Effects of E-selectin and P-selectin blockade on neutrophil sequestration in tissues and neutrophil oxidative burst in burned rats.
Neutrophil deposition in tissues (leukosequestration) after shock may produce local tissue injury from proteases and high-energy oxygen species released from sequestered neutrophils. The initial step in the binding of neutrophils to capillary endothelium is the interaction of adhesion molecule (selectin) receptors between neutrophils and endothelial cells. We quantified leukosequestration in the tissues of burned rats using two methods of analysis: a) measurement of lung myeloperoxidase; and b) measurement of radiolabeled neutrophils and erythrocytes deposited in multiple tissues. We then determined the ability of a selectin receptor blocking agent to affect neutrophil deposition in tissues after burn injury. Prospective, controlled, laboratory study. University research laboratory. Male Wistar rats (200 to 300 g). After tracheostomy and venous cannulation, rats received 17% total body surface area full-thickness contact burns and were resuscitated with saline (20 mL i.p.). Experimental animals received 2 mg/kg body weight i.v. administration of a P- and E-selectin blocking monoclonal antibody, CY-1747, immediately after burn. Lung tissue neutrophils were estimated by measuring myeloperoxidase in lung tissue. Neutrophil retention in lung, liver, spleen, gut, skin, muscle, kidney, and brain tissues was determined by removing (preburn) and differentially radiolabeling neutrophils (111In) and erythrocytes (51Cr), reinfusing cells 4.5 hrs after burn, and measuring tissue radioactivity 30 mins later. Edema was estimated by measuring extravasated 125 I-labeled albumin in the various tissues. Peripheral blood neutrophils were analyzed for intracellular hydrogen peroxide content, utilizing a fluorescent dye that reacts with hydrogen peroxide, coupled with analysis of cell fluorescence by flow cytometry. Myeloperoxidase concentration was increased in lungs 5 hrs after burn (p < .05), indicating neutrophil deposition. Radioisotope studies demonstrated significant (p < .05) leukosequestration into the lung, gut, kidney, skin, and brain tissues at 5 hrs after burn. Flow cytometry showed increased intracellular hydrogen peroxide content in peripheral blood neutrophils 5 hrs after burn. Tissue edema, manifested by radiolabeled albumin retention, was not seen in any tissues. Postburn neutrophil deposition in lungs and liver was blocked (p < .05) by administration of CY-1747 after burn, but maximal neutrophil hydrogen peroxide content was unaffected. Burn injury in rats results in accumulation of neutrophils in multiple tissues. Neutrophil deposition in the lungs and liver is blocked by administration of the E/P-selectin blocking antibody, CY-1747. Since sequestration of metabolically active neutrophils may induce tissue injury, therapies that block postburn leukosequestration may improve clinical outcomes by limiting remote tissue injury.


Microprocessor-controlled freezing device for cryopreservation of cell samples.
A freezing device for cryopreservation of blood mononuclear cells has been developed. The device is microcontroller operated, allowing cell freezing by a fully automatic, unattended process. To ensure optimum preservation, the temperature in the cell suspension uniformly decreases from room temperature to -100 degrees C and then the samples are transferred to long-term storage. The performance of the device has been tested using both physiological solution and a sample of cell suspension. The control of temperature variation of cell suspension in the entire temperature range has been realised with an accuracy better than +/- 0.1%. The viability of cells recovered from the frozen samples was 95%. The nitrogen consumption for one cycle of cryopreservation was 1.51. In addition to the fully automatic mode, the manual and semi-automatic modes are available for research purposes. The device has been designed using low cost and widely used electronic components and materials, it is compact and simple to operate.


Triplet Energy Transfer from Perovskite Nanocrystals Mediated by Electron Transfer.
Triplet energy transfer from colloidal nanocrystals is a novel approach to sensitizing molecular triplets that are important for many applications. Recent studies suggest that this triplet transfer can be mediated by a hole transfer process when it is energetically allowed. In contrast, electron-transfer-mediated triplet transfer has not been observed yet, which is likely due to hole-trapping in typical II-VI group nanocrystals inhibiting the hole transfer step following initial electron transfer and hence disrupting a complete triplet exciton transfer. Here we report electron-transfer-mediated triplet energy transfer from CsPbCl3 and CsPbBr3 perovskite nanocrystals to surface-anchored rhodamine molecules. The mechanism was unambiguously established by ultrafast spectroscopy; control experiments using CdS nanocrystals also confirmed the role of hole-trapping in inhibiting this mechanism. The sensitized rhodamine triplets engaged in a variety of applications such as photon upconversion and singlet oxygen generation. Compared to conventional one-step triplet transfer, the electron-transfer-mediated mechanism is less demanding in terms of interfacial electronic coupling and hence is more generally implementable. Overall, this study not only establishes a complete framework of triplet energy transfer across nanocrystal/molecule interfaces but also greatly expands the scope of molecular triplet sensitization using nanocrystals.


[Familial hypertrophic cardiomyopathy: genes, mutations and animal models. A review].
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, which may afflict as many as 1 in 500 subjects (0.2%), being probably the most common hereditary cardiovascular disease and the most common cause of sudden cardiac death (SCD). Hypertrophic cardiomyopathy is characterized by the presence of unexplained left ventricular hypertrophy (in absence of hypertension, valvular disease, etc), which is usually asymmetric and involves the ventricular septum. Molecular genetic studies have identified eleven genes that code proteins of the sarcomere that are associated with the HCM; the beta-myosin heavy chain gene (MYH7), alpha-myosin heavy chain (MYH6), cardiac troponin T (TNNT2); cardiac troponin C (TNNC1), alpha-tropomyosin (TPM1), myosin binding protein-C (MYBPC3), cardiac troponin (TNNI3), essential and regulatory light chain genes (MYL3 and MYL2, respectively), cardiac alpha-actin gene (ACTC) and titin (TTN). The objective of this paper is the revision of the current state of the knowledge on (1) the organization and mutations of the HCM causing genes and their proteins and (2) the animal models developed for the study of the genes, mutations and proteins in the hypertrophic cardiomyopathy.


Ethnic differences of the care pathway following an out-of-hospital cardiac event: A systematic review.
This systematic review aimed to determine to what extent and why the care pathways for acute cardiac events in the community might differ for minoritised ethnic populations compared to non-minoritised populations. It also sought to identify the barriers and enablers that could influence variations in access to care for minoritised populations. A multi-database search was conducted for articles published between 1 January 2000 and 1 January 2023. A combination of MeSH terms and keywords was used. Inclusion criteria for papers were published in English, adult population, the primary health condition was an acute cardiac event, and the primary outcomes were disaggregated by ethnicity or race. A narrative review of extracted data was performed, and findings were reported according to the PRISMA 2020 guidelines. Of the 3552 articles identified using the search strategy, 40 were deemed eligible for the review. Studies identified a range of variables in the care pathway that differed by ethnicity or race. These could be grouped as time to care, transportation, event related-variables, EMS interactions and symptoms. A meta-analysis was not performed due to heterogeneity across the studies. The extent and reasons for differences in cardiac care pathways are considerable. There are several remediable barriers and enablers that require attention to achieve equitable access to care for minoritised populations.


Sialic acid: effect of removal on calcium exchangeability of cultured heart cells.
Specific removal of sialic acid from cultured heart cells with purified neuraminidase increases cellular calcium exchangeability. Potassium exchange is unaffected or slightly decreased. Sialic acid removal also permits lanthanum, normally restricted to the cellular surface, to enter the cells and displace more than 80 percent of cellular calcium. The results indicate a specific role of cellular surface components in the control of calcium exchangeability in the heart.


A case of orbital apex syndrome due to Pseudomonas aeruginosa infection.
Orbital apex syndrome is commonly been thought to have a poor prognosis. Many cases of this syndrome have been reported to be caused by paranasal sinus mycosis. We encountered a very rare case (60-year-old woman) of sinusitis with orbital apex syndrome due to Pseudomonas aeruginosa infection. She had received insulin and dialysis for diabtes and diabetic nephropathy, moreover anticoagulants after heart by-pass surgery. She underwent endoscopic sinus operation and was treated with antibiotics, but her loss of left vision did not improve. Recently, sinusitis cases due to Pseudomonas aeruginosa were reported to be a increasing. Therefore, we should consider the possibility of Pseudomonas aeruginosa as well as mycosis as infections of the sinus, especially inpatients who are immunocompromised body.


Clonal analysis of the proliferation potential of human bone marrow mesenchymal stem cells as a function of potency.
Human mesenchymal stem cells (MSCs) from bone marrow are a heterogeneous ensemble of progenitors and lineage-committed cells, with a broad range of regenerative properties. Ex vivo expansion to produce sufficient quantities of MSCs is essential for most therapeutic applications. The present study resolves the relationship between proliferation potential of MSCs and their potency. Clonal analysis generated single-cell derived colonies of MSCs that were classified according to their trilineage potential to exhibit adipo- (A), chondro- (C), and osteogenesis (O) as a measure of potency. Multipotent OAC clones were highly proliferative with colony-forming efficiencies that ranged from 35% to 90%; whereas, O clones formed colonies with an efficiency of 5% or less (P < 0.01). Similar trends were evident during ex vivo expansion: for example, the median specific growth rate was 0.8 day(-1) (20 h doubling time) for cultures inoculated with OAC clones and was 5-fold less for inocula of O clones (P < 0.01). OA and OC clones had similar proliferation potentials. More than 75% of cells in subconfluent cultures inoculated with O clones stained positive for senescence-associated β-galactosidase activity vs. less than 10% for OAC clones (P < 0.001). Apoptotic cells were in the minority for all potency groups. Preliminary data generated during clonal analysis suggest that osteogenic potential of MSCs to produce mineralized matrix is a function of potency, as well. These results are discussed in the context of the preparation of efficacious MSC therapies by ex vivo expansion.


