Identifying the unmet supportive care needs of men living with and beyond prostate cancer: A systematic review.
Men affected by prostate cancer are a patient population in need of on-going person-centred supportive care. Our aim was to synthesise current available evidence with regard to the unmet supportive care needs of men living with and beyond prostate cancer. A systematic review was conducted according to the PRISMA Statement Guidelines. Electronic databases (DARE, Cochrane MEDLINE, BNI, PsychINFO, EMBASE and CIHAHL) were searched to identify studies employing qualitative and/or quantitative methods. Methodological evaluation was conducted, and findings were integrated in a narrative synthesis. 7521 references were retrieved, 17 articles met the eligibility criteria. Individual needs were classified into the following domains: social needs (2/17: 11.8%), spiritual needs (4/7: 23.5%), practical needs (4/17: 23.5%), daily living needs (5/17: 29.4%), patient-clinician communication (5/17: 29.4%), family-related needs (7/17: 41.2%), physical needs (8/17: 47.1%), psychological emotional needs (9/17: 52.9%), interpersonal/intimacy needs (11/17: 64.7%) and health system/Information needs (13/17: 76.5%). This systematic review has identified that men can experience a range of unmet supportive care needs with the most frequently reported being needs related to intimacy, informational, physical and psychological needs. Despite the emerging evidence-base, the current with-in study limitations precludes our understanding about how the needs of men evolve over time from diagnosis to living with and beyond prostate cancer. Whether demographic or clinical variables play a moderating role, only remains to be addressed in future studies. This review has made an important contribution by informing clinicians about the complex unmet supportive care needs of men affected by this disease.


Biochemical changes in the serum of patients with chronic toxigenic mold exposures: a risk factor for multiple renal dysfunctions.
This paper analyzes and presents the biochemical abnormalities in the sera of patients presenting with chronic mycosis in order to investigate the relationship with the risks of multiple renal disorders. The study population (n = 10) consisted of six females and four males (mean age 36.3 years) exposed by toxic molds in their homes and offices for an average of 2.8 years. The control group comprised ten people, five males and five females (mean age 35.9 years) without any known exposures to toxic molds. Blood samples were obtained from both the patients and the controls and were processed using specific biochemical methods that included enzyme-linked immunoabsorbent assay (ELISA). There were biochemical abnormal concentrations in creatinine, uric acid, phosphorus, alkaline phosphotase, cholesterol, HDH, SGOT/AST, segmented neutrophils, lymphocytes, total T3, IgG and IgA immunoglobulins with significant differences between patients and controls. These abnormalities were consistent with multiple renal disorders. The major complaints of the mycosis patients were headaches, pulmonary symptoms, allergic reactions, memory loss, skin rashes, blurred vision symptoms, fatigue, and runny nose. These findings were depictive of a strong association of chronic mycosis with abnormal renal indicators. It was concluded that, although this research was a pilot investigation, based on the overall results, people exposed to chronic indoor environmental toxic molds were at risk of multiple renal complications.


Hyperbaric oxygen improves tumor radiation response significantly more than carbogen/nicotinamide.
This laboratory previously demonstrated that hyperbaric oxygen and hyperbaric carbogen improved oxygenation in the R3230Ac tumor, but normobaric 100% O2 and carbogen did not. The current study assessed tumor growth after exposure to radiation plus either hyperbaric oxygen, carbogen or carbogen/nicotinamide and the relationship between pretreatment tumor oxygenation and growth time. R3230Ac carcinomas were grown in the flanks of F344 rats. Animals were randomized to one of seven radiation treatment groups: sham irradiation or irradiation plus room air, hyperbaric oxygen (100% O2/3 atmospheres), nicotinamide (0.3 mg/g intraperitoneally 20 min before irradiation), carbogen, carbogen/nicotinamide or hyperbaric oxygen/nicotinamide. Tumors received 20 Gy in a single dose. Median growth times were 6, 18, 18, 20, 22, 28 and 27 days for controls and irradiation plus room air, carbogen, nicotinamide, carbogen/nicotinamide, hyperbaric oxygen and hyperbaric oxygen/nicotinamide, respectively. Irradiation with hyperbaric oxygen, hyperbaric oxygen/ nicotinamide and carbogen/nicotinamide increased growth time (P < 0.001, P < 0.001 and P = 0.003, respectively) relative to room air. Hyperbaric oxygen was significantly more effective than carbogen/nicotinamide (P = 0.001). Growth times for all tumors exposed to hyperbaric oxygen were longer than those of the most fully oxygenated tumors (no baseline pO2 values < 10 mm Hg) not exposed to hyperbaric oxygen (P < 0.001). These results suggest that hyperbaric oxygen may improve radiation response by additional mechanisms separate from overcoming the oxygen effect.


The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer.
The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.


Escape behavior during academic tasks: a preliminary analysis of idiosyncratic establishing operations.
The presence or absence of idiosyncratic stimuli has been demonstrated to predictably alter the occurrence of problem behavior. By specifying stimuli related to negatively reinforced behavior during academic tasks, it may be possible to identify methods of instruction that decrease the occurrence of problem behavior. The current study used a four-step procedure that involved a functional analysis, descriptive assessment, establishing operations (EO) analysis, and follow-up evaluation (a) to identify the operant function of destructive behavior and (b) to evaluate the effects of idiosyncratic features of academic task demands and related methods of instruction on the occurrence of negatively reinforced destructive behavior of 3 boys with developmental disabilities and autism in a classroom setting. The data suggest that the four-step procedure was effective in identifying methods of instruction that decreased the likelihood of destructive behavior without disrupting the maintaining contingencies for destructive behavior. Results are discussed in terms of establishing operations for negatively reinforced destructive behavior during academic tasks and related methods of instruction in classroom settings.


Fatigue, general health, and ischemic heart disease in older adults.
Fatigue has been shown to predict ischemic heart disease (IHD) and mortality in nonsmoking middle-aged men free of cardiovascular disease. The aim of this study was to investigate the predictive value of fatigue for IHD and general health in nondisabled individuals free of cardiovascular disease and older than 70 years. The study population was drawn from The Longitudinal Study of Aging Danish Twins. In total, 1,696 participants were followed up for 2-10 years by questionnaires and 10-16 years through registries. Kaplan Meier, Cox Proportional Hazard and logistic regression were used to analyze data. Fatigue was measured with the mobility-tiredness scale, and multivariable-adjusted models included age, sex, socioeconomic position, life style factors, and depression symptomatology. Good general health was defined as no hospitalization due to IHD, no self-reported IHD-related diagnoses, no use of heart medication, sustained good mobility, and participation at follow-up. IHD was defined as first hospitalization due to IHD (ICD10: I20-I25) or death due to IHD as primary cause. Participants without fatigue had higher chances of a sustained good general health at 2 (odds ratio [OR] = 1.45 confidence interval [CI] 95%: 1.08-1.93) and 4 years of follow-up (OR = 1.55 CI 95%: 1.11-2.16), compared with participants with fatigue. Further, participants with fatigue had a significantly higher hazard of IHD during the 10-16 years of follow-up (hazard ratio [HR] = 1.47 CI 95%: 1.08-2.00) compared with participants without fatigue. We concluded that fatigue in nondisabled older adults free of cardiovascular disease is an early predictor for development of subsequent poor general health and IHD.


Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions.
Transplantation of bone marrow mesenchymal stem cells (MSCs) has been shown to effectively lower blood glucose levels in diabetic individuals, but the mechanism has not been adequately explained. We hypothesized that MSCs exert beneficial paracrine actions on the injured islets by releasing biologically active factors. To prove our hypothesis, we tested the cytoprotective effect of conditioned medium from cultured MSCs on isolated islets exposed to STZ in vitro and on mice islets after the experimental induction of diabetes in vivo. We assessed islet regeneration in the presence of conditioned medium and explored the possible mechanisms involved. Transplantation of MSCs can ameliorate hyperglycemia in diabetic mice by promoting the regeneration of β cells. Both β cell replication and islet progenitors differentiation contribute to β cell regeneration. MSC transplantation resulted in increases in pAkt and pErk expression by islets in vivo. Treatment with MSC-CM promoted islet cell proliferation and resulted in increases in pAkt and pErk expression by islets in vitro. The MSC-CM-mediated induction of β cell proliferation was completely blocked by the PI3K/Akt inhibitor LY294002 but not by the MEK/Erk inhibitor PD98059. Together, these data suggest that the PI3K/Akt signal pathway plays a critical role in β cell proliferation after MSC transplantation.


Genetic delimitation of Oreocharis species from Hainan Island.
Hainan Island harbours an extraordinary diversity of Gesneriaceae with 14 genera and 23 species, amongst which two species and one variety are recognised in the genus Oreocharis. These three Oreocharis taxa are all Hainan-endemics and show a complex geographical distribution pattern with considerable morphological intermixtures. In this study, we combined DNA (nuclear ITS sequences and cpDNAtrnL-trnF and ycf1b) to evaluate genetic delimitation for 12 Oreocharis populations from the island, together with morphological similarity analysis using 16 morphological traits. The results showed Hainan Oreocharis taxa were monophyletic with relative low genetic diversity within populations, highly significant genetic differentiation amongst populations and a significant phylogeographical structure. The 12 populations formed three genetically distinct groups, roughly correspondent to the currently recognised two species and one unknown lineage. The PCA analyses of morphological traits indicate three distinctive groups, differing mainly in petal colour and corolla shapes. The roles of river and mountain isolations in the origin and distribution of these three lineages are discussed.


