and the comorbid depression in chronic pain; compensating this circuit has potential to effectively treat pain related conditions.


[The factors determining the efficacy of the rehabilitative treatment of patients who have had a myocardial infarct].
Factors responsible for the efficacy of rehabilitative treatment of patients with a history of myocardial infarction were defined on the basis of the 2-year follow-up of 235 patients who suffered myocardial infarction, bicycle ergometry data, studies into intracardiac hemodynamics, oxygen supply in exercise tests, and criteria for the significance of the tetrachoric indicator with regard to the confidence limits. In patients who suffered uncomplicated myocardial infarction, prediction of the decreased work fitness in the long-term period is determined by the presence of angina pectoris and arterial hypertension. It has been established that whether will be lowered in future can be judged from the changes seen in the magnitude of the liminal power and the end diastolic volume of the left ventricle during the first 6 months following myocardial infarction.


During lytic infection herpes simplex virus type 1 is associated with histones bearing modifications that correlate with active transcription.
Herpes simplex virus type 1 (HSV-1) is a large (150-kb) double-stranded DNA virus that forms latent infections in neuronal cells of the human peripheral nervous system. Previous work determined that the HSV-1 genome is found in an ordered nucleosomal structure during latent infection. However, during lytic infection, it was unclear whether viral DNA was in a chromatin state. We examined HSV-1 during lytic infection using micrococcal nuclease digestion and chromatin immunoprecipitation. The HSV-1 genome is at least partially nucleosomal, although apparently not in a regular repeating structure. Analysis of histones associated with HSV-1, within both the promoter and the transcribed regions, revealed covalent amino tail modifications similar to those associated with active host mammalian genes. Certain of the modifications were detected in the temporal order expected of the immediate-early, early, and late gene classes. These data suggest that productive infection may be accompanied by acquisition of a permissive chromatin state.


Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor.
Glucocorticoid (GC) receptors (GRs) have profound anti-survival effects on human small cell lung cancer (SCLC). To explore the basis of these effects, protein partners for GRs were sought using a yeast two-hybrid screen. We discovered a novel gene, FAM33A, subsequently identified as a SKA1 partner and involved in mitosis, and so renamed Ska2. We produced an anti-peptide antibody that specifically recognized full-length human SKA2 to measure expression in human cell lines and tissues. There was a wide variation in expression across multiple cell lines, but none was detected in the liver cell line HepG2. A xenograft model of human SCLC had intense staining and archival tissue revealed SKA2 in several human lung and breast tumours. SKA2 was found in the cytoplasm, where it co-localized with GR, but nuclear expression of SKA2 was seen in breast tumours. SKA2 overexpression increased GC transactivation in HepG2 cells while SKA2 knockdown in A549 human lung epithelial cells decreased transactivation and prevented dexamethasone inhibition of proliferation. GC treatment decreased SKA2 protein levels in A549 cells, as did Staurosporine, phorbol ester and trichostatin A; all agents that inhibit cell proliferation. Overexpression of SKA2 potentiated the proliferative response to IGF-I exposure, and knockdown with shRNA caused cells to arrest in mitosis. SKA2 has recently been identified in HeLa S3 cells as part of a complex, which is critical for spindle checkpoint silencing and exit from mitosis. Our new data show involvement in cell proliferation and GC signalling, with implications for understanding how GCs impact on cell fate.


Biochemical background and compartmentalized functions of cytosolic glutamine synthetase for active ammonium assimilation in rice roots.
Rice plants in paddy fields prefer to utilize ammonium as a major nitrogen source. Glutamine synthetase (GS) serves for assimilation of ammonium in rice root, and ameliorates the toxic effect of ammonium excess. Among the three isoenzymes of the cytosolic GS1 gene family in rice, OsGLN1;1 and OsGLN1;2 were abundantly expressed in roots. Analysis of the purified enzymes showed that OsGLN1;1 and OsGLN1;2 can be classified into high-affinity subtypes with relatively high V(max) values, as compared with the major high-affinity isoenzyme, GLN1;1, in Arabidopsis. Low-affinity forms of GS1 comparable to those in Arabidopsis (GLN1;2 and GLN1;3) were absent in rice roots. The OsGLN1;1 and OsGLN1;2 transcripts showed reciprocal responses to ammonium supply in the surface cell layers of roots. OsGLN1;1 accumulated in dermatogen, epidermis and exodermis under nitrogen-limited condition. By contrast, OsGLN1;2 was abundantly expressed in the same cell layers under nitrogen-sufficient conditions, replenishing the loss of OsGLN1;1 following ammonium treatment. Within the central cylinder of elongating zone, OsGLN1;1 and OsGLN1;2 were both induced by ammonium, which was distinguishable from the response observed in the surface cell layers. The high-capacity Gln synthetic activities of OsGLN1;1 and OsGLN1;2 facilitate active ammonium assimilation in specific cell types in rice roots.