Synchrotron-based Mössbauer spectroscopy characterization of sublimated spin crossover molecules.
The spin crossover (SCO) efficiency of [57Fe(bpz)2(phen)] (where bpz = bis(pyrazol-1-yl)borohydride and phen = 9,10-phenantroline) molecules deposited on gold substrates was investigated by means of synchrotron Mössbauer spectroscopy. The spin transition was driven thermally, or light induced via the LIESST (light induced excited spin-state trapping) effect. Both sets of measurements show that, once deposited on a gold substrate, the efficiency of the SCO mechanism is modified with respect to molecules in the bulk phase. A correlation in the distribution of hyperfine parameters in the sublimated films, not evidenced so far in the bulk phase, is reported. This translates into geometrical distortions of the first coordination sphere of the iron atom that seem to correlate with the decreased spin conversion. The work reported clearly shows the potentiality of synchrotron Mössbauer spectroscopy for the characterization of nanostructured Fe-based SCO systems, thus resulting as a key tool in view of their applications in innovative nanoscale devices.


Cell therapy from bench to bedside: Hepatocytes from fibroblasts - the truth and myth of transdifferentiation.
Hepatocyte transplantation is an alternative to liver transplantation in certain disorders such as inherited liver diseases and liver failure. It is a relatively less complicated surgical procedure, and has the advantage that it can be repeated several times if unsuccessful. Another advantage is that hepatocytes can be isolated from partly damaged livers which are not suitable for liver transplantation. Despite these advantages hepatocyte transplantation is less popular. Important issues are poor engraftment of the transplanted cells and the scarcity of donor hepatocytes. Generation of "hepatocyte like cells"/iHeps from embryonic stem cells (ES) and induced pluripotent stem cells (iPSCs) by directed differentiation is an emerging solution to the latter issue. Direct conversation or trans-differentiation of fibroblasts to "hepatocyte like cells" is another way which is, being explored. However this method has several inherent and technical disadvantages compared to the directed differentiation from ES or iPSC. There are several methods claiming to be "highly efficient" for generating "highly functional" "hepatocyte like cells". Currently different groups are working independently and coming up with differentiation protocols and each group claiming an advantage for their protocol. Directed differentiation protocols need to be designed, compared, analyzed and tweaked systematically and logically than empirically. There is a need for a well-coordinated global initiative comparable to the Human Genome Project to achieve this goal in the near future.


Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome.
ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The "epi-ADNP-1" episignature included ~ 6000 mostly hypomethylated CpGs, and the "epi-ADNP-2" episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome.


Polyphenol-rich foods and risk of gestational diabetes: a systematic review and meta-analysis.
Animal studies have demonstrated anti-diabetic properties of several food-derived polyphenols, but data in humans remains unclear. This study aimed to review and meta-analyse evidence concerning the effect of the intake of several polyphenol-rich foods on gestational diabetes (GDM) risk. A systematic literature search was conducted in PubMed, Web of Science and Embase databases for observational studies on the association between dietary intake of foods/diets rich in polyphenols and GDM risk. Inclusion criteria were original research articles with full texts published in peer-reviewed English language journals, which investigated foods within the top 100 richest dietary sources of polyphenols and reported odds ratio/relative risk with their corresponding 95% confidence intervals. The quality of included studies was assessed using the Newcastle-Ottawa Scale. The intake of polyphenol-rich foods and dietary patterns in relation to GDM were pooled with fixed- and random-effects models. In total, 12 (10 cohort, 1 cross-sectional and 1 case-control) studies were included for the final systematic review, comprising 124,959 participants and including 5,786 women with GDM. Five studies found a significant, inverse association between the intake of polyphenol-rich foods or Mediterranean diet and GDM, whereas five studies reported no association and two exhibited a positive association. Meta-analyses further showed that the risk of GDM was about halved amongst women with the highest score of Mediterranean diet compared to those with the lowest score. The results suggest that dietary patterns rich in polyphenols may reduce the risk of GDM despite inconclusive evidence for polyphenol-rich food groups.


Medicaid Expansion Increased Coverage, Improved Affordability, And Reduced Psychological Distress For Low-Income Parents.
Despite receiving less attention than their childless counterparts, low-income parents also experienced significant expansions of Medicaid eligibility under the Affordable Care Act (ACA). We used data for the period 2010-15 from the National Health Interview Survey to examine the impacts of the ACA's Medicaid expansion on coverage, access and use, affordability, and health status for low-income parents. We found that eligibility expansions increased coverage, reduced problems paying medical bills, and reduced severe psychological distress. We found only limited evidence of increased use of care among parents in states with the smallest expansions, and no significant effects of the expansions on general health status or problems affording prescription drugs or mental health care. Together, our results suggest that the improvements in mental health status may be driven by reduced stress associated with improved financial security from insurance coverage. We also found large missed opportunities for low-income parents in states that did not expand Medicaid: If these states had expanded Medicaid, uninsurance rates for low-income parents would have fallen by an additional 28 percent.


Chemotactic sensing towards ambient and secreted attractant drives collective behaviour of E. coli.
We simulate the dynamics of a suspension of bacterial swimmers, which chemotactically sense gradients in either ambient or self-secreted attractants (e.g. nutrient or aspartate respectively), or in both. Unlike previous mean field models based on a set of continuum partial differential equations, our model resolves single swimmers and therefore incorporates stochasticity and effects due to fluctuations in the bacterial density field. The algorithm we use is simple enough that we can follow the evolution of colonies of up to over a million bacteria for timescales relevant to pattern formation for E. coli growing in semisolid medium such as agar, or in confined geometries. Our results confirm previous mean field results that the patterns observed experimentally can be reproduced with a model incorporating chemoattractant secretion, chemotaxis (towards gradients in the chemoattractant field), and bacterial reproduction. They also suggest that further experiments with bacterial strains chemotactically moving up both nutrient and secreted attractant field may yield yet more dynamical patterns.


The use of technical-tactical and physical performance indicators to classify between levels of match-play in elite rugby league.
This study aimed to identify which physical and technical-tactical performance indicators (PI) can classify between levels of rugby league match-play. Data were collected from 46 European Super League (ESL) and 36 under-19 Academy (Academy) level matches over two seasons. Thirty-one ESL players and 41 Academy players participated. Microtechnology units were used to analyse the physical PI and matches were videoed and coded for individual technical-tactical PI, resulting in 157 predictor variables. Data were split into training and testing datasets. Random forests (RF) were built to reduce the dimensionality of the data, identify variables of importance and build classification models. To aid practical interpretation, conditional inference (CI) trees were built. Nine variables were identified as most important for backs, classifying between levels with 83% (RF) and 78% (CI tree) accuracy. The combination of variables with the highest classification rate was PlayerLoad2D, PlayerLoadSLOW per Kg body mass and high-speed running distance. Four variables were identified as most important for forwards, classifying with 68% (RF) and 64% (CI tree) accuracy. Defensive play-the-ball losses alone had the highest classification rate for forwards. The identified PI and their unique combinations can be developed during training to aid in progression through the rugby league playing pathway.


Retrospective individual tracking of body mass index in obese and thin adolescents back to childhood.
The objective of this study is to track body mass index (BMI) in obese or thin adolescents from adolescence to childhood on an individual basis. This was performed at a single school with a 12-year combination education system in an urban city in Japan. A total of 617 students in the 3rd grade of senior high school (17 years old) during 2005-2009 were enrolled. Based on the Japanese BMI reference in childhood adjusted for age and gender, obesity and thinness were defined as >=90th percentile and <=5th percentile, respectively. Sixty-three (10.2%) and 84 (13.6%) students were found to be obese and thin, respectively. Complete annual tracking of BMI back to the 1st grade of elementary school (6 years old) (1994-1998) was possible in 47 obese (74.6%) and 67 thin students (80.0%). The most common ages when obesity was first detected were 6-8 years for males, and 12-14 years for females, and the most common ages when thinness was first detected were 12-14 years for males, and 15-17 years for females. Once obesity or thinness started, these conditions remained until 17 years old in most students. Obese students whose obesity started earlier tended to have higher BMIs at 17 years old in both genders. This will be the first tracking study of BMI in obese and thin adolescents on an individual basis. A longitudinal study of BMI during childhood is useful for establishing intervention programs to prevent obesity or thinness in adolescence.


Identification of a novel integrin alphavbeta3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells.
CCN1 (CYR61) is a matricellular inducer of angiogenesis essential for successful vascular development. Though devoid of the canonical RGD sequence motif recognized by some integrins, CCN1 binds to, and functions through integrin alphavbeta3 to promote pro-angiogenic activities in activated endothelial cells. In this study we identify a 20-residue sequence, V2 (NCKHQCTCIDGAVGCIPLCP), in domain II of CCN1 as a novel binding site for integrin alphavbeta3. Immobilized synthetic V2 peptide supports alphavbeta3-mediated cell adhesion; soluble V2 peptide inhibits endothelial cell adhesion to CCN1 and the homologous family members CCN2 (connective tissue growth factor, CTGF) or CCN3 (NOV) but not to collagen. These activities are obliterated by mutation of the aspartate residue in the V2 peptide to alanine. The corresponding D125A mutation in the context of the N-terminal half of CCN1 (domains I and II) greatly diminished direct solid phase binding to purified integrin alphavbeta3 and abolished alphavbeta3-mediated cell adhesion activity. Likewise, soluble full-length CCN1 with the D125A mutation is defective in binding purified alphavbeta3 and impaired in alphavbeta3-mediated pro-angiogenic activities in vascular endothelial cells, including stimulation of cell migration and enhancement of DNA synthesis. In contrast, immobilized full-length CCN1-D125A mutant binds alphavbeta3 and supports alphavbeta3-mediated cell adhesion similar to wild type CCN1. These results indicate that V2 is the primary alphavbeta3 binding site in soluble CCN1, whereas additional cryptic alphavbeta3 binding site(s) in the C-terminal half of CCN1 becomes exposed when the protein is immobilized. Together, these results identify a novel and functionally important binding site for integrin alphavbeta3 and provide a new approach for dissecting alphavbeta3-specific CCN1 functions both in cultured cells and in the organism.