A flexible enzyme-electrode sensor with cylindrical working electrode modified with a 3D nanostructure for implantable continuous glucose monitoring.
A novel cylindrical flexible enzyme-electrode sensor was fabricated with a bigger working electrode (WE) surface than the traditional pin-like one for implantable continuous glucose monitoring. On the WE surface, a 3D nanostructure consisting of graphene and platinum nanoparticles was constructed to enhance the sensitivity; in conjunction with the bigger WE, this nanostructure enabled hypoglycemia detection, which is still a big challenge in clinics. The cylindrical sensor was fabricated by rotated inkjet printing which enabled direct patterning of microstructures on a curved surface, thus overcoming the restriction of the traditional planar micromachining by photolithography. Specifically, the cylindrical substrate (polyetheretherketone, PEEK) was modified by (3-aminopropyl) trimethoxysilane and (3-mercaptopropyl) trimethoxysilane to facilitate surface wettability, which discourages the coalescence of adjacent droplets, and to facilitate the adhesion of metals to PEEK in order to construct robust electrodes. A synchronous heating method was used to evaporate the solvent of the droplets quickly to prevent them from running along the cylindrical surface, which affects the formation of the printed electrode significantly. In vitro experimental results showed that the proposed sensor was able to detect the glucose concentration ranging from 0 to 570 mg dL-1 which demonstrated its capability for physiological glucose detection. In vivo experiments were conducted with rats, and the measurement results recorded using the implanted cylindrical sensor showed great compliance to those recorded using a commercial glucometer which exhibited the viability of the proposed sensor for implantable continuous glucose monitoring, even under the hypoglycemic conditions.


The standard of spirometry in the RSA.
Standards for high-quality lung function testing have not yet been formally adopted in the RSA, despite the increase in the performance of spirometry. A study was undertaken to determine the standard of spirometry in clinical practice in this country. Forty-five spirometer users agreed to participate. Responses to a questionnaire, administered by personal interview, were graded according to the proportion of correct or appropriate answers: completely unsatisfactory less than 33.3%; poor 33.3-66.6%; and satisfactory greater than 66.6%. Only 6 spirometers were regularly calibrated. Knowledge of international standards for spirometry, the basic working mechanism of the spirometer being used and calibration ranged from poor to completely unsatisfactory in most of the practices. Instructions to the patients for performing the manoeuvres were satisfactory, but elevation of the result for acceptability, reproducibility, selection of the best test and diagnosis of a positive bronchodilator response were generally completely unsatisfactory. Only 18 practitioners knew the source of the reference values they used and 5 had proved their validity with a sample. Fourteen of the 45 practitioners were unable to make the correct diagnoses from two typical test results. Of the 45 practitioners, 40 were interested in a course in practical, clinical spirometry. In the light of the predominantly unsatisfactory results obtained in this study, we consider clinical spirometry to be an urgent priority for all levels of medical education.


Reflectance measurements on cavity radiators.
A knowledge of the emissivity of a cavity radiator may be deduced from reflectance measurements, but these may be difficult to make if the cavity has a small aperture and low reflectance. The use of a He-Ne laser as a source facilitates such measurements. Results are presented for one ceramic and three metallic cavities that have been used in photometric and spectroradoimetric standards work. An integrating sphere method appears more satisfactory than a goniophotometric approach.


Screening and Functional Profiling of Small-Molecule HIV-1 Entry and Fusion Inhibitors.
HIV-1 entry and fusion with target cells is an important target for antiviral therapy. However, a few currently approved treatments are not effective as monotherapy due to the emergence of drug resistance. This consideration has fueled efforts to develop new bioavailable inhibitors targeting different steps of the HIV-1 entry process. Here, a high-throughput screen was performed of a large library of 100,000 small molecules for HIV-1 entry/fusion inhibitors, using a direct virus-cell fusion assay in a 384 half-well format. Positive hits were validated using a panel of functional assays, including HIV-1 specificity, cytotoxicity, and single-cycle infectivity assays. One compound-4-(2,5-dimethyl-pyrrol-1-yl)-2-hydroxy-benzoic acid (DPHB)-that selectively inhibited HIV-1 fusion was further characterized. Functional experiments revealed that DPHB caused irreversible inactivation of HIV-1 Env on cell-free virions and that this effect was related to binding to the third variable loop (V3) of the gp120 subunit of HIV-1 Env. Moreover, DPHB selectively inhibited HIV-1 strains that use CXCR4 or both CXCR4 and CCR5 co-receptors for entry, but not strains exclusively using CCR5. This selectivity was mapped to the gp120 V3 loop using chimeric Env glycoproteins. However, it was found that pure DPHB was not active against HIV-1 and that its degradation products (most likely polyanions) were responsible for inhibition of viral fusion. These findings highlight the importance of post-screening validation of positive hits and are in line with previous reports of the broad antiviral activity of polyanions.


An investigation of large inhibitors binding to phosphoglycerate kinase and their effect on anion activation.
This study extends, to a series of larger anions, our earlier investigation of the interaction of the trypanocidal drug suramin and other small negatively charged molecules with yeast phosphoglycerate kinase. 1H-NMR structural studies of phosphoglycerate kinase in the presence of varying concentrations of these large molecules (designed to mimic, at one end, the anionic charge distribution in the substrate 3-phosphoglycerate, while possibly being able to interact across the cleft of the enzyme) including inositol 1,4,5-triphosphate, 4-amino-6-trichloroethenyl-1,3- benzenedisulphonamide, gallic acid and sulphasalazine are described. The anion activation and/or inhibition of the enzyme by these molecules are also reported. Evidence that binding to the general anion site in the 'basic patch' region of the protein may be responsible for either the activating or inhibiting effects, while binding at the hydrophobic (catalytic) site leads to inhibition only is presented. A reaction scheme which explains these observations is given.


Secrecy, disclosure and accidental discovery: perspectives of diaphragm users in Mombasa, Kenya.
The diaphragm is receiving renewed attention as a promising female-controlled method of preventing HIV and other sexually-transmitted infections. It is anticipated that female-controlled technologies will reduce women's biological susceptibility and assist in counteracting their sociocultural vulnerability to HIV. Understanding the subjective experiences of diaphragm users in different settings has the potential to inform the development and promotion of such methods. This paper explores the perspectives of female sex workers and women attending sexual and reproductive health services in Mombasa, Kenya. Data are reported from focus group discussions and in-depth interviews with women and men, following a prospective study investigating diaphragm continuation rates over six months. Discussions highlighted covert use of the diaphragm, during sex work or with casual partners, and coital independence as favourable attributes. These features were especially pronounced compared with male condoms. Few difficulties with diaphragm use were reported, although its insertion and removal occasionally presented problems. Many women--especially those in long term partnerships--wished to disclose its use but found the disclosure process highly problematic. Accidental discovery often resulted in partner conflict. Although future uptake of the diaphragm may be high in this setting, its use may be limited to certain types of relationships and relationship context.


Preliminary Report on Interleukin-22, GM-CSF, and IL-17F in the Pathogenesis of Acute Anterior Uveitis.
Purpose:Anterior uveitis is the most common anatomic subset of uveitis. We developed a novel multi-parametric flow cytometry panel to identify immune dysregulation signatures in HLA B27-associated acute anterior uveitis (AAU) and axial spondyloarthritis (AxSpA).Methods: We used fluorescence activated cell sorting to characterize T cell cytokine expression in stimulated T cell subsets from patients with AAU (n = 4) compared to healthy controls (n = 14) or subjects with AxSpA (n = 6).Results: Positive findings among subjects with AAU included a statistically significant increase in stimulated granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, and IL-22 synthesized by CD8 cells, a trend for stimulated ILC (innate lymphoid cells)-3 cells to synthesize more IL-22 (p = .07), and stimulated MAIT (mucosa associated innate lymphoid cells)-like cells that express the T cell receptor V alpha 7.2 to express IL-17A, IL-17F, and IL-22 in a greater percentage of cells relative to controls. IL-17F, GM- CSF, and IL-22 represent potentially novel targets in AAU.Conclusion: Our report is arguably the first to implicate IL-17F or ILC-3 and MAIT cells in the pathogenesis of AAU.Abbreviations AAU: acute anterior uveitis; AxSpA: axial spondyloarthritis; BASDAI: Bath ankylosing spondylitis disease activity index; CCR: chemokine receptor; DMSO: dimethylsulfoxide; EULAR:European League Against Rheumatism; FACS: fluorescence activated cell sorter; FBS: fetal bovine serum; FSC: orward light scatter; GM-CSF: granulocyte-macrophage colony stimulating factor; HC: healthy control; ILC: innate lymphoid cell; KIR: killer immunoglobulin receptor; MAIT: mucosal associated immune T cell; ND: not detected; NK: natural killer cell; OHSU-Oregon Health & Science University; PBMC: peripheral blood mononuclear cell; SSC: side light scatter; TCR: T cell receptor.


Ins and Outs of Multipartite Positive-Strand RNA Plant Viruses: Packaging versus Systemic Spread.
Viruses possessing a non-segmented genome require a specific recognition of their nucleic acid to ensure its protection in a capsid. A similar feature exists for viruses having a segmented genome, usually consisting of viral genomic segments joined together into one viral entity. While this appears as a rule for animal viruses, the majority of segmented plant viruses package their genomic segments individually. To ensure a productive infection, all viral particles and thereby all segments have to be present in the same cell. Progression of the virus within the plant requires as well a concerted genome preservation to avoid loss of function. In this review, we will discuss the "life aspects" of chosen phytoviruses and argue for the existence of RNA-RNA interactions that drive the preservation of viral genome integrity while the virus progresses in the plant.