The nature of "spots" on soft lenses.
Of 278 consecutive therapeutic soft lens wearers, 19 (6.8%) developed discrete lens opacities on the anterior (air) surface of the lens. The incidence rose to 16.6% in patients fitted for dry eye syndromes, to 19% in bullous keratopathy and to 20% in exposure keratitis and trichiasis, if worn for longer than 2 weeks. These opacities were not associated with medications. Scanning electron microscopy demonstrated cracks on the anterior lens surface associated with these opacities. Transmission electron microscopy demonstrated the opacities to be amorphous material with extensions of the contact lens polymer into the substance of these opacities. Lipid, as demonstrated by histochemical methods, was found in these opacities. It is likely that the combination of dryness, stress on the lens surface, and lipid deposition act to alter the structure of the plastic and cause these opacities.


Frontoethmoidal encephalomeningocele: new morphological findings and a new classification.
Given a lack of a comprehensive classification for the frontoethmoidal encephalomeningocele (FEEM), clinical, photographic, and computed tomography (CT) data of 23 nonoperated patients were reviewed. Extracranial pathological findings of interest included herniation masses, facial deformities, and frontonasal bone morphology. Intracranial pathological findings of interest included morphology of the anterior cranial floor and brain malformations. Stereographic software processed data from a new-generation CT scanner into three-dimensional pictures that revealed some interesting morphological findings not often appreciated (eg, herniation mass without underlying external bone defect; mass at location far from external bone defect ["sequestrated cephalocele"]; new type of external bone defect characterized by a combination of nasoethmoidal and naso-orbital defects; correlation between mass, external bone defect, and exit pathway of herniation). Given these observations plus current knowledge available in the medical literature, a new classification system was developed that covers phenotypes and severity of the disease. The "FEEM classification" is an alphanumeric system based on facial deformities, external bone defect, exit pathway of herniation, and malformation of brain. It was tested in 42 patients for usability and validity. When combined with a newly designed "FEEM diagram," relevant pathological findings can be recorded in an objective manner so that diagnosis becomes more precise and uniform and comparison of outcome is possible. It also emphasizes the fact that FEEM has a range of manifestations governed by dynamic interaction between structural defects and herniation. Each clinical entity is a final result of its own disease course (stable, progressive, or regressive FEEM), with a varying degree of communication between the external mass and the central nervous system.


Incidence of trapezius myofascial trigger points in patients with the possible carpal tunnel syndrome.
Patients with carpal tunnel syndrome (CTS) often complain of prominent pain in shoulder and arm, also there are patients that have pain in their shoulder and arm which is due to myofascial trigger point (MTP) located in their upper trapezius muscle. Despite the frequency of this observation, few studies have previously sought to establish possible relationship between the CTS and MTP in shoulder area. Samples were 160 patients (221 hands) consist of 130 females and 30 males, with suspected diagnosis of CTS, from March 2008 to October 2008. In this study after performing electrodiagnosis searches, another evaluation was performed to find out if there was any sign of myofascial trigger point. The correlation between these two was sought. It was found that all of 36 hands with normal electrodiagnostic findings had myofascial trigger points in their upper trapezius muscle. Out of 185 hands, 130 hands (70%) with electrophysiological evidences of CTS showed myofascial trigger points in their trapezius muscles. Statistical analysis revealed significant (p < 0.001) reverse correlation between the severity of CTS and the presence of MTP. The findings of this study imply the significant correlation between occurrence of CTS and MTP. It is suggested that clinicians consider the probability of existence of MTP in patients referred for diagnosis of CTS.