Chronic effects of dietary selenium on juvenile Sacramento splittail (Pogonichthys macrolepidotus).
The chronic effects of dietary selenium (Se) exposure in juvenile Sacramento splittail (Pogonichthys macrolepidotus) were investigated in the laboratory. A total of 960 (40 fish per tank, 3 tanks per diet) 7-month-old juvenile splittail were fed one of eight Purified-Casein diets supplemented with selenized yeast for 9 months in a flow-through system. These diets contained the following: 0.4 (control), 0.7, 1.4, 2.7, 6.6, 12.6, 26.0, and 57.6 mg of Se kg(-1) dry weight. Survival, Se tissue concentration, growth, gross morphology, and liver histopathology were assessed at 5- and 9-month of exposure. Mortalities occurred only in the two highest Se treatments and were accounted for 8.3 and 18.3% at 5-month and 10.0 and 34.3% at 9-month, respectively. Liver and muscle Se concentration were significantly correlated with dietary Se concentration. Fish exposed to 0.4-12.6 mg of Se kg(-1) diets had reached equilibrium in liver Se concentration by 5 month. Splittail fed diets at concentrations > or =26.0 mg of Se kg(-1) had not reached equilibrium in liver, and muscle Se concentrations and grew significantly slower (p < 0.05) at 5- and 9-month exposure. Se-induced deformities were observed in fish fed > or =2.7 mg of Se kg(-1) diets at 5-month and in fish fed > or =0.7 mg of Se kg(-1) diets at 9-month. Fish fed 26.0 and 57.6 mg of Se kg(-1) diets had higher liver lesion scores at 5-month while fish fed 6.6 and 57.6 mg of Se kg(-1) diet had higher liver lesion scores at 9-month. Results indicate that survivals, growth, changes of tissue Se concentrations, and histopathology of juvenile splittail were dose-dependent, but their response thresholds to dietary Se concentrations differed and depended on treatment concentrations and duration of exposure. Chronic exposure to 6.6 mg of Se kg(-1) diet induced deleterious health effects that can potentially impact survival of juvenile splittail.


LncRNA CDKN2B-AS1/miR-141/cyclin D network regulates tumor progression and metastasis of renal cell carcinoma.
The molecular heterogeneity of renal cell carcinoma (RCC) complicates the therapeutic interventions for advanced metastatic disease and thus its management remains a significant challenge. This study investigates the role of the lncRNA CDKN2B-AS1 and miR-141-3p interactions in the progression and metastasis of kidney cancer. Human renal cancer cell lines (ACHN and Caki1), normal RPTEC cells, tissue cohorts, and a series of in vitro assays and in vivo mouse model were used for this study. An overexpression of CDKN2B-AS1 was observed in RCC compared to normal samples in TCGA and our in-house SFVAMC tissue cohorts. Reciprocally, we observed reduced expression of miR-141 in RCC compared to normal in the same cohorts. CDKN2B-AS1 shares regulatory miR-141 binding sites with CCND1 and CCND2 genes. Direct interactions of CDKN2B-AS1/miR-141/Cyclin D1-D2 were confirmed by RNA immunoprecipitation and luciferase reporter assays indicating that CDKN2B-AS1/miR-141/Cyclin D1-D2 acts as a ceRNA network in RCC. Functionally, attenuation of CDKN2B-AS1 and/or overexpression of miR-141 inhibited proliferation, clonogenicity, migration/invasion, induced apoptosis in vitro and suppressed tumor growth in xenograft mouse model. Further, overexpression of CDKN2B-AS1 is positively correlated with poor overall survival of RCC patients. Expression of miR-141 also robustly discriminated malignant from non-malignant tissues and its inhibition in normal RPTEC cells induced pro-cancerous characteristics. CDKN2B-AS1 attenuation or miR-141 overexpression decreased CCND1/CCND2 expression, resulting in reduced RAC1/pPXN that are involved in migration, invasion and epithelial-mesenchymal transition. This study, for the first time, deciphered the role of CDKN2B-AS1/miR-141/Cyclin D axis in RCC and highlights this network as a promising therapeutic target for the regulation of EMT driven metastasis in RCC.


Intravenous colistin use for infections due to MDR Gram-negative bacilli in critically ill paediatric patients: a systematic review and meta-analysis.
Data are limited regarding the clinical effectiveness and safety of intravenous colistin for treatment of infections due to MDR Gram-negative bacilli (GNB) in paediatric ICUs (PICUs). Systematic review of intravenous colistin use in critically ill paediatric patients with MDR-GNB infection in PubMed, Scopus and EMBASE (up to 31 January 2018). Out of 1181 citations, 7 studies were included on the use of intravenous colistin for 405 patients in PICUs. The majority of patients were diagnosed with lower respiratory tract infections, Acinetobacter baumannii being the predominant pathogen. Colistin dosages ranged between 2.6 and 18 mg/kg/day, with only one case reporting a loading dose. Emergence of colistin resistance during treatment was reported in two cases. Nephrotoxicity and neurotoxicity were reported in 6.1% and 0.5%, respectively, but concomitant medications and severe underlying illness limited our ability to definitively associate use of colistin with nephrotoxicity. Crude mortality was 29.5% (95% CI = 21.7%-38.1%), whereas infection-related mortality was 16.6% (95% CI = 12.2%-21.5%). While the reported incidence of adverse events related to colistin was low, reported mortality rates for infections due to MDR-GNB in PICUs were notable. In addition to severity of disease and comorbidities, inadequate daily dosage and the absence of a loading dose may have contributed to mortality. As the use of colistin for treatment of MDR-GNB infections increases, it is imperative to understand whether optimal dosing of colistin in paediatric patients differs across different age groups. Thus, future studies to establish the pharmacokinetic properties of colistin in different paediatric settings are warranted.


Factors determining species richness patterns of breeding birds along an elevational gradient in the Horn of Africa region.
To document the species richness patterns of breeding birds along elevational gradients and explore its drivers in the Horn of Africa region. Horn of Africa region. Breeding birds. Distributional data for breeding birds were collected. Elevational distribution data were extracted, interpolated, and assembled for all birds, passerines, and nonpasserines. In order to tease apart how different environmental factors contributed to the variation in species richness, we found it is necessary to divide the area into four subregions with different climatic regimes and topographic structure, namely western slope, eastern slope, wet side, and dry side. Then, the species richness in each 100-m elevational band was counted along the elevational gradients of each subregion. Pearson's correlation analyses and ordinary least squares (OLS) regressions were used to examine the relationships between species richness and factors. The variation in species richness followed hump-shaped patterns for all subregions, although with peak values at different elevations. The bird species groups on the western and eastern slopes showed low and high plateaus with mid-elevation peaks, respectively, but very low species diversities at the highest elevations. Species richness was significantly correlated with temperature range and productivity in each subregion. The temperature range, area, and productivity explained 82% of the species richness variations for all birds on the western slope. The separate analyses of four area subdivisions provide strong indications of how various factors interact. Productivity and temperature range were the major driving factors for shaping the richness patterns, but deviations from expected patterns suggest modifying roles of mist formation zones in the valleys that deeply intersect the large highlands in the west and rich riparian vegetation where water from cool and humid environments at high elevation reaches lower elevations in the arid east. Conservation is recommended in each subregion based on the elevational richness scenarios.


Diagnosis of pneumococcal pneumonia.
Pneumococcal pneumonia presents peculiar problems to the diagnostician. It is at once the most common form of community-acquired bacterial pneumonia and simultaneously the most difficult to document microbiologically. Bacteremia, empyema, meningitis, or septic arthritis due to S pneumoniae unmistakably verifies this bacterium as the cause of a coexistent pneumonia; this coexistence fortunately occurs infrequently. The diagnostic dilemma arises in the less sick patient. While recognizing the common presence of pneumococci in the oropharynx of healthy individuals, we give undue credence to S pneumoniae cultured from sputum obtained by expectoration. At the same time, pneumococci are frequently not found in cultures of sputum obtained from patients with confirmed bacteremic disease. More invasive techniques (transtracheal aspiration, protected bronchoscopic catheter, lung needle aspiration) are too complex, dangerous, or both for routine use. Attempts to detect pneumococcal antigen in blood, sputum, or urine by modern immunologic techniques give promise of avoiding the problems of either contamination or lack of bacteriologic growth. However, they have not yet been evaluated in sufficiently large groups with pneumonia of independently determined bacterial etiology to calculate test sensitivity and specificity. At the present time then, the careful clinician will use all the epidemiologic and clinical evidence at hand, including a careful Gram's stain and culturing of sputum, blood, and other sources, to arrive at the most likely etiology. The probabilities must be weighed in light of the imprecision of current laboratory confirmation and modified by clinical course. Choice of antimicrobial therapy still favor penicillin for patients with community pneumonia severe enough to warrant hospitalization, despite ominous trends in multiple resistance of S pneumoniae.


Toward Human Rights-Consistent Responses to Health Emergencies: What Is the Overlap between Core Right to Health Obligations and Core International Health Regulation Capacities?
COVID-19 has highlighted the responsibilities of states under the International Health Regulations (IHR), as well as state accountability in case of a breach. These approaches and dimensions are valuable, as many COVID responses have breached human rights. We should also look beyond this crisis and address country preparedness for effective and equitable responses to future infectious disease outbreaks. This paper assesses countries' international legal obligations to be prepared to respond to this and future public health emergencies. It does so from the perspective of the right to health, in interaction with the IHR. We analyze the functional relationship between the right to health and the IHR, focusing in particular on "core obligations" under the right to health and "core capacities" under the IHR. We find considerable parallels between the two regimes and argue in favor of more cross-fertilization between them. This regime interaction may enrich both frameworks from a normative perspective while also enhancing accountability and public health and human rights outcomes.