Towards computational specificity screening of DNA-binding proteins.
DNA-binding proteins are key players in the regulation of gene expression and, hence, are essential for cell function. Chimeric proteins composed of DNA-binding domains and DNA modifying domains allow for precise genome manipulation. A key prerequisite is the specific recognition of a particular nucleotide sequence. Here, we quantitatively assess the binding affinity of DNA-binding proteins by molecular dynamics-based alchemical free energy simulations. A computational framework was developed to automatically set up in silico screening assays and estimate free energy differences using two independent procedures, based on equilibrium and non-equlibrium transformation pathways. The influence of simulation times on the accuracy of both procedures is presented. The binding specificity of a zinc-finger transcription factor to several sequences is calculated, and agreement with experimental data is shown. Finally we propose an in silico screening strategy aiming at the derivation of full specificity profiles for DNA-binding proteins.


Commercial Gene Expression Tests for Prostate Cancer Prognosis Provide Paradoxical Estimates of Race-Specific Risk.
Commercial gene expression signatures of prostate cancer prognosis were developed and validated in cohorts of predominantly European American men (EAM). Limited research exists on the value of such signatures in African American men (AAM), who have poor prostate cancer outcomes. We explored differences in gene expression between EAM and AAM for three commercially available panels recommended by the National Comprehensive Cancer Network for prostate cancer prognosis. A total of 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using NanoString for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. A continuous expression-based risk score was approximated for each. Differential expression, intrapanel coexpression, and risk by race were assessed. Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, although the magnitudes of expression differences were small. Coexpression patterns were more strongly preserved by race group for Oncotype DX and Decipher than Prolaris. Poorer prognosis was estimated in EAM versus AAM for Oncotype DX (P < 0.001), whereas negligible prognostic differences were predicted between AAM and EAM using Prolaris or Decipher (P > 0.05). Because of observed racial differences across three commercial gene expression panels for prostate cancer prognosis, caution is warranted when applying these panels in clinical decision-making in AAM. Differences in gene expression by race for three commercial panels for prostate cancer prognosis indicate that further study of their effectiveness in AAM with long-term follow-up is warranted.


Autophagy, organelles and ageing.
As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death.


Preliminary comparison of four anaesthetic techniques in badgers (Meles meles).
To investigate the use of four ketamine-based anaesthetic combinations in wild badgers. Prospective, randomized, clinical trial. Twenty-four adult badgers. Animals were divided into four groups of six and were anaesthetized using either intramuscular (IM) ketamine alone (20 mg kg(-1)), ketamine (15 mg kg(-1) IM) and midazolam (0.4 mg kg(-1) IM), ketamine (10 mg kg(-1) IM) and midazolam (1 mg kg(-1) IM) or ketamine (5 mg kg(-1) IM) and medetomidine (80 microg kg(-1) IM) antagonized with atipamezole (0.8 mg kg(-1); IM). Features of each technique, i.e. quality of induction, maintenance and recovery, and the need for additional doses, were assessed using a simple descriptive scale. Physiological variables, i.e. rectal temperature, respiratory rate, heart rate and blood pressure, were also recorded. Combinations of ketamine and midazolam did not produce adequate anaesthesia. The combination of medetomidine and ketamine had few advantages over ketamine alone. These data will contribute to a wider study attempting to refine anaesthetic techniques in badgers.


Metal-organic framework nanosheets in polymer composite materials for gas separation.
Composites incorporating two-dimensional nanostructures within polymeric matrices have potential as functional components for several technologies, including gas separation. Prospectively, employing metal-organic frameworks (MOFs) as versatile nanofillers would notably broaden the scope of functionalities. However, synthesizing MOFs in the form of freestanding nanosheets has proved challenging. We present a bottom-up synthesis strategy for dispersible copper 1,4-benzenedicarboxylate MOF lamellae of micrometre lateral dimensions and nanometre thickness. Incorporating MOF nanosheets into polymer matrices endows the resultant composites with outstanding CO2 separation performance from CO2/CH4 gas mixtures, together with an unusual and highly desired increase in the separation selectivity with pressure. As revealed by tomographic focused ion beam scanning electron microscopy, the unique separation behaviour stems from a superior occupation of the membrane cross-section by the MOF nanosheets as compared with isotropic crystals, which improves the efficiency of molecular discrimination and eliminates unselective permeation pathways. This approach opens the door to ultrathin MOF-polymer composites for various applications.


Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort.
Growth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor-β superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population. Between 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.4 ± 5.96 years, 38.6% men) who were participants in the Malmö Diet and Cancer-Cardiovascular Cohort. After a follow-up of 19.0 ± 5.16 years (mean ± SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP). During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p < 0.001) per SD increase of GDF-15. If participants were grouped according to baseline fasting glucose, the association between GDF-15 and diabetes risk was only evident in the group without impaired fasting glucose (n = 3973). The association tended to be less significant with increasing age: multivariate-adjusted HRs for diabetes per SD increase of GDF-15 were 1.24 (95% CI 1.08, 1.42), 1.19 (95% CI 1.00, 1.41) and 1.04 (95% CI 0.89, 1.23) for participants aged ≤55, 56-60 (>55 and ≤60) and >60 years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p = 0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061). GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are ≤60 years old.


Giving voice to wildlands visitors: selecting indicators to protect and sustain experiences in the eastern arctic of Nunavut.
Many public land management agencies are committed to understanding and protecting recreation visitor experiences. Parks Canada is deeply committed to that objective for visitors to Canada's National Parks. This 2004 study, informed by a 2003 qualitative study of visitor experiences and influences on those experiences at Auyuittuq National Park in Nunavut, worked to bring 50 potential elements of visitor experiences down to five articulated dimensions of the experience that is currently being received at this remote eastern arctic park. A hypothesized set of 17 influences on experiences, also reduced to just two factors with similar response patterns, and with some items that did not flow into the two factors, were used in a regression analysis to understand the relationship between experiences and factors of influence. A sample of 61.8% (84) of the total recreation visitor population 16 years of age or older was surveyed during deregistration after the trip. Knowledge about the dimensions of the experiences currently received and factors of influence on those experiences can be used to guide selection of indicators for describing objectives and prescribing monitoring protocol.


Interleukin-3Ralpha+ myeloid dendritic cells and mast cells develop simultaneously from different bone marrow precursors in cultures with interleukin-3.
The distinct developmental routes of dendritic cells and mast cells from murine bone marrow cultures with interleukin-3 are unclear. We found that short-term bone marrow cultures with interleukin-3 after 8-10 d consist of about 10%-30% dendritic cells and 70%-90% mast cell precursors, and only after 4-6 wk do homogeneous populations of mast cells emerge. Phenotypical and functional analysis of interleukin-3/dendritic cells revealed a high similarity with myeloid dendritic cells generated with granulocyte-macrophage colony stimulating factor in the expression of myeloid dendritic cell markers (CD11c+ B220- CD8alpha- CD11b+), major histocompatibility complex II and costimulatory molecules, endocytosis, maturation potential, interleukin-12 production, and T cell priming. Interleukin-3/dendritic cells expressed higher levels of interleukin-3 receptor, however. To dissect the interleukin-3/dendritic cell and mast cell development, we sorted fresh bone marrow cells into six subsets by the antibodies ER-MP12 (CD31) and ER-MP20 (Ly-6C). Both interelukin-3/dendritic cells and granulocyte-macrophage colony stimulating factor/dendritic cells develop from the same bone marrow populations, including the ER-MP12neg, ER-MP20high bone marrow monocytes. In contrast, mast cells only developed from ER-MP12(int+high), ER-MP20neg bone marrow cell subsets, indicating that different precursors exist for interleukin-3/dendritic cells and mast cells. Established mast cell cultures could not be converted to dendritic cells or stimulated to express major histocompatibility complex II molecules in vitro or home to lymph node T cell areas in vivo. In summary, we show that dendritic cells generated from bone marrow precursors with interleukin-3 are clearly myeloid and develop via a different pathway compared to bone marrow mast cells.


Remote blood pressure monitoring and behavioral intensification for stroke: A randomized controlled feasibility trial.
Measuring blood pressure (BP) at home and remote monitoring can improve the patient's adherence to BP control and vascular outcomes. This study evaluated the feasibility of a trial regarding the effects of an intensive mobile BP management strategy versus usual care in acute ischemic stroke patients. A feasibility-testing, randomized, open-labeled controlled trial was conducted. Remote BP measurement, data transmission, storage, and centralized monitoring system were organized through a Bluetooth-equipped sphygmomanometer paired to the participants' smartphones. Participants were randomized equally into intensive management (behavioral intensification to measure BP at home by texting, direct telephone call, or breakthrough visit) and control (usual care) groups. The primary feasibility outcomes were: 1) recruitment time for the pre-specified number of participants, 2) retention of participants, 3) frequency of breakthrough visit calls, 4) response to breakthrough visit call, and 5) proportions satisfying BP measurement criteria. Sixty participants were randomly assigned to the intensive management (n = 31) and control (n = 29) groups, of which 57 participants were included in the primary analysis with comparable baseline characteristics. Recruitment time from the first to the last participant was 350 days, and 95% of randomized participants completed the final visit (intensive, 94%; control, 98%). Eight breakthrough visit calls were made to 7 participants (23%), with complete and immediate responses within 3 ± 4 days. The median of half-day blocks fulfilling the BP measurement criteria per patient were 91% in the intensive group and 83% in the control group (difference, 12.2; 95% confidence interval, 2.2-22.2). No adverse events related to the trial procedures were reported. The intensive monitoring, including remote BP measurement, data transfer, and centralized monitoring system, engaged with behavioral intensification was feasible if the patients complied with the intervention. However, the device utilized would need further improvement prior to a large trial.