Simple Model for Dynamic Heterogeneity in Glass-Forming Liquids.
Liquids near the glass transition exhibit dynamical heterogeneity, i.e., local relaxation rates fluctuate strongly over space and time. Here, we introduce a simple continuum model that allows for quantitative predictions for the correlators describing these fluctuations. We find remarkable agreement of the model predictions for the dynamic susceptibility χ_{4}(t) with numerical results for a binary hard-sphere liquid and for a Kob-Andersen Lennard-Jones mixture. Under this model, the lifetime τ_{ex} of the heterogeneities has little effect on the position t=t_{4}∼τ_{α} of the peak of χ_{4}(t), but it controls the decay of χ_{4}(t) after the peak, and we show how to estimate it from this decay.


Shape analysis of odontocete mandibles: functional and evolutionary implications.
Odontocete mandibles serve multiple functions, including feeding and hearing. We consider that these two major functions have their primary influence in different parts of the mandibles: the anterior feeding component and the posterior sound reception component, though these divisions are not mutually exclusive. One hypothesis is that sound enters the hearing apparatus via the pan bone of the posterior mandibles (Norris, Evolution and Environment,1968, pp 297-324). Another viewpoint, based on finite element models, suggests that sound enters primarily through the gular region and the opening created by the absent medial lamina of the posterior mandibles. This unambiguous link between form and function has catalyzed this study, which uses Geometric Morphometrics to quantify mandibular shape across all major lineages of Odontoceti. The majority of shape variation was found in the anterior (feeding) region: Jaw Flare (45.0%) and Symphysis Elongation (35.5%). Shape differences in the mandibular foramen, within the posterior (sound reception) region, also accounted for a small portion of the total variation (10.9%). The mandibles are an integral component of the sound reception apparatus in toothed whales and the geometry of the mandibular foramen likely plays a role in hearing. Furthermore, model goodness-of-fit tests indicate that mandibular foramina shapes, which appear conserved, evolved under a selective regime, possibly driven by sound reception requirements across Odontoceti.


[Impact of the COVID-19 epidemic in Friuli Venezia Giulia Region (Northern Italy): assessment of factors associated with the risk of death by competing risks analysis].
to investigate the role of gender, age, province of residence, and nursing home residency on the risk of death for residents in the Friuli Venezia Giulia (FVG) Region (Northern Italy) tested positive for Covid-19, considering recovery as a competing event. The secondary objective is to describe the impact of the Covid-19 epidemic in FVG and in the Regions of Northern and Central Italy in terms of incidence and mortality compared to the national data. retrospective cohort study. resident population in FVG in the period between 29 February and 25 June 2020. in order to describe the impact of the Covid-19 outbreak in FVG, in terms of incidence and mortality compared to the national data, the standardized incidence (SIR) and mortality (SMR) ratios and their respective 95% confidence intervals (95%CI) were calculated compared to the Italian population for the northern and central Regions of Italy and the autonomous Provinces (PA) of Trento and Bolzano. A retrospective cohort study was conducted on subjects residing in FVG to whom at least one naso-oropharyngeal swab (hereafter, named swab) resulted positive for Covid-19. For each subject included in the cohort, the observation period started with the first positive swab and ended with the first of the following events: death, recovery or censored, which means that at the end of the observation period the subject was still alive and positive. The cause of death was assigned to Covid-19 if a subject had not yet recovered at the time when the event occurred. Cohort members were considered recovered after two negative consecutive swabs. The sub-hazard ratio (SHR) was estimated by applying the regression model of competing risks by Fine and Gray, in which the event of interest was the death caused by Covid-19 and the competing event was recovery. The explanatory variables included in the multiple models are: gender, age at the beginning of the observation period, the Province of residence, and nursing home residency. The cause-specific hazard was estimated using Cox proportional hazard regression. during the observation period, 3,305 cases and 345 deaths were recorded in FVG; SIR and SMR resulted, respectively, equal to 0.64 (95%CI 0.61-0.68) and 0.43 (95%CI 0.37-0.50). The FVG was the Northern Region one with the lowest incidence and mortality. The cohort consisted of 3,121 residents in FVG with at least one swab with a positive Covid-19 result during the study period. The SHR of dying for Covid-19 is equal to 16.13 (95%CI 9.73-26.74) for people with age 70-79 years and 35.58 (95%CI 21.77-58.15) with age >=80 years respect those with age <70 years. It is higher in males (SHR 1.71; 95%CI 1.34-2.17). There is no evidence that being resident in a nursing home affects the SHR (SHR 0.91 and 95%CI 0.69-1.20). As regards the province as an explanatory variable, the sub-hazard of death in the province of Trieste appears to overlap to the sub-hazard of Pordenone used as a reference; for the provinces of Udine and Gorizia the sub-hazards seem lower than the reference. while other Northern Regions and autonomous Provinces show higher standardized incidence and mortality compared with Italy, FVG and Veneto do not. In FVG, male gender and age are important determinants of death while there is no evidence that the condition of guest in a nursing home increases the sub-hazard of death.