Hypophosphatasia: phenotypic variability and possible Croatian origin of the c.1402g>A mutation of TNSALP gene.
Hypophosphatasia is a metabolic bone disease characterized by bone and teeth hypomineralization due to defective function of tissue-nonspecific alkaline phosphatase (TNSALP). The disorder is caused by various mutations in the TNSALP gene localized on short arm of chromosome 1. Infantile hypophosphatasia is a severe form of the disease inherited as an autosomal recessive trait which presents before age of six months and often has fatal outcome. We report a patient with typical clinical course for infantile hypophosphatasia who was homozygous for the c.1402G>A mutation. The same mutation has been previously associated with a more severe perinatal form also in a Croatian family what indicates a possible common ancestral origin and phenotypic variability potential of c.1402G>A mutation of TNSALP gene.


Extremely efficient indium-tin-oxide-free green phosphorescent organic light-emitting diodes.
This paper demonstrates extremely efficient (η(P,max) = 118 lm W(-1) ) ITO-free green phosphorescent OLEDs (PHOLEDs) with multilayered, highly conductive poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) films as the anode. The efficiency is obtained without any outcoupling-enhancing structures and is 44% higher than the 82 lm W(-1) of similar optimized ITO-anode PHOLEDs. Detailed simulations show that this improvement is due largely to the intrinsically enhanced outcoupling that results from a weak microcavity effect.


Association of cerebrospinal fluid parameters with treatment and complications among children with cerebrospinal fluid shunt infections: a multicenter study.
Cerebrospinal fluid (CSF) white blood cell (WBC) count, neutrophil percentage, protein concentration, and glucose level are typically measured at diagnosis and serially during the treatment of CSF shunt infections. The objective of this retrospective cohort study was to describe the longitudinal profile of CSF parameters in children with CSF shunt infections and assess their association with treatment and outcome. Participants were children treated at 11 tertiary pediatric hospitals in Canada and the United States for CSF shunt infection, from July 1, 2013, through June 30, 2019, with hardware removal, external ventricular drain placement, intravenous antibiotics, and subsequent permanent shunt reinsertion. The relationship between CSF parameters and a complicated course (a composite outcome representing children with at least one of the following: contiguous soft-tissue infection, worsening hydrocephalus, CSF leak, intracranial bleed, brain abscess, venous thrombosis, reinfection after insertion of the new shunt, other complication, ICU admission, or death) was analyzed. A total of 109 children (median age 2.8 years, 44% female) were included in this study. CSF pleocytosis, elevated protein, and hypoglycorrhachia had sensitivities of 69%, 47%, and 38% for the diagnosis of culture-confirmed CSF shunt infection, respectively. The longitudinal profile of the neutrophil percentage followed a monotonic trend, decreasing by 1.5% (95% CI 1.0%-2.0%, p < 0.0001) per day over the course of treatment. The initial WBC count differed significantly between pathogens (p = 0.011), but the proportion of neutrophils, protein concentration, and glucose level did not, and was lowest with Cutibacterium acnes. The duration of antibiotic treatment and the time to shunt reinsertion were longer in patients with a higher initial neutrophil percentage. Fifty-eight patients (53%) had one or more complications during their admission. A neutrophil percentage > 44% (Youden index) in the initial CSF sample was associated with a 1.8-fold (95% CI 1.2- to 2.8-fold) higher relative risk of a complicated course. In a random-intercept, random-slope linear mixed-effects model, the longitudinal neutrophil trajectory differed significantly between patients with and without complications (p = 0.030). A higher proportion of neutrophils in the CSF at diagnosis was associated with a complicated clinical course. Other CSF parameters were associated with treatment and outcome; however, wide variability in values may limit their clinical utility.


Carbohydrate cravings: a disorder of food intake and mood.
Current findings on the relationship between excessive appetite for carbohydrate-rich foods and mood disorders may explain repetitive weight gain or the inability to lose weight among some obese individuals. Obese individuals who crave carbohydrates, exhibit positive changes in mood after carbohydrate intake; individuals suffering from Seasonal Affective Disorder experience a craving for carbohydrate-rich foods in association with their mood disturbances. Brain serotonin may be involved in these disorders of affect and appetite; thus therapies that mimic the effect of carbohydrate intake on the synthesis and release of this neurotransmitter may be useful in treating obesity arising from these causes.


The effect of plantar flexor lengthening on foot pressure in ambulatory children with cerebral palsy.
This study aimed to assess the effects of plantar flexor lengthening (PFL) on dynamic foot pressures of children with cerebral palsy using pedobarographs. Of 97 enrolled, 13 children with 18 legs had PFL. Age at surgery was 4.7 (2.8-8.8) years. A significant increase in ankle dorsiflexion and heel impulse was achieved postoperatively and was maintained at 5 years. The coronal plane pressure index increased postoperatively, but reverted to preoperative levels at the 5-year follow-up. Children tend to have more valgus after PFL. In young children, there caution should be exercised to avoid over treating varus at the time of equinus correction to avoid overcorrection.


[Online information supplied by Italian Hospitals and Local Healthcare Units: a descriptive research on their compliance with the guidelines issued by the Italian Ministry of Health].
In most countries where Internet is widely used the number of people surfing the web for healthcare information equals (and in some countries is more than) the number of people looking for healthcare assistance. More and more often, all over the world, Internet is integrated by advanced healthcare systems as a cornerstone of their e-health infrastructure, to meet citizens' needs for health information. Therefore, information plays a key role in the relationship between healthcare providers and citizenship. In 2010 the Italian Ministry of Health has worked out a set of guidelines to improve online communication, within the framework of health promotion. To analyze if the web sites of the Italian public hospitals (PH) and the local healthcare units (LHU) comply with the guidelines of the Italian Ministry of Health (IMH) on the improvement of online communication within the framework of healthcare promotion. All Italian PH and LHU web sites have been analyzed using the self evaluation tool of the IMH. The total number of web sites analyzed was 245. Their compliance with the IMH guidelines was low. Web sites linking to other professional sites, such as the College of Physicians, the College of Pharmacists, or the College of Nurses, were 32 (13%). One hundred and forty-two (58%) were the sites that did not offer any kind of health information, such as pathophysiology of diseases, the most relevant pathologic conditions, risky behaviors, primary and secondary prevention's interventions. A web navigation menu organized according to the most relevant life events or according to categories of users (I am ... /dedicated to...) was available only in 53 web sites (22%). The IMH's guidelines on online communication -- with reference to the aspects here analyzed -- have been in some ways disregarded and the criteria suggested by them have not been fully adopted by PHs and LHUs. Overall, communication is globally meant (and directed) "towards" citizenship and not "together with" the citizens. To reach this type of communication, experts suggest to redirect resources and efforts towards a different context, different tools and different models of communication, such as social networking. Further studies will be needed to fully understand information needs and expectations of users and the way to use social networking on behalf of healthcare providers.


Treatment of venous ulcers with human skin equivalent.
In the author's clinical experience in rating venous ulcers, human skin equivalent has been efficacious, safe, cost-effective, and easy to use. This innovation is likely to become an important therapeutic tool for podiatric physicians who treat venous ulcers. Leg ulcers are a large economic burden to society, both in direct and total costs, including patient time lost from work for labor- and time-intensive therapies. The cost-containing measures of the managed care environment encourage treatment of venous ulcers in an outpatient center. Because human skin equivalent can be applied in such a setting, podiatric physicians will be able to treat venous ulcers routinely without referring patients to more costly settings such as hospitals or surgical centers. Because human skin equivalent is an effective alternative to standard venous ulcer therapies, this agent, which is currently under review by the Food and Drug Administration, should provide a viable treatment that may reduce the total costs associated with venous ulcer care.


Impact of knowledge and attitude on the utilization rate of cervical cancer screening tests among Ethiopian women: A systematic review and meta-analysis.
Cervical cancer is a major public health problem, particularly in resource-limited settings. The use of vaccination and screening tests has reduced the burden of cervical cancer in developed countries. However, the situation is quite the reverse in developing countries, including Ethiopia. Hence, this study aimed to estimate the pooled impact of knowledge and attitude on the prevalence of cervical cancer screening service utilization rates among Ethiopian women. Studies that examined cervical cancer screening service utilization among women in Ethiopia were searched from five international databases. Cochran's Q chi-square and the I-squared test statistics were used to check the presence of heterogeneity among the included studies. The funnel plot and Egger's regression tests were also used to assess the presence of publication bias. A weighted DerSimonian and Laird random-effects model was employed. Subgroup analysis was performed by the study population concerning the prevalence of cervical cancer screening service utilization rates. Sensitivity analysis was also conducted to assess the effect of a single study on the pooled estimates. Data analysis was performed using STATA™ Version 14 software. A total of 44 studies with 28,186 study participants were included. The estimated pooled prevalence of cervical cancer screening service utilization was 8.11% (95% CI: 7.26, 8.97). After adjustment for publication bias with the trim and fill analysis, the estimated prevalence rate appeared to be 5.47% (95% CI: 4.66, 6.28). The prevalence of cervical cancer screening service utilization was higher among HIV-positive women, 16.85%, and in studies conducted among health care workers, 10.24%, than the general population. The pooled effect of knowledge on the utilization of cervical cancer screening tests among Ethiopian women was statistically significant (AOR = 3.20, 95% CI: 1.63, 6.31). Similarly, the pooled estimated odds of utilizing cervical cancer screening tests were 6.1 times higher (AOR = 6.09, 95% CI: 1.09, 34.36) among women who had a favorable attitude towards the screening tests. Knowledge and attitude had a significant impact on the prevalence of cervical cancer screening test utilization rates among women in Ethiopia. However, the prevalence of cervical cancer screening service utilization among Ethiopian women is very low. Hence, large-scale awareness programs and situation-based strategies need to be designed to increase the uptake of cervical cancer screening services in the country.