Peer support of complex health behaviors in prevention and disease management with special reference to diabetes: systematic reviews.
Examine Peer Support (PS) for complex, sustained health behaviors in prevention or disease management with emphasis on diabetes prevention and management. PS was defined as emotional, motivational and practical assistance provided by nonprofessionals for complex health behaviors. Initial review examined 65 studies drawn from 1442 abstracts identified through PubMed, published 1/1/2000-7/15/2011. From this search, 24 reviews were also identified. Extension of the search in diabetes identified 30 studies published 1/1/2000-12/31/2015. In initial review, 54 of all 65 studies (83.1%) reported significant impacts of PS, 40 (61.5%) reporting between-group differences and another 14 (21.5%) reporting significant within-group changes. Across 19 of 24 reviews providing quantifiable findings, a median of 64.5% of studies reviewed reported significant effects of PS. In extended review of diabetes, 26 of all 30 studies (86.7%) reported significant impacts of PS, 17 (56.7%) reporting between-group differences and another nine (30.0%) reporting significant within-group changes. Among 19 of these 30 reporting HbA1c data, average reduction was 0.76 points. Studies that did not find effects of PS included other sources of support, implementation or methodological problems, lack of acceptance of interventions, poor fit to recipient needs, and possible harm of unmoderated PS. Across diverse settings, including under-resourced countries and health care systems, PS is effective in improving complex health behaviors in disease prevention and management including in diabetes.


Cross presentation of antigen by dendritic cells: mechanisms and implications for immunotherapy.
Dendritic cells (DCs) possess the specialized potential to present exogenously derived antigen to cytotoxic T lymphocytes to elicit an immune response. This process, termed cross presentation, is crucial in the generation of immune response to viruses, tumors and in autoimmune disease. The ability of DCs to cross-present exogenous antigen to cytotoxic T lymphocytes makes them an attractive target for exploitation in immunotherapy. In recent years, significant advances have been made in understanding the mechanism of cross-presentation and the DC subsets involved. The recent discovery of the human cross presenting DC has given this field a new lease of life. In this report, the authors provide an overview of cross-presentation of antigen by DCs, focusing on the current understanding of the molecular mechanisms of the process. The authors also discuss the DC subsets involved in cross presentation and its role in health and disease.


Differentiation of Tobacco Plants from Single, Isolated Cells in Microcultures.
Single cells isolated from pith callus of fresh stem of hybrid tobacco (Nicotiana glutinosa male symbol x N. tabacum female symbol) gave rise to small colonies of cells in microcultures which upon transfer to agar medium produced clones of callus tissue. These single-cell clones differentiated roots, and shoots with green leaves, on a completely defined nutrient medium. The rooted shoots developed into normal plants after transfer to soil in pots in the greenhouse. Buds and flowers were produced by these plants.


Integrated electrochemical microsystems for genetic detection of pathogens at the point of care.
The capacity to achieve rapid, sensitive, specific, quantitative, and multiplexed genetic detection of pathogens via a robust, portable, point-of-care platform could transform many diagnostic applications. And while contemporary technologies have yet to effectively achieve this goal, the advent of microfluidics provides a potentially viable approach to this end by enabling the integration of sophisticated multistep biochemical assays (e.g., sample preparation, genetic amplification, and quantitative detection) in a monolithic, portable device from relatively small biological samples. Integrated electrochemical sensors offer a particularly promising solution to genetic detection because they do not require optical instrumentation and are readily compatible with both integrated circuit and microfluidic technologies. Nevertheless, the development of generalizable microfluidic electrochemical platforms that integrate sample preparation and amplification as well as quantitative and multiplexed detection remains a challenging and unsolved technical problem. Recognizing this unmet need, we have developed a series of microfluidic electrochemical DNA sensors that have progressively evolved to encompass each of these critical functionalities. For DNA detection, our platforms employ label-free, single-step, and sequence-specific electrochemical DNA (E-DNA) sensors, in which an electrode-bound, redox-reporter-modified DNA "probe" generates a current change after undergoing a hybridization-induced conformational change. After successfully integrating E-DNA sensors into a microfluidic chip format, we subsequently incorporated on-chip genetic amplification techniques including polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) to enable genetic detection at clinically relevant target concentrations. To maximize the potential point-of-care utility of our platforms, we have further integrated sample preparation via immunomagnetic separation, which allowed the detection of influenza virus directly from throat swabs and developed strategies for the multiplexed detection of related bacterial strains from the blood of septic mice. Finally, we developed an alternative electrochemical detection platform based on real-time LAMP, which not is only capable of detecting across a broad dynamic range of target concentrations, but also greatly simplifies quantitative measurement of nucleic acids. These efforts represent considerable progress toward the development of a true sample-in-answer-out platform for genetic detection of pathogens at the point of care. Given the many advantages of these systems, and the growing interest and innovative contributions from researchers in this field, we are optimistic that iterations of these systems will arrive in clinical settings in the foreseeable future.


Allee effect from parasite spill-back.
The exchange of native pathogens between wild and domesticated animals can lead to novel disease threats to wildlife. However, the dynamics of wild host-parasite systems exposed to a reservoir of domesticated hosts are not well understood. A simple mathematical model reveals that the spill-back of native parasites from domestic to wild hosts may cause a demographic Allee effect in the wild host population. A second model is tailored to the particulars of pink salmon (Oncorhynchus gorbuscha) and salmon lice (Lepeophtheirus salmonis), for which parasite spill-back is a conservation and fishery concern. In both models, parasite spill-back weakens the coupling of parasite and wild host abundance-particularly at low host abundance-causing parasites per host to increase as a wild host population declines. These findings show that parasites shared across host populations have effects analogous to those of generalist predators and can similarly cause an unstable equilibrium in a focal host population that separates persistence and extirpation. Allee effects in wildlife arising from parasite spill-back are likely to be most pronounced in systems where the magnitude of transmission from domestic to wild host populations is high because of high parasite abundance in domestic hosts, prolonged sympatry of domestic and wild hosts, a high transmission coefficient for parasites, long-lived parasite larvae, and proximity of domesticated populations to wildlife migration corridors.


RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria.
Previous studies have identified RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) as a potential chemotherapeutic agent. VES induces human breast cancer cells to undergo apoptosis in a concentration- and time-dependent manner by restoring transforming growth factor beta (TGF-beta) and Fas (CD95) apoptotic signaling pathways, that contribute to the activation of c-Jun NH(2)-terminal kinase (JNK)-mediated apoptosis. The objective of these studies was to clarify biochemical events involved in VES-induced apoptosis. Data show that VES-induced apoptosis involves: (a) translocation of Bax from the cytosol to the mitochondria and cytochrome c release from the mitochondria to the cytosol as determined by Western immunoblot analyses of mitochondrial- and cytosolic-enriched cellular fractions; (b) increased permeabilization of mitochondrial membranes as determined by confocal and fluorescence-activated cell sorting analyses of loss of a mitochondrial selective fluorescent dye; (c) processing of caspase-9 and -3 but not caspase-8 to active forms and cleavage of poly(ADP-ribose) polymerase (PARP) as determined by Western immunoblot analyses using antibodies capable of detecting both proenzyme and processed enzyme forms or the intact or cleaved forms of PARP. Transient transfection of cells with antisense oligonucleotides to Bax or transient overexpression of Bcl-2 prevented VES-induced mitochondrial permeability transition and apoptosis. The use of cell-permeable caspase inhibitors indicated that caspase-9 and -3 but not caspase-8 are involved in VES-induced apoptosis. JNK inhibitor II blocked VES-induced Bax conformational change, indicating a role for JNK in Bax translocation to the mitochondria. Taken together, these data suggest that the activation of JNK, translocation of Bax to the mitochondria, increased mitochondrial membrane permeability with release of cytochrome c, and activation of caspase-9 and -3 are critical events in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.


TM14 is a new member of the fibulin family (fibulin-7) that interacts with extracellular matrix molecules and is active for cell binding.
We identified a new extracellular protein, TM14, by differential hybridization using mouse tooth germ cDNA microarrays. TM14 cDNA encodes 440 amino acids containing a signal peptide. The protein contains 3 EGF modules at the center, a C-terminal domain homologous to the fibulin module, and a unique Sushi domain at the N terminus. In situ hybridization revealed that TM14 mRNA was expressed by preodontoblasts and odontoblasts in developing teeth. TM14 mRNA was also expressed in cartilage, hair follicles, and extraembryonic tissues of the placenta. Immunostaining revealed that TM14 was localized at the apical pericellular regions of preodontoblasts. When the dentin matrix was fully formed and dentin mineralization occurred, TM14 was present in the predentin matrix and along the dentinal tubules. We found that the recombinant TM14 protein was glycosylated with N-linked oligosaccharides and interacted with heparin, fibronectin, fibulin-1, and dentin sialophosphoprotein. We also found that TM14 preferentially bound dental mesenchyme cells and odontoblasts but not dental epithelial cells or nondental cells such as HeLa, COS7, or NIH3T3 cells. Heparin, EDTA, and anti-integrin beta1 antibody inhibited TM14 binding to dental mesenchyme cells, suggesting that both a heparan sulfate-containing cell surface receptor and an integrin are involved in TM14 cell binding. Our findings indicate that TM14 is a cell adhesion molecule that interacts with extracellular matrix molecules in teeth and suggest that TM14 plays important roles in both the differentiation and maintenance of odontoblasts as well as in dentin formation. Because of its protein characteristics, TM14 can be classified as a new member of the fibulin family: fibulin-7.


Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children.
The ability to predict the course in children with newly diagnosed minimal change nephrotic syndrome (MCNS) may have significant therapeutic implications. Previous attempts based on data available at disease onset have not been successful. Therefore, it was investigated whether characterization of the initial response to adrenocortical steroids and the course during the early months of disease are predictive of the subsequent outcome. Three hundred-eighty-nine children with MCNS, diagnosed at onset, were treated with standard prednisone regimens and monitored for up to 17 yr (mean, 9.4 yr). They were classified, after 8 wk of therapy, as initial responders (complete remission) or initial nonresponders (continued proteinuria). Subsequent classifications included nonrelapsers, infrequent relapsers, and frequent relapsers. At 8 yr of follow-up, 80% of patients were in remission. Three-fourths of initial responders who remained in remission during the first 6-month period after initial therapy (nonrelapsers; 40% of the entire series) either continued in remission during their entire course or relapsed rarely. In contrast, initial relapsers, both frequent and infrequent, achieved a nonrelapsing course only after an average of 3 yr. Unremitting proteinuria during the initial 8 wk of treatment was followed by progression to ESRD in 21%. When proteinuria during the initial 8 wk continued through the subsequent 6 months, progression to renal failure occurred for 35%. Although 95% of children with MCNS do well, 4 to 5% die from complications or undergo progression to ESRD. Documentation of the early course aids in identifying those at increased risk for a poor outcome. More aggressive therapy may be indicated for these individuals.


Characterization of the spatial-frequency spectrum in the perception of shape from texture.
The major cue to shape from texture is the compression of texture as a function of surface curvature [J. Exp. Psychol. 13, 242 (1987); Vision Res. 33, 827 (1993)]. A number of computational models have been proposed in which compression is measured by detection of changes in the spatial-frequency spectrum [Comput. Graphics Image Process. 5, (1976)]. We propose that the visual system uses a strategy of characterizing the frequency spectrum by a simple set of measures and of tracking the changes in this characterization rather than determining changes in the shape of the actual spectra. Our evidence is based on a number of psychophysical demonstrations that use stimuli with specifically tailored frequency spectra, constructed from white noise filtered in the frequency domain. Our evidence suggests that the visual system determines the average peak frequency of the spectrum and uses this measure as its characterization. Changes in fp are strongly correlated with the degree of surface curvature, and, over a range of stimuli, fp takes account of the variance in local estimates of the frequency spectrum. One computes fp by determining the peak frequency at each spatial location and then averaging these frequency values over a local spatial region. We show that fp is related to the second-order moment but is more biologically plausible and shows superior ability to function in the presence of noise. As a test of this model, we have constructed a neural network architecture for computing shape from texture. Our model is limited to orthographically projected, homogeneous textures without in-surface rotation. The early stages of the model consist of multiple simple-cell units tuned to different orientations and spatial frequencies. We show that these simple cells are inadequate for the determination of compression but that the outputs of complex-cell-like units after normalization generate estimates of surface slant and tilt. The network shows qualitative agreement with human perception of shape from texture over a wide range of real and artificial stimuli.


First Report of 16SrIII-B Phytoplasma Subgroup Associated with Virescence of Arnica montana in Serbia.
Arnica montana L. is a high altitude perennial plant, indigenous to Europe, but it is not native in the flora of Serbia. Plantain introduction of A. montana began a few years ago in the Tara mountain region, Western Serbia (43°53'44.17″N 19°33'11.62″E, 1,008 m ASL). The mountainous climate in this region is characterized by 850 mm of precipitation per year and an average decade temperature range from 11 to 25°C in the vegetation period of May through September. The main soil type is dystric cambisol, exhibiting a slightly acidic reaction (pH 6.4). Seeds of A. montana cv. ARBO were obtained from the Agricultural Research Centre of Finland. Seedlings were produced in a greenhouse during the period March through April and planted in May 2008. Virescence symptoms were observed starting from May 2010. A. montana exhibited symptoms mainly on flowers, like green leaflike structures instead of flowers and proliferation of acillary buds. Later in the season, flowers were malformed and consequently failed to produce seeds. Plant material for analyses was collected during 2010 and 2011 from an experimental field located at Tara mountain. Total DNA was extracted from the leaf midveins of 14 symptomatic and six symptomless plants (3). Nested PCR was carried out with primers P1/P7 followed by P1/16S-Sr and R16F2n/R16R2 primers, resulting with the DNA fragments amplification of expected size: 1.8, 1.5, and 1.2 kb, respectively, in all symptomatic samples tested. No phytoplasmas were detected in symptomless samples. PCR products of 1.2 kb, obtained by R16F2n/R16R2 primers from symptomatic samples, were digested independently with four restriction enzymes (Alu I, Tru I, Hpa II and Hha I) and the RFLP patterns were compared with those of Stolbur (Stol), Aster Yellows (AY), Flavescence Doree-C (FD-C), Poinsettia Branch-Inducing (PoiBI) and Clover Yellow Edge (CYE) phytoplasmas (2). RFLP patterns from all symptomatic A. montana samples were identical to CYE pattern. Comparison of the 16S rDNA sequence of representative symptomatic sample Am4, deposited under accession number JX297491 in NCBI GenBank, with other phytoplasmas from the database revealed 99% identity with members of 16SrIII-B phytoplasma group: Clover yellow edge phytoplasma strain CYE (JQ944798.1), 'Euscelidius variegatus' phytoplasma strain AP-I (HQ589197.1), Clover phyllody phytoplasma strain CP (HQ589196.1), etc. In Serbia, phytoplasma belonging 16SrIII-B subgroup has been identified in Cirsium arvense (4) and pear plants (1). To our knowledge, this is the first report of a natural infection of A. montana by phytoplasma. Cultivation of A. montana provides the necessary raw material for medicament production. The flower heads are widely used for the topical treatment of bruises and sprains in phytopharmaceutical preparations.Taking into consideration that monoculture plantation growing of perennials favorites rapid spreading of infections, the present study tended to examine the potential threat of virescence, which could be the limiting factor of ex-situ conservation of this endangered plant by its cultivation. References: (1) B. Duduk et al. Acta Hortic. 781:351, 2008. (2) I. M. Lee et al. Int. J. Syst. Bacteriol. 48:1153, 1998. (3) J. P. Prince. Phytopathology 83:1130, 1993. (4) D. Rancic et al. Plant Pathology 54:561, 2005.


Thermal modeling of polymerizing polymethylmethacrylate, considering temperature-dependent heat generation.
A methodology for the modeling of unsteady heat conduction in polymethylmethacrylate (PMMA) during its exothermic polymerization is presented. The emphasis is on the formulation of a model for the volumetric rate of heat generation, including its temperature-dependent characteristics. Three parameters appear in the proposed model. The empirical determination of these parameters using Differential Scanning Calorimetry is demonstrated. The incorporation of the proposed model into finite volume methods is also demonstrated, in the context of unsteady, one-dimensional, radial heat conduction in cylindrical coordinates. In addition, the application of the proposed model to two test problems is presented and discussed. The results are encouraging, and the proposed methodology appears to be applicable to the thermal modeling of exothermic polymerization processes in general.


The genesis of a heterogeneous catalyst: in situ observation of a transition metal complex adsorbing onto an oxide surface in solution.
Understanding the interactions between metal complexes and oxide surfaces is crucial to the synthesis of supported metal catalysts. Recently developed in situ techniques have made it possible to closely characterize the solid/liquid interface. For the first time, the adsorption of platinum complexes on alumina and silica has been probed using a quartz crystal microbalance; we were able to observe the adsorption of metal complexes in real time, and to observe the reversibility of this adsorption.


Comparison of digital tomosynthesis and chest radiography for the detection of pulmonary nodules: systematic review and meta-analysis.
To compare the diagnostic accuracy of digital tomosynthesis (DTS) with that of chest radiography for the detection of pulmonary nodules by meta-analysis. A systematic literature search was performed to identify relevant original studies from 1 January 1 1976 to 31 August 31 2016. The quality of included studies was assessed by quality assessment of diagnostic accuracy studies-2. Per-patient data were used to calculate the sensitivity and specificity and per-lesion data were used to calculate the detection rate. Summary receiver-operating characteristic curves were drawn for pulmonary nodule detection. 16 studies met the inclusion criteria. 1017 patients on a per-patient basis and 2159 lesions on a per-lesion basis from 16 eligible studies were evaluated. The pooled patient-based sensitivity of DTS was 0.85 [95% confidence interval (CI) 0.83-0.88] and the specificity was 0.95 (0.93-0.96). The pooled sensitivity and specificity of chest radiography were 0.47 (0.44-0.51) and 0.37 (0.34-0.40), respectively. The per-lesion detection rate was 2.90 (95% CI 2.63-3.19). DTS has higher diagnostic accuracy than chest radiography for detection of pulmonary nodules. Chest radiography has low sensitivity but similar specificity, comparable with that of DTS. Advances in knowledge: DTS has higher diagnostic accuracy than chest radiography for the detection of pulmonary nodules.