Endogenous digitalis-like factor and ouabain immunoreactivity in adrenalectomized patients and normal subjects after acute and prolonged salt loading.
The aim of our study was to evaluate whether adrenals are involved in the secretion of endogenous digitalis-like factor(s) with polarity similar to (or less than) that of ouabain (EDLF-1), and whether acute plasma volume expansion is a physiological releasing stimulus for this factor(s) in humans. For this purpose, we measured the concentration of this substance(s) by a human placenta radioreceptor assay (RRA) and by the Du-Pont-NEN ouabain-EIA (immunoreactive ouabain, I-Oua) in plasma C18-extracts of eight normotensives and six patients with bilateral adrenalectomy before and after acute salt loading (2 lt 0.9% NaCl/2 h). The study was repeated after 2 weeks of increased sodium intake (200 mEq/day). Under basal conditions, EDLF-1 by RRA and I-Oua were similar in adrenalectomized patients and in controls and were not significantly modified by saline infusion. After 15 days of high sodium intake, basal plasma EDLF-1 and I-Oua were not significantly different from prediet levels, both in adrenalectomized patients and controls and were likewise unaffected by saline loading. Saline infusion, by contrast, significantly (P < or = .05) suppressed hematocrit and PRA and increased ANP both in controls and in patients, either before or after prolonged high dietary sodium. Plasma aldosterone (ALD) was similarly reduced (P < .001) in controls and, as expected, was undetectable in adrenalectomized patients. Our data indicate that in adrenalectomized patients circulating levels of EDLF-1 and I-Oua are similar to those of controls and that, in both groups, acute saline loading before and after sodium repletion does not influence circulating levels of these compounds. These findings suggest that, at least in humans, adrenals are not the main source of endogenous digitalis-like factor(s) with polarity similar to (or less than) that of ouabain, and that plasma volume expansion may be not a sufficient stimulus for the release of this factor(s).


Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix.
In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of advanced carcinoma of the uterine cervix a total of 320 cases were contributed by four radiotherapy centres in the United Kingdom. The use of hyperbaric oxygen resulted in improved local control and survival. The benefit was greatest in patients under the age of 55 who presented with stage III disease. There was a slight increase in radiation morbidity but it seemed that the benefit of hyperbaric oxygen outweighed this increase in morbidity and that there was a true improvement in the therapeutic ratio.


Boron ketoiminate-based conjugated polymers with tunable AIE behaviours and their applications for cell imaging.
Three new boron ketoiminate-based conjugated polymers P1, P2, and P3 were designed and synthesized through the Sonogashira coupling reaction of 4,6-bis(4-bromophenyl)-2,2-difluoro-3-phenyl-2H-1,3,2-oxazaborinin-3-ium-2-uide (M1) with 1,4-diethynyl-2,5-bis(octyloxy)benzene (M2), 3,6-diethynyl-9-octyl-9H-carbazole (M3) and 3,7-diethynyl-10-octyl-10H-phenothiazine-S,S-dioxide (M4), respectively. All the resulting polymers showed obvious aggregation-induced emission (AIE) behaviours. Interestingly, it was found that a great difference in the electron-donating abilities of the D-A type polymer linkers can lead to the unique AIE behaviour of the alternating polymers in the aggregate state, which provides us with a practical strategy to design tunable AIE-active conjugated polymers. Most importantly, studies on MCF-7 breast cancer cell imaging revealed that the nanoparticles fabricated from the conjugated polymers could serve as promising fluorescent probes with low cytotoxicity and high photostability.