Assessment of a new approach to family planning services in rural Pakistan.
In 1993, the government of Pakistan started a new approach to the delivery of contraceptive services by training literate married women to provide doorstep advice and supplies in their own and neighboring communities. This report assesses whether this community-based approach is starting to have an impact on contraceptive use in rural areas. A clustered nationally representative survey was used to collect data on contraceptive use and access to services in each cluster. Two-level logistic regression was applied to assess the effects of service access, after potential confounders were taken into account. Married women living within 5 km of 2 community-based workers were significantly more likely to be using a modern, reversible method of contraception than those with no access (odds ratio = 1.74; 95% confidence interval = 1.11, 2.71). After decades of failure, the managers of the family planning program have designed a way of presenting modern contraceptives that is appropriate to the conditions of rural Pakistan. The new community-based approach should be steadily expanded.


Adenylate cyclase blockers dissociate PTH-stimulated bone resorption from cAMP production.
It is uncertain whether adenosine 3',5'-cyclic monophosphate (cAMP) or the inositol-calcium pathway mediates the stimulation of bone resorption by parathyroid hormone (PTH). Incubation of bone organ cultures with cAMP analogues and forskolin has not resolved this question because of the cellular inhomogeneity of bone and the consequent presence of adenylate cyclase-linked receptors for both PTH and calcitonin, hormones with opposite effects on bone resorption. We have used two new inhibitors of adenylate cyclase, 9-(tetrahydro-2-furyl)adenine (SQ 22536) and 2',5'-dideoxyadenosine (DDA), to directly reassess the role of cAMP in PTH-stimulated osteolysis. SQ 22536 (0.01-1.0 mM) and DDA (0.01-1.0 mM) completely blocked PTH stimulation of cAMP production measured in the absence of a phosphodiesterase blocker. In the presence of 1 mM 3-isobutyl-1-methylxanthine, half-maximal inhibition of PTH-induced cAMP production occurred with 0.2 mM SQ and 0.1 mM DDA, respectively. These concentrations of SQ and DDA had no effect on PTH-stimulated 45Ca release from calvaria, although both agents inhibited bone resorption when present at concentrations of 1-2 mM. At these levels, SQ and DDA caused equivalent inhibition of 45Ca release stimulated by 1,25-dihydroxyvitamin D3 but did not affect basal 45Ca release or [3H]-phenylalanine incorporation. It is concluded that substantial blockade of PTH-induced cAMP production does not affect this hormone's stimulation of bone resorption, which is therefore likely to be mediated by another intracellular messenger system, possibly calcium. In millimolar concentrations, SQ and DDA appear to be nonspecific blockers of osteoclastic bone resorption.


Peroxynitrite-induced nitration of cyclooxygenase-2 and inducible nitric oxide synthase promotes their binding in diabetic angiopathy.
Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) play crucial roles in diabetic angiopathy. In vivo, however, the following facts remain unknown: whether COX-2 and iNOS bind, how peroxynitrite-induced nitration of COX-2 and iNOS affects their binding if they do bind and what effects of this mechanism contribute to diabetic angiopathy. This study focused on the issues above. Diabetes was induced in Wistar male rats by intraperitoneal injection of streptozotocin. As a specific scavenger of peroxynitrite, urate was used. After 13 wks of diabetes, the morphological and biochemical changes of the rats showed obvious diabetic angiopathy. There exists in vivo colocalization and binding of COX-2 and iNOS in diabetic angiopathy. The nitration level of total and co-immunoprecipitated COX-2 and iNOS increased significantly, and, simultaneously, their binding and activity increased in the diabetes group. In the diabetes + urate group, the nitration level of COX-2 and iNOS decreased and their binding reduced, consistent with their decreased activity and the attenuated pathological changes in the rat aorta and glomerulus. The results provide in vivo evidence that COX-2 and iNOS can bind in diabetic angiopathy and that peroxynitrite-induced nitration of COX-2 and iNOS promotes their binding, contributing to diabetic angiopathy.


A national cholera epidemic with high case fatality rates--Kenya 2009.
Cholera remains endemic in sub-Saharan Africa. We characterized the 2009 cholera outbreaks in Kenya and evaluated the response. We analyzed surveillance data and estimated case fatality rates (CFRs). Households in 2 districts, East Pokot (224 cases; CFR = 11.7%) and Turkana South (1493 cases; CFR = 1.0%), were surveyed. We randomly selected 15 villages and 8 households per village in each district. Healthcare workers at 27 health facilities (HFs) were surveyed in both districts. In 2009, cholera outbreaks caused a reported 11 425 cases and 264 deaths in Kenya. Data were available from 44 districts for 6893 (60%) cases. District CFRs ranged from 0% to 14.3%. Surveyed household respondents (n = 240) were aware of cholera (97.5%) and oral rehydration solution (ORS) (87.9%). Cholera deaths were reported more frequently from East Pokot (n = 120) than Turkana South (n = 120) households (20.7% vs. 12.3%). The average travel time to a HF was 31 hours in East Pokot compared with 2 hours in Turkana South. Fewer respondents in East Pokot (9.8%) than in Turkana South (33.9%) stated that ORS was available in their village. ORS or intravenous fluid shortages occurred in 20 (76.9%) surveyed HFs. High CFRs in Kenya are related to healthcare access disparities, including availability of rehydration supplies.


[Age dependent changes in cervical region of the spine according to data of nuclear magnetic tomography].
Morphological characteristics of spine cervical region were studied in 132 patients (62 female and 70 male) aged 12-76 years using magnetic resonance tomography. The imaging was performed with the use of T1 and T2--weighting regimes. The study revealed sex- and age-dependent differences in the dimensions of cervical vertebrae. Height and sagittal dimensions of vertebral bodies were significantly smaller in females than in males. With advancing age the reduction in vertebral body height was more expressed in women, while the increase of vertebral body sagittal dimensions was similar in both males and females. The sagittal dimension of vertebral canal was correlated with sagittal dimension of vertebral body (r = 0.69) in males and with transverse dimension of vertebral body (r = 0.82) in females. The data obtained should be taken into consideration during evaluation of the state of bony structures of cervical vertebrae, intervertebral discs and in the diagnosis of pathological processes in the spine cervical region.


The association between childhood physical and sexual abuse and functioning and psychiatric symptoms in a sample of U.S. Army soldiers.
We examined associations between abusive childhood experiences and functioning and psychiatric symptoms in an active duty sample of U.S. Army soldiers. Cross-sectional survey of 204 soldiers stationed at a southern U.S. Army facility. Forty-six percent of individuals reported childhood physical abuse alone, whereas 25% reported both childhood physical and sexual abuse. Soldiers' work, role, and social functioning; physical functioning; depression severity; and severity of alcohol misuse did not differ significantly with childhood abuse status (p > 0.22 for all). However, individuals who reported both childhood physical and sexual abuse reported severer posttraumatic stress disorder symptoms than did soldiers who reported no childhood abuse or childhood physical abuse only (p = 0.007). Although abusive childhood experiences were common, soldiers with such experiences reported functioning as well as those soldiers without such experiences. Posttraumatic stress disorder symptoms were significantly elevated only in those who reported both childhood physical and sexual abuse.


Soil carbon persistence governed by plant input and mineral protection at regional and global scales.
Elucidating the processes underlying the persistence of soil organic matter (SOM) is a prerequisite for projecting soil carbon feedback to climate change. However, the potential role of plant carbon input in regulating the multi-layer SOM preservation over broad geographic scales remains unclear. Based on large-scale soil radiocarbon (∆14 C) measurements on the Tibetan Plateau, we found that plant carbon input was the major contributor to topsoil carbon destabilisation despite the significant associations of topsoil ∆14 C with climatic and mineral variables as well as SOM chemical composition. By contrast, mineral protection by iron-aluminium oxides and cations became more important in preserving SOM in deep soils. These regional observations were confirmed by a global synthesis derived from the International Soil Radiocarbon Database (ISRaD). Our findings illustrate different effects of plant carbon input on SOM persistence across soil layers, providing new insights for models to better predict multi-layer soil carbon dynamics under changing environments.


Nitrogen metabolism and route of excretion in beef feedlot cattle fed barley-based finishing diets varying in protein concentration and rumen degradability.
The objectives were to characterize the effects of supplemental CP concentration and ruminal degradability in barley-based finishing diets on microbial protein synthesis, ruminal fermentation and nutrient digestion, and route and chemical form of N excretion in beef cattle. Four Angus heifers (564 ± 18 kg BW) with ruminal and duodenal cannulas were used in an experiment designed as a 4 × 4 Latin square with four 28-d periods (9 d for diet adaptation and 19 d for measurements). The basal diet consisted of 9% barley silage and 91% barley-based concentrate (DM basis). Dietary treatments included the basal diet with no added protein (13% CP) or diets containing 14.5% CP by supplementation with urea (UREA), urea and canola meal (UREA+CM), or urea, corn gluten meal, and xylose-treated soybean meal (UREA+CGM+xSBM). Nutrient digestion was determined using Yb as a digesta flow marker and purine N as a microbial marker with the collection of ruminal, duodenal, and fecal samples over 5 d. The next week, total collections of feces and urine were performed for 5 d to quantify route and chemical form of N excretion. Feed offered was restricted (95% of ad libitum) and there was no effect of the dietary treatments on DMI (P = 0.55); therefore, N intake was less (P < 0.05) in heifers fed the 13% CP diets than the 14.5% CP diets. Supplemental RDP and RUP had no effect on ruminal NH3-N (P = 0.17), peptide N (P = 0.46), and VFA (P = 0.62) concentrations, flow of microbial (P = 0.69) and feed (P = 0.22) N, and ruminal and total tract nutrient digestibility (P ≥ 0.18). Nutrient digestion in the rumen and total tract averaged 75.4 ± 3.8% and 84.6 ± 0.9% for OM, 80.8 ± 3.6% and 95.8 ± 0.8% for starch, and 41.2 ± 7.9% and 60.4 ± 3.3% of intake for NDF, respectively. Daily output of N in feces (P = 0.91) and urine (P = 0.14) were not affected by the dietary treatments. Fecal N output averaged 19.9 ± 1.9% (P = 0.30) and urine N output averaged 44.1 ± 2.8% (P = 0.63) of N intake. Urea N output, however, was greater (P < 0.05) in heifers fed the 14.5% CP than the 13% CP diets and was the major form of N in urine (68.3% in heifers fed the 13% CP diet and 78.7 ± 2.9% in heifers fed the 14.5% CP diets; P < 0.10). Beef cattle fed barley-based finishing diets containing 13% CP do not require additional RDP or RUP to meet microbial or host N requirements. Barley-based finishing diets with no supplemental CP minimized urea N excretion and the potential loss of N from the system.