Chaperonology: The Third Eye on Brain Gliomas.
The European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial has validated as a current regimen for high-grade gliomas (HGG) a maximal safe surgical resection followed by radiotherapy with concurrent temozolamide. However, it is essential to balance maximal tumor resection with preservation of the patient's neurological functions. Important developments in the fields of pre-operative and intra-operative neuro-imaging and neuro-monitoring have ameliorated the survival rate and the quality of life for patients affected by HGG. Moreover, even though the natural history remains extremely poor, advancement in the molecular and genetic fields have opened up new potential frontiers in the management of this devastating brain disease. In this review, we aim to present a comprehensive account of the main current pre-operative, intra-operative and molecular approaches to HGG with particular attention to specific chaperones, also called heat shock proteins (Hsps), which represent potential novel biomarkers to detect and follow up HGG, and could also be therapeutic agents.


A 140-bp-long palindromic sequence induces double-strand breaks during meiosis in the yeast Saccharomyces cerevisiae.
Palindromic sequences have the potential to form hairpin or cruciform structures, which are putative substrates for several nucleases and mismatch repair enzymes. A genetic method was developed to detect such structures in vivo in the yeast Saccharomyces cerevisiae. Using this method we previously showed that short hairpin structures are poorly repaired by the mismatch repair system in S. cerevisiae. We show here that mismatches, when present in the stem of the hairpin structure, are not processed by the repair machinery, suggesting that they are treated differently than those in the interstrand base-paired duplex DNA. A 140-bp-long palindromic sequence, on the contrary, acts as a meiotic recombination hotspot by generating a site for a double-strand break, an initiator of meiotic recombination. We suggest that long palindromic sequences undergo cruciform extrusion more readily than short ones. This cruciform structure then acts as a substrate for structure-specific nucleases resulting in the formation of a double-strand break during meiosis in yeast. In addition, we show that residual repair of the short hairpin structure occurs in an MSH2-independent pathway.


Predictive ability of the CHADS2 and CHA2DS2-VASc scores for stroke after transcatheter aortic balloon-expandable valve implantation: an Italian Transcatheter Balloon-Expandable Valve Implantation Registry (ITER) sub-analysis.
Stroke incidence after transcatheter aortic valve implantation (TAVI) still represents a concern. This multicentre study aimed at investigating the hypothesis that CHADS2 and CHA2DS2-VASc scores may be used to predict perioperative stroke after TAVI. The Italian Transcatheter Balloon-Expandable Valve Implantation Registry (ITER) is a multicentre, prospective registry of patients undergoing balloon-expandable TAVI using Edwards Sapien and Sapien XT prosthesis between 2007 and 2012. The primary end-point of this study was the 30-day stroke rate. Secondary safety end-points were all the major adverse events based on Valve Academic Research Consortium (VARC-2) criteria. One thousand nine hundred and four patients were enrolled in the registry. Mean age was 81.6 ± 6.2 years and 1147 (60.2%) patients were female; mean CHADS2 and CHA2DS2-VASc scores were 2.2 ± 0.8 and 4.4 ± 1.1, respectively. Fifty-four (2.8%) patients had a stroke within 30 days. At multivariable logistic regression analysis, CHA2DS2-VASc (OR: 1.35, 95% CI: 1.03-1.78; P = 0.031) and previous cardiac surgery (OR: 1.96, 95% CI: 1.06-3.6; P = 0.033) but not CHADS2 (OR: 1.05, 95% CI: 0.76-1.44; P = 0.77) were found to be independent predictors of in-hospital stroke. A CHA2DS2-VASc score ≥5 was strongly related to the occurrence of in-hospital stroke (OR: 2.51, 95% CI: 1.38-4.57; P= 0.001). However, CHA2DS2-VASc score showed only poor accuracy for in-hospital stroke with a trend for better accuracy when compared with CHADS2 score (area under the curve: 0.61, 95% CI: 0.59-0.63 vs 0.51; 95% CI: 0.49-0.54, respectively, P = 0.092). In TAVI patients, CHA2DS2-VASc provided a strong correlation for in-hospital stroke but with low accuracy. Dedicated scores to properly tailor procedures and preventive strategies are needed.


Minimal haemodynamic system model including ventricular interaction and valve dynamics.
Characterising circulatory dysfunction and choosing a suitable treatment is often difficult and time consuming, and can result in a deterioration in patient condition, or unsuitable therapy choices. A stable minimal model of the human cardiovascular system (CVS) is developed with the ultimate specific aim of assisting medical staff for rapid, on site modelling to assist in diagnosis and treatment. Models found in the literature simulate specific areas of the CVS with limited direct usefulness to medical staff. Others model the full CVS as a closed loop system, but they were found to be very complex, difficult to solve, or unstable. This paper develops a model that uses a minimal number of governing equations with the primary goal of accurately capturing trends in the CVS dynamics in a simple, easily solved, robust model. The model is shown to have long term stability and consistency with non-specific initial conditions as a result. An "open on pressure close on flow" valve law is created to capture the effects of inertia and the resulting dynamics of blood flow through the cardiac valves. An accurate, stable solution is performed using a method that varies the number of states in the model depending on the specific phase of the cardiac cycle, better matching the real physiological conditions. Examples of results include a 9% drop in cardiac output when increasing the thoracic pressure from -4 to 0 mmHg, and an increase in blood pressure from 120/80 to 165/130 mmHg when the systemic resistance is doubled. These results show that the model adequately provides appropriate magnitudes and trends that are in agreement with existing data for a variety of physiologically verified test cases simulating human CVS function.


Cardiac autonomic functions derived from short-term heart rate variability recordings associated with nondiagnostic results of treadmill exercise testing.
Analysis of short-term (5-minute) heart rate variability (HRV) may provide useful information about autonomic nervous control of the cardiovascular system. The aim of the present study was to evaluate the association between the results of treadmill exercise testing (TET) and short-term (5-minute) HRV. Patients undertaking TET were anteriorly evaluated with short-term (5-minute) HRV over time (SDNN, RMSSD, NN50 count, pNN50) and frequency (LF, HF, total power) domains. Among 414 patients, 32 individuals (7.7%; 14 men) had nondiagnostic results. The nondiagnostic group had older age, higher body mass index, more hypertension, lower SDNN, lower LF, and higher HF than the negative group. After adjustment for potential confounders, SDNN (OR 0.94, 95% CI 0.91-0.97; P = 0.01), RMSSD (OR 0.96, 95% CI 0.93-0.99; P = 0.02), NN50 count (OR 0.98, 95% CI 0.97-1.00; P = 0.04) and LF (OR 0.96, 95% CI 0.96-0.99; P = 0.03) were negatively related to nondiagnostic results, and HF showed a positive effect (OR 1.04, 95% CI 1.01-1.05; P = 0.02). No HRV indices were significantly associated with positive results. Our study suggested that cardiac autonomic indices derived from short-term HRV recordings might predict nondiagnostic results of TET.


A family of intermediate filament-like proteins is sequentially assembled into the cytoskeleton of Toxoplasma gondii.
The intracellular protozoan parasite Toxoplasma gondii divides by a unique process of internal budding that involves the assembly of two daughter cells within the mother. The cytoskeleton of Toxoplasma, which is composed of microtubules associated with an inner membrane complex (IMC), has an important role in this process. The IMC, which is directly under the plasma membrane, contains a set of flattened membranous sacs lined on the cytoplasmic side by a network of filamentous proteins. This network contains a family of intermediate filament-like proteins or IMC proteins. In order to elucidate the division process, we have characterized a 14-member subfamily of Toxoplasma IMC proteins that share a repeat motif found in proteins associated with the cortical alveoli in all alveolates. By creating fluorescent protein fusion reporters for the family members we determined the spatiotemporal patterns of all 14 IMC proteins through tachyzoite development. This revealed several distinct distribution patterns and some provide the basis for novel structural models such as the assembly of certain family members into the basal complex. Furthermore we identified IMC15 as an early marker of budding and, lastly, the dynamic patterns observed throughout cytokinesis provide a timeline for daughter parasite development and division.


[Surgical robotics, short state of the art and prospects].
State-of-the-art robotized systems developed for surgery are either remotely controlled manipulators that duplicate gestures made by the surgeon (endoscopic surgery applications), or automated robots that execute trajectories defined relatively to pre-operative medical imaging (neurosurgery and orthopaedic surgery). This generation of systems primarily applies existing robotics technologies (the remote handling systems and the so-called "industrial robots") to current surgical practices. It has contributed to validate the huge potential of surgical robotics, but it suffers from several drawbacks, mainly high costs, excessive dimensions and some lack of user-friendliness. Nevertheless, technological progress let us anticipate the appearance in the near future of miniaturised surgical robots able to assist the gesture of the surgeon and to enhance his perception of the operation at hand. Due to many in-the-body articulated links, these systems will have the capability to perform complex minimally invasive gestures without obstructing the operating theatre. They will also combine the facility of manual piloting with the accuracy and increased safety of computer control, guiding the gestures of the human without offending to his freedom of action. Lastly, they will allow the surgeon to feel the mechanical properties of the tissues he is operating through a genuine "remote palpation" function. Most probably, such technological evolutions will lead the way to redesigned surgical procedures taking place inside new operating rooms featuring a better integration of all equipments and favouring cooperative work from multidisciplinary and sometimes geographically distributed medical staff.


Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses.
We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor-alpha or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.