[Radiation effect in normal tissue - principles of damage and protection].
The curative effectivity of external or internal radiotherapy necessitates exposure of normal tissues with significant radiation doses, and hence must be associated with an accepted rate of side effects. These complications can not a priori be considered as an indication of a too aggressive therapy. Based on the time of first diagnosis, early (acute) and late (chronic) radiation sequelae in normal tissues can be distinguished. Early reactions per definition occur within 90 days after onset of the radiation exposure. They are based on impairment of cell production in turnover tissues, which in face of ongoing cell loss results in hypoplasia and eventually a complete loss of functional cells. The latent time is largely independent of dose and is defined by tissue biology (turn-over time). Usually, complete healing of early reactions is observed. Late radiation effects can occur after symptom-free latent times of months to many years, with an inverse dependence of latency on dose. Late normal tissue changes are progressive and usually irreversible. They are based on a complex interaction of damage to various cell populations (organ parenchyma, connective tissue, capillaries), with a contribution from macrophages. Late effects are sensitive for a reduction in dose rate (recovery effects). A number of biologically based strategies for protection of normal tissues or for amelioration of radiation effects was and still is tested in experimental systems, yet, only a small fraction of these approaches has so far been introduced into clinical studies. One advantage of most of the methods is that they may be effective even if the treatment starts way after the end of radiation exposure. For a clinical exploitation, hence, the availability of early indicators for the progression of subclinical damage in the individual patient would be desirable. Moreover, there is need to further investigate the molecular pathogenesis of normal tissue effects in more detail, in order to optimise biology based preventive strategies, as well as to identify the precise mechanisms of already tested approaches (e.g. stem cells).


Urinary excretions of albumin and type IV collagen in normotensive and hypertensive subjects.
Plasma albumin leaks into urine as a result of glomerular hypertension and basement membrane injury, while urinary type IV collagen derives from mesangial matrix and glomerular basement membrane. The purpose of this study was to elucidate the pathophysiological significance of these urinary microproteins as an indicator of cardiovascular organ injuries in hypertension. In health-checkup participants without diabetes, proteinuria, or microhematuria, and who were not being treated for hypertension or any other disease at the time of enrollment, urinary albumin and type IV collagen were measured and their relations to organ injuries and cardiovascular risk factors were evaluated. Of 1,079 subjects (40- to 65-year-old; 256 men and 823 women) enrolled in the study, 120 (11.1%) had untreated hypertension exceeding 140/90 mmHg. Urinary albumin was positively correlated with both age (r=0.16, p<0.001) and systolic blood pressure (r=0.27, p<0.001). Urinary type IV collagen was not only positively correlated with age (r=0.12, p<0.001) and diastolic blood pressure (r=0.14, p<0.001) but also negatively correlated with blood hemoglobin (r=-0.12, p<0.001). Urinary albumin, but not type IV collagen, had a significant relation to electrocardiographic signs of left ventricular hypertrophy (p=0.012) and retinal arteriosclerosis on fundoscopy (p <0.001). Thus both albumin and type IV collagen would seem to have increased in association with age and hypertension in this cohort. It is suggested that urinary albumin is an indicator not only of renal injury, but also possibly of development of cardiac hypertrophy and arteriosclerotic changes. Urinary type IV collagen, on the other hand, may be associated with renal tissue injuries that affect erythrokinetics.


Sports and leisure time physical activity during pregnancy in nulliparous women.
To describe patterns of leisure time physical activity during pregnancy in relation to pre-pregnancy leisure time physical activity, socio-demographic characteristics, fertility history, and lifestyle factors. 4,718 nulliparous with singleton pregnancy and intended spontaneous vaginal delivery were included in the study at gestational week 33 from May 2004 to July 2005. Information was provided by self-administered questionnaires. Leisure time physical activity was categorised into four categories: competitive sport, moderate-to-heavy, light or sedentary. In this population of nulliparous women, 4% participated in competitive sport, 25% in moderate-to-heavy activities, 66% in light activities, and 5% in sedentary activities in the year prior to pregnancy. Physical activity before pregnancy was statistically significantly associated with age, pre-pregnancy BMI, chronic diseases, number of years at school, and smoking habits. The proportion of women who took part in competitive sports, and moderate-to-heavy activities decreased over the three trimesters of pregnancy. The proportion of women with light physical activity was stable during pregnancy while the proportion of women with sedentary activity increased from 6% to 29%. During the third trimester women performing competitive sports or moderate-to-heavy activities before pregnancy continued to have a higher level of physical activity than women with light activities or sedentary activities before pregnancy. In general the intensity and time spent on exercise decreased during pregnancy. Women with the highest level of exercise prior to pregnancy continued to be the most active during pregnancy. Among women with sedentary activities before pregnancy one-fourth changed to light activity during pregnancy.


[Changes in cellular microfilaments in viral infection].
The effect of disorders in actin microfilament polymerization by cytochalasin B (CB) on the development of cytopathic changes was studied in two models. CB in concentrations of 0.1-1.0 microgram/ml enhanced 3-5-fold the formation of symplasts in a line of kidney cells from green monkey 4647 infected with carnivore distemper virus and inhibited this process in higher concentrations (2.5-5.0 micrograms/ml). The addition of CB in concentrations 5-10 micrograms/ml into the medium of a line of Chinese striped hamster cells infected with Sindbis virus led to disorders in the permeability of plasmolemma and destruction of cells although virus reproduction and production of virus antigens remained uninvolved. The above results not only demonstrate the role of actin microfilaments in the development of cytopathic lesions caused by paramyxo- and alphaviruses but also allow the assessment of separate stages of these processes.


Severe murine lung immunopathology elicited by the pathogenic equine herpesvirus 1 strain RacL11 correlates with early production of macrophage inflammatory proteins 1alpha, 1beta, and 2 and tumor necrosis factor alpha.
The CBA mouse model was used to investigate the immunopathology induced in the lung by the pathogenic equine herpesvirus 1 (EHV-1) strain RacL11 in comparison to infection with the attenuated vaccine candidate strain KyA. Intranasal infection with KyA resulted in almost no inflammatory infiltration in the lung. In contrast, infection with the pathogenic RacL11 strain induced a severe alveolar and interstitial inflammation, consisting primarily of lymphocytes, macrophages, and neutrophils. Infection with either EHV-1 strain resulted in the accumulation of similar numbers and ratios of CD4 and CD8 T lymphocytes in the lung and bronchoalveolar lavage (BAL) fluid. Further analysis of these T-cell populations revealed identical EHV-1-specific cytotoxic T-lymphocyte responses. RNase protection analysis of RNA isolated from the BAL fluid of RacL11-infected mice on day 3 postinfection revealed much higher levels of RNA specific for macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and MIP-2 than were observed for KyA-infected mice. Furthermore, significantly higher levels of transcripts specific for tumor necrosis factor alpha were induced on day 3 postinfection with RacL11 compared with KyA. These findings suggest that the early production of proinflammatory beta chemokines plays a major role in the severe, most often lethal, respiratory inflammatory response induced by the pathogenic EHV-1 strain RacL11.


Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma.
To better understand the complete genomic architecture of lung adenocarcinoma. We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes. We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma. Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients.


Bladder Paraganglioma: Clinicopathology and Magnetic Resonance Imaging Study of Five Patients.
To investigate the clinicopathology and magnetic resonance imaging (MRI) features of bladder paraganglioma, an extremely rare clinical entity. Five patients with bladder paraganglioma (3 males and 2 females, 27-52 years old) were retrospectively reviewed. All cases underwent baseline MRI and contrast-enhanced scans, and three cases underwent diffusion weighted imaging (DWI) and cystoscopy. Cases were immunohistochemically examined with neuroendocrine markers (chromogranin and synaptophysin) and Ki-67, and histology was reviewed by a pathologist. Three cases exhibited painless gross hematuria, including one case with hypertension, whereas two cases were asymptomatic. One of the three patients who underwent cystoscopy was negative. The tumors were round (n = 1) or oval (n = 4) and located in the anterior wall (n = 1), posterior wall (n = 1), lateral wall (n = 2) or trigone (n = 1). All tumors were located in the submucosal or lamina propria. Four cases presented with well-circumscribed margins, whereas one case was poorly circumscribed. All tumors exhibited slight hyperintensity on T1-weighted images (T1WI) and hyperintensity with "salt and pepper" appearance on T2-weighted images (T2WI). DWI indicated strong hyperintensity, and all cases exhibited conspicuous enhancement after intravenous gadobenate dimeglumine (Gd-DTPA) injection. Pathological evaluation confirmed paraganglioma. MRI plays an important role in the preoperative diagnosis of bladder paraganglioma. This rare condition has a characteristic round or oval appearance, located in the submucosal area, with slight hyperintensity on T1WI and hyperintensity with "salt and pepper" appearance on T2WI. DWI indicated strong hyperintensity and conspicuous enhancement on contrast-enhanced scans.


Role of specific cell-mediated cytotoxicity in protecting fish from viral infections.
We report the in vivo role of specific cytotoxic cells in protecting fish from acute viral infections. Specifically, we found that (1) there is an inverse relationship between cytotoxic activities and viral load and (2) adoptive transfer of immune leukocytes prevented viral infection. Crucian carp hematopoietic necrosis virus (CHNV), which has a virulence to ginbuna crucian carp, was recently found and identified in Japan. Specific cell-mediated cytotoxicity of ginbuna leukocytes against CHNV-infected syngeneic cells was induced as a result of intraperitoneal inoculation with CHNV. This cytotoxicity was not induced against either virus-infected allogeneic cells or eel rhabidovirus- (EVA) infected syngeneic cells. In these respects, the cytotoxic activity was similar to that of mammalian cytotoxic T-lymphocyte (CTL) activity. Viral titers of tissues from infected fish were remarkably reduced 8 days after infections, when specific cytotoxic activity reached a peak. This result suggested that specific cytotoxic cells were responsible for the early control of CHNV replication. On the other hand, CHNV-specific antibody was greatly increased when the virus was eliminated by cytotoxic activities. The effectiveness of the virus-specific cytotoxicity was evaluated using adoptive cell transfer. Recipients that received leukocytes from immune syngeneic donors escaped CHNV infection. These findings suggest that virus-specific cytotoxic cells have a role in controlling viral infections in a fish.


Uses of ultrasound in stroke prevention.
Ultrasound methods are useful in stroke prevention in several ways. Measurement of carotid plaque burden, as either total plaque area (TPA) or total plaque volume (TPV) are strong predictors of cardiovascular risk: much stronger than intima-media thickness, which does not represent true atherosclerosis, but a biologically and genetically distinct phenotype. Measurement of plaque burden is also useful for the study of genetics, and of new risk factors such as toxic products of the intestinal microbiome. Carotid plaque burden is highly correlated with and as predictive of risk as coronary calcium scores, but is less costly and does not require radiation. Furthermore, because carotid plaques change in time over a period of months, they can be used for a new approach to vascular prevention: "Treating arteries instead of treating risk factors". In high-risk patients with asymptomatic carotid stenosis (ACS), this approach, implemented in 2003 in our clinics, was associated with a >80% reduction of stroke and myocardial infarction over 2 years. "Treating arteries without measuring plaque would be like treating hypertension without measuring blood pressure". Ultrasound methods can also be used to assess plaque vulnerability, by detecting echolucency, ulceration and plaque inhomogeneity on assessment of plaque texture. Transcranial Doppler (TCD) embolus detection is useful for risk stratification in patients with ACS; patients with two or more microemboli in an hour of monitoring have a 1-year risk of 15.6%, vs. 1% without microemboli, so this very clearly distinguishes which patients with ACS could benefit from intervention. TCD saline studies are more sensitive than trans-esophageal echocardiography for detection of patent foramen ovale, and more predictive of recurrent stroke. These methods should be more widely used, to reduce the increasing burden of stroke in our aging populations.


From solution to the gas phase: stepwise dehydration and kinetic trapping of substance P reveals the origin of peptide conformations.
Past experimental results and molecular dynamics simulations provide evidence that, under some conditions, electrospray ionization (ESI) of biomolecules produces ions that retain elements of solution phase structures. However, there is a dearth of information regarding the question raised by Breuker and McLafferty, "for how long, under what conditions, and to what extent, can solution structure be retained without solvent?" (Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 18145). Here, we use cryogenic ion mobility-mass spectrometry to experimentally probe the structural evolution of the undecapeptide substance P (SP) during the final stages of ESI. The results reveal that anhydrous SP conformers originate from evaporation of cluster ions, specifically, [SP + 2H](2+) (H2O)n (n = 0 to ∼50) and [SP + 3H](3+) (H2O)n (n = 0 to ∼30), and that major structural changes do not occur during the evaporative process. In the case of [SP + 3H](3+), the results demonstrate that a compact dehydrated conformer population can be kinetically trapped on the time scale of several milliseconds, even when an extended gas phase conformation is energetically favorable.


DNA copy number, including telomeres and mitochondria, assayed using next-generation sequencing.
DNA copy number variations occur within populations and aberrations can cause disease. We sought to develop an improved lab-automatable, cost-efficient, accurate platform to profile DNA copy number. We developed a sequencing-based assay of nuclear, mitochondrial, and telomeric DNA copy number that draws on the unbiased nature of next-generation sequencing and incorporates techniques developed for RNA expression profiling. To demonstrate this platform, we assayed UMC-11 cells using 5 million 33 nt reads and found tremendous copy number variation, including regions of single and homogeneous deletions and amplifications to 29 copies; 5 times more mitochondria and 4 times less telomeric sequence than a pool of non-diseased, blood-derived DNA; and that UMC-11 was derived from a male individual. The described assay outputs absolute copy number, outputs an error estimate (p-value), and is more accurate than array-based platforms at high copy number. The platform enables profiling of mitochondrial levels and telomeric length. The assay is lab-automatable and has a genomic resolution and cost that are tunable based on the number of sequence reads.


Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands.
To investigate the potentially protective of periconceptional folic acid use on the risk of congenital heart defects (CHDs) relative to other non-folate related malformations. We analysed data from a large regional register of birth defects (EUROCAT-Northern Netherlands), over a 10 year period (1996-2005) for a case-control study. The cases were mothers who had delivered infants with isolated or complex heart defects, without any related syndrome or genetic abnormality (n = 611). We used two control groups; one from the EUROCAT database and another from the general population. The registry controls consisted of mothers of children with a known chromosomal or genetic defect, and with infants with other non-folate related congenital malformations (n = 2401). Additional folic acid was taken as a single supplement or as a multivitamin containing folic acid in a dose of >or=400 microg daily. Mothers who had used folate antagonists or who had diabetes, and mothers of children with oral clefts, hypospadias, limb reduction- or neural tube defects, were excluded from both groups. Potentially confounding factors of periconceptional folic acid use in relation to CHD were explored, including baby's birth year, maternal body mass index, education, maternal age at delivery of index baby, smoking behaviour, and alcohol use during pregnancy. Periconceptional folic acid use revealed an odds ratio (OR) of 0.82 (95% CI 0.68-0.98) for all types of CHD relative to other malformations. The estimated relative risk for CHDs of additional folic acid use compared with the general population was comparable [OR 0.74 (95%CI 0.62-0.88)]. Subgroup analysis showed an OR of 0.62 (95% CI 0.47-0.82) for isolated septal defects. The proportions of the potential confounders between mothers of case and control infants did not differ significantly. Our results support the hypothesis that additional periconceptional folic acid use reduces CHD risk in infants. Use of periconceptional folic acid supplements was related to approximately 20% reduction in the prevalence of any CHD. Given the relatively high prevalence of CHD worldwide, our findings are important for public health.


Periarthritis: another duration-related complication of diabetes mellitus.
The association between periarthritis of the shoulder and diabetes mellitus is well recognized. A study of 100 hospitalized patients with diabetes was performed, comparing them with 100 control subjects. The mean +/- SEM age of the subjects was 47 +/- 2 yr. Nineteen percent of the patients with diabetes had periarthritis. The afflicted subjects had a higher incidence of retinopathy (P less than 0.005) and albuminuria (P less than 0.005). The duration of shoulder pain correlated with the duration of the diabetes mellitus (P less than 0.001). However, the presence of other complications in subjects with periarthritis was not as well correlated with the duration of the diabetes mellitus. These data emphasize the common occurrence of periarthritis in subjects with diabetes mellitus and its extension to people of diverse backgrounds.


Pre-incubation of subcellular fractions from rat cerebral cortex inactivates protein phosphorylation.
Pre-incubation of various subcellular fractions from rat brain caused a significant decrease in the phosphorylation of individual polypeptides. The rate and extent of this loss of labelling was not uniform and polypeptides whose phosphorylation was independent of cyclic AMP were primarily affected, whereas substrate availability remained unaltered. It is recommended that pre-incubation effects must be carefully monitored if valid conclusions are to be made about the physiological relevance of changes in protein phosphorylation observed in vitro.


Pulmonary infiltrates in the immunocompromised host.
Patients with a compromised immune system suffer a wide variety of insults. Interstitial lung changes are one of the most common and serious complications in this group of patients. The morbidity rate reaches 50% and up to 90% if endotracheal intubation and mechanical ventilation are necessary. Opportunistic and bacterial infections are common causes of pulmonary infiltrates and must be distinguished from other conditions such as drug reactions, volume overload, pulmonary hemorrhage, and malignant diseases. Accurate and prompt diagnosis of potentially treatable causes can be life-saving. Noninvasive diagnostic methods for evaluation are often of little value, and an invasive procedure--such as bronchoalveolar lavage, transbronchial biopsy or even open lung biopsy--is therefore performed to obtain a histologic diagnosis. Yet, even when a specific diagnosis is made it may not improve the patient's survival. Numerous textbook and review articles have focused on the management of this condition. The present review attempts to provide a comprehensive and systematic picture of current knowledge and an integrated approach to these challenging patients.


PP2A function toward mitotic kinases and substrates during the cell cycle.
To maintain cellular homeostasis against the demands of the extracellular environment, a precise regulation of kinases and phosphatases is essential. In cell cycle regulation mechanisms, activation of the cyclin-dependent kinase (CDK1) and cyclin B complex (CDK1:cyclin B) causes a remarkable change in protein phosphorylation. Activation of CDK1:cyclin B is regulated by two auto-amplification loops-CDK1:cyclin B activates Cdc25, its own activating phosphatase, and inhibits Wee1, its own inhibiting kinase. Recent biological evidence has revealed that the inhibition of its counteracting phosphatase activity also occurs, and it is parallel to CDK1:cyclin B activation during mitosis. Phosphatase regulation of mitotic kinases and their substrates is essential to ensure that the progression of the cell cycle is ordered. Outlining how the mutual control of kinases and phosphatases governs the localization and timing of cell division will give us a new understanding about cell cycle regulation.