Efficacy and Application Strategies for Propiconazole as a New Postharvest Fungicide for Managing Sour Rot and Green Mold of Citrus Fruit.
Few postharvest treatments are available for managing sour rot of citrus caused by Galactomyces citri-aurantii and they are generally not very effective. The demethylation-inhibiting (DMI) triazole fungicides propiconazole and cyproconazole were found to be highly effective and more efficacious than other DMIs evaluated, such as metconazole and tebuconazole, in reducing postharvest sour rot of citrus. Additional studies were conducted with propiconazole as a postharvest treatment because it has favorable toxicological characteristics for food crop registration in the United States and the registrant supports a worldwide registration. Regression and covariance analyses were performed to determine optimal time of application after inoculation and fungicide rate. In laboratory studies, decay incidence increased when propiconazole applications were delayed from 8 to 24 h (lemon) or 18 to 42 h (grapefruit) after inoculation. Effective rates of the fungicide were 64 to 512 μg/ml and were dependent on inoculum concentration of the sour rot pathogen and on the type of citrus fruit. Propiconazole was found to be compatible with sodium hypochlorite at 100 μg/ml and 1 to 3% sodium bicarbonate without loss of efficacy for decay control on lemon. The addition of hydrogen peroxide/peroxyacetic acid at 80 μg/ml slightly decreased the effectiveness of propiconazole. Heated (48°C) solutions of propiconazole did not significantly improve the efficacy compared with solutions at 22°C. In experimental packing-line studies, aqueous in-line drenches applied alone or followed by applications of the fungicide in storage or packing fruit coatings were highly effective, reducing sour rot to between 0 and 1.2% compared with 83.8% decay incidence in the control when treatments were made up to 16 h after inoculation. When the fungicide was applied in either fruit coating, decay was only reduced to 49.1 to 57.1% incidence. Tank mixtures of propiconazole with the citrus postharvest fungicides fludioxonil and azoxystrobin were highly effective in reducing green mold caused by isolates of Penicillium digitatum sensitive or moderately resistant to imazalil and sour rot. Propiconazole will be an important postharvest fungicide for managing sour rot of citrus and potentially can be integrated into current management practices to reduce postharvest crop losses caused by DMI-sensitive isolates of P. digitatum.


Biochemical characterization of the dicing activity of Dicer-like 2 in the model filamentous fungus Neurospora crassa.
Dicing of double-stranded RNA (dsRNA) into small RNA is an essential process to trigger transcriptional and post-transcriptional gene silencing. Using cell-free extracts of the model filamentous fungus Neurospora crassa, we successfully detected the dicing activity of one of two N. crassa Dicers NcDCL2. The predominant 23-nucleotide (nt) cleavage product was always detected from 30-nt to 130-nt dsRNA substrates, and additional products of approximately 18 to 28 nt were occasionally produced. The enzymatic properties of NcDCL2 are different from those of insect and plant small interfering RNA (siRNA)-producing Dicers, Drosophila melanogaster Dicer-2 and Arabidopsis thaliana DCL3 and DCL4 (AtDCL3 and AtDCL4). Whereas AtDCL3 and AtDCL4 preferentially cleave short and long dsRNAs, respectively, NcDCL2 cleaved both short and long dsRNAs. These results suggest that N. crassa has a single siRNA-producing Dicer NcDCL2, which is a prototype of plant siRNA-producing Dicers with distinct functions in diverse RNA silencing pathways. The dicing assay reported here is convenient to detect and biochemically characterize the dicing activities of both plant and fungal Dicers, and is likely applicable to other organisms.


Changes in hippocampal volume during a preceding 10-year period do not correlate with cognitive performance and hippocampal blood‒brain barrier permeability in cognitively normal late-middle-aged men.
Hippocampal blood-brain barrier (BBB) permeability may increase in normal healthy ageing and contribute to neurodegenerative disease. To examine this hypothesis, we investigated the correlation between blood-brain barrier (BBB) permeability, regional brain volume, memory functions and health and lifestyle factors in The Metropolit 1953 Danish Male Birth Cohort. We used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a gadolinium-based contrast agent to assess BBB permeability in 77 participants in the cohort. BBB permeability was measured as Ki values in the hippocampus, thalamus and white matter. Over a 10-year period, we observed progressive atrophy of both the left and right hippocampus (p = 0.001). There was no significant correlation between current BBB permeability and hippocampal volume, prior atrophy or cognition. The hippocampus volume ratio was associated with better visual and verbal memory scores (p < 0.01). Regional BBB differences revealed higher Ki values in the hippocampus and white matter than in the thalamus (p < 0.001). Participants diagnosed with type II diabetes had significantly higher BBB permeability in the white matter (p = 0.015) and thalamus (p = 0.016), which was associated with a higher Fazekas score (p = 0.024). We do not find evidence that BBB integrity is correlated with age-related hippocampal atrophy or cognitive functions. The association between diabetes, white matter hyperintensities and increased BBB permeability is consistent with the idea that cerebrovascular disease compromises BBB integrity. Our findings suggest that the hippocampus is particularly prone to age-related atrophy, which may explain some of the cognitive changes that accompany older age, but this prior atrophy is not correlated with current BBB permeability.


Modeling Superimposed Preeclampsia Using Ang II (Angiotensin II) Infusion in Pregnant Stroke-Prone Spontaneously Hypertensive Rats.
Hypertensive disorders of pregnancy are the second leading cause of maternal deaths worldwide. Superimposed preeclampsia is an increasingly common problem and often associated with impaired placental perfusion. Understanding the underlying mechanisms and developing treatment options are crucial. The pregnant stroke-prone spontaneously hypertensive rat has impaired uteroplacental blood flow and abnormal uterine artery remodeling. We used Ang II (angiotensin II) infusion in pregnant stroke-prone spontaneously hypertensive rats to mimic the increased cardiovascular stress associated with superimposed preeclampsia and examine the impact on the maternal cardiovascular system and fetal development. Continuous infusion of Ang II at 500 or 1000 ng/kg per minute was administered from gestational day 10.5 until term. Radiotelemetry and echocardiography were used to monitor hemodynamic and cardiovascular changes, and urine was collected prepregnancy and throughout gestation. Uterine artery myography assessed uteroplacental vascular function and structure. Fetal measurements were made at gestational day 18.5, and placentas were collected for histological and gene expression analyses. The 1000 ng/kg per minute Ang II treatment significantly increased blood pressure (P<0.01), reduced cardiac output (P<0.05), and reduced diameter and increased stiffness of the uterine arteries (P<0.01) during pregnancy. The albumin:creatinine ratio was increased in both Ang II treatment groups (P<0.05; P<0.0001). The 1000 ng/kg per minute-treated fetuses were significantly smaller than vehicle treatment (P<0.001). Placental expression of Ang II receptors was increased in the junctional zone in 1000 ng/kg per minute Ang II-treated groups (P<0.05), with this zone showing depletion of glycogen content and structural abnormalities. Ang II infusion in pregnant stroke-prone spontaneously hypertensive rats mirrors hemodynamic, cardiac, and urinary profiles observed in preeclamptic women, with evidence of impaired fetal growth.


Estimating health expenditure shares from household surveys.
To quantify the effects of household expenditure survey characteristics on the estimated share of a household's expenditure devoted to health. A search was conducted for all country surveys reporting data on health expenditure and total household expenditure. Data on total expenditure and health expenditure were extracted from the surveys to generate the health expenditure share (i.e. fraction of the household expenditure devoted to health). To do this the authors relied on survey microdata or survey reports to calculate the health expenditure share for the particular instrument involved. Health expenditure share was modelled as a function of the survey's recall period, the number of health expenditure items, the number of total expenditure items, the data collection method and the placement of the health module within the survey. Data exists across space and time, so fixed effects for territory and year were included as well. The model was estimated by means of ordinary least squares regression with clustered standard errors. A one-unit increase in the number of health expenditure questions was accompanied by a 1% increase in the estimated health expenditure share. A one-unit increase in the number of non-health expenditure questions resulted in a 0.2% decrease in the estimated share. Increasing the recall period by one month was accompanied by a 6% decrease in the health expenditure share. The characteristics of a survey instrument examined in the study affect the estimate of the health expenditure share. Those characteristics need to be accounted for when comparing results across surveys within a territory and, ultimately, across territories.


Acute compartment syndrome due to extravasation of peripheral intravenous blood transfusion.
Extravasation is an inadvertent injection or leakage of fluid and drugs in the extravascular or subcutaneous space. The extravasation by massive transfused blood results in the elevation of intra-compartmental pressures. Severely increased pressure may lead to acute compartment syndrome (ACS). A 50-year-old man underwent craniectomy for traumatic subdural hemorrhage of the brain. During intraoperative periods, the blood components were transfused by rapid transfusion device and manual pressurized pumping through the central and peripheral lines because of hemorrhagic hypovolemic shock. Approximately 30 minutes after transfusion, we found a hardened right low leg that was obscured by the surgical drape. Immediately, fasciotomy was performed to release all four compartments. The early recognition and treatment of ACS were important factors contributing to anatomical structure salvage and preservation of function. Anesthesia providers should check the site of the insertion of the intravenous catheter, especially while pressurized massive transfusion via the peripheral intravenous catheter.


Functional outcomes by age for inpatient cancer rehabilitation: a retrospective chart review.
Cancer-related impairments result in disabilities similar to those typically encountered in inpatient rehabilitation settings; however, the use of rehabilitation services by cancer survivors is low. This is particularly important for older adults as they are at higher risk for cancer. This retrospective study collected data from medical records from 215 charts of patients admitted to an inpatient physical rehabilitation hospital, within a 5-year period, with a primary diagnosis of cancer. Mean age was 61 years (SD = 15.7) for 109 (51%) females and 106 (49%) males. Regardless of age, patients achieved significant functional improvement, as shown by their FIM scores (t = 23.06, p < .0001), from admission to discharge. The results have several important implications related to cancer survivorship among older adults. With a push toward aging in place, maintaining optimal physical functioning is crucial. Physical rehabilitation benefited the functional outcomes of this group of cancer survivors regardless of age.


Predictive modelling of the 3-D structure of interleukin-13.
Several atomic structures are now available for the family of helical cytokines, which includes growth hormone as well as many of the interleukins. Using structural information from five members of this family, two alternative models of interleukin (IL)-13 are proposed. IL-13 has biological properties similar to those of IL-4 and, like the other interleukins, is a potentially important pharmaceutical target. The model of IL-13 is discussed and compared with the known interleukin structures.


Protein-polyelectrolyte interactions: Monitoring particle formation and growth by nanoparticle tracking analysis and flow imaging microscopy.
The purpose of this study was to investigate the formation and growth kinetics of complexes of proteins and oppositely charged polyelectrolytes. Equal volumes of IgG and dextran sulfate (DS) solutions, 0.01 mg/ml each in 10mM phosphate, pH 6.2, were mixed. At different time points, samples were taken and analyzed by nanoparticle tracking analysis (NTA), Micro-Flow Imaging (MFI) and size-exclusion chromatography (SEC). SEC showed a huge drop in monomer content (approximately 85%) already 2 min after mixing, while a very high nanoparticle (size up to 500 nm) concentration (ca. 9 × 10(8)/ml) was detected by NTA. The nanoparticle concentration gradually decreased over time, while the average particle size increased. After a lag time of about 1.5h, a steady increase in microparticles was measured by MFI. The microparticle concentration kept increasing up to about 1.5 × 10(6)/ml until it started to slightly decrease after 10h. The average size of the microparticles remained in the low-μm range (1-2 μm) with a slight increase and broadening of the size distribution in time. The experimental data could be fitted with Smoluchowski's perikinetic coagulation model, which was validated by studying particle growth kinetics in IgG:DS mixtures of different concentrations. In conclusion, the combination of NTA and MFI provided novel insight into the kinetics and mechanism of protein-polyelectrolyte complex formation.


One-Year Follow-Up of the Effectiveness of Cognitive Behavioral Group Therapy for Patients' Depression: A Randomized, Single-Blinded, Controlled Study.
The aim of the study was to investigate the long-term (one year) effectiveness of a 12-session weekly cognitive behavior group therapy (CBGT) on patients with depression. This was a single-blind randomized controlled study with a 2-arm parallel group design. Eighty-one subjects were randomly assigned to 12 sessions intervention group (CBGT) or control group (usual outpatient psychiatric care group) and 62 completed the study. The primary outcome was depression measured with Beck Depression Inventory (BDI-II) and Hamilton Rating Scale for Depression (HRSD). The secondary outcomes were automatic thoughts measured by automatic thoughts questionnaire (ATQ). Both groups were evaluated at the pretest (before 2 weeks), posttest (after 12 therapy sessions), and short- (3 months), medium- (6 months), and long-term (12 months) follow-up. After receiving CBGT, the experimental group had a statistically significant reduction in the BDI-II from 40.30 at baseline to 17.82 points at session eight and to 10.17 points at postintervention (P < 0.001). Similar effects were seen on the HRSD. ATQ significantly decreased at the 12th session, 6 months after sessions, and 1 year after the sessions ended (P < 0.001). We concluded that CBGT is effective for reducing depression and continued to be effective at 1 year of follow-up.


The PCP pathway instructs the planar orientation of ciliated cells in the Xenopus larval skin.
Planar cell polarity (PCP) is a property of epithelial tissues where cellular structures coordinately orient along a two-dimensional plane lying orthogonal to the axis of apical-basal polarity. PCP is particularly striking in tissues where multiciliate cells generate a directed fluid flow, as seen, for example, in the ciliated epithelia lining the respiratory airways or the ventricles of the brain. To produce directed flow, ciliated cells orient along a common planar axis in a direction set by tissue patterning, but how this is achieved in any ciliated epithelium is unknown. Here, we show that the planar orientation of Xenopus multiciliate cells is disrupted when components in the PCP-signaling pathway are altered non-cell-autonomously. We also show that wild-type ciliated cells located at a mutant clone border reorient toward cells with low Vangl2 or high Frizzled activity and away from those with high Vangl2 activity. These results indicate that the PCP pathway provides directional non-cell-autonomous cues to orient ciliated cells as they differentiate, thus playing a critical role in establishing directed ciliary flow.


CT colonography and cost-effectiveness.
CT colonography (CTC) is increasingly advocated as an effective initial screening tool for colorectal cancer. Nowadays, policy-makers are increasingly interested in cost-effectiveness issues. A number of studies assessing the cost-effectiveness of CTC have been published to date. The majority of findings indicate that CTC is probably not cost-effective when colonoscopy is available, but this conclusion is sensitive to a number of key parameters. This review discusses the findings of these studies, and considers those factors which most influence final conclusions, notably intervention costs, compliance rates, effectiveness of colonoscopy, and the assumed prevalence and natural history of diminutive advanced polyps.


NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist.
The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca(2+) signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca(2+) mobilization by d-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca(2+) entry. BZ194 specifically and effectively blocked NAADP-stimulated [(3)H]ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca(2+) mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca(2+) mobilization, such as nuclear translocation of "nuclear factor of activated T cells" (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4(+) effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases.


Smart chemical taste sensor for determination and prediction of taste qualities based on a two-phase optimized radial basis function network.
A novel, smart, chemical taste sensor that realistically mimics the behavior of the human gustatory system is described. The taste sensor consists of an array of electrochemical sensors that represent the gustatory receptors on the human tongue, and a two-phase optimized radial basis function network (RBFN) to represent the human brain, which comprehensively analyzes the gustatory stimulation and judges the overall taste. In the illustrated model, eight electrodes were fabricated to determine the eight major taste-causing substances, Na+, K+, Cl-, H+, sucrose, glucose, glutamate, and caffeine. The detected signals were fed to a two-phase RBFN optimized by the implementation of a basis optimization algorithm and weight decay term for appropriate data processing. The first phase of the two-phase RBFN quantifies the amount of taste-causing substances in food samples from the responses of the electrodes. These results are then fed to the second phase, which correlates the amount of substances with the overall taste. The final output is scored on a scale of 1-5 for each of the five basic tastes sensed by the human gustatory system, which are saltiness, sourness, sweetness, bitterness, and umami. The constructed network estimated the intensity of the basic tastes of 30 drink varieties with an average relative error of 7.0% compared to the human scores. The network could also estimate the variance in the human sensory perception. Moreover, the sensor successfully predicted the interactions of tastes such as suppression of bitterness by sweetness and enhancement of umami by saltiness, which are illusions sensed by the human gustatory system. With these abilities, the novel taste sensor can be considered as a quantitative yet humanlike sensor with a great potential for practical applications.


Incidental finding of retrocaval ureter in a patient without hydronephrosis.
Retrocaval or circuncaval ureters are rare congenital anomaly, in which the ureter is located posterior to the inferior vena cava (IVC). Usually, patients present symptoms in the 3rd or 4th decade of life due to compression of the ureter by the IVC, with obstruction of the urinary flow and consequent hydronephrosis. Herein we report the case of a 62-year-old patient who underwent ultrasonography to investigate abdominal pain. The patient had bilateral renal lithiasis associated with urinary tract dilation with no obvious obstruction. Computed tomography of the abdomen demonstrated a retrocaval ureter without hydronephrosis.


Monitoring Countries in a Changing World: A New Look at DIF in International Surveys.
This paper discusses the issue of differential item functioning (DIF) in international surveys. DIF is likely to occur in international surveys. What is needed is a statistical approach that takes DIF into account, while at the same time allowing for meaningful comparisons between countries. Some existing approaches are discussed and an alternative is provided. The core of this alternative approach is to define the construct as a large set of items, and to report in terms of summary statistics. Since the data are incomplete, measurement models are used to complete the incomplete data. For that purpose, different models can be used across countries. The method is illustrated with PISA's reading literacy data. The results indicate that this approach fits the data better than the current PISA methodology; however, the league tables are nearly identical. The implications for monitoring changes over time are discussed.


Public perceptions of disease severity but not actionability correlate with interest in receiving genomic results: nonalignment with current trends in practice.
Frameworks highlighting disease actionability and severity are evolving to address the need to organize results from genome-wide analyses. This approach represents a paradigm shift from consultations focused on one or more genes to multiple genes for multiple disorders. Empirical input from the general population is lacking, yet seems essential for understanding how to maximize patient autonomy and satisfaction in the decision-making process. We conducted a cross-sectional online survey with a representative sample of 900 US adults and assessed the participants' perceptions and attitudes toward disease actionability and severity, ranking hypothetical scenarios for these properties, and explored correlations with interest in learning test results. Most respondents (>85%) rated actionability and severity as useful concepts; 46.6% indicated actionability alone would be adequate for decision making. Over half of them (53.8%) reported being very/extremely confident in their ability to score for actionability and severity. The participants' scoring of medical scenarios varied significantly between individuals. Scores for severity but not actionability were correlated with interest in learning genetic results. Subsets of the respondents projected wanting all results (30%) or no results (16%). The use of expert-created lists was acceptable to 43%. The respondents from the general population were confident in making their own decisions. The responses suggested different priorities than current expert-driven approaches. The emphasis on binning genes may be missing a complementary, simplifying approach of grouping patients based upon their all/none interest in genomic results. This study illuminates important differences between the general public and genetic experts.