Ethynylbenzene monolayers on gold: a metal-molecule binding motif derived from a hydrocarbon.
Exposure of a Au(111) surface to ethynylbenzene in solution leads to the formation of a bound monolayer. A chemisorption process occurs to give a stable layer consisting of oxygen-containing hydrocarbon species. Ethynylbenzene itself does not oxidize under the deposition conditions indicating that the gold surface facilitates the oxidation process. Calculations show that ethynylbenzene and its oxidation products phenylacetic acid and phenyloxirane have positive binding energies to the gold surface. 1,4-Diethynylbenzene also binds to Au(111) and anchors gold nanoparticles deposited from solution to form dense, semiregular arrays.


An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I.
The insulin-like growth factors IGF-I and IGF-II circulate in blood bound to carrier proteins. The higher molecular mass IGF-binding protein complex (150 kDa) is composed of subunits, and one subunit that forms this complex is growth hormone dependent. In addition, many cell types and tissues secrete another form of IGF binding protein that is not growth hormone dependent. Both forms of the IGF binding protein are believed to inactivate the IGFs and to function as delivery systems to tissues. This conclusion was based on studies that determined the effects of impure preparations of these binding proteins or that examined the effect of these proteins only on the insulin-like actions of the IGFs. We report here that a pure preparation of the extracellular form of the IGF binding protein (purified from human amniotic fluid) markedly potentiated replication of several cell types in response to human IGF-I. Secondary cultures of human, mouse, and chicken embryo fibroblasts as well as porcine aortic smooth muscle cells showed marked enhancement of their DNA synthesis response (2.8- to 4.4-fold increases) to IGF-I in the presence of this protein. These responses were synergistic since the sum of the responses to either IGF-I or to the binding protein alone was between 8 and 17% of the increase obtained in cultures exposed to both peptides. The binding protein not only potentiated the DNA synthesis response but also enhanced the increase in cell number in response to IGF-I. This stimulation is specific for growth factors that bind to the binding protein since incubation with insulin, which binds to the type I IGF receptor but not to the binding protein, did not result in potentiation of this response. We conclude that a form of IGF binding protein that is present in extracellular fluids and is secreted by many types of cells can markedly potentiate the cellular response to IGF-I.


Anal human papillomavirus infection: a comparative study of cytology, colposcopy and DNA hybridisation as methods of detection.
To compare anal cytology, colposcopy and DNA hybridisation as methods of detecting anal HPV infection. Patients attending: (1) a genitourinary medicine (GUM) clinic with ano-genital warts; (2) a surgical out-patient department with anal fissure or haemorrhoids were examined for evidence of anal HPV infection. Considering GUM clinic attenders, 17% (38/225) and 40% (90/225) had perianal or anal canal warts respectively. Colposcopic examination revealed anal acetowhite lesions without warts in 28% (63/225). Cytological evidence of HPV infection was found in 98%, 83%, and 90% of patients with anal canal warts, perianal warts and acetowhite lesions respectively. Anal intraepithelial neoplasia (AIN) was documented in 22% of patients with anal canal warts compared with 6% with perianal warts (p less than 0.01). HPV DNA was detected from the anal brushings of 71%, 50%, 32%, and 29% of patients with anal canal warts, perianal warts, acetowhite lesions and a normal anal examination respectively. HPV type 6/11 was detected in the majority of HPV positive samples. Considering surgical out-patient attenders with no history or signs of anal warts, 25% showed cytological evidence of anal HPV infection and HPV DNA was detected from anal brushings in 3% (2/71). Anal examination with the colposcope is a useful method for detecting subclinical HPV infection. Anal cytology may prove helpful for detecting AIN, however, since koilocytosis was rarely seen, the specificity of the cytological criteria for anal HPV infection in the absence of AIN is uncertain. DNA analysis of anal brushings proved only moderately sensitive.


Protocol for a systematic review of living labs in healthcare.
Healthcare is increasingly challenged to meet the demands of user involvement and knowledge mobilisation required by the 21st-century patient-centred and knowledge-based economies. Innovations are needed to reduce problematic barriers to knowledge exchange and improve collaborative problem solving. Living labs, as open knowledge systems, have the potential to address these gaps but are underexplored in healthcare. We will conduct the first systematic review of living labs across healthcare contexts. We will comprehensively search the following online databases from inception to 31 December 2020: Scopus, the Cochrane Library (Wiley), Medline (OVID), Embase (OVID), Web of Science, PsycINFO (OVID) and EBSCOhost databases including Academic Search Complete, Business Source Premier, Canadian Reference Centre, CINAHL, MasterFILE Premier, SPORTDiscus, Library & Information Science Source, Library, Information Science & Technology Abstracts, AgeLine, EconLit, Art Full Text, Women's Studies International and Social Work Abstracts. We will search for grey literature using Google advanced techniques and books/book chapters through scholarly and bibliographical databases. We will use a dual-reviewer, two-step selection process with pre-established inclusion criteria and limit to English language publications. Empirical studies of any design examining living lab development, implementation or evaluation in health or healthcare will be included. We will use the Mixed Methods Appraisal Tool (MMAT) for methodological quality appraisal and Covidence software for review management, and we will extract data on pre-established variables such as lab context and technological platforms. We will create evidence tables and analyse across variables such as focal aim and achievement of living lab principles, such as the use of cocreation and multimethod approaches. We will tabulate data for descriptive reporting and narrative synthesis to identify current applications, approaches and promising areas for living lab development across health contexts. Ethical approval was not required for this review. This review will inform research into living labs in health environments, including guidance for a living lab in paediatric rehabilitation. Academic publications shared through collaborative networks and social media channels will provide substantive knowledge to the growing tech-health development sector and to researchers, practitioners and organisations seeking enhanced patient/stakeholder engagement and innovations in knowledge translation and evidence-based practice. CRD42020175275.


A beta-catenin/engrailed chimera selectively suppresses Wnt signaling.
beta-catenin plays an integral role in cell-cell adhesion by linking the cadherin complex of the adherens junction to the underlying actin cytoskeleton. In addition, beta-catenin transduces intracellular signals within the Wnt developmental pathway that are crucial to the proper establishment of embryonic axes and pattern formation of early mesoderm and ectoderm. For example, in the context of a defined dorsal 'organizer' region of early Xenopus embryos, beta-catenin enters the nucleus and associates with transcription factors of the HMG (High Mobility Group) Lef/Tcf protein family. Consequently, genes such as siamois, a homeobox gene contributing to the specification of the dorsoanterior axis, are activated. To further examine the role that beta-catenin plays in Wnt signaling, we generated a chimeric protein, beta-Engrailed (beta-Eng), in which the C-terminal trans-activation domain of beta-catenin is replaced with the transcriptional repression domain of Drosophila Engrailed. Dorsal overexpression of this mRNA in early Xenopus embryos leads to suppression of organizer-specific molecular markers such as siamois, Xnr-3 and goosecoid, corresponding with the dramatic morphological ventralization of embryos. Ventralized embryos further exhibit reduced activity of the Wnt pathway, as indicated by the loss of the notochord/organizer marker, chordin. Importantly, beta-Eng associates and functions normally with the known components of the cadherin complex, providing the experimental opportunity to repress beta-catenin's signaling function apart from its role in cadherin-mediated cell-cell adhesion.


Hodgkin's disease with direct extension into pulmonary parenchyma from a mediastinal mass: a presentation requiring special therapeutic considerations.
The significance of limited extranodal Hodgkin's disease involving pulmonary parenchyma by direct extension from a mediastinal mass (E stage) was evaluated in 177 patients with stages IA-IIIB. Disease-free and total survival rates of four groups were compared: 58 patients without and 13 patients with pulmonary E stage treated with radiotherapy followed by six courses of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and 86 patients without and 20 patients with E stage treated with radiotherapy alone. The 12-year disease-free and total survival rates projected by life-table analysis were significantly poorer for E stage patients treated with radiotherapy alone. It is concluded that pulmonary E stage requires special therapeutic considerations if end results are to equal those obtained with standard radiotherapy for Hodgkin's disease confined to lymph nodes, and that combined modality therapy is one method by which pulmonary E stage may be treated successfully.


Photoluminescence spectra of self-assembling helical supramolecular assemblies: a theoretical study.
The reversible assembly of helical supramolecular polymers of chiral molecular building blocks is known to be governed by the interplay between mass action and the competition between weakly and strongly bound states of these building blocks. The highly co-operative transition from free monomers at high temperatures to long helical aggregates at low temperatures can be monitored by photoluminescence spectroscopy that probes the energetically lowest-lying optical excitations in the assemblies. In order to provide the interpretation of obtained spectroscopic data with a firm theoretical basis, we present a comprehensive model that combines a statistical theory of the equilibrium polymerization with a quantum-mechanical theory that not only accounts for the conformational properties of the assemblies but also describes the impact of correlated energetic disorder stemming from deformations within the chromophores and their interaction with solvent molecules. The theoretical predictions are compared to fluorescence spectra of chiral oligo(p-phenylene-vinylene) molecules in the solvent dodecane and we find them to qualitatively describe the red-shift of the main fluorescence peak and its decreasing intensity upon aggregation.


The role of non-governmental organizations in the prevention and reduction of drug abuse: the Philippine experience.
A wide range of non-governmental organizations are involved in the prevention and reduction of drug abuse in the Philippines. The numerous activities and substantive achievements of non-governmental organizations in combating the problems of drug abuse are manifestations of their commitment to and involvement in an avowed partnership with the Government to promote care for young people and quality of life in general. The Dangerous Drugs Board, the Government's policy-making and co-ordinating body, has facilitated and encouraged the development of existing approaches and strategies and, in co-operation with non-governmental organizations, has made drug-abuse prevention programmes more viable and relevant. This co-operation strengthened agency relationships, encouraged resource-sharing and generated a more balanced approach towards programme planning and implementation. The various government services, in co-operation with non-governmental organizations, have adopted the models and strategies that are action-oriented activities, primarily intended to promote positive values, attitudes, self-development, creative productivity and skills of young